Constitutional hypomorphic telomerase mutations in patients with acute myeloid leukemia

Loss-of-function mutations in telomerase complex genes can cause bone marrow failure, dyskeratosis congenita, and acquired aplastic anemia, both diseases that predispose to acute myeloid leukemia. Loss of telomerase function produces short telomeres, potentially resulting in chromosome recombination, end-to-end fusion, and recognition as damaged DNA. We investigated whether mutations in telomerase genes also occur in acute myeloid leukemia. We screened bone marrow samples from 133 consecutive patients with acute myeloid leukemia and 198 controls for variations in TERT and TERC genes. An additional 89 patients from a second cohort, selected based on cytogenetic status, and 528 controls were further examined for mutations. A third cohort of 372 patients and 384 controls were specifically tested for one TERT gene variant. In the first cohort, 11 patients carried missense TERT gene variants that were not present in controls (P<0.0001); in the second cohort, TERT mutations were associated with trisomy 8 and inversion 16. Mutation germ-line origin was demonstrated in 5 patients from whom other tissues were available. Analysis of all 3 cohorts (n = 594) for the most common gene variant (A1062T) indicated a prevalence 3 times higher in patients than in controls (n = 1,110; P = 0.0009). Introduction of TERT mutants into telomerase-deficient cells resulted in loss of enzymatic activity by haploinsufficiency. Inherited mutations in TERT that reduce telomerase activity are risk factors for acute myeloid leukemia. We propose that short and dysfunctional telomeres limit normal stem cell proliferation and predispose for leukemia by selection of stem cells with defective DNA damage responses that are prone to genome instability.

Constitutional Telomerase Mutations Are Genetic Risk Factors for Cirrhosis

Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004). Conclusion: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis. (HEPATOLOGY 2011;53:1600-1607)

Re McBain; ex parte Australian Catholic Bishops Conference

The case of Re McBain; ex parte Australian Catholic Bishops Conference sought to make an order under s 76 of the Constitution that the decision of the Federal Court was incorrect in law - decision was made on the basis of constitutional and procedural issues - High Court consolidated the definition of 'matter' in sections 75 and 76 of the Constitution - writ of certiorari considered - role of the Attorney-General in proceedings in which he had granted a fiat - case reiterated the role of the judiciary in Australia.

O parlamento e a regulação das comunicações : estudo sobre a atividade legislativa do congresso nacional para a radiodifusão

Dissertação (mestrado)—Universidade de Brasília, Faculdade de Comunicação, Programa de Pós-Graduação em Comunicação, 2016.

Gender wage and productivity differentials in the Portuguese tourism industry

The objective of this paper is to provide empirical evidence on the determinants of gender wage inequality in the Portuguese tourism industry. Relying on firm level wage equations and production functions, gender wage and productivity differentials are estimated and then compared in order to infer whether observed gender disparities are justifiable on the grounds that women are relatively less productive than men, or instead disparities are due to gender wage discrimination. This approach is applied to tourism industry data gathered in the matched employer-employee data set Quadros de Pessoal (Employee Records). The main findings indicate that female employees in the tourism industry in Portugal are less productive than their male colleagues and that gender differences in wages are fully explained by gender differences in productivity.

Motivations to visit and image destination of Guimarães: differences between Portuguese and foreign tourists during 2012 Guimarães European Capital of Culture (ECOC)

Guimarães hosted the European Capital of Culture (ECOC) during the year of 2012. This study investigates the differences between Portuguese and foreign tourists regarding the main motivations to visit Guimarães and the retained perceived image of the destination. To achieve that purpose a survey was administered to 390 tourists that visited the city during the cultural event. The results show that tourists who visited Guimarães are relatively young, wealthy, employed and well educated. They are touring around the northern part of the country which includes an itinerary beginning in Porto, and extended to other important neighboring cities such as Braga or Viana do Castelo. The main motivations to visit the city, for both Portuguese and foreign tourists, are its historical heritage and the title of ECOC, the associated cultural events and celebrations that take place during 2012. However, these items were more valued by foreigners than Portuguese tourists. Using a factor analysis the tourists’ perceived attributes of Guimarães were described in four dimensions: “material heritage”, “intangible heritage”, “cultural performance”, and “sport and education”. Although foreigners and nationals perceived the tourism attributes of the city differently, the comparison of the mean scores of the four factors across Portuguese and foreigner tourists reveals that the most valued and least valued factors are common to both groups.