Interethnic diversity of NAT2 polymorphisms in Brazilian admixed populations

<p>Abstract</p> <p>Background</p> <p>N-acetyltransferase type 2 (Nat2) is a phase II drug- metabolizing enzyme that plays a key role in the bioactivation of aromatic and heterocyclic amines. Its relevance in drug metabolism and disease susceptibility remains a central theme for pharmacogenetic research, mainly because of its genetic variability among human populations. In fact, the evolutionary and ethnic-specific SNPs on the <it>NAT2 </it>gene remain a focus for the potential discoveries in personalized drug therapy and genetic markers of diseases. Despite the wide characterization of <it>NAT2 </it>SNPs frequency in established ethnic groups, little data are available for highly admixed populations. In this context, five common <it>NAT2 </it>SNPs (<it>G191A</it>, <it>C481T</it>, <it>G590A</it>, <it>A803G </it>and G<it>857A</it>) were investigated in a highly admixed population comprised of Afro-Brazilians, Whites, and Amerindians in northeastern Brazil. Thus, we sought to determine whether the distribution of <it>NAT2 </it>polymorphism is different among these three ethnic groups.</p> <p>Results</p> <p>Overall, there were no statistically significant differences in the distribution of <it>NAT2 </it>polymorphism when Afro-Brazilian and White groups were compared. Even the allele frequency of <it>191A</it>, relatively common in African descendents, was not different between the Afro-Brazilian and White groups. However, allele and genotype frequencies of <it>G590A </it>were significantly higher in the Amerindian group than either in the Afro-Brazilian or White groups. Interestingly, a haplotype block between <it>G590A </it>and <it>A803G </it>was verified exclusively among Amerindians.</p> <p>Conclusions</p> <p>Our results indicate that ethnic admixture might contribute to a particular pattern of genetic diversity in the <it>NAT2 </it>gene and also offer new insights for the investigation of possible new <it>NAT2 </it>gene-environment effects in admixed populations.</p

Effects of a Peripheral Enamel Margin on the Long-term Bond Strength and Nanoleakage of Composite/Dentin Interfaces Produced by Self-adhesive and Conventional Resin Cements

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Purpose: This study evaluated the effects of peripheral enamel margins on the long-term bond strength (mu TBS) and nanoleakage in resin/dentin interfaces produced by self-adhesive and conventional resin cements. Materials and Methods: Five self-adhesive [RelyX-Unicem (UN), RelyX-U100 (UC), GCem (GC), Maxcem (MC), Set (SET)] and 2 conventional resin cements [RelyX-ARC(RX), Panavia F(PF)] were used. An additional group included the use of a two-step self-etching adhesive (SE Bond) with Panavia F (PS). One hundred ninety-two molars were assigned to 8 groups according to luting material. Five-mm-thick composite disks were cemented and assigned to 3 subgroups according to water-exposure condition (n = 6): 24-h peripheral exposure (24h-PE-enamel margins), or 1 year of peripheral (1yr-PE) or direct exposure (1yr-DE-dentin margin). Restored teeth were sectioned into beams and tested in tension at 1 mm/min. Data were analyzed by two-way ANOVA and Tukey's test. Two additional specimens in each group were prepared for nanoleakage evaluation. Nanoleakage patterns were observed under SEM/TEM. Results: Except for RX, no significant reduction in mu TBS was observed between 24h-PE and 1yr-PE. 1yr-DE reduced mu TBS for RX, PF, GC, MC, and SET. No significant reduction in mu TBS was observed for PS, UC, and UN after 1 year. After 1yr-DE, RX and PS presented the highest mu TBS, and SET and MC the lowest. Nanoleakage was reduced when there was a peripheral enamel margin. SET and MC presented more silver deposition than other groups. Conclusion: The presence of a peripheral enamel margin reduced the degradation rate in resin/dentin interfaces for most materials. The mu TBS values produced by the multi-step luting agents RX and PS were significantly higher than those observed for self-adhesive cement143251263Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [2007/06083-4, 2007/06447-6

Phase 1 Expansion Cohort of Ramucirumab Plus Pembrolizumab in Advanced Treatment-Naive NSCLC

INTRODUCTION: Data of first-line ramucirumab plus pembrolizumab treatment of programmed death-ligand 1 (PD-L1)-positive NSCLC (cohort E) are reported (NCT02443324). METHODS: In this multicenter, open-label phase 1a/b trial, patients received ramucirumab 10 mg/kg and pembrolizumab 200 mg every 21 days for up to 35 cycles. PD-L1 positivity was defined as tumor proportion score (TPS) greater than or equal to 1%. Exploratory NanoString biomarker analyses included three T-cell signatures (T-cell-inflamed, Gajewski, and effector T cells) and CD274 gene expression. RESULTS: Cohort E included 26 patients. Treatment-related adverse events of any grade occurred in 22 patients (84.6%). Treatment-related adverse events of grade greater than or equal to 3 were reported in 11 patients (42.3%); the most frequent was hypertension (n = 4, 15.4%). Objective response rate was 42.3% in the treated population and 56.3% and 22.2% for patients with high (TPS ≥ 50%) and lower levels (TPS 1%-49%) of PD-L1 expression, respectively. Median progression-free survival (PFS) in the treated population was 9.3 months, and 12-month and 18-month PFS rates were 45% each. Median PFS was not reached in patients with PD-L1 TPS greater than or equal to 50% and was 4.2 months in patients with PD-L1 TPS 1% to 49%. Median overall survival was not reached in the treated population, and 12-month and 18-month overall survival rates were 73% and 64%, respectively. Biomarker data suggested a positive association among clinical response, three T-cell signatures, CD274 gene expression, and PD-L1 immunohistochemistry. CONCLUSIONS: First-line therapy with ramucirumab plus pembrolizumab has a manageable safety profile in patients with NSCLC, and the efficacy signal seems to be strongest in tumors with high PD-L1 expression

Ramucirumab in combination with pembrolizumab in treatment-naïve advanced gastric or gej adenocarcinoma: Safety and antitumor activity from the phase 1a/b jvdf trial

Ramucirumab (anti-VEGFR2) plus pembrolizumab (anti-PD1) demonstrated promising antitumor activity and tolerability among patients with previously treated advanced cancers, supporting growing evidence that combination therapies modulating the tumor microenvironment may expand the spectrum of patients who respond to checkpoint inhibitors. Here we present the results of this combination in first-line patients with metastatic G/GEJ cancer. Twenty-eight patients (≥18 years) with no prior systemic chemotherapy in the advanced/metastatic setting received ramucirumab (8 mg/kg days 1 and 8) plus pembrolizumab (200 mg day 1) every 3 weeks as part of JVDF phase 1a/b study. The primary endpoint was safety. Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), and overall survival (OS). Tumors were PD-L1-positive (combined positive score ≥ 1) in 19 and-negative in 6 patients. Eighteen patients experienced grade 3 treatment-related adverse events, most commonly hypertension (14%) and elevated alanine/aspartate aminotransferase (11% each), with no grade 4 or 5 reported. The ORR was 25% (PD-L1-positive, 32%; PD-L1-negative, 17%) with duration of response not reached. PFS was 5.6 months (PD-L1-positive, 8.6 months; PD-L1-negative, 4.3 months), and OS 14.6 months (PD-L1-positive, 17.3 months; PD-L1-negative, 11.3 months). Acknowledging study design limitations, ramucirumab plus pembrolizumab had encouraging durable clinical activity with no unexpected toxicities in treatment-naïve biomarker-unselected metastatic G/GEJ cancer, and improved outcomes in patients with PD-L1-positive tumors

Comfort from the perspective of families of people hospitalized in the intensive care unit

This study aimed at understanding the meaning of comfort to the families of people in intensive care units. It consists of a qualitative study carried out in the intensive care unit of a hospital in Salvador-Bahia. Fourteen family members were interviewed. The authors utilized the theoretical principles of symbolic interactionism and the technique of qualitative data analysis. Results indicated that the categories Safety, Receptiveness, Information, Proximity, Social and Spiritual Support, Convenience and Integration expressed the meaning of comfort, which was comprised of reliability in terms of technical-scientific competence and a supportive and sensitive attitude of the team, chance of recovery, access to information and the opportunity to be close to the patient, support of people in their social life, spiritual sources and the environmental structure of the hospital, preservation of self-care and routine activities. It was concluded that the family is important as objects and subjects of the actions in healthcare and must be the focus in public health policies and programs in Brazil

Sources of decline, turnaround strategy and HR strategies and practices: The case of Iberia Airlines

This study investigates the coevolution of the sources of decline, the turnaround strategy and the human resource strategy (HRS) at Iberia Airlines, together with the influence of employee responses to these strategies. The analysis of several moments of organisational decline at Iberia, comparing measures adopted in pre- and post-financial crisis periods, shows that, in a sector experiencing a fiercely competitive transformation that negatively affects established companies, the use of downsizing in an organisation with internal deficiencies may create further problems within the company, while an HRS based on flexibility-oriented practices and a fostering approach to strategic negotiations will improve the requisite recovery strategy.Management and Marketing Department (University of Pablo de Olavide