This document is an update to the 2011 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2C9 and VKORC1 genotypes and warfarin dosing. Evidence from the published literature ...is presented for CYP2C9, VKORC1, CYP4F2, and rs12777823 genotype‐guided warfarin dosing to achieve a target international normalized ratio of 2–3 when clinical genotype results are available. In addition, this updated guideline incorporates recommendations for adult and pediatric patients that are specific to continental ancestry.
Kelp forests (Order Laminariales) form key biogenic habitats in coastal regions of temperate and Arctic seas worldwide, providing ecosystem services valued in the range of billions of dollars ...annually. Although local evidence suggests that kelp forests are increasingly threatened by a variety of stressors, no comprehensive global analysis of change in kelp abundances currently exists. Here, we build and analyze a global database of kelp time series spanning the past half-century to assess regional and global trends in kelp abundances. We detected a high degree of geographic variation in trends, with regional variability in the direction and magnitude of change far exceeding a small global average decline (instantaneous rate of change = −0.018 y−1). Our analysis identified declines in 38% of ecoregions for which there are data (−0.015 to −0.18 y−1), increases in 27% of ecoregions (0.015 to 0.11 y−1), and no detectable change in 35% of ecoregions. These spatially variable trajectories reflected regional differences in the drivers of change, uncertainty in some regions owing to poor spatial and temporal data coverage, and the dynamic nature of kelp populations. We conclude that although global drivers could be affecting kelp forests at multiple scales, local stressors and regional variation in the effects of these drivers dominate kelp dynamics, in contrast to many other marine and terrestrial foundation species.
Protoporphyrin IX: the Good, the Bad, and the Ugly Sachar, Madhav; Anderson, Karl E; Ma, Xiaochao
The Journal of pharmacology and experimental therapeutics,
02/2016, Letnik:
356, Številka:
2
Journal Article
Recenzirano
Odprti dostop
Protoporphyrin IX (PPIX) is ubiquitously present in all living cells in small amounts as a precursor of heme. PPIX has some biologic functions of its own, and PPIX-based strategies have been used for ...cancer diagnosis and treatment (the good). PPIX serves as the substrate for ferrochelatase, the final enzyme in heme biosynthesis, and its homeostasis is tightly regulated during heme synthesis. Accumulation of PPIX in human porphyrias can cause skin photosensitivity, biliary stones, hepatobiliary damage, and even liver failure (the bad and the ugly). In this work, we review the mechanisms that are associated with the broad aspects of PPIX. Because PPIX is a hydrophobic molecule, its disposition is by hepatic rather than renal excretion. Large amounts of PPIX are toxic to the liver and can cause cholestatic liver injury. Application of PPIX in cancer diagnosis and treatment is based on its photodynamic effects.
Asparaginyl endopeptidases (AEPs) are proteases that have crucial roles in plant defense and seed storage protein maturation. Select plant AEPs, however, do not function as proteases but as ...transpeptidases (ligases) catalyzing the intra-molecular ligation of peptide termini, which leads to peptide cyclization. These ligase-type AEPs have potential biotechnological applications ranging from in vitro peptide engineering to plant molecular farming, but the structural features enabling these enzymes to catalyze peptide ligation/cyclization rather than proteolysis are currently unknown. Here, we compare the sequences, structures, and functions of diverse plant AEPs by combining molecular modeling, sequence space analysis, and functional testing in planta. We find that changes within the substrate-binding pocket and an adjacent loop, here named the "marker of ligase activity", together play a key role for AEP ligase efficiency. Identification of these structural determinants may facilitate the discovery of more ligase-type AEPs and the engineering of AEPs with tailored catalytic properties.
Trophic cascades have been documented in a diversity of ecological systems and can be important in determining biomass distribution within a community. To date, the literature on trophic cascades has ...focused on whether and in which systems cascades occur. Many biological (e.g., productivity : biomass ratios) and methodological (e.g., experiment size or duration) factors vary with the ecosystem in which data were collected, but ecosystem type, per se, does not provide mechanistic insights into factors controlling cascade strength. Here, we tested various hypotheses about why trophic cascades occur and what determines their magnitude using data from 114 studies that measured the indirect trophic effects of predators on plant community biomass in seven aquatic and terrestrial ecosystems. Using meta-analysis, we examined the relationship between the indirect effect of predator manipulation on plants and 18 biological and methodological factors quantified from these studies. We found, in contrast to predictions, that high system productivity and low species diversity do not consistently generate larger trophic cascades. A combination of herbivore and predator metabolic factors and predator taxonomy (vertebrate vs. invertebrate) explained 31% of the variation in cascade strength among all 114 studies. Within systems, 18% of the variation in cascade strength was explained with similar predator and herbivore characteristics. Within and across all systems, the strongest cascades occurred in association with invertebrate herbivores and endothermic vertebrate predators. These associations may result from a combination of true biological differences among species with different physiological requirements and bias among organisms studied in different systems. Thus, although cascade strength can be described by biological characteristics of predators and herbivores, future research on indirect trophic effects must further examine biological and methodological differences among studies and systems.
Regular use of aspirin has been associated with a reduced risk of cancer at several sites but the data for endometrial cancer are conflicting. Evidence regarding use of other analgesics is limited.
...We pooled individual-level data from seven cohort and five case–control studies participating in the Epidemiology of Endometrial Cancer Consortium including 7120 women with endometrial cancer and 16 069 controls. For overall analyses, study-specific odds ratios (ORs) and 95% confidence intervals (CI) were estimated using logistic regression and combined using random-effects meta-analysis; for stratified analyses, we used mixed-effects logistic regression with study as a random effect.
At least weekly use of aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) was associated with an approximately 15% reduced risk of endometrial cancer among both overweight and obese women (OR = 0.86 95% CI 0.76–0.98 and 0.86 95% CI 0.76–0.97, respectively, for aspirin; 0.87 95% CI 0.76–1.00 and 0.84 0.74–0.96, respectively, for non-aspirin NSAIDs). There was no association among women of normal weight (body mass index < 25 kg/m2, Pheterogeneity = 0.04 for aspirin, Pheterogeneity = 0.003 for NSAIDs). Among overweight and obese women, the inverse association with aspirin was stronger for use 2–6 times/week (OR = 0.81, 95% CI 0.68–0.96) than for daily use (0.91, 0.80–1.03), possibly because a high proportion of daily users use low-dose formulations. There was no clear association with use of acetaminophen.
Our pooled analysis provides further evidence that use of standard-dose aspirin or other NSAIDs may reduce risk of endometrial cancer among overweight and obese women.
Body mass index (BMI), a measure of obesity typically assessed in middle age or later, is known to be positively associated with pancreatic cancer. However, little evidence exists regarding the ...influence of central adiposity, a high BMI during early adulthood, and weight gain after early adulthood on pancreatic cancer risk.
We conducted a pooled analysis of individual-level data from 20 prospective cohort studies in the National Cancer Institute BMI and Mortality Cohort Consortium to examine the association of pancreatic cancer mortality with measures of central adiposity (e.g. waist circumference; n = 647 478; 1947 pancreatic cancer deaths), BMI during early adulthood (ages 18–21 years) and BMI change between early adulthood and cohort enrollment, mostly in middle age or later (n = 1 096 492; 3223 pancreatic cancer deaths). Multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards regression models.
Higher waist-to-hip ratio (HR = 1.09, 95% CI 1.02–1.17 per 0.1 increment) and waist circumference (HR = 1.07, 95% CI 1.00–1.14 per 10cm) were associated with increased risk of pancreatic cancer mortality, even when adjusted for BMI at baseline. BMI during early adulthood was associated with increased pancreatic cancer mortality (HR = 1.18, 95% CI 1.11–1.25 per 5 kg/m2), with increased risk observed in both overweight and obese individuals (compared with BMI of 21.0 to <23 kg/m2, HR = 1.36, 95% CI 1.20–1.55 for BMI 25.0 < 27.5 kg/m2, HR = 1.48, 95% CI 1.20–1.84 for BMI 27.5 to <30 kg/m2, HR = 1.43, 95% CI 1.11–1.85 for BMI ≥30 kg/m2). BMI gain after early adulthood, adjusted for early adult BMI, was less strongly associated with pancreatic cancer mortality (HR = 1.05, 95% CI 1.01–1.10 per 5 kg/m2).
Our results support an association between pancreatic cancer mortality and central obesity, independent of BMI, and also suggest that being overweight or obese during early adulthood may be important in influencing pancreatic cancer mortality risk later in life.
The broad variation in phenotypes and severities within autism spectrum disorders suggests the involvement of multiple predisposing factors, interacting in complex ways with normal developmental ...courses and gradients. Identification of these factors, and the common developmental path into which they feed, is hampered by the large degrees of convergence from causal factors to altered brain development, and divergence from abnormal brain development into altered cognition and behaviour. Genetic, neurochemical, neuroimaging, and behavioural findings on autism, as well as studies of normal development and of genetic syndromes that share symptoms with autism, offer hypotheses as to the nature of causal factors and their possible effects on the structure and dynamics of neural systems. Such alterations in neural properties may in turn perturb activity-dependent development, giving rise to a complex behavioural syndrome many steps removed from the root causes. Animal models based on genetic, neurochemical, neurophysiological, and behavioural manipulations offer the possibility of exploring these developmental processes in detail, as do human studies addressing endophenotypes beyond the diagnosis itself.
Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease and not well understood. The forced expiratory volume in one second is used for the diagnosis and staging of COPD, but there is ...wide acceptance that it is a crude measure and insensitive to change over shorter periods of time. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points (ECLIPSE) is a 3-yr longitudinal study with four specific aims: 1) definition of clinically relevant COPD subtypes; 2) identification of parameters that predict disease progression in these subtypes; 3) examination of biomarkers that correlate with COPD subtypes and may predict disease progression; and 4) identification of novel genetic factors and/or biomarkers that both correlate with clinically relevant COPD subtypes and predict disease progression. ECLIPSE plans to recruit 2,180 COPD subjects in Global Initiative for Chronic Obstructive Lung Disease categories II-IV and 343 smoking and 223 nonsmoking control subjects. Study procedures are to be performed at baseline, 3 months, 6 months and every 6 months thereafter. Assessments include pulmonary function measurements (spirometry, impulse oscillometry and plethysmography), chest computed tomography, biomarker measurement (in blood, sputum, urine and exhaled breath condensate), health outcomes, body impedance, resting oxygen saturation and 6-min walking distance. Evaluation of COPD Longitudinally to Identify Predictive Surrogate End-points is the largest study attempting to better describe the subtypes of chronic obstructive pulmonary disease, as well as defining predictive markers of its progression.
We present and describe the astro-photometric catalog of more than 800,000 sources found in the Hubble Tarantula Treasury Project (HTTP). HTTP is a Hubble Space Telescope Treasury program designed to ...image the entire 30 Doradus region down to the sub-solar (~0.5 M sub(middot in circle)) mass regime using the Wide Field Camera 3 and the Advanced Camera for Surveys. We observed 30 Doradus in the near-ultraviolet (F275W, F336W), optical (F555W, F658N, F775W), and near-infrared (F110W, F160W) wavelengths. The stellar photometry was measured using point-spread function fitting across all bands simultaneously. The relative astrometric accuracy of the catalog is 0.4 mas. The astro-photometric catalog, results from artificial star experiments, and the mosaics for all the filters are available for download. Color-magnitude diagrams are presented showing the spatial distributions and ages of stars within 30 Dor as well as in the surrounding fields. HTTP provides the first rich and statistically significant sample of intermediate- and low-mass pre-main sequence candidates and allows us to trace how star formation has been developing through the region. The depth and high spatial resolution of our analysis highlight the dual role of stellar feedback in quenching and triggering star formation on the giant H II region scale. Our results are consistent with stellar sub-clustering in a partially filled gaseous nebula that is offset toward our side of the Large Magellanic Cloud.
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