•DEHP and MEHP induced the migration and enlargement of A549 cells.•Phthalates decreased the surfactant proteins suggesting a change in the epithelial phenotype of A459 cells.•Phthalates changed the ...levels of fibronectin and E- cadherin suggesting an epithelial-mesenchymal-transition.•The change on the epithelial phenotype can be a mechanism of DEHP and MEHP toxicity.
Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is metabolized to mono(2-ethylhexyl) phthalate (MEHP). Inhalation is an important exposure route for both phthalates, and their effects on lungs include inflammation, alteration of postnatal maturation (alveolarization), enlarged airspaces and cell differentiation changes, suggesting that alveolar epithelial cells-2 (AEC) are targets of phthalates. This study evaluated the cell progression, epithelial and mesenchymal markers, including surfactant secretion in A549 cells (AEC) that were exposed to DEHP (1–100 μM) or MEHP (1–50 μM) for 24–72 h. The results showed an increased cell proliferation at all concentrations of each phthalate at 24 and 48 h. Cell migration showed a concentration-dependent increase at 24 and 48 h of exposure to either phthalate and enlarged structures were seen. Decreased levels of both surfactants (SP-B/SP-C) were observed after the exposure to either phthalate at 48 h, and of SP-C positive cells exposed to MEHP, suggesting a loss of the epithelial phenotype. While a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal marker fibronectin were observed following exposure to either phthalate. Our results showed that DEHP and MEHP altered the structure and migration of A549 cells and promoted the loss of the epithelial phenotype.
Background
Large‐scale population studies demonstrate an association between mothers’ deaths and child mortality in both lower and higher income countries. The authors estimated children’s deaths in ...association with mothers’ deaths from breast or cervical cancer, 2 common cancers in low‐income and middle‐income countries affecting women of reproductive age, to develop a comprehensive assessment of the death burden of these cancers.
Methods
A Monte Carlo simulation model was devised whereby women were at risk of dying from breast cancer, cervical cancer, or another cause. Compared with children who have living mothers, children of women who die before they reached age 10 years have an elevated risk of death from all causes. Therefore, simulations were conducted, and the impact of mothers’ deaths from cervical and breast cancer on associated child mortality was quantified for Bangladesh, Burkina Faso, and Denmark (benchmark analysis), then the analyses were extended to all African countries.
Results
Benchmark estimates of child deaths associated with mothers’ deaths from breast and cervical cancer resulted in an increment in cancer‐related mortality of approximately 2% in Bangladesh, 14% in Burkina Faso, and less than 1% in Denmark. The model predicted an increment in comprehensive cancer deaths when including child death estimates by as high as 30% in certain African countries.
Conclusions
To the authors’ knowledge, this is the first study to estimate the impact of a mother’s death from cancer on child mortality. The model’s estimates call for further investigation into this correlation and underscore the relevance of adequate access to prevention and treatment among women of childbearing age.
It has been demonstrated in different geographic and socioeconomic settings that children of mothers who die have a higher risk of death compared with children who have living mothers. The model estimates in this study identify an increment in comprehensive cancer deaths when including child death estimates of up to 30% in certain African countries, and the predicted results call for further investigation and underscore the relevance of adequate access to prevention and treatment among women of childbearing age.
The current uncertainty surrounding the Earth's equilibrium climate sensitivity is an important driver for climate hazard projections. While the implications for projected global temperature changes ...have been extensively studied, the impacts on sea level projections have been relatively unexplored. Here we analyze the relationship between the climate sensitivity and sea level projections, with a particular focus on the high‐impact upper tail. We utilize a Bayesian calibration of key climate and sea level parameters using historical observations and the reduced‐complexity Earth system model, Hector‐BRICK. This methodology allows us to focus on plausible realizations of the climate system in a probabilistic framework. We analyze the effects of high‐end climate sensitivity (above 5 K) on projections and spatial patterns of sea level change. The sea level projections hinge critically on the upper tail of the climate sensitivity, especially for the highly decision‐relevant upper tail. Results have important implications for timing of threshold exceedances and regional variability.
Plain Language Summary
The upper tail of sea level rise over the coming century can be an important factor for adaptation planning and the assessment of vulnerabilities and risks. One way to estimate this upper tail is with a simple climate model, which can provide useful constraints on sea level rise informed by historical observations. The model range reflects uncertainty about the evolution of the climate system and physical processes related to sea level, such as melting land ice. Here we investigate the effect of a key climate uncertainty, Earth's long‐term temperature response to a doubling of atmospheric CO2, on the model range of 21st century sea level rise, using the simple climate model Hector‐BRICK. While all of the model realizations generally match historical observations, those with a high temperature sensitivity to atmospheric CO2 have generally higher 21st century sea level rise. We explore the time evolution of this effect and focus on the particularly large change in the upper tail of sea level.
Key Points
We analyze the effect of high climate sensitivity on sea level rise projections using a reduced‐complexity Earth system model, Hector‐BRICK
Modeled sea level projections, particularly at the upper tail, depend substantially on equilibrium climate sensitivity
Results influence regional sea level change projections and the timing of sea level rise exceedances
Shales are low‐permeability caprocks that confine fluid, such as CO2, nuclear waste, and hydrogen, in storage formations. Stress‐induced fractures in shale caprocks provide pathways for fluid to leak ...and potentially contaminate fresh water aquifers. Fractured shales are also increasingly considered as resources for CO2 sequestration, enhanced geothermal, and unconventional energy recovery. Injecting reactive fluids into shales introduces chemical disequilibrium, causing an onset of a series of dissolution, precipitation, and fines mobilization mechanisms. The reactions have rapid kinetics and significant impact on porosity and permeability; consequently, flow and storage properties of caprocks. While previous research has explored the separate effects of these reactions, this study aims to uncover their simultaneous occurrence and collective influence. This study unveils these highly coupled transport and reactivity mechanisms by tracking and visualizing the reaction‐induced alterations in the matrix, microcracks, and fractures of shales over time. We conducted brine injection experiments sequentially at pH 4 and 2 in a naturally fractured Wolfcamp shale sample while simultaneously imaging the dynamic processes using X‐ray computed tomography (CT). CT images are validated by finer resolution images obtained using micro‐CT and scanning electron microscopy. We also tracked the sample permeability and fluid chemistry using brine permeability and inductively coupled plasma mass spectrometry, respectively. Findings show that fluid primarily flowed through fractures, dissolving reactive minerals and mobilizing fines on fracture surfaces. Dissolution of fracture asperities under confining stress resulted in the closing of fractures. Clogging in narrow fracture pathways, caused by fines accumulation, diverted fluid flow into matrix pores.
Plain Language Summary
Geological formations have significant potential to store CO2 and other fluids. Overlying low‐permeability shale caprocks prevent the upward movement of such fluids. Naturally occurring or induced fractures in caprocks may serve as potential leakage routes. Our research employs a range of experimental approaches to investigate the behavior of reactive fluids within shale rock fractures. Our findings indicate that, in the rock‐fluid system studied, fractures undergo a self‐sealing process due to a combination of geochemical and geomechanical phenomena. This discovery enhances our ability to assess risks and develop effective management strategies for fractured caprocks.
Key Points
Permeability responds to changes in fracture characteristics as a result of reaction and stress
Fractures seal under confining stress when fracture‐propping minerals and fines dissolve or are displaced
Fracture clogging diverts injected fluid into matrix pores where it is sequestered
There is a lack of level I evidence to guide radiation therapy recommendations for patients receiving neoadjuvant chemotherapy for breast cancer. We used 4 neoadjuvant chemotherapy trials to ...determine which patients benefit from regional nodal irradiation (RNI).
We obtained data from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B-18, B-27, B-40, and B-41 clinical trials. B-40 and B-41 allowed RNI at physician's discretion. We evaluated locoregional recurrence (LRR), distant recurrence, disease-free survival, and overall survival (OS). Kaplan-Meier, Peto-Peto, χ
, Fisher exact, and Wilcoxon rank-sum tests were used for survival estimates and comparison.
Median follow-up for B-18, B-27, B-40, and B-41 was 13.7, 9.7, 4.5, and 5.1 years, respectively, including 742, 2254, 1154, and 504 patients for analysis. On multivariable analysis, factors significantly associated with RNI included tumor size, ypN status, and tumor subtype; Hispanic patients were less likely to receive RNI. Patients with ypN+HER2+ disease who received RNI had improved OS. B-40 patients with ypN+HR+ disease had improved LRR. On multivariable analysis for the B-40 and B-41 study population, RNI was not associated with significantly improved OS, disease-free survival, distant recurrence, or LRR.
RNI was associated with a clinical benefit for patients with ypN+HER2+ and ypN+HR+ disease. RNI was not significantly associated with a clinically beneficial outcome for the entire cohort. Prospective phase 3 clinical trials are needed to establish guidelines for patients who should receive RNI after neoadjuvant treatment, and action is necessary to eliminate the disparity in care delivery shown for Hispanic women.
Age-related declines in cardiorespiratory fitness and physical function are mitigated by regular endurance exercise in older adults. This may be due, in part, to changes in the transcriptional ...program of skeletal muscle following repeated bouts of exercise. However, the impact of chronic exercise training on the transcriptional response to an acute bout of endurance exercise has not been clearly determined. Here, we characterized baseline differences in muscle transcriptome and exercise-induced response in older adults who were active/endurance trained or sedentary. RNA-sequencing was performed on vastus lateralis biopsy specimens obtained before, immediately after, and 3 h following a bout of endurance exercise (40 min of cycling at 60%-70% of heart rate reserve). Using a recently developed bioinformatics approach, we found that transcript signatures related to type I myofibers, mitochondria, and endothelial cells were higher in active/endurance-trained adults and were associated with key phenotypic features including V̇o
, ATP
, and muscle fiber proportion. Immune cell signatures were elevated in the sedentary group and linked to visceral and intermuscular adipose tissue mass. Following acute exercise, we observed distinct temporal transcriptional signatures that were largely similar among groups. Enrichment analysis revealed catabolic processes were uniquely enriched in the sedentary group at the 3-h postexercise timepoint. In summary, this study revealed key transcriptional signatures that distinguished active and sedentary adults, which were associated with difference in oxidative capacity and depot-specific adiposity. The acute response signatures were consistent with beneficial effects of endurance exercise to improve muscle health in older adults irrespective of exercise history and adiposity.
Muscle transcript signatures associated with oxidative capacity and immune cells underlie important phenotypic and clinical characteristics of older adults who are endurance trained or sedentary. Despite divergent phenotypes, the temporal transcriptional signatures in response to an acute bout of endurance exercise were largely similar among groups. These data provide new insight into the transcriptional programs of aging muscle and the beneficial effects of endurance exercise to promote healthy aging in older adults.
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