SHOC2 scaffold protein modulates daunorubicin-induced cell death through p53 modulation in lymphoid leukemia cells

SHOC2 scaffold protein has been mainly related to oncogenic ERK signaling through the RAS-SHOC2-PP1 phosphatase complex. In leukemic cells however, SHOC2 upregulation has been previously related to an increased 5-year event-free survival of pediatric pre-B acute lymphoid leukemia, suggesting that SHOC2 could be a potential prognostic marker. To address such paradoxical function, our study investigated how SHOC2 impact leukemic cells drug response. Our transcriptome analysis has shown that SHOC2 can modulate the DNA-damage mediated by p53. Notably, upon genetic inhibition of SHOC2 we observed a significant impairment of p53 expression, which in turn, leads to the blockage of key apoptotic molecules. To confirm the specificity of DNA-damage related modulation, several anti-leukemic drugs has been tested and we did confirm that the proposed mechanism impairs cell death upon daunorubicin-induced DNA damage of human lymphoid cells. In conclusion, our study uncovers new insights into SHOC2 function and reveals that this scaffold protein may be essential to activate a novel mechanism of p53-induced cell death in pre-B lymphoid cells

Resource Selection and Its Implications for Wide-Ranging Mammals of the Brazilian Cerrado

Conserving animals beyond protected areas is critical because even the largest reserves may be too small to maintain viable populations for many wide-ranging species. Identification of landscape features that will promote persistence of a diverse array of species is a high priority, particularly, for protected areas that reside in regions of otherwise extensive habitat loss. This is the case for Emas National Park, a small but important protected area located in the Brazilian Cerrado, the world's most biologically diverse savanna. Emas Park is a large-mammal global conservation priority area but is too small to protect wide-ranging mammals for the long-term and conserving these populations will depend on the landscape surrounding the park. We employed novel, noninvasive methods to determine the relative importance of resources found within the park, as well as identify landscape features that promote persistence of wide-ranging mammals outside reserve borders. We used scat detection dogs to survey for five large mammals of conservation concern: giant armadillo (Priodontes maximus), giant anteater (Myrmecophaga tridactyla), maned wolf (Chrysocyon brachyurus), jaguar (Panthera onca), and puma (Puma concolor). We estimated resource selection probability functions for each species from 1,572 scat locations and 434 giant armadillo burrow locations. Results indicate that giant armadillos and jaguars are highly selective of natural habitats, which makes both species sensitive to landscape change from agricultural development. Due to the high amount of such development outside of the Emas Park boundary, the park provides rare resource conditions that are particularly important for these two species. We also reveal that both woodland and forest vegetation remnants enable use of the agricultural landscape as a whole for maned wolves, pumas, and giant anteaters. We identify those features and their landscape compositions that should be prioritized for conservation, arguing that a multi-faceted approach is required to protect these species

Brazilian multicenter study on prevalence of preterm birth and associated factors

<p>Abstract</p> <p>Background</p> <p>The occurrence of preterm birth remains a complex public health condition. It is considered the main cause of neonatal morbidity and mortality, resulting in a high likelihood of sequelae in surviving children. With variable incidence in several countries, it has grown markedly in the last decades. In Brazil, however, there are still difficulties to estimate its real occurrence. Therefore, it is essential to establish the prevalence and causes of this condition in order to propose prevention actions. This study intend to collect information from hospitals nationwide on the prevalence of preterm births, their associated socioeconomic and environmental factors, diagnostic and treatment methods resulting from causes such as spontaneous preterm labor, prelabor rupture of membranes, and therapeutic preterm birth, as well as neonatal results.</p> <p>Methods/Design</p> <p>This proposal is a multicenter cross-sectional study plus a nested case-control study, to be implemented in 27 reference obstetric centers in several regions of Brazil (North: 1; Northeast: 10; Central-west: 1; Southeast: 13; South: 2). For the cross sectional component, the participating centers should perform, during a period of six months, a prospective surveillance of all patients hospitalized to give birth, in order to identify preterm birth cases and their main causes. In the first three months of the study, an analysis of the factors associated with preterm birth will also be carried out, comparing women who have preterm birth with those who deliver at term. For the prevalence study, 37,000 births will be evaluated (at term and preterm), corresponding to approximately half the deliveries of all participating centers in 12 months. For the case-control study component, the estimated sample size is 1,055 women in each group (cases and controls). The total number of preterm births estimated to be followed in both components of the study is around 3,600. Data will be collected through a questionnaire all patients will answer after delivery. The data will then be encoded in an electronic form and sent online by internet to a central database. The data analysis will be carried out by subgroups according to gestational age at preterm birth, its probable causes, therapeutic management, and neonatal outcomes. Then, the respective rates, ratios and relative risks will be estimated for the possible predictors.</p> <p>Discussion</p> <p>These findings will provide information on preterm births in Brazil and their main social and biological risk factors, supporting health policies and the implementation of clinical trials on preterm birth prevention and treatment strategies, a condition with many physical and emotional consequences to children and their families.</p

Preventive drugs in the last year of life of older adults with cancer: Is there room for deprescribing?

BACKGROUND: The continuation of preventive drugs among older patients with advanced cancer has come under scrutiny because these drugs are unlikely to achieve their clinical benefit during the patients' remaining lifespan. METHODS: A nationwide cohort study of older adults (those aged ≥65 years) with solid tumors who died between 2007 and 2013 was performed in Sweden, using routinely collected data with record linkage. The authors calculated the monthly use and cost of preventive drugs throughout the last year before the patients' death. RESULTS: Among 151,201 older persons who died with cancer (mean age, 81.3 years [standard deviation, 8.1 years]), the average number of drugs increased from 6.9 to 10.1 over the course of the last year before death. Preventive drugs frequently were continued until the final month of life, including antihypertensives, platelet aggregation inhibitors, anticoagulants, statins, and oral antidiabetics. Median drug costs amounted to $1482 (interquartile range [IQR],$700-$2896]) per person, including$213 (IQR, $77-$490) for preventive therapies. Compared with older adults who died with lung cancer (median drug cost, $205; IQR,$61-$523), costs for preventive drugs were higher among older adults who died with pancreatic cancer (adjusted median difference,$13; 95% confidence interval, $5-$22) or gynecological cancers (adjusted median difference, $27; 95$18-$36). There was no decrease noted with regard to the cost of preventive drugs throughout the last year of life. CONCLUSIONS: Preventive drugs commonly are prescribed during the last year of life among older adults with cancer, and often are continued until the final weeks before death. Adequate deprescribing strategies are warranted to reduce the burden of drugs with limited clinical benefit near the end of life

Genome of the Avirulent Human-Infective Trypanosome—Trypanosoma rangeli

Background: Trypanosoma rangeli is a hemoflagellate protozoan parasite infecting humans and other wild and domestic mammals across Central and South America. It does not cause human disease, but it can be mistaken for the etiologic agent of Chagas disease, Trypanosoma cruzi. We have sequenced the T. rangeli genome to provide new tools for elucidating the distinct and intriguing biology of this species and the key pathways related to interaction with its arthropod and mammalian hosts.  Methodology/Principal Findings: The T. rangeli haploid genome is ,24 Mb in length, and is the smallest and least repetitive trypanosomatid genome sequenced thus far. This parasite genome has shorter subtelomeric sequences compared to those of T. cruzi and T. brucei; displays intraspecific karyotype variability and lacks minichromosomes. Of the predicted 7,613 protein coding sequences, functional annotations could be determined for 2,415, while 5,043 are hypothetical proteins, some with evidence of protein expression. 7,101 genes (93%) are shared with other trypanosomatids that infect humans. An ortholog of the dcl2 gene involved in the T. brucei RNAi pathway was found in T. rangeli, but the RNAi machinery is non-functional since the other genes in this pathway are pseudogenized. T. rangeli is highly susceptible to oxidative stress, a phenotype that may be explained by a smaller number of anti-oxidant defense enzymes and heatshock proteins.  Conclusions/Significance: Phylogenetic comparison of nuclear and mitochondrial genes indicates that T. rangeli and T. cruzi are equidistant from T. brucei. In addition to revealing new aspects of trypanosome co-evolution within the vertebrate and invertebrate hosts, comparative genomic analysis with pathogenic trypanosomatids provides valuable new information that can be further explored with the aim of developing better diagnostic tools and/or therapeutic targets

Global, regional, and national comparative risk assessment of 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015

SummaryBackground The Global Burden of Diseases, Injuries, and Risk Factors Study 2015 provides an up-to-date synthesis of the evidence for risk factor exposure and the attributable burden of disease. By providing national and subnational assessments spanning the past 25 years, this study can inform debates on the importance of addressing risks in context. Methods We used the comparative risk assessment framework developed for previous iterations of the Global Burden of Disease Study to estimate attributable deaths, disability-adjusted life-years (DALYs), and trends in exposure by age group, sex, year, and geography for 79 behavioural, environmental and occupational, and metabolic risks or clusters of risks from 1990 to 2015. This study included 388 risk-outcome pairs that met World Cancer Research Fund-defined criteria for convincing or probable evidence. We extracted relative risk and exposure estimates from randomised controlled trials, cohorts, pooled cohorts, household surveys, census data, satellite data, and other sources. We used statistical models to pool data, adjust for bias, and incorporate covariates. We developed a metric that allows comparisons of exposure across risk factors—the summary exposure value. Using the counterfactual scenario of theoretical minimum risk level, we estimated the portion of deaths and DALYs that could be attributed to a given risk. We decomposed trends in attributable burden into contributions from population growth, population age structure, risk exposure, and risk-deleted cause-specific DALY rates. We characterised risk exposure in relation to a Socio-demographic Index (SDI). Findings Between 1990 and 2015, global exposure to unsafe sanitation, household air pollution, childhood underweight, childhood stunting, and smoking each decreased by more than 25%. Global exposure for several occupational risks, high body-mass index (BMI), and drug use increased by more than 25% over the same period. All risks jointly evaluated in 2015 accounted for 57·8% (95% CI 56·6–58·8) of global deaths and 41·2% (39·8–42·8) of DALYs. In 2015, the ten largest contributors to global DALYs among Level 3 risks were high systolic blood pressure (211·8 million [192·7 million to 231·1 million] global DALYs), smoking (148·6 million [134·2 million to 163·1 million]), high fasting plasma glucose (143·1 million [125·1 million to 163·5 million]), high BMI (120·1 million [83·8 million to 158·4 million]), childhood undernutrition (113·3 million [103·9 million to 123·4 million]), ambient particulate matter (103·1 million [90·8 million to 115·1 million]), high total cholesterol (88·7 million [74·6 million to 105·7 million]), household air pollution (85·6 million [66·7 million to 106·1 million]), alcohol use (85·0 million [77·2 million to 93·0 million]), and diets high in sodium (83·0 million [49·3 million to 127·5 million]). From 1990 to 2015, attributable DALYs declined for micronutrient deficiencies, childhood undernutrition, unsafe sanitation and water, and household air pollution; reductions in risk-deleted DALY rates rather than reductions in exposure drove these declines. Rising exposure contributed to notable increases in attributable DALYs from high BMI, high fasting plasma glucose, occupational carcinogens, and drug use. Environmental risks and childhood undernutrition declined steadily with SDI; low physical activity, high BMI, and high fasting plasma glucose increased with SDI. In 119 countries, metabolic risks, such as high BMI and fasting plasma glucose, contributed the most attributable DALYs in 2015. Regionally, smoking still ranked among the leading five risk factors for attributable DALYs in 109 countries; childhood underweight and unsafe sex remained primary drivers of early death and disability in much of sub-Saharan Africa. Interpretation Declines in some key environmental risks have contributed to declines in critical infectious diseases. Some risks appear to be invariant to SDI. Increasing risks, including high BMI, high fasting plasma glucose, drug use, and some occupational exposures, contribute to rising burden from some conditions, but also provide opportunities for intervention. Some highly preventable risks, such as smoking, remain major causes of attributable DALYs, even as exposure is declining. Public policy makers need to pay attention to the risks that are increasingly major contributors to global burden. Funding Bill & Melinda Gates Foundation