16 research outputs found
Recommended from our members
Factors associated with bone microstructural alterations assessed by HR-pQCT in long-term HIV-infected individuals.
PurposeIn adults with long-term HIV infection, low bone density and increased fracture risk have emerged as significant comorbidities. Our aim was to assess the association of exercise, nutrition, and medications with bone quality in adults with long-term HIV infection.MethodsForty-three adults with HIV infection were enrolled (median BMI 25.7, range 18.2-35.6 kg/m2; median age 57, range 50-69 years). Participants underwent ultradistal radius and tibia high-resolution peripheral quantitative CT (HR-pQCT). Questionnaires included the revised Community Healthy Activities Model Program for Seniors (CHAMPS), the Mini Nutritional Assessment (MNA) as well as medication assessments. Multivariable linear regression models were used to evaluate the association of exercise, nutritional status, tenofovir disoproxil fumarate (TDF) and protease inhibitor (PI) use with bone density and microstructure, adjusting for demographic risk factors.ResultsIn regression models, higher nutrition scores were associated with higher tibia cortical thickness (R2 = 0.23; β = 0.03; p = 0.044) and higher radius cortical BMD (R2 = 0.43; β = 8.4; p = 0.026). Higher weekly frequency of all physical activities was significantly associated with higher radius trabecular BMD (R2 = 0.38; β = 0.96; p = 0.050), higher radius trabecular number (R2 = 0.31; β = 0.01; p = 0.026), lower tibia and radius trabecular separation (tibia: R2 = 0.30; β = -0.003; p = 0.038; radius: R2 = 0.35; β = -0.003; p = 0.021), and higher radius bone stiffness (R2 = 0.45; β = 0.38; p = 0.047). Higher frequency of bone loading physical activities was significantly associated with higher tibia trabecular density (R2 = 0.44; β = 4.06; p = 0.036), higher tibia bone stiffness (R2 = 0.46; β = 3.06; p = 0.050), and higher tibia estimated failure load (R2 = 0.46; β = 0.17; p = 0.049). TDF used in combination with a PI was associated with lower radius trabecular BMD (R2 = 0.39; β = -41.2; p = 0.042), lower radius trabecular number (R2 = 0.34; β = -0.44; p = 0.009) and greater radius trabecular separation (R2 = 0.42; β = 0.16; p = 0.002), while TDF use without a PI was not associated with reduced bone quality.ConclusionsIn adults with HIV infection, malnutrition is associated with poor cortical bone quality, while reduced frequency of physical activities and specifically reduced frequency of mechanical loading activities are associated with deficient trabecular bone structure and reduced estimates of bone strength. TDF use in combination with a PI is associated with deleterious effects on trabecular bone structure
GLUT3 upregulation promotes metabolic reprogramming associated with antiangiogenic therapy resistance
Clinical trials revealed limited response duration of glioblastomas to VEGF-neutralizing antibody bevacizumab. Thriving in the devascularized microenvironment occurring after antiangiogenic therapy requires tumor cell adaptation to decreased glucose, with 50% less glucose identified in bevacizumab-treated xenografts. Compared with bevacizumab-responsive xenograft cells, resistant cells exhibited increased glucose uptake, glycolysis, (13)C NMR pyruvate to lactate conversion, and survival in low glucose. Glucose transporter 3 (GLUT3) was upregulated in bevacizumab-resistant versus sensitive xenografts and patient specimens in a HIF-1α–dependent manner. Resistant versus sensitive cell mitochondria in oxidative phosphorylation–selective conditions produced less ATP. Despite unchanged mitochondrial numbers, normoxic resistant cells had lower mitochondrial membrane potential than sensitive cells, confirming poorer mitochondrial health, but avoided the mitochondrial dysfunction of hypoxic sensitive cells. Thin-layer chromatography revealed increased triglycerides in bevacizumab-resistant versus sensitive xenografts, a change driven by mitochondrial stress. A glycogen synthase kinase-3β inhibitor suppressing GLUT3 transcription caused greater cell death in bevacizumab-resistant than -responsive cells. Overexpressing GLUT3 in tumor cells recapitulated bevacizumab-resistant cell features: survival and proliferation in low glucose, increased glycolysis, impaired oxidative phosphorylation, and rapid in vivo proliferation only slowed by bevacizumab to that of untreated bevacizumab-responsive tumors. Targeting GLUT3 or the increased glycolysis reliance in resistant tumors could unlock the potential of antiangiogenic treatments
Recommended from our members
Biomass-burning smoke's properties and its interactions with marine stratocumulus clouds in WRF-CAM5 and southeastern Atlantic field campaigns
A large part of the uncertainty in climate projections comes from uncertain aerosol properties and aerosol-cloud interactions as well as the difficulty in remotely sensing them. The southeastern Atlantic functions as a natural laboratory to study biomass-burning smoke and to constrain this uncertainty. We address these gaps by comparing the Weather Research and Forecasting with Chemistry Community Atmosphere Model (WRF-CAM5) to the multi-campaign observations ORACLES (ObseRvations of Aerosols above CLouds and their intEractionS), CLARIFY (CLoud-Aerosol-Radiation Interaction and Forcing), and LASIC (Layered Atlantic Smoke Interactions with Clouds) in the southeastern Atlantic in August 2017 to evaluate a large range of the model's aerosol chemical properties, size distributions, processes, and transport, as well as aerosol-cloud interactions. Overall, while WRF-CAM5 is able to represent smoke properties and transport, some key discrepancies highlight the need for further analysis. Observations of smoke composition show an overall decrease in aerosol mean diameter as smoke ages over 4-12 d, while the model lacks this trend. A decrease in the mass ratio of organic aerosol (OA) to black carbon (BC), OA:BC, and the OA mass to carbon monoxide (CO) mixing ratio, OA:CO, suggests that the model is missing processes that selectively remove OA from the particle phase, such as photolysis and heterogeneous aerosol chemistry. A large (factor of ∼2.5) enhancement in sulfate from the free troposphere (FT) to the boundary layer (BL) in observations is not present in the model, pointing to the importance of properly representing secondary sulfate aerosol formation from marine dimethyl sulfide and gaseous SO2 smoke emissions. The model shows a persistent overprediction of aerosols in the marine boundary layer (MBL), especially for clean conditions, which multiple pieces of evidence link to weaker aerosol removal in the modeled MBL than reality. This evidence includes several model features, such as not representing observed shifts towards smaller aerosol diameters, inaccurate concentration ratios of carbon monoxide and black carbon, underprediction of heavy rain events, and little evidence of persistent biases in modeled entrainment. The average below-cloud aerosol activation fraction (NCLD/NAER) remains relatively constant in WRF-CAM5 between field campaigns (∼0.65), while it decreases substantially in observations from ORACLES (∼0.78) to CLARIFY (∼0.5), which could be due to the model misrepresentation of clean aerosol conditions. WRF-CAM5 also overshoots an observed upper limit on liquid cloud droplet concentration around NCLDCombining double low line 400-500 cm-3 and overpredicts the spread in NCLD. This could be related to the model often drastically overestimating the strength of boundary layer vertical turbulence by up to a factor of 10. We expect these results to motivate similar evaluations of other modeling systems and promote model development to reduce critical uncertainties in climate simulations. Copyright
Recommended from our members
Evaluation of modeled aerosol-cloud interactions using data from the ORACLES and LASIC field campaigns
Aerosol-cloud interactions are both uncertain and important in global and regional climate models, and especially in the southeast Atlantic Ocean. This uncertainty in the region is largely due to two correlated factors—the expansive, bright, semi-permanent stratocumulus cloud deck and the fact that southern Africa is the largest source of biomass-burning aerosols in the world. We study this region using the WRF-Chem model with CAM5 aerosols and in situ observations from the ORACLES and LASIC field campaigns in August-October of 2016 through 2018. We compare aerosol and cloud properties to measure and improve model performance and expand upon observational findings of aerosol-cloud effects. Relevant comparison variables include aerosol number concentration, mean particle diameter and spread, CCN activation tendency, hygroscopicity, and cloud droplet number concentrations. Specifically, our approach is to analyze colocated model data along flight tracks to resolve aerosol-cloud interactions. Within and between single-day flights, there is high spatiotemporal variability that can get lost to large-scale averaging analyses. We have found that CCN is substantially under-represented in the model compared to observations. For a given aerosol number concentration, size, supersaturation and hygroscopicity, the model will consider fewer particles as CCN than observations indicate. We plan to explore this result further, diagnosing the model-observation differences more consistently and updating the model with more physically accurate values of aerosol size, concentration, or hygroscopicity based on observations. We will also intercompare multiple instrument platforms involved with the ORACLES and LASIC campaigns. With improved small-scale aerosol-cloud interactions, this work also shows promise to substantially improve that representation in climate models