The next-generation cystic fibrosis transmembrane conductance regulator (CFTR) corrector VX-659, in triple combination with tezacaftor and ivacaftor (VX-659-tezacaftor-ivacaftor), was developed to ...restore the function of Phe508del CFTR protein in patients with cystic fibrosis.
We evaluated the effects of VX-659-tezacaftor-ivacaftor on the processing, trafficking, and function of Phe508del CFTR protein using human bronchial epithelial cells. A range of oral VX-659-tezacaftor-ivacaftor doses in triple combination were then evaluated in randomized, controlled, double-blind, multicenter trials involving patients with cystic fibrosis who were heterozygous for the Phe508del CFTR mutation and a minimal-function CFTR mutation (Phe508del-MF genotypes) or homozygous for the Phe508del CFTR mutation (Phe508del-Phe508del genotype). The primary end points were safety and the absolute change from baseline in the percentage of predicted forced expiratory volume in 1 second (FEV
).
VX-659-tezacaftor-ivacaftor significantly improved the processing and trafficking of Phe508del CFTR protein as well as chloride transport in vitro. In patients, VX-659-tezacaftor-ivacaftor had an acceptable safety and side-effect profile. Most adverse events were mild or moderate. VX-659-tezacaftor-ivacaftor resulted in significant mean increases in the percentage of predicted FEV
through day 29 (P<0.001) of up to 13.3 points in patients with Phe508del-MF genotypes; in patients with the Phe508del-Phe508del genotype already receiving tezacaftor-ivacaftor, adding VX-659 resulted in a further 9.7-point increase in the percentage of predicted FEV
. The sweat chloride concentrations and scores on the respiratory domain of the Cystic Fibrosis Questionnaire-Revised improved in both patient populations.
Robust in vitro activity of VX-659-tezacaftor-ivacaftor targeting Phe508del CFTR protein translated into improvements for patients with Phe508del-MF or Phe508del-Phe508del genotypes. VX-659 triple-combination regimens have the potential to treat the underlying cause of disease in approximately 90% of patients with cystic fibrosis. (Funded by Vertex Pharmaceuticals; VX16-659-101 and VX16-659-001 ClinicalTrials.gov numbers, NCT03224351 and NCT03029455 .).
Identifying air pollutants that pose a potential hazard indoors can facilitate exposure mitigation. In this study, we compiled summary results from 77 published studies reporting measurements of ...chemical pollutants in residences in the United States and in countries with similar lifestyles. These data were used to calculate representative mid‐range and upper‐bound concentrations relevant to chronic exposures for 267 pollutants and representative peak concentrations relevant to acute exposures for five activity‐associated pollutants. Representative concentrations are compared to available chronic and acute health standards for 97 pollutants. Fifteen pollutants appear to exceed chronic health standards in a large fraction of homes. Nine other pollutants are identified as potential chronic health hazards in a substantial minority of homes, and an additional nine are identified as potential hazards in a very small percentage of homes. Nine pollutants are identified as priority hazards based on the robustness of measured concentration data and the fraction of residences that appear to be impacted: acetaldehyde; acrolein; benzene; 1,3‐butadiene; 1,4‐dichlorobenzene; formaldehyde; naphthalene; nitrogen dioxide; and PM2.5. Activity‐based emissions are shown to pose potential acute health hazards for PM2.5, formaldehyde, CO, chloroform, and NO2.
Practical Implications
This analysis identifies key chemical contaminants of concern in residential indoor air using a comprehensive and consistent hazard‐evaluation protocol. The identification of a succinct group of chemical hazards in indoor air will allow for successful risk ranking and mitigation prioritization for the indoor residential environment. This work also indicates some common household activities that may lead to the acute levels of pollutant exposure and identifies hazardous chemicals for priority removal from consumer products and home furnishings.
Computers, printers, copier machines and other electronic equipment are a common part of the home and office environments. However, human exposure to potentially harmful pollutants emitted from ...office equipment has not been systematically evaluated, and is currently not well understood. In this review, we summarize available information on emission rates and/or indoor concentrations of various pollutants that are related to office equipment use, briefly describe experimental methods used to characterize emissions and identify critical research needs in this field. The office equipment evaluated in this review includes computers (desktops and notebooks), printers (laser, ink-jet and all-in-one machines) and photocopy machines. We summarize reported emission rates for the following pollutant groups: volatile organic chemicals (VOCs), ozone, particulate matter and several semivolatile organic chemicals (SVOCs). The latter includes phthalate esters, brominated flame retardants, organophosphate flame retardants, and polycyclic aromatic hydrocarbons (PAHs). We also review studies reporting airborne concentrations in indoor environments (offices, residences, schools, electronics recycling plants) where office equipment was present and deemed to be a significant contributor to the total pollutant burden. We find that for some pollutants, such as organophosphate flame retardants, the link between office-equipment emissions and indoor air concentrations is relatively well established. However, indoor VOCs, ozone, PAHs and phthalate esters can originate from a variety of sources, and their source apportionment is less straightforward. We then observe that personal exposures may be significantly larger than those estimated through average pollutant indoor concentrations, due to proximity of users to the sources over extended periods of time. Finally, we observe that the magnitude of emissions, the link from emissions to personal exposure, the toxicological significance of the chemicals emitted, and the costs and impacts of alternate materials should all be considered in order to evaluate potential importance of human exposures and health risks.
Approximately 13 million U.S. children less than 6 years old spend some time in early childhood education (ECE) facilities where they may be exposed to potentially harmful chemicals during critical ...periods of development. We measured five phthalate esters in indoor dust (n = 39) and indoor and outdoor air (n = 40 and 14, respectively) at ECE facilities in Northern California. Dust and airborne concentrations were used to perform a probabilistic health risk assessment to compare estimated exposures with risk levels established for chemicals causing reproductive toxicity and cancer under California’s Proposition 65. Di(2-ethylhexyl) phthalate (DEHP) and butyl benzyl phthalate (BBzP) were the dominant phthalates present in floor dust (medians = 172.2 and 46.8 μg/g, respectively), and dibutyl phthalate (DBP), diethyl phthalate (DEP), and diisobutyl phthalate (DIBP) were the dominant phthalates in indoor air (medians = 0.52, 0.21, and 0.10 μg/m3, respectively). The risk assessment results indicate that 82–89% of children in California ECE had DBP exposure estimates exceeding reproductive health benchmarks. Further, 8–11% of children less than 2 years old had DEHP exposure estimates exceeding cancer benchmarks. This is the largest study to measure phthalate exposure in U.S. ECE facilities and findings indicate wide phthalate contamination and potential risk to developing children.
Energy and human health Smith, Kirk R; Frumkin, Howard; Balakrishnan, Kalpana ...
Annual review of public health,
01/2013, Letnik:
34
Journal Article
Recenzirano
Odprti dostop
Energy use is central to human society and provides many health benefits. But each source of energy entails some health risks. This article reviews the health impacts of each major source of energy, ...focusing on those with major implications for the burden of disease globally. The biggest health impacts accrue to the harvesting and burning of solid fuels, coal and biomass, mainly in the form of occupational health risks and household and general ambient air pollution. Lack of access to clean fuels and electricity in the world's poor households is a particularly serious risk for health. Although energy efficiency brings many benefits, it also entails some health risks, as do renewable energy systems, if not managed carefully. We do not review health impacts of climate change itself, which are due mostly to climate-altering pollutants from energy systems, but do discuss the potential for achieving near-term health cobenefits by reducing certain climate-related emissions.
Deletion of phenylalanine 508 of the cystic fibrosis transmembrane conductance regulator (ΔF508 CFTR) is a major cause of cystic fibrosis (CF), one of the most common inherited childhood diseases. ...ΔF508 CFTR is a trafficking mutant that is retained in the endoplasmic reticulum (ER) and unable to reach the plasma membrane. Efforts to enhance exit of ΔF508 CFTR from the ER and improve its trafficking are of utmost importance for the development of treatment strategies. Using protein interaction profiling and global bioinformatics analysis we revealed mammalian target of rapamycin (mTOR) signalling components to be associated with ∆F508 CFTR. Our results demonstrated upregulated mTOR activity in ΔF508 CF bronchial epithelial (CFBE41o-) cells. Inhibition of the Phosphatidylinositol 3-kinase/Akt/Mammalian Target of Rapamycin (PI3K/Akt/mTOR) pathway with 6 different inhibitors demonstrated an increase in CFTR stability and expression. Mechanistically, we discovered the most effective inhibitor, MK-2206 exerted a rescue effect by restoring autophagy in ΔF508 CFBE41o- cells. We identified Bcl-2-associated athanogene 3 (BAG3), a regulator of autophagy and aggresome clearance to be a potential mechanistic target of MK-2206. These data further link the CFTR defect to autophagy deficiency and demonstrate the potential of the PI3K/Akt/mTOR pathway for therapeutic targeting in CF.
Human exposure to indoor pollutant concentrations is receiving increasing interest in Life Cycle Assessment (LCA). We address this issue by incorporating an indoor compartment into the USEtox model, ...as well as by providing recommended parameter values for households in four different regions of the world differing geographically, economically, and socially. With these parameter values, intake fractions and comparative toxicity potentials for indoor emissions of dwellings for different air tightness levels were calculated. The resulting intake fractions for indoor exposure vary by 2 orders of magnitude, due to the variability of ventilation rate, building occupation, and volume. To compare health impacts as a result of indoor exposure with those from outdoor exposure, the indoor exposure characterization factors determined with the modified USEtox model were applied in a case study on cooking in non-OECD countries. This study demonstrates the appropriateness and significance of integrating indoor environments into LCA, which ensures a more holistic account of all exposure environments and allows for a better accountability of health impacts. The model, intake fractions, and characterization factors are made available for use in standard LCA studies via www.usetox.org and in standard LCA software.
•People with CF often have exocrine pancreatic insufficiency (PI) and altered fecal microbiomes.•Whether the PI and resulting nutrient malabsorption causes the fecal dysbiosis is unknown.•In a pilot ...study, the effects of CFTR modulators on nutrient absorption and dysbiosis depended on whether the recipient was PI or not.•People with PI had trends towards improvement in both.•These findings must be validated in larger studies.
Studies have demonstrated that people with CF with pancreatic insufficiency (PI) have fecal dysbioses. Evidence suggests the causes of these dysbioses are multifactorial, and that important drivers include antibiotic exposure, dietary intake, and CF gastrointestinal tract dysfunction, including nutrient malabsorption. In this pilot study, we tested whether initiation of the CFTR modulator treatments ivacaftor (in a cohort of pancreatic sufficient (PS) people with CF and an R117H CFTR variant) or lumacaftor/ivacaftor (in a cohort of PI people with CF and an F508del variant) changed fecal measures of malabsorption or fecal microbiomes. While we identified no statistically significant fecal changes with either treatment, we detected trends in the PI cohort when initiating lumacaftor/ivacaftor towards decreased fecal fat content and towards fecal microbiomes that more closely resembled the fecal microbiota of people without PI. While these findings support a model in which nutrient malabsorption resulting from CF-induced PI drives fecal dysbiosis, they must be validated in future, larger studies of fecal microbiome and malabsorption outcomes with highly effective CFTR modulator therapies.
Studies report that residential use of pesticides in low-income homes is common because of poor housing conditions and pest infestations; however, exposure data on contemporary-use pesticides in ...low-income households is limited. We conducted a study in low-income homes from urban and agricultural communities to: characterize and compare house dust levels of agricultural and residential-use pesticides; evaluate the correlation of pesticide concentrations in samples collected several days apart; examine whether concentrations of pesticides phased-out for residential uses, but still used in agriculture (i.e., chlorpyrifos and diazinon) have declined in homes in the agricultural community; and estimate resident children's pesticide exposures via inadvertent dust ingestion.
In 2006, we collected up to two dust samples 5-8 days apart from each of 13 urban homes in Oakland, California and 15 farmworker homes in Salinas, California, an agricultural community (54 samples total). We measured 22 insecticides including organophosphates (chlorpyrifos, diazinon, diazinon-oxon, malathion, methidathion, methyl parathion, phorate, and tetrachlorvinphos) and pyrethroids (allethrin-two isomers, bifenthrin, cypermethrin-four isomers, deltamethrin, esfenvalerate, imiprothrin, permethrin-two isomers, prallethrin, and sumithrin), one phthalate herbicide (chlorthal-dimethyl), one dicarboximide fungicide (iprodione), and one pesticide synergist (piperonyl butoxide).
More than half of the households reported applying pesticides indoors. Analytes frequently detected in both locations included chlorpyrifos, diazinon, permethrin, allethrin, cypermethrin, and piperonyl butoxide; no differences in concentrations or loadings were observed between locations for these analytes. Chlorthal-dimethyl was detected solely in farmworker homes, suggesting contamination due to regional agricultural use. Concentrations in samples collected 5-8 days apart in the same home were strongly correlated for the majority of the frequently detected analytes (Spearman ρ = 0.70-1.00, p < 0.01). Additionally, diazinon and chlorpyrifos concentrations in Salinas farmworker homes were 40-80% lower than concentrations reported in samples from Salinas farmworker homes studied between 2000-2002, suggesting a temporal reduction after their residential phase-out. Finally, estimated non-dietary pesticide intake for resident children did not exceed current U.S. Environmental Protection Agency's (U.S. EPA) recommended chronic reference doses (RfDs).
Low-income children are potentially exposed to a mixture of pesticides as a result of poorer housing quality. Historical or current pesticide use indoors is likely to contribute to ongoing exposures. Agricultural pesticide use may also contribute to additional exposures to some pesticides in rural areas. Although children's non-dietary intake did not exceed U.S. EPA RfDs for select pesticides, this does not ensure that children are free of any health risks as RfDs have their own limitations, and the children may be exposed indoors via other pathways. The frequent pesticide use reported and high detection of several home-use pesticides in house dust suggests that families would benefit from integrated pest management strategies to control pests and minimize current and future exposures.
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