A role for GPx3 in activity of normal and leukemia stem cells

The determinants of normal and leukemic stem cell self-renewal remain poorly characterized. We report that expression of the reactive oxygen species (ROS) scavenger glutathione peroxidase 3 (GPx3) positively correlates with the frequency of leukemia stem cells (LSCs) in Hoxa9+Meis1-induced leukemias. Compared with a leukemia with a low frequency of LSCs, a leukemia with a high frequency of LSCs showed hypomethylation of the Gpx3 promoter region, and expressed high levels of Gpx3 and low levels of ROS. LSCs and normal hematopoietic stem cells (HSCs) engineered to express Gpx3 short hairpin RNA (shRNA) were much less competitive in vivo than control cells. However, progenitor cell proliferation and differentiation was not affected by Gpx3 shRNA. Consistent with this, HSCs overexpressing Gpx3 were significantly more competitive than control cells in long-term repopulation experiments, and overexpression of the self-renewal genes Prdm16 or Hoxb4 boosted Gpx3 expression. In human primary acute myeloid leukemia samples, GPX3 expression level directly correlated with adverse prognostic outcome, revealing a potential novel target for the eradication of LSCs

Dietary inflammatory index and prevalence of overweight and obesity in Brazilian graduates from the Cohort of Universities of Minas Gerais (CUME project)

Objectives: The aim of this study was to evaluate the independent association of the dietary inflammatory index (DII ) score with overweight and obesity in Brazilian participants of the Cohort of Universities of Minas Gerais (CUME project). Methods: This was a cross-sectional study consisting of 3,151 graduates and postgraduates (2197 women) with a mean (SD) age of 36.3 y (§9.4 y). Sociodemographic characteristics, lifestyle, and anthropometric data were assessed via online self-reported questionnaire. Additionally, a validated food frequency questionnaire with 144 food items was used to generate energy-adjusted DII (E-DIITM) scores, which evaluated the inflammatory potential of the diet. Results: The prevalence of overweight and obesity were 28.2% and 11%, respectively. Participants in the highest E-DII quartile (most proinflammatory diet) were more likely to be smokers/former smokers; sedentary; and consumers of red and ultra-processed meats, fats and oils (excluding olive oil), bottled fruit juices and soft drinks, sugars, sweets, and higher overall caloric intake, compared with the first quartile of E-DII. Both men and women in the fourth E-DII quartile had the highest prevalence of overweight and obesity (prevalence ratio [PR], 1.35; 95% confidence interval [CI], 1.14 1.59 and PR, 1.97; 95% CI, 1.20 3.22, respectively, in men; PR, 1.38; 95% CI, 1.17 to 1.65 and PR, 1.95; 95% CI, 1.31 2.90, respectively, in women). Conclusion: The most proinflammatory dietary pattern was associated with a higher prevalence of overweight and obesity and other unhealthy lifestyles including being sedentary, smoking, and consuming a obesogenic diet

The current status of species recognition and identification in Aspergillus

The species recognition and identification of aspergilli and their teleomorphs is discussed. A historical overview of the taxonomic concepts starting with the monograph of Raper & Fennell (1965) is given. A list of taxa described since 2000 is provided. Physiological characters, particularly growth rates and the production of extrolites, often show differences that reflect phylogenetic species boundaries and greater emphasis should be placed on extrolite profiles and growth characteristics in species descriptions. Multilocus sequence-based phylogenetic analyses have emerged as the primary tool for inferring phylogenetic species boundaries and relationships within subgenera and sections. A four locus DNA sequence study covering all major lineages in Aspergillus using genealogical concordance theory resulted in a species recognition system that agrees in part with phenotypic studies and reveals the presence of many undescribed species not resolved by phenotype. The use of as much data from as many sources as possible in making taxonomic decisions is advocated. For species identification, DNA barcoding uses a short genetic marker in an organism”s DNA to quickly and easily identify it to a particular species. Partial cytochrome oxidase subunit 1 sequences, which are used for barcoding animal species, were found to have limited value for species identification among black aspergilli. The various possibilities are discussed and at present partial β-tubulin or calmodulin are the most promising loci for Aspergillus identification. For characterising Aspergillus species one application would be to produce a multilocus phylogeny, with the goal of having a firm understanding of the evolutionary relationships among species across the entire genus. DNA chip technologies are discussed as possibilities for an accurate multilocus barcoding tool for the genus Aspergillus

Dietary inflammatory index and incidence of cardiovascular disease in the SUN cohort

BACKGROUND: Diet is known to play a key role in atherogenesis and in the development of cardiovascular events. Dietary factors may mediate these processes acting as potential modulators of inflammation. Potential Links between inflammatory properties of diet and the occurrence of cardiovascular events have not been tested previously. OBJECTIVE: We aimed to assess the association between the dietary inflammatory index (DII), a method to assess the inflammatory potential of the diet, and incident cardiovascular disease. METHODS: In the prospective, dynamic SUN cohort, 18,794 middle-aged, Spanish university graduates were followed up for 8.9 years (median). A validated 136-item food-frequency questionnaire was used to calculate the DII. The DII is based on scientific evidence about the relationship between diet and inflammatory biomarkers (C-reactive protein, IL-1β, IL-4, IL-6, IL-10 and TNF-α). Cox proportional hazard models were used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between the DII and incident cardiovascular disease (myocardial infarction, stroke or cardiovascular death). RESULTS: The risk for cardiovascular events progressively increased with each increasing quartile of DII (ptrend = 0.017). The multivariable-adjusted HR for participants in the highest (most pro-inflammatory) vs. the lowest quartile of the DII was 2.03 (95% CI 1.06-3.88). CONCLUSIONS: A pro-inflammatory diet was associated with a significantly higher risk for developing cardiovascular events

Effect of Lanadelumab Compared with Placebo on Prevention of Hereditary Angioedema Attacks : a Randomized Clinical Trial

Importance: Current treatments for long-term prophylaxis in hereditary angioedema have limitations. Objective: To assess the efficacy of lanadelumab, a fully human monoclonal antibody that selectively inhibits active plasma kallikrein, in preventing hereditary angioedema attacks. Design, Setting, and Participants: Phase 3, randomized, double-blind, parallel-group, placebo-controlled trial conducted at 41 sites in Canada, Europe, Jordan, and the United States. Patients were randomized between March 3, 2016, and September 9, 2016; last day of follow-up was April 13, 2017. Randomization was 2:1 lanadelumab to placebo; patients assigned to lanadelumab were further randomized 1:1:1 to 1 of the 3 dose regimens. Patients 12 years or older with hereditary angioedema type I or II underwent a 4-week run-in period and those with 1 or more hereditary angioedema attacks during run-in were randomized. Interventions: Twenty-six-week treatment with subcutaneous lanadelumab 150 mg every 4 weeks (n = 28), 300 mg every 4 weeks (n = 29), 300 mg every 2 weeks (n = 27), or placebo (n = 41). All patients received injections every 2 weeks, with those in the every-4-week group receiving placebo in between active treatments. Main Outcome and Measures: Primary efficacy end point was the number of investigator-confirmed attacks of hereditary angioedema over the treatment period. Results: Among 125 patients randomized (mean age, 40.7 years [SD, 14.7 years]; 88 females [70.4%]; 113 white [90.4%]), 113 (90.4%) completed the study. During the run-in period, the mean number of hereditary angioedema attacks per month in the placebo group was 4.0; for the lanadelumab groups, 3.2 for the every-4-week 150-mg group; 3.7 for the every-4-week 300-mg group; and 3.5 for the every-2-week 300-mg group. During the treatment period, the mean number of attacks per month for the placebo group was 1.97; for the lanadelumab groups, 0.48 for the every-4-week 150-mg group; 0.53 for the every-4-week 300-mg group; and 0.26 for the every-2-week 300-mg group. Compared with placebo, the mean differences in the attack rate per month were -1.49 (95% CI, -1.90 to -1.08; P <.001); -1.44 (95% CI, -1.84 to -1.04; P <.001); and -1.71 (95% CI, -2.09 to -1.33; P <.001). The most commonly occurring adverse events with greater frequency in the lanadelumab treatment groups were injection site reactions (34.1% placebo, 52.4% lanadelumab) and dizziness (0% placebo, 6.0% lanadelumab). Conclusions and Relevance: Among patients with hereditary angioedema type I or II, treatment with subcutaneous lanadelumab for 26 weeks significantly reduced the attack rate compared with placebo. These findings support the use of lanadelumab as a prophylactic therapy for hereditary angioedema. Further research is needed to determine long-term safety and efficacy. Trial Registration: EudraCT Identifier: 2015-003943-20; ClinicalTrials.gov Identifier: NCT02586805

The Antarctic Impulsive Transient Antenna Ultra-high Energy Neutrino Detector Design, Performance, and Sensitivity for 2006-2007 Balloon Flight

We present a detailed report on the experimental details of the Antarctic Impulsive Transient Antenna (ANITA) long duration balloon payload, including the design philosophy and realization, physics simulations, performance of the instrument during its first Antarctic flight completed in January of 2007, and expectations for the limiting neutrino detection sensitivity. Neutrino physics results will be reported separately.Comment: 50 pages, 49 figures, in preparation for PR

Dietary inflammatory index and anthropometric measures of obesity in a population sample at high cardiovascular risk from the PREDIMED trial

The dietary inflammatory index (DII) is a new tool to assess the inflammatory potential of diet. We aimed to determine the association between the DII and body mass index (BMI), waist circumference and waist to height ratio (WHtR). We conducted a cross-sectional study of 7,236 participants recruited into the PREDIMED trial (PREvención con DIeta MEDiterránea). Information from a validated 137-item food frequency questionnaire was used to calculate energy, foods and nutrients. A 14-item dietary screener was used to assess adherence to the Mediterranean diet (MeDiet). Sex-specific multivariable linear regression models were fitted to estimate differences (and 95% confidence intervals) in BMI, waist circumference and WHtR across quintiles of the DII. All nutrient intakes, healthy foods and adherence to the MeDiet were higher in the quintile with lowest DII score (more anti-inflammatory values) except for animal protein, saturated and monounsaturated fat. Though an inverse association between DII and total energy was apparent, the DII was associated with higher average BMI, waist circumference and WHtR after adjusting for known risk factors. The adjusted difference in WHtR for women and men between the highest and lowest quintile of DII was 1.60% (95% CI 0.87-2.33) and 1.04% (95% CI 0.35-1.74), respectively. Pro-inflammatory scores remained associated with obesity after controlling for the effect that adherence to a MeDiet had on inflammation. In conclusion, this study shows a direct association between the DII and indices of obesity and supports the hypothesis that diet may have a role in the development of obesity through inflammatory modulation mechanisms

Dietary inflammatory index and incidence of cardiovascular disease in the PREDIMED study

Previous studies have reported an association between a more pro-inflammatory diet profile and various chronic metabolic diseases. The Dietary Inflammatory Index (DII) was used to assess the inflammatory potential of nutrients and foods in the context of a dietary pattern. We prospectively examined the association between the DII and the incidence of cardiovascular disease (CVD: myocardial infarction, stroke or cardiovascular death) in the PREDIMED (Prevención con Dieta Mediterránea) study including 7216 high-risk participants. The DII was computed based on a validated 137-item food frequency questionnaire. Multivariate-adjusted hazard ratios (HR) and 95% confidence intervals of CVD risk were computed across quartiles of the DII where the lowest (most anti-inflammatory) quartile is the referent. Risk increased across the quartiles (i.e., with increasing inflammatory potential): HRquartile2 = 1.42 (95%CI = 0.97–2.09); HRquartile3 = 1.85 (1.27–2.71); and HRquartile4 = 1.73 (1.15–2.60). When fit as continuous the multiple-adjusted hazard ratio for each additional standard deviation of the DII was 1.22 (1.06–1.40). Our results provide direct prospective evidence that a pro-inflammatory diet is associated with a higher risk of cardiovascular clinical events