Imigração, patrimônio cultural e turismo no Brasil

The heritage of immigration, like all cultural expression, has multiple forms and understanding permeates the approach to several issues, among them: the various manifestations of cultural heritage, the intentions of conservation actions and appreciation of the cultural heritage of immigrant groups and practices for the resonance of this heritage, such as tourism. The objective of this paper is to analyze the heritage of immigration as a phenomenon that was constituted in a particular environment, not only by the above issues, but also as a particular form of instituting the past in the present and its consequences for the construction of collective identitiesO patrimônio da imigração, como toda expressão cultural, possui múltiplas formas e sua compreensão perpassa pela abordagem de várias questões, dentre elas: as várias manifestações do patrimônio cultural; as intencionalidades das ações de preservação e valorização da herança cultural de grupos de imigrantes; e as práticas para a ressonância deste patrimônio, como é o caso do turismo. O objetivo deste artigo é analisar o patrimônio da imigração como fenômeno que se constituiu num ambiente determinado, não só pelas questões acima, mas também como uma forma particular de instituir o passado no presente e seus desdobramentos para a construção de identidades coletivas

Effect of aliskiren on post-discharge outcomes among diabetic and non-diabetic patients hospitalized for heart failure: insights from the ASTRONAUT trial

Aims The objective of the Aliskiren Trial on Acute Heart Failure Outcomes (ASTRONAUT) was to determine whether aliskiren, a direct renin inhibitor, would improve post-discharge outcomes in patients with hospitalization for heart failure (HHF) with reduced ejection fraction. Pre-specified subgroup analyses suggested potential heterogeneity in post-discharge outcomes with aliskiren in patients with and without baseline diabetes mellitus (DM). Methods and results ASTRONAUT included 953 patients without DM (aliskiren 489; placebo 464) and 662 patients with DM (aliskiren 319; placebo 343) (as reported by study investigators). Study endpoints included the first occurrence of cardiovascular death or HHF within 6 and 12 months, all-cause death within 6 and 12 months, and change from baseline in N-terminal pro-B-type natriuretic peptide (NT-proBNP) at 1, 6, and 12 months. Data regarding risk of hyperkalaemia, renal impairment, and hypotension, and changes in additional serum biomarkers were collected. The effect of aliskiren on cardiovascular death or HHF within 6 months (primary endpoint) did not significantly differ by baseline DM status (P = 0.08 for interaction), but reached statistical significance at 12 months (non-DM: HR: 0.80, 95% CI: 0.64-0.99; DM: HR: 1.16, 95% CI: 0.91-1.47; P = 0.03 for interaction). Risk of 12-month all-cause death with aliskiren significantly differed by the presence of baseline DM (non-DM: HR: 0.69, 95% CI: 0.50-0.94; DM: HR: 1.64, 95% CI: 1.15-2.33; P < 0.01 for interaction). Among non-diabetics, aliskiren significantly reduced NT-proBNP through 6 months and plasma troponin I and aldosterone through 12 months, as compared to placebo. Among diabetic patients, aliskiren reduced plasma troponin I and aldosterone relative to placebo through 1 month only. There was a trend towards differing risk of post-baseline potassium ≥6 mmol/L with aliskiren by underlying DM status (non-DM: HR: 1.17, 95% CI: 0.71-1.93; DM: HR: 2.39, 95% CI: 1.30-4.42; P = 0.07 for interaction). Conclusion This pre-specified subgroup analysis from the ASTRONAUT trial generates the hypothesis that the addition of aliskiren to standard HHF therapy in non-diabetic patients is generally well-tolerated and improves post-discharge outcomes and biomarker profiles. In contrast, diabetic patients receiving aliskiren appear to have worse post-discharge outcomes. Future prospective investigations are needed to confirm potential benefits of renin inhibition in a large cohort of HHF patients without D

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Exploring the contribution of genetic and environmental factors to cancer risk and development

Krebs entsteht durch das Zusammenspiel von Keimbahn- und somatischen Mutationen sowie Umweltfaktoren. Für Fortschritte in Prävention, Früherkennung und Behandlung von Krebs ist es essenziell die phänotypischen Folgen dieser Mutationen und die Rolle von Umweltfaktoren bei der Steigerung des Krebsrisikos zu verstehen. In dieser Arbeit untersuche ich zunächst die Auswirkungen von Mutationen in einfachen Sequenzwiederholungsregionen (SSRs) auf das Zellwachstum in einem Hefemodell. In einem Mutationsakkumulationsexperiment in Stämmen mit defektem Mismatch-Reparatursystem zeige ich, dass die Störung von MutSβ zu einer erhöhten SSR-Mutationsrate führt, insbesondere bei SSR-Loci die länger als 8 bp sind. Meine Ergebnisse legen nahe, dass MutSβ hauptsächlich für die Reparatur an längeren Repeat-Loci verantwortlich ist. Schließlich zeige ich, dass SSR-Mutationen meist geringfügige, negative Auswirkungen auf das Zellwachstum haben. Als Nächstes untersuche ich die Auswirkungen von Zigarettenrauch auf das Transkriptom von zugänglichem Atemwegsgewebe am Beispiel des Nasenepithels von gesunden Freiwilligen und Patienten mit Verdacht auf oder diagnostiziertem Lungenkrebs. Ich stelle fest, dass Gene und biologische Funktionen, die durch das Rauchen beeinträchtigt werden, bei Patienten langsamer auf ein gesundes Ausgangsniveau zurückkehren. Zudem zeige ich, dass Patienten durch anhaltende, Rauch-assoziierte Immunveränderungen gekennzeichnet sind. Schließlich präsentiere ich einen innovativen Lungenkrebs-Klassifikator, der durch die Berücksichtigung der nasalen Genexpression von Rauch-assoziierten Genen eindeutig bessere Ergebnisse erzielt als ein Modell, das ausschließlich auf klinischen Informationen basiert. Damit belege ich das Potenzial der Genexpression des Nasenepithels zur Verbesserung der Risikostratifizierung auf Bevölkerungsebene anhand eines nicht-invasiven Tests.Cancer is initiated and sustained by the interplay of germline and somatic mutations and environmental factors. Understanding the phenotypic consequences of mutations and the role of environmental factors in increasing cancer risk is key to improving cancer prevention, early detection, and treatment. In this thesis, I first take advantage of a yeast model to investigate the effects of mutations in simple sequence repeat regions (SSRs) on cell growth. I describe a mutation accumulation experiment conducted in strains with a deletion of the MutSβ gene, a component of the mismatch repair system (MMR). I show that abrogating MutSβ function leads to an increased SSR mutation rate, with a bias towards deletions. I also report a drastic increase in mutation rate in SSR loci longer that 8-bp, suggesting MutSβ is primarily responsible for repair at longer repeat loci. Finally, I show that many SSR mutations have small deleterious effects on cell growth. Next, I investigate the effects of cigarette smoke on the transcriptome of an accessible airway tissue, nasal epithelium, in a cohort of healthy volunteers and patients with suspected or diagnosed lung cancer. I find that smoke injury response is strikingly different in healthy individuals and clinic patients, with genes and biological functions affected by smoking showing a slower reversal to healthy baseline level in clinic patients. I find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Finally, I show that a lung cancer classifier including nasal expression of smoke-injury-associated genes performs better than a model based exclusively on clinical information, providing evidence for the potential of nasal epithelial gene expression to improve population-level risk stratification with the use of a non-invasive test

The rate of spontaneous mutations in yeast deficient for MutS beta function

Mutations in simple sequence repeat loci underlie many inherited disorders in humans, and are increasingly recognized as important determinants of natural phenotypic variation. In eukaryotes, mutations in these sequences are primarily repaired by the MutS beta mismatch repair complex. To better understand the role of this complex in mismatch repair and the determinants of simple sequence repeat mutation predisposition, we performed mutation accumulation in yeast strains with abrogated MutS beta function. We demonstrate that mutations in simple sequence repeat loci in the absence of mismatch repair are primarily deletions. We also show that mutations accumulate at drastically different rates in short (<8 bp) and longer repeat loci. These data lend support to a model in which the mismatch repair complex is responsible for repair primarily in longer simple sequence repeats

Smoking-dependent expression alterations in nasal epithelium reveal immune impairment linked to germline variation and lung cancer risk

Abstract Lung cancer is the leading cause of cancer-related death in the world. In contrast to many other cancers, a direct connection to lifestyle risk in the form of cigarette smoke has long been established. More than 50% of all smoking-related lung cancers occur in former smokers, often many years after smoking cessation. Despite extensive research, the molecular processes for persistent lung cancer risk are unclear. CT screening of current and former smokers has been shown to reduce lung cancer mortality by up to 26%. To examine whether clinical risk stratification can be improved upon by the addition of genetic data, and to explore the mechanisms of the persisting risk in former smokers, we have analyzed transcriptomic data from accessible airway tissues of 487 subjects. We developed a model to assess smoking associated gene expression changes and their reversibility after smoking is stopped, in both healthy subjects and clinic patients. We find persistent smoking-associated immune alterations to be a hallmark of the clinic patients. Integrating previous GWAS data using a transcriptional network approach, we demonstrate that the same immune and interferon related pathways are strongly enriched for genes linked to known genetic risk factors, demonstrating a causal relationship between immune alteration and lung cancer risk. Finally, we used accessible airway transcriptomic data to derive a non-invasive lung cancer risk classifier. Our results provide initial evidence for germline-mediated personalised smoke injury response and risk in the general population, with potential implications for managing long-term lung cancer incidence and mortality

The complete 12 Mb genome and transcriptome of Nonomuraea gerenzanensis with new insights into its duplicated "magic" RNA polymerase

In contrast to the widely accepted consensus of the existence of a single RNA polymerase in bacteria, several actinomycetes have been recently shown to possess two forms of RNA polymerases due the to co-existence of two rpoB paralogs in their genome. However, the biological significance of the rpoB duplication is obscure. In this study we have determined the genome sequence of the lipoglycopeptide antibiotic A40926 producer Nonomuraea gerenzanensis ATCC 39727, an actinomycete with a large genome and two rpoB genes, i.e. rpoB(S) (the wild-type gene) and rpoB(R) (the mutant-type gene). We next analyzed the transcriptional and metabolite profiles in the wild-type gene and in two derivative strains over-expressing either rpoB(R) or a mutated form of this gene to explore the physiological role and biotechnological potential of the "mutant-type" RNA polymerase. We show that rpoB(R) controls antibiotic production and a wide range of metabolic adaptive behaviors in response to environmental pH. This may give interesting perspectives also with regard to biotechnological applications