FASL polymorphism is associated with response to bacillus Calmette-Guérin immunotherapy in bladder cancer

Objective Deregulation of FAS/FASL system may lead to immune escape and influence bacillus Calmette-Guérin (BCG) immunotherapy outcome, which is currently the gold standard adjuvant treatment for high-risk non–muscle invasive bladder tumors. Among other events, functional promoter polymorphisms of FAS and FASL genes may alter their transcriptional activity. Therefore, we aim to evaluate the role of FAS and FASL polymorphisms in the context of BCG therapy, envisaging the validation of these biomarkers to predict response. Patients and methods DNA extracted from peripheral blood from 125 patients with bladder cancer treated with BCG therapy was analyzed by Polymerase Chain Reaction—Restriction Fragment Length Polymorphism for FAS-670 A/G and FASL-844 T/C polymorphisms. FASL mRNA expression was analyzed by real-time Polymerase Chain Reaction. Results Carriers of FASL-844 CC genotype present a decreased recurrence-free survival after BCG treatment when compared with FASL-844 T allele carriers (mean 71.5 vs. 97.8 months, P = 0.030) and have an increased risk of BCG treatment failure (Hazard Ratio = 1.922; 95% Confidence Interval: [1.064–3.471]; P = 0.030). Multivariate analysis shows that FASL-844 T/C and therapeutics scheme are independent predictive markers of recurrence after treatment. The evaluation of FASL gene mRNA levels demonstrated that patients carrying FASL-844 CC genotype had higher FASL expression in bladder tumors (P = 0.0027). Higher FASL levels were also associated with an increased risk of recurrence after BCG treatment (Hazard Ratio = 2.833; 95% Confidence Interval: [1.012–7.929]; P = 0.047). FAS-670 A/G polymorphism analysis did not reveal any association with BCG therapy outcome. Conclusions Our results suggest that analysis of FASL-844 T/C, but not FAS-670 A/G polymorphisms, may be used as a predictive marker of response to BCG immunotherapy.

Young people's blood alcohol concentration and the alcohol consumption city law, Brazil

The paper assesses blood alcohol concentration and risk behaviors for traffic accidents before and after the implementation of a law which prohibits the use of alcoholic beverages on city gas stations. In Porto Alegre, Southern Brazil, young people go out at night and drive to gas station convenience stores to buy alcoholic beverages which are consumed on the premises of parking lots in gas stations. Data were obtained from self-administered questionnaires and breath analyzers in two cross-sectional collections with purposive samples of youngsters in May and July 2006 (n=62, and n=50, respectively). There were no significant differences between the groups before and after the city law was passed. Blood alcohol concentration greater than 0.06% was found in 35.5% of pre-law group and 40% of post-law group (p=0.62). Results point out heavy alcohol use in both groups, which did not change after the law was passed.

The influence of the blood pressure on the venous cerebral flow measured by magnetic susceptibility (SWI) technique

Susceptibility Weighted Image (SWI) is a Magnetic Resonance Imaging (MRI) technique that combines high spatial resolution and sensitivity to provide magnetic susceptibility differences between tissues. It is extremely sensitive to venous blood due to its iron content of deoxyhemoglobin. The aim of this study was to evaluate, through the SWI technique, the differences in cerebral venous vasculature according to the variation of blood pressure values. 20 subjects divided in two groups (10 hypertensive and 10 normotensive patients) underwent a MRI system with a Siemens® scanner model Avanto of 1.5T using a synergy head coil (4 channels). The obtained sequences were T1w, T2w-FLAIR, T2* and SWI. The value of Contrast-to-Noise Ratio (CNR) was assessed in MinIP (Minimum Intensity Projection) and Magnitude images, through drawing free hand ROIs in venous structures: Superior Sagittal Sinus (SSS) Internal Cerebral Vein (ICV) and Sinus Confluence (SC). The obtained values were presented in descriptive statistics-quartiles and extremes diagrams. The results were compared between groups. CNR shown higher values for normotensive group in MinIP (108.89 ± 6.907) to ICV; (238.73 ± 18.556) to SC and (239.384 ± 52.303) to SSS. These values are bigger than images from Hypertensive group about 46 a.u. in average. Comparing the results of Magnitude and MinIP images, there were obtained lower CNR values for the hypertensive group. There were differences in the CNR values between both groups, being these values more expressive in the large vessels-SSS and SC. The SWI is a potential technique to evaluate and characterize the blood pressure variation in the studied vessels adding a physiological perspective to MRI and giving a new approach to the radiological vascular studies.

Comparison of the pencil beam convolution algorithm and the analytical anisotropic algorithm in breast tumors

The calculation of the dose is one of the key steps in radiotherapy planning1-5. This calculation should be as accurate as possible, and over the years it became feasible through the implementation of new algorithms to calculate the dose on the treatment planning systems applied in radiotherapy. When a breast tumour is irradiated, it is fundamental a precise dose distribution to ensure the planning target volume (PTV) coverage and prevent skin complications. Some investigations, using breast cases, showed that the pencil beam convolution algorithm (PBC) overestimates the dose in the PTV and in the proximal region of the ipsilateral lung. However, underestimates the dose in the distal region of the ipsilateral lung, when compared with analytical anisotropic algorithm (AAA). With this study we aim to compare the performance in breast tumors of the PBC and AAA algorithms.

The predominance of M2-polarized macrophages in the stroma of low-hypoxic bladder tumors is associated with BCG immunotherapy failure

OBJECTIVE: Bacillus Calmette-Guérin (BCG) immunotherapy is the gold standard treatment for superficial bladder tumors with intermediate/high risk of recurrence or progression. However, approximately 30% of patients fail to respond to the treatment. Effective BCG therapy needs precise activation of the type 1 helper cells immune pathway. Tumor-associated macrophages (TAMs) often assume an immunoregulatory M2 phenotype and may directly interfere with the BCG-induced antitumor immune response. Thus, we aim to clarify the influence of TAMs, in particular of the M2 phenotype in stroma and tumor areas, in BCG treatment outcome. PATIENTS AND METHODS: The study included 99 patients with bladder cancer treated with BCG. Tumors resected before treatment were evaluated using immunohistochemistry for CD68 and CD163 antigens, which identify a lineage macrophage marker and a M2-polarized specific cell surface receptor, respectively. CD68+ and CD163+ macrophages were evaluated within the stroma and tumor areas, and high density of infiltrating cells spots were selected for counting. Hypoxia, an event known to modulate macrophage phenotype, was also assessed through hypoxia induced factor (HIF)-1α expression. RESULTS: Patients in whom BCG failed had high stroma-predominant CD163+ macrophage counts (high stroma but low tumor CD163+ macrophages counts) when compared with the ones with a successful treatment (71% vs. 47%, P = 0.017). Furthermore, patients presenting this phenotype showed decreased recurrence-free survival (log rank, P = 0.008) and a clear 2-fold increased risk of BCG treatment failure was observed in univariate analysis (hazard ratio = 2.343; 95% CI: 1.197-4.587; P = 0.013). Even when adjusted for potential confounders, such as age and therapeutic scheme, multivariate analysis revealed 2.6-fold increased risk of recurrence (hazard ratio = 2.627; 95% CI: 1.340-5.150; P = 0.005). High stroma-predominant CD163+ macrophage counts were also associated with low expression of HIF-1α in tumor areas, whereas high counts of CD163+ in the tumor presented high expression of HIF-1α in tumor nests. CONCLUSIONS: TAMs evaluation using CD163 is a good indicator of BCG treatment failure. Moreover, elevated infiltration of CD163+ macrophages, predominantly in stroma areas but not in the tumor, may be a useful indicator of BCG treatment outcome, possibly owing to its immunosuppressive phenotype.

Size at birth and blood pressure in young adults: findings from a Brazilian birth cohort study

^len^lpt^aOBJETIVO: Descrever a prevalência de pressão arterial limítrofe (PAL) e hipertensão (HT) entre adultos jovens e avaliar a associação entre tamanho ao nascer e PAL/HT. MÉTODOS: Dados foram coletados do primeiro estudo brasileiro de coorte de nascimentos em Ribeirão Preto (sudeste do Brasil), iniciado em 1978/79. De 6.827 recém-nascidos de parto único hospitalar, 2.060 foram avaliados aos 23/25 anos. Foram realizadas coleta de sangue, avaliação antropométrica e obtidas informações sobre ocupação, escolaridade, hábitos de vida e doenças crônicas. Pressão arterial (PA) foi classificada em: 1) PAL: PA sistólica (PAS) ≥ 130 e < 140 mm Hg e/ou PA diastólica (PAD) ≥ 85 e < 90 mmHg; 2) HT: PAS ≥ 140 e/ou PAD ≥ 90 mm Hg. Foi aplicado modelo de regressão logística politômica. RESULTADOS: A prevalência de PAL foi de 13,5% (homens 23,2%) e a de HT, 9,5% (homens 17,7%). PAL foi independentemente associada com sexo masculino (RR 8,84; IC95%: 6,09;12,82), comprimento ao nascer ≥ 50 cm (RR 1,97; 1,04; 3,73), índice de massa corporal (IMC) ≥ 30 kg/m² (RR 3,23; 2,02; 5,15) e circunferência de cintura alterada (RR 1,61; 1,13;2,29), enquanto HT associou-se com sexo masculino (RR 15,18; 8,92;25,81), IMC ≥ 30 kg/m² (RR 3,68; 2,23;6,06), circunferência de cintura alterada (RR 2,68; 1,77;4,05) e glicemia elevada (RR 2,55; 1,27;5,10), mas não com comprimento ao nascer. CONCLUSÕES: As prevalências de PAL e HT entre os adultos jovens dessa coorte foram maiores em homens que em mulheres. Maior comprimento ao nascer foi associado com PAL, mas não com HT, enquanto peso ao nascer não foi associado com PAL ou HT. Fatores de risco do adulto explicaram a maioria dos aumentos de PAL ou HT.^les^aOBJETIVO: Describir la prevalencia de presión arterial limítrofe (PAL) e hipertensión (HT) entre adultos jóvenes y evaluar la asociación entre tamaño al nacer y PAL/HT. MÉTODOS: : Los datos fueron colectados en el primer estudio de cohorte de nacimientos brasileño en Ribeirao Preto (sureste de Brasil), iniciado en 1978/79. De 6.827 recién nacidos de parto único hospitalario, 2.060 fueron evaluados a los 23/25 años. Se realizaron colecta de sangre, evaluación antropométrica y obtenidas informaciones sobre ocupación, escolaridad, hábitos de vida y enfermedades crónicas. Presión arterial (PA) fue clasificada en: 1) PAL: PA sistólica (PAS) ≥ 130 y < 140 mm Hg y/o PA diastólica (PAD) ≥ 85 y < 90 mm Hg; 2) HT: PAS ≥ 140 y/o PAD ≥ 90 mm Hg. Se aplicó modelo de regresión logística politómica. RESULTADOS: La prevalencia de PAL fue de 13,5% (hombres 23,2%) y la de HT, 9,5% (hombres 17,7%). PAL fue independientemente asociada con sexo masculino (Riesgo Relativo - RR) 8,84; 95%IC: 6,09;12,82), estatura al nacer ≥ 50 cm (RR 1,97; 1,04; 3,73), índice de masa corporal (IMC) ≥ 30 kg/m2 (RR 3,23; 2,02; 5,15) y circunferencia de cintura alterada (RR 1,61; 1,13;2,29), mientras el HT se asoció con sexo masculino (RR 15,18; 8,92;25,81), IMC ≥ 30 kg/m2 (RR 3,68; 2,23;6,06), circunferencia de cintura alterada (RR 2,68; 1,77;4,05) y glicemia elevada (RR 2,55; 1,27;5,10), pero no con estatura al nacer. CONCLUSIONES: Las prevalencias de PAL y HT entre los adultos jóvenes de la cohorte fueron mayores en hombres que en mujeres. Mayor estatura al nacer fue asociado con PAL, pero no con HT, mientras que el peso al nacer no estuvo asociado con PAL o HT. Factores de riesgo de adulto explicaron la mayoría de los aumentos de PAL o HT.

Insights into the mechanims underlyng the antiproliferative potential of a Co(II) coordination compound bearing 1,10-Phenanthroline-5,6-Dione: DNA and protein interaction studies

The very high antiproliferative activity of [Co(Cl)(H2O)(phendione)(2)][BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 mu M) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that [Co(Cl)(phendione)(2)(H2O)][BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 % at 1 mu M, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K (b) (+/- A standard error of the mean) of (3.48 +/- A 0.03) x 10(5) M-1 and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K (b) similar to 4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma.

Interrelation between parasitic infections and hypovitaminosis A: Schistosoma mansoni infection and the retinol blood levels in an endemic area of State of Minas Gerais (Brazil)

The interrelation between schistosomiasis and the retinol blood levels was studied in a double blind method, by comparing the serum vitamin A of the infected and non-infected group of an endemic area of Schistosoma mansoni infection. The infected group was characterized by 106 parasitized persons in the intestinal and hepatointestinal forms, who eliminated less than 500 eggs/gram of feces (Modified Kato's method); the non-infected group was characterized by 112 inhabitants of this endemic area without eggs in the stools and presenting negative intradermal reactions, and absence of previous specific treatment. The blood levels of retinol was determinated using trifluoracetic acid method, regarding the normal levels > 20,0mg/100ml. The results of this study point out the absence of correlation between S. mansoni infection and blood levels of vitamin A.

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.

Potential infectivity of blood from HBsAG asymptomatic carriers due to the presence of HBV-DNA and comparison with other markers of hbv infection

Serum samples from 356 HBsAg positive asymptomatic carriers, which were titrated by reverse passive hemagglutination, were analysed for the presence of HBV-DNA, HBsAg and IgM anti-HBc. The samples were divided in three classes, according to the titers of HBsAg and IgM anti-HBc and the distribution of HBV-DNA and HBsAg among these classes was studied. In the high titer class of HBsAg, 65% of samples have one or both markers against only 19% in the low titer class. From the total of 356 samples, 121 gave positive results for IgM anti-HBc (33.9%). From these, 38.9% of HBV-DNA and 47.9% of HBeAg were observed, whereas in samples with absence of IgM anti-HBc, 18.3% and 16.6% were respectively found. A higher frequency of agreement between all these markers was found in the class of high titers of HBsAg; however, HBV-DNA was detected in the low titer class of HBsAg and little or no IgM anti-HBc, showing potential blood infectivity even in HBsAg positive borderline samples.

Trends of T. cruzi infection based on data from blood bank screening

Between October 1988 and April 1989 a cross-sectional survey was carried out in six out of eight blood banks of Goiânia, Central Brazil. Subjects attending for first-time blood donation in the mornings of the study period (n = 1358) were interviewed and screened for T. cruzi infection as a part of a major study among blood donors. Tests to anti-T. cruzi antibodies were performed, simultaneously, by indirect hem agglutination test (IHA) and complement fixation test (CFT). A subject was considered seropositive when any one of the two tests showed a positive result. Information on age, sex, place of birth, migration and socio-economic level was recorded. Results from this survey were compared with seroprevalence rates obtained in previous studies in an attempt to analyse trend of T. cruzi infection in an endemic urban area. The overall seroprevalence of T. cruzi infection among first-time donors was found to be 3.5% (95% confidence interval 2.5%-4.5% ). The seroprevalence rate increased with age up to 45 years and then decreased. Migrants from rural areas had higher seroprevalence rates than subjects from urban counties (1.8%-16.2% vs. 0%-3.6%). A four fold decrease in prevalence rates was observed when these rates were compared with those of fifteen years ago. Two possible hypotheses to explain this difference were suggested: 1. a cohort effect related with the decrease of transmission in rural areas and/or 2. a differential proportion of people of rural origin among blood donors between the two periods. The potential usefulness of blood banks as a source of epidemiological information to monitor trends of T. cruzi infection in an urban adult population was stressed.

Lethality of triatomines (Hemiptera: Reduviiae), vectors of Chagas' disease, feeding on blood baits containing synthetic insecticides, under laboratory conditions

A laboratory study was conducted to test the toxicity of synthetic insecticides added to defibrinated sheep blood kept at room temperature and offered as food to the following triatomine species: Triatoma infestans, Panstrongylus megistus, Triatoma vitticeps, Triatoma pseudomaculata, Triatoma brasiliensis and Rhodnius prolixus. The insecticides used, at a concentration of 1g/l, were: HCH, DDT, Malathion and Trichlorfon, and the lethalithy observed at the end of a 7-day period varied according to the active principle of each. HCH was the most effective by the oral route, killing 100% of the insects, except P. megistus (95.7%) and T. pseudomaculata (94.1%). Trichlorfon killed the insects at rates ranging from 71.8% (T. vitticeps) to 98% (R. prolixus). Malathion was slightly less efficient, killing the insects at rates from 56.8% (T. vitticeps) to 97% (T.brasiliensis). DDT was the least effective, with a killing rate of 10% (T. vitticeps) to 75% (T.brasiliensis). Since the tests were performed at room temperature, we suggest that baits of this type should be tried for the control of triatomines in the field.

Exposure to acellular blood products and risk of HIV infection in hemophiliacs from Belo Horizonte, Brazil

Results of a HIV prevalence study conducted in hemophiliacs from Belo Horizonte, Brazil are presented. History of exposure to acellular blood components was determined for the five year period prior to entry in the study, which occurred during 1986 and 1987. Patients with coagulations disorders (hemophilia A = 132, hemophilia B = 16 and coagulation disorders other than hemophilia = 16) were transfused with liquid cryoprecipitate, locally produced, lyophilized cryoprecipitate, imported from São Paulo (Brazil) and factor VIII and IX, imported from Rio de Janeiro (Brazil), Europe, and United States. Thirty six (22%) tested HIV seropositive. The univariate and multivariate analysis (logistic model) demonstrated that the risk of HIV infection during the study period was associated with the total units of acellular blood components transfused. In addition, the proportional contribution of the individual components to the total acellular units transfused, namely a increase in factor VIII/IX and lyophilized cryoprecipitate proportions, were found to be associated with HIV seropositivity. This analysis suggest that not only the total amount of units was an important determinant of HIV infection, but that the risk was also associated with the specific component of blood transfused

Low frequency of TERT promoter mutations in gastrointestinal stromal tumors (GISTs)

Somatic mutations in the promoter region of telomerase reverse transcriptase (TERT) gene, mainly at positions c.-124 and c.-146 bp, are frequent in several human cancers; yet its presence in gastrointestinal stromal tumor (GIST) has not been reported to date. Herein, we searched for the presence and clinicopathological association of TERT promoter mutations in genomic DNA from 130 bona fide GISTs. We found TERT promoter mutations in 3.8% (5/130) of GISTs. The c.-124C>T mutation was the most common event, present in 2.3% (3/130), and the c.-146C>T mutation in 1.5% (2/130) of GISTs. No significant association was observed between TERT promoter mutation and patient's clinicopathological features. The present study establishes the low frequency (4%) of TERT promoter mutations in GISTs. Further studies are required to confirm our findings and to elucidate the hypothetical biological and clinical impact of TERT promoter mutation in GIST pathogenesis.