Association of the germline TP53 R337H mutation with breast cancer in southern Brazil

<p>Abstract</p> <p>Background</p> <p>The germline <it>TP53</it>-R337H mutation is strongly associated with pediatric adrenocortical tumors (ACT) in southern Brazil; it has low penetrance and limited tissue specificity in most families and therefore is not associated with Li-Fraumeni syndrome. However, other tumor types, mainly breast cancer, have been observed in carriers of several unrelated kindreds, raising the possibility that the R337H mutation may also contribute to breast tumorigenesis in a genetic background-specific context.</p> <p>Methods</p> <p>We conducted a case-control study to determine the prevalence of the R337H mutation by sequencing <it>TP</it>53 exon 10 in 123 women with breast cancer and 223 age- and sex-matched control subjects from southern Brazil. Fisher's test was used to compare the prevalence of the R337H.</p> <p>Results</p> <p>The R337H mutation was found in three patients but in none of the controls (p = 0.0442). Among the carriers, two had familial history of cancer meeting the Li-Fraumeni-like criteria. Remarkably, tumors in each of these three cases underwent loss of heterozygosity by eliminating the mutant <it>TP53 </it>allele rather than the wild-type allele. Polymorphisms were identified within the <it>TP53 </it>(R72P and Ins16) and <it>MDM2 </it>(SNP309) genes that may further diminish <it>TP53 </it>tumor suppressor activity.</p> <p>Conclusion</p> <p>These results demonstrate that the R337H mutation can significantly increase the risk of breast cancer in carriers, which likely depends on additional cooperating genetic factors. These findings are also important for understanding how low-penetrant mutant <it>TP53 </it>alleles can differentially influence tumor susceptibility.</p

Respiratory functional characteristics of human leptospirosis

Introdução: O comprometimento respiratório da leptospirose humana pode ser sua principal manifestação clínica e comumente está associado a maior morbimortalidade. Métodos: Objetivando descrever aspectos funcionais respiratórios nessa doença, foram analisados 21 pacientes com oximetrias de pulso e espirometrias em dois momentos: em avaliação inicial e após cerca de 28 dias. Resultados: Dois (9,5%) doentes tinham saturação periférica de oxigênio menor que 95%. Padrões espirométricos normais foram observados em 8 (38,1%) casos; distúrbios ventilatórios restritivos foram inferidos em 7 (33,3%), obstrutivos com capacidade vital forçada reduzida em 4 (19%), e inespecíficos em 2 (9,5%). Espirometrias anormais se associaram a pior escore APACHE II (p=0,02) e anormalidades na radiografia de tórax (p=0,05). Após resolução clínica, verificou-se ganho funcional significativo (p<0,05) no grupo de pacientes com espirometria alterada. Conclusões: Alterações espirométricas foram detectadas no curso da enfermidade e estiveram associadas a pior gravidade clínica e maior freqüência de anormalidades radiológicas torácicas. _________________________________________________________________________________________ ABSTRACT: Introduction: Respiratory impairment may be the main clinical manifestation of human leptospirosis. Methods: With the aim of describing the respiratory functional characteristics of this disease, 21 patients were evaluated using pulse oximetry and spirometry at two times: an initial evaluation and after around 28 days. Results: Two (9.5%) patients presented peripheral oxygen saturation of less than 95%. Normal spirometric patterns were observed in eight (38.1%); cases restrictive ventilatory disorders were inferred in seven (33.3%), obstructive disorders with reduced forced vital capacity in four (19%), and nonspecific disorders in two (9.5%). Abnormal spirometry findings were associated with worse APACHE II scores (p = 0.02) and abnormalities on chest x-ray (p = 0.05). After clinical resolution, significant functional gain was observed (p < 0.05) in the group of patients with abnormal spirometry findings. Conclusions: It was concluded that respiratory functional abnormalities were detected during the course of the disease and were associated with greater clinical severity and higher frequency of chest radiographic abnormalities

In-depth characterization of congenital Zika syndrome in immunocompetent mice : antibody-dependent enhancement and an antiviral peptide therapy

Background: Zika virus (ZIKV) infection during pregnancy may cause major congenital defects, including microcephaly, ocular, articular and muscle abnormalities, which are collectively defined as Congenital Zika Syndrome. Here, we performed an in-depth characterization of the effects of congenital ZIKV infection (CZI) in immunocompetent mice. Methods: Pregnant dams were inoculated with ZIKV on embryonic day 5.5 in the presence or absence of a sub-neutralizing dose of a pan-flavivirus monoclonal antibody (4G2) to evaluate the potential role of antibody-dependent enhancement phenomenon (ADE) during short and long outcomes of CZI. Findings: ZIKV infection induced maternal immune activation (MIA), which was associated with occurrence of foetal abnormalities and death. Therapeutic administration of AH-D antiviral peptide during the early stages of pregnancy prevented ZIKV replication and death of offspring. In the post-natal period, CZI was associated with a decrease in whole brain volume, ophthalmologic abnormalities, changes in testicular morphology, and disruption in bone microarchitecture. Some alterations were enhanced in the presence of 4G2 antibody. Interpretation: Our results reveal that early maternal ZIKV infection causes several birth defects in immunocompetent mice, which can be potentiated by ADE phenomenon and are associated with MIA. Additionally, antiviral treatment with AH-D peptide may be beneficial during early maternal ZIKV infection.NRF (Natl Research Foundation, S’pore)Published versio

Implementation of a Brazilian Cardioprotective Nutritional (BALANCE) Program for improvement on quality of diet and secondary prevention of cardiovascular events: A randomized, multicenter trial

Background: Appropriate dietary recommendations represent a key part of secondary prevention in cardiovascular disease (CVD). We evaluated the effectiveness of the implementation of a nutritional program on quality of diet, cardiovascular events, and death in patients with established CVD. Methods: In this open-label, multicenter trial conducted in 35 sites in Brazil, we randomly assigned (1:1) patients aged 45 years or older to receive either the BALANCE Program (experimental group) or conventional nutrition advice (control group). The BALANCE Program included a unique nutritional education strategy to implement recommendations from guidelines, adapted to the use of affordable and regional foods. Adherence to diet was evaluated by the modified Alternative Healthy Eating Index. The primary end point was a composite of all-cause mortality, cardiovascular death, cardiac arrest, myocardial infarction, stroke, myocardial revascularization, amputation, or hospitalization for unstable angina. Secondary end points included biochemical and anthropometric data, and blood pressure levels. Results: From March 5, 2013, to Abril 7, 2015, a total of 2534 eligible patients were randomly assigned to either the BALANCE Program group (n = 1,266) or the control group (n = 1,268) and were followed up for a median of 3.5 years. In total, 235 (9.3%) participants had been lost to follow-up. After 3 years of follow-up, mean modified Alternative Healthy Eating Index (scale 0-70) was only slightly higher in the BALANCE group versus the control group (26.2 ± 8.4 vs 24.7 ± 8.6, P <.01), mainly due to a 0.5-serving/d greater intake of fruits and of vegetables in the BALANCE group. Primary end point events occurred in 236 participants (18.8%) in the BALANCE group and in 207 participants (16.4%) in the control group (hazard ratio, 1.15; 95% CI 0.95-1.38; P =.15). Secondary end points did not differ between groups after follow-up. Conclusions: The BALANCE Program only slightly improved adherence to a healthy diet in patients with established CVD and had no significant effect on the incidence of cardiovascular events or death. © 2019 The Author