Matrix metalloproteinase-2 polymorphism is associated with prognosis in prostate cancer

Objective: Prostate cancer (PCa) is the most frequent tumor in males in Brazil. Single nucleotide polymorphisms (SNP) have been demonstrated in the promoter region of matrix metalloproteinases (MMPs) genes and have been associated with development and progression of some cancers. In this study, our aim was to investigate a possible relation between polymorphism of the promoter region of the MMP2 gene and classical prognostic parameters in prostate cancer. Materials and methods: Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by real-time polymerase chain reaction, using fluorescent probes (TaqMan). Results: In patients with tumors of a higher stage (pT3), a polymorphic allele in the MMP2 gene was more frequent (P = 0.026) than in patients with lower tumor stage. A polymorphic allele in the MMP2 gene was more frequent in Gleason >= 7 than in Gleason <= 6 (P = 0.042). Conclusions: We conclude that MMP2 polymorphism can be used together with pathological stage and Gleason score to identify patients with worse prognosis. Our results illustrate the potential use of MMP2 SNP as a molecular marker for prostate cancer. (C) 2010 Elsevier Inc. All rights reserved.

Short- and long-term survival of patients with metastatic solid cancer admitted to the intensive care unit: prognostic factors

Decisions for intensive care unit (ICU) admissions in patients with advanced cancer are complex, and the knowledge of survival rates and prognostic factors are essential to these decisions. Ours objectives were to describe the short- and long-term survival of patients with metastatic solid cancer admitted to an ICU due to emergencies and to study the prognostic factors presented at ICU admission that could be associated with hospital mortality. We retrospectively analysed the charts of all patients with metastatic solid cancer admitted over a 1-year period. This gave a study sample of 83 patients. The ICU, hospital, 1-year and 2-year survival rates were 55.4%, 28.9%, 12.0% and 2.4% respectively. Thrombocytopenia (odds ratio 26.2; P = 0.006) and simplified acute physiology score (SAPS II) (odds ratio 1.09; P = 0.026) were independent factors associated with higher hospital mortality. In conclusion, the survival rates of patients with metastatic solid cancer admitted to the ICU due to emergencies were low, but of the same magnitude as other groups of cancer patients admitted to the ICU. The SAPS II score and thrombocytopenia on admission were associated with higher hospital mortality. The characteristics of the metastatic disease, such as number of organs with metastasis and central nervous system metastasis were not associated with the hospital mortality.

Genetic Polymorphisms of Matrix Metalloproteinases: Susceptibility and Prognostic Implications for Prostate Cancer

Purpose: Prostate cancer is the most common tumor in males in Brazil. Single nucleotide polymorphisms have been demonstrated to exist in the promoter regions of matrix metalloproteinase genes and they are associated with the development and progression of some cancers. We investigated the correlation between MMP1, 2, 7 and 9 polymorphisms with susceptibility to prostate cancer, and classic prognostic parameters of prostate cancer. Materials and Methods: Genomic DNA was extracted using conventional protocols. The DNA sequence containing the polymorphic site was amplified by realtime polymerase chain reaction using TaqMan (R) fluorescent probes. Results: For the MMP1 gene the polymorphic allele was more common in the control group than in the prostate cancer group (p <0.001). For the MMP9 gene the incidence of the polymorphic homozygote genotype was higher in the prostate cancer group (p <0.001). For higher stage tumors (pT3) a polymorphic allele in the MMP2 gene was more common (p = 0.026). When considering Gleason score, the polymorphic homozygote genotype of MMP9 was more common in Gleason 6 or less tumors (p = 0.003), while a polymorphic allele in the MMP2 gene was more common in Gleason 7 or greater tumors (p = 0.042). Conclusions: MMP1 and MMP2 may protect against prostate cancer development and MMP9 may be related to higher risk. In contrast, MMP9 polymorphism was associated with a lower Gleason score and MMP2 polymorphism was associated with nonorgan confined disease.

Polymorphisms of the matrix metalloproteinases associated with prostate cancer

Prostate cancer (PCa) is the most common type of malignant tumor in Brazilian males. Single nucleotide polymorphisms (SNPs) have been demonstrated to be present in the promoter region of matrix metalloproteinase (MMP) genes and have been associated with the development and progression of some cancers. In this study, our aim was to investigate the association between the polymorphisms of MMP1, 2, 7, and 9 and susceptibility, and their correlation with the classic prognostic parameters of PCa. For genes MMP1, 2 and 9, the frequencies of the polymorphic homozygote genotypes were higher in the control group than in the PCa group (P<0.0001). We conclude that the MMP1, 2 and 9 polymorphisms are more common in the control group than in patients with PCa, and may have a protective effect in the development of this neoplasia.

Abnormal Methylation of Histone Deacetylase Genes: Implications on Etiology and Epigenetic Therapy of Astrocytomas

Background: A growing body of evidence has revealed, the involvement of epigenetic alterations in the etiology of astrocytomas. In the present study, we aimed to evaluate the association of DNA methylation of histone deacetylase genes (HDAC) with the etiology of astrocytoma, and the implications for epigenetic therapy. Materials and Methods: Methylation of the HDAC4, HDAC5 and HDAC6 genes was assessed in 29 tumor samples (astrocytomas grades I, III, and IV) and in the glioblastoma cell lines U87, U251, U343, SF188, and T98G by methylation-specific quantitative PCR (MSED-qPCR). Results: Significantly increased methylation of the HDAC5 gene was observed in astrocytomas when compared to non-neoplastic brain samples (p=0.0007) and to glioblastomas cell lines (p=0.001). A heterogenic methylation pattern was evidenced when compared to the glioblastoma cell lines. Distinct effects on methylation and gene expression were observed after in vitro treatment of the different cell lines with decitabine. Conclusion: Our results suggest that abnormal methylation of HDAC genes is involved in the etiology of astrocytomas and indicate that loci-specific epigenetic interindividualities might be associated to the differential responses to treatment with decitabine.

Autologous stem cell transplantation for early type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is the result of the autoimmune response against pancreatic insulin producing cells. This autoimmune response begins months or even years before the first presentation of signs and symptoms of hyperglycemia and at the time of clinical diagnosis near 30% of -cell mass still remains. In daily clinical practice, the main therapeutic option for T1DM is multiple subcutaneous insulin injections that are shown to promote tight glucose control and reduce much of diabetic chronic complications, especially microvascular complications. Another important aspect related to long-term complications of diabetes is that patients with initially larger -cell mass suffer less microvascular complications and less hypoglycemic events than those patients with small -cell mass. In face of this, -cell preservation is another important target in the management of type 1 diabetes and its related complications. For many years, various immunomodulatory regimens were tested aiming at blocking autoimmunity against -cell mass and at promoting -cell preservation, mainly in secondary prevention trials. In this review, we summarize some of the most important studies involving -cell preservation by immunomodulation and discuss our preliminary data on autologous nonmyeloablative hematopoietic stem cell transplantation in newly-diagnosed T1DM.

Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine

Currently, the combination of cisplatin and gemcitabine is considered a standard chemotherapeutic protocol for bladder cancer. However, the mechanism by which these drugs act on tumor cells is not completely understood. The aim of the present study was to investigate the effects of these two antineoplastic drugs on the apoptotic index and cell cycle kinetics of urinary bladder transitional carcinoma cell lines with wild-type or mutant TP53 (RT4: wild type for TP53; 5637 and T24: mutated TP53). Cytotoxicity, cell survival assays, clonogenic survival assays and flow cytometric analyses for cell cycle kinetics and apoptosis detection were performed with three cell lines treated with different concentrations of cisplatin and gemcitabine. G(1) cell cycle arrest was observed in the three cell lines after treatment with gemcitabine and gemcitabine plus cisplatin. A significant increase in cell death was also detected in all cell lines treated with cisplatin or gemcitabine. Lower survival rates occurred with the combined drug protocol independent of TP53 status. TP53-wild type cells (RT4) were more sensitive to apoptosis than were mutated TP53 cells when treated with cisplatin or gemcitabine. Concurrent treatment with cisplatin and gemcitabine was more effective on transitional carcinoma cell lines than either drug alone; the drug combination led to a decreased cell survival that was independent of TP53 status. Therefore, the synergy between low concentrations of cisplatin and gemcitabine may have clinical relevance, as high concentrations of each individual drug are toxic to whole organisms.

Polymorphisms at the glutathione S-transferase GSTM1, GSTT1 and GSTP1 loci: risk of ovarian cancer by histological subtype

The phase II glutathione S-transferases (GSTs) GSTT1, GSTM1 and GSTP1 catalyse glutathione-mediated reduction of exogenous and endogenous electrophiles. These GSTs have broad and overlapping substrate specificities and it has been hypothesized that allelic variants associated with less effective detoxification of potential carcinogens may confer an increased susceptibility to cancer. To assess the role of GST gene variants in ovarian cancer development, we screened 285 epithelial ovarian cancer cases and 299 unaffected controls for the GSTT1 deletion (null) variant, the GSTM1 deletion (null) variant and the GSTP1 codon 104 A-->G Ile-->Val amino acid substitution variant, The frequencies of the GSTT1, GSTM1 and GSTP1 polymorphic variants did not vary with tumour behaviour (low malignant potential or invasive) or p53 immunohistochemical status. There was a suggestion that ovarian cancers of the endometrioid or clear cell histological subtype had a higher frequency of the GSTT1 and GSTM1 deletion genotype than other histological subgroups. The GSTT1, GSTM1 and GSTP1 genotype distributions did not differ significantly between unaffected controls and ovarian cancer cases (overall or invasive cancers only). However, the GSTM1 null genotype was associated with increased risk of endometrioid/clear cell invasive cancer [age-adjusted OR (95% CI) = 2.04 (1.01-4.09), P = 0.05], suggesting that deletion of GSTM1 may increase the risk of ovarian cancer of these histological subtypes specifically. This marginally significant finding will require verification by independent studies.

A global health problem caused by arsenic from natural sources

Arsenic is a carcinogen to both humans and animals. Arsenicals have been associated with cancers of the skin, lung, and bladder. Clinical manifestations of chronic arsenic poisoning include non-cancer end point of hyper- and hypo-pigmentation, keratosis, hypertension, cardiovascular diseases and diabetes. Epidemiological evidence indicates that arsenic concentration exceeding 50 mug l(-1) in the drinking water is not public health protective. The current WHO recommended guideline value for arsenic in drinking water is 10 mug l(-1), whereas many developing countries are still having a value of 50 mug 1(-1). It has been estimated that tens of millions of people are. at risk exposing to excessive levels of arsenic from both contaminated water and arsenic-bearing coal from natural sources. The global health implication and possible intervention strategies were also discussed in this review article. (C) 2003 Elsevier Ltd. All rights reserved.

Comparação do cálculo de dose com os algoritmos Analytical Anisotropic Algorithm e Pencil Beam Convolution na patologia de pulmão

Mestrado em Radioterapia.

O impacto da Lei nº 37/2007 (Lei do Tabaco) no consumo de tabaco em ambiente profissional na ilha Terceira e a sua influência na produtividade e absentismo laboral

Dissertação de Mestrado, Ambiente, Saúde e Segurança, 19 de Julho de 2013, Universidade dos Açores.

Economic burden of expected epidemiological changes in diseases related to tobacco, Mexico

OBJECTIVE: To determine health care costs and economic burden of epidemiological changes in diseases related to tobacco consumption. METHODS: A time-series analysis in Mexico (1994-2005) was carried out on seven health interventions: chronic obstructive pulmonary diseases, lung cancer with and without surgical intervention, asthma in smokers and non-smokers, full treatment course with nicotine gum, and full treatment course with nicotine patch. According with Box-Jenkins methodology, probabilistic models were developed to forecast the expected changes in the epidemiologic profile and the expected changes in health care services required for selected interventions. Health care costs were estimated following the instrumentation methods and validated with consensus technique. RESULTS: A comparison of the economic impact in 2006 vs. 2008 showed 20-90% increase in expected cases depending on the disease (p<0.05), and 25-93% increase in financial requirements (p<0.01). The study data suggest that changes in the demand for health services for patients with respiratory diseases related to tobacco consumption will continue showing an increasing trend. CONCLUSIONS: In economic terms, the growing number of cases expected during the study period indicates a process of internal competition and adds an element of intrinsic competition in the management of preventive and curative interventions. The study results support the assumption that if preventive programs remain unchanged, the increasing demands for curative health care may cause great financial and management challenges to the health care system of middle-income countries like Mexico.

Influence of tobacco smoke on carcinogenic PAH composition in indoor PM10 and PM2.5

Because of the mutagenic and/or carcinogenic properties, Polycyclic Aromatic Hydrocarbons (PAH), have a direct impact on human population. Consequently, there is a widespread interest in analysing and evaluating the exposure to PAH in different indoor environments, influenced by different emission sources. The information on indoor PAH is still limited, mainly in terms of PAH distribution in indoor particles of different sizes; thus, this study evaluated the influence of tobacco smoke on PM10 and PM2.5 characteristics, namely on their PAH compositions, with further aim to understand the negative impact of tobacco smoke on human health. Samples were collected at one site influenced by tobacco smoke and at one reference (non-smoking) site using low-volume samplers; the analyses of 17 PAH were performed by Microwave Assisted Extraction combined with Liquid Chromatography (MAE–LC). At the site influenced by tobacco smoke PM concentrations were higher 650% for PM10, and 720% for PM2.5. When influenced by smoking, 4 ring PAH (fluoranthene, pyrene, and chrysene) were the most abundant PAH, with concentrations 4600–21 000% and 5100–20 800% higher than at the reference site for PM10 and PM2.5, respectively, accounting for 49% of total PAH (SPAH). Higher molecular weight PAH (5–6 rings) reached concentrations 300–1300% and 140–1700% higher for PM10 and PM2.5, respectively, at the site influenced by tobacco smoke. Considering 9 carcinogenic PAH this increase was 780% and 760% in PM10 and PM2.5, respectively, indicating the strong potential risk for human health. As different composition profiles of PAH in indoor PM were obtained for reference and smoking sites, those 9 carcinogens represented at the reference site 84% and 86% of SPAH in PM10 and PM2.5, respectively, and at the smoking site 56% and 55% of SPAH in PM10 and PM2.5, respectively. All PAH (including the carcinogenic ones) were mainly present in fine particles, which corresponds to a strong risk for cardiopulmonary disease and lung cancer; thus, these conclusions are relevant for the development of strategies to protect public health.

Polycyclic aromatic hydrocarbons in gas and particulate phases of indoor environments influenced by tobacco smoke: levels, phase distributions, and health risks

As polycyclic aromatic hydrocarbons (PAHs) have a negative impact on human health due to their mutagenic and/or carcinogenic properties, the objective of this work was to study the influence of tobacco smoke on levels and phase distribution of PAHs and to evaluate the associated health risks. The air samples were collected at two homes; 18 PAHs (the 16 PAHs considered by U.S. EPA as priority pollutants, dibenzo[a,l]pyrene and benzo[j]fluoranthene) were determined in gas phase and associated with thoracic (PM10) and respirable (PM2.5) particles. At home influenced by tobacco smoke the total concentrations of 18 PAHs in air ranged from 28.3 to 106 ngm 3 (mean of 66.7 25.4 ngm 3),∑PAHs being 95% higher than at the non-smoking one where the values ranged from 17.9 to 62.0 ngm 3 (mean of 34.5 16.5 ngm 3). On average 74% and 78% of ∑PAHs were present in gas phase at the smoking and non-smoking homes, respectively, demonstrating that adequate assessment of PAHs in air requires evaluation of PAHs in both gas and particulate phases. When influenced by tobacco smoke the health risks values were 3.5e3.6 times higher due to the exposure of PM10. The values of lifetime lung cancer risks were 4.1 10 3 and 1.7 10 3 for the smoking and nonsmoking homes, considerably exceeding the health-based guideline level at both homes also due to the contribution of outdoor traffic emissions. The results showed that evaluation of benzo[a]pyrene alone would probably underestimate the carcinogenic potential of the studied PAH mixtures; in total ten carcinogenic PAHs represented 36% and 32% of the gaseous ∑PAHs and in particulate phase they accounted for 75% and 71% of ∑PAHs at the smoking and non-smoking homes, respectively.

Levels and risks of particulate-bound PAHs in indoor air influenced by tobacco smoke: a field measurement

Considering tobacco smoke as one of the most health-relevant indoor sources, the aim of this work was to further understand its negative impacts on human health. The specific objectives of this work were to evaluate the levels of particulate-bound PAHs in smoking and non-smoking homes and to assess the risks associated with inhalation exposure to these compounds. The developed work concerned the application of the toxicity equivalency factors approach (including the estimation of the lifetime lung cancer risks, WHO) and the methodology established by USEPA (considering three different age categories) to 18 PAHs detected in inhalable (PM10) and fine (PM2.5) particles at two homes. The total concentrations of 18 PAHs (ΣPAHs) was 17.1 and 16.6 ng m−3 in PM10 and PM2.5 at smoking home and 7.60 and 7.16 ng m−3 in PM10 and PM2.5 at non-smoking one. Compounds with five and six rings composed the majority of the particulate PAHs content (i.e., 73 and 78 % of ΣPAHs at the smoking and non-smoking home, respectively). Target carcinogenic risks exceeded USEPA health-based guideline at smoking home for 2 different age categories. Estimated values of lifetime lung cancer risks largely exceeded (68–200 times) the health-based guideline levels at both homes thus demonstrating that long-term exposure to PAHs at the respective levels would eventually cause risk of developing cancer. The high determined values of cancer risks in the absence of smoking were probably caused by contribution of PAHs from outdoor sources.