Epigenetic and oncogenic regulation of SLC16A7 (MCT2) results in protein over-expression, impacting on signalling and cellular phenotypes in prostate cancer

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Need for a continuing education program for toxoplasmosis control

The Toxoplasma gondii infection is very important from the point of view of public health and affects almost all homeothermic animal species, including birds and mammals. In this study, thirty teachers from elementary schools in the northwest area of the state of São Paulo, Brazil, were interviewed about toxoplasmosis. Their students frequented of first to fourth series of the fundamental teaching. The questionnaire with closed questions were: 1) is the cat the main transmitter of toxoplasmosis in humans?; 2) If the cat can transmit toxoplasmosis, how happens?; 3) “If the dog can transmit toxoplasmosis, how happens?”; Is there any other way to acquire toxoplasmosis?; If there are other means of transmission, which can be? After this stage, lectures of short duration were supplied about this disease and reapplied the interview form. The data were analyzed with base in descriptive statistics. We found that there was an assimilation of the concepts on the control of toxoplasmosis by the teachers. In conclusion, there is the need of implanting one continuing education program for the community in general directed to the improvement of basic concepts of toxoplasmosis control.

Effectiveness of an exercise program on postural control in frail older adults

Background: Exercise programs have proved to be helpful for frail older adults. This study aimed to investigate the effects of an exercise program with a focus on postural control exercises in frail older adults. Method: Twenty-six older adults (76.7 +/- 4.9 years) deemed clinically stable, chosen from the Falls Unit, University Hospital Mutua Terrassa, Barcelona, Spain, participated in this single-group study. Volunteers' postural control was evaluated using the Timed Up and Go test (TUG) and the Guralnik test battery, and their static and dynamic posturography were evaluated using the Synapsys Posturography System (R). These evaluations were performed before and after the intervention program, which included an educational session and two weekly 1-hour sessions over an 8-week period of stretching exercises, proprioception, balance, and motor coordination. Data were analyzed using the Student's t-test or the Wilcoxon test, with a significance level of 5%. Results: The TUG and Guralnik tests did not show significant differences. Concerning static posturography, there was improvement in the base of support (P = 0.006), anteroposterior displacement with eyes open (P = 0.02) and closed (P = 0.03), and the total amplitude of the center of pressure with eyes closed (P = 0.02). Regarding dynamic posturography, a decrease of the oscillation speed in the anteroposterior direction (P = 0.01) was observed in individuals with their eyes open. Conclusion: The program used in this study was safe and was able to promote some improvement in postural control, especially in the anteroposterior direction and in the base of support. However, it is noteworthy that further improvements could be obtained from a program of longer duration and greater frequency.

Biochemical control of prostate cancer with iodine-125 brachytherapy alone: experience from a single institution

Brachytherapy is an adequate option as monotherapy for localised prostate cancer. The objective of this study was to evaluate and compare biochemical failure free survival (BFFS) after low-dose-rate brachytherapy (LDRB) alone for patients with prostate cancer using ASTRO and Phoenix criteria, and detect prognostic factors. Data on 220 patients treated between 1998 and 2002 with LDRB were retrospectively analysed. Neoadjuvant hormone therapy was used in 74 (33.6%) patients. Median follow-up was 53.5 months (24-116). Five year BFFS was 83.0% and 83.7% using, respectively, the ASTRO and Phoenix criteria. Low -and intermediate-risk patients presented, respectively, 86.7% and 77.8% 5-year BFFS using the ASTRO definition (p=0.069), and 88.5% and 78.6% considering the Phoenix criteria (p=0.016). Bounce was observed in 66 (30%) patients. Multivariate analysis detected PSA at diagnosis < 10 ng/ml and less than 50% positive biopsy fragments as favourable prognostic factors, regarding BF using both criteria. For the Phoenix criteria, also Gleason score < 7 and low-risk group were identified as independent favourable prognostic factors. LDRB alone should be considered mostly for low-risk patients. PSA level was a strong independent prognostic factor. We support the use of the Phoenix criteria for detection of BF in patients submitted to LDRB alone.

PTTG expression in different experimental and human prolactinomas in relation to dopaminergic control of lactotropes

Abstract Background Pituitary tumor transforming gene (pttg) is a novel oncogene that is expressed at higher level in most of the tumors analyzed to date compared to normal tissues. Nevertheless, its expression in prolactinomas and its relation with the pituitary dopamine receptor 2 (D2R) are not well defined. We sought to determine the pituitary level of pttg in three different experimental models of prolactinomas with altered dopaminergic control of the pituitary: the dopaminergic D2R knockout female mouse, the estrogen-treated rat, and the senescent female rat. These three models shared the characteristics of increased pituitary weight, hyperprolactinemia, lactotrope hyperplasia and reduced or absent dopaminergic action at the pituitary level. We also studied samples from human macroprolactinomas, which were characterized as responsive or resistant to dopamine agonist therapy. Results When compared to female wild-type mice, pituitaries from female D2R knockout mice had decreased PTTG concentration, while no difference in pttg mRNA level was found. In senescent rats no difference in pituitary PTTG protein expression was found when compared to young rats. But, in young female rats treated with a synthetic estrogen (Diethylstylbestrol, 20 mg) PTTG protein expression was enhanced (P = 0.029). Therefore, in the three experimental models of prolactinomas, pituitary size was increased and there was hyperprolactinemia, but PTTG levels followed different patterns. Patients with macroprolactinomas were divided in those in which dopaminergic therapy normalized or failed to normalize prolactin levels (responsive and resistant, respectively). When pituitary pttg mRNA level was analyzed in these macroprolactinomas, no differences were found. We next analyzed estrogen action at the pituitary by measuring pituitary estrogen receptor α levels. The D2R knockout female mice have low estrogen levels and in accordance, pituitary estrogen receptors were increased (P = 0.047). On the other hand, in senescent rats estrogen levels were slightly though not significantly higher, and estrogen receptors were similar between groups. The estrogen-treated rats had high pharmacological levels of the synthetic estrogen, and estrogen receptors were markedly lower than in controls (P < 0.0001). Finally, in patients with dopamine resistant or responsive prolactinomas no significant differences in estrogen receptor α levels were found. Therefore, pituitary PTTG was increased only if estrogen action was increased, which correlated with a decrease in pituitary estrogen receptor level. Conclusion We conclude that PTTG does not correlate with prolactin levels or tumor size in animal models of prolactinoma, and its pituitary content is not related to a decrease in dopaminergic control of the lactotrope, but may be influenced by estrogen action at the pituitary level. Therefore it is increased only in prolactinomas generated by estrogen treatment, and not in prolactinomas arising from deficient dopamine control, or in dopamine resistant compared with dopamine responsive human prolactinomas. These results are important in the search for reliable prognostic indicators for patients with pituitary adenomas which will make tumor-specific therapy possible, and help to elucidate the poorly understood phenomenon of pituitary tumorigenesis.

Assessment of metabolic control among patients in a capillary glucose self-monitoring program

OBJECTIVE: To assess the metabolic control of diabetes mellitus patients registered in a capillary glucose self-monitoring program at home. METHODS: In this longitudinal retrospective study, 97 subjects at four health institutions in a Brazilian city were followed during 37 months between 2005 and 2008. The health files were analyzed of patients selected to register the evolution of variables related to capillary glucose self-monitoring at home and metabolic control of diabetes mellitus. RESULTS: During the assessment, both mean and monthly percentages of capillary blood glucose measurements at home decreased from 34.1 (65.1%) to 33.6 (64.8%), respectively (p <0.001). Mean HbA1c levels dropped from 9.20% to 7.94% (p<0.001). HDL cholesterol decreased from 51 mg/dl to 47 mg/dl (p=0.001). CONCLUSION: Patients' metabolic control improved, characterized by a significant reduction in HbA1C.

Prevention of skin reactions due to teletherapy in women with breast cancer: a comprehensive review

One of the possible courses of cancer treatment is teletherapy, and one of the most important adverse side effects are skin reactions, an ailment more commonly called radiodermatitis. The main purpose of this study is to analyze knowledge of the evidence about topical products used in the prevention of radiodermatitis, to support care delivery to women with breast cancer during teletherapy. The research method used here is the comprehensive literature review. Four databases were used to select the bibliography. The sample consists of 15 articles. The data shows that, among the topical products analyzed here, Calendula, corticosteroids and Xclair have shown significant protective effects, underlining their actions. The lack of articles published in Brazil highlights the need for further research in this area, seeking better care quality through the use of products with scientifically proven efficiency.

Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain)

[EN] Background: All the relevant risk factors contributing to breast cancer etiology are not fully known. Exposure to organochlorine pesticides has been linked to an increased incidence of the disease, although not all data have been consistent. Most published studies evaluated the exposure to organochlorines individually, ignoring the potential effects exerted by the mixtures of chemicals. Methods: This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk.Results: The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024).Conclusions: This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk.

Myc-mediated control of gene transcription in cancer cells

The Myc oncoproteins belong to a family of transcription factors composed by Myc, N-Myc and L-Myc. The most studied components of this family are Myc and N-Myc because their expressions are frequently deregulated in a wide range of cancers. These oncoproteins can act both as activators or repressors of gene transcription. As activators, they heterodimerize with Max (Myc associated X-factor) and the heterodimer recognizes and binds a specific sequence elements (E-Box) onto gene promoters recruiting histone acetylase and inducing transcriptional activation. Myc-mediated transcriptional repression is a quite debated issue. One of the first mechanisms defined for the Myc-mediated transcriptional repression consisted in the interaction of Myc-Max complex Sp1 and/or Miz1 transcription factors already bound to gene promoters. This interaction may interfere with their activation functions by recruiting co-repressors such as Dnmt3 or HDACs. Moreover, in the absence of , Myc may interfere with the Sp1 activation function by direct interaction and subsequent recruitment of HDACs. More recently the Myc/Max complex was also shown to mediate transcriptional repression by direct binding to peculiar E-box. In this study we analyzed the role of Myc overexpression in Osteosarcoma and Neuroblastoma oncogenesis and the mechanisms underling to Myc function. Myc overexpression is known to correlate with chemoresistance in Osteosarcoma cells. We extended this study by demonstrating that c-Myc induces transcription of a panel of ABC drug transporter genes. ABCs are a large family trans-membrane transporter deeply involved in multi drug resistance. Furthermore expression levels of Myc, ABCC1, ABCC4 and ABCF1 were proved to be important prognostic tool to predict conventional therapy failure. N-Myc amplification/overexpression is the most important prognostic factor for Neuroblastoma. Cyclin G2 and Clusterin are two genes often down regulated in neuroblastoma cells. Cyclin G2 is an atypical member of Cyclin family and its expression is associated with terminal differentiation and apoptosis. Moreover it blocks cell cycle progression and induces cell growth arrest. Instead, CLU is a multifunctional protein involved in many physiological and pathological processes. Several lines of evidences support the view that CLU may act as a tumour suppressor in Neuroblastoma. In this thesis I showed that N-Myc represses CCNG2 and CLU transcription by different mechanisms. • N-Myc represses CCNG2 transcription by directly interacting with Sp1 bound in CCNG2 promoter and recruiting HDAC2. Importantly, reactivation of CCNG2 expression through epigenetic drugs partially reduces N-Myc and HDAC2 mediated cell proliferation. • N-Myc/Max complex represses CLU expression by direct binding to a peculiar E-box element on CLU promoter and by recruitment of HDACs and Polycomb Complexes, to the CLU promoter. Overall our findings strongly support the model in which Myc overexpression/amplification may contribute to some aspects of oncogenesis by a dual action: i) transcription activation of genes that confer a multidrug resistant phenotype to cancer cells; ii), transcription repression of genes involved in cell cycle inhibition and cellular differentiation.

Body Mass Index and Cancer Risk: The Evidence for Causal Association

Increased body mass index (BMI), as an approximation of body adiposity, is a risk factor for developing several adult malignancies. To quantify these risks, we reported a comprehensive systematic review (Lancet 2008; 371: 569-78) of prospective observational studies determining associations between BMI and risk of incident cancer for 20 cancer types. We demonstrated that associations are: (i) sex-specific; (ii) exist for a wider range of malignancies than previously thought; and (iii) are broadly consistent across geographic populations. In the present paper, we tested these data against the Bradford-Hill criteria of causal association, and argue that the available data support strength of association, consistency, specificity, temporality, biological gradient, plausibility, coherence and probably analogy. However, the experimental evidence supporting reversibility is currently lacking, though indirect evidence from longitudinal data in cohort studies and long-term follow-up post-bariatric surgery is emerging. We additionally assessed these data against appropriate adjustment for available confounding factors; measurement error and study design; and residual confounding; and found lack of alternative explanations. We conclude that there is considerable evidence to support a causal association between BMI and risk for many cancer types, but in order to establish the role of weight control in cancer prevention, there is a need to develop trial frameworks in which to better test reversibility.

miR-34a and miR-15a/16 are co-regulated in non-small cell lung cancer and control cell cycle progression in a synergistic and Rb-dependent manner

microRNAs (miRNAs) are small non-coding RNAs that are frequently involved in carcinogenesis. Although many miRNAs form part of integrated networks, little information is available how they interact with each other to control cellular processes. miR-34a and miR-15a/16 are functionally related; they share common targets and control similar processes including G1-S cell cycle progression and apoptosis. The aim of this study was to investigate the combined action of miR-34a and miR-15a/16 in non-small cell lung cancer (NSCLC) cells.