Functional contributions of individual cellular components of the bone-marrow microenvironment to myelofibrosis (MF) in patients with myeloproliferative neoplasms (MPNs) are incompletely understood. ...We aimed to generate a comprehensive map of the stroma in MPNs/MFs on a single-cell level in murine models and patient samples. Our analysis revealed two distinct mesenchymal stromal cell (MSC) subsets as pro-fibrotic cells. MSCs were functionally reprogrammed in a stage-dependent manner with loss of their progenitor status and initiation of differentiation in the pre-fibrotic and acquisition of a pro-fibrotic and inflammatory phenotype in the fibrotic stage. The expression of the alarmin complex S100A8/S100A9 in MSC marked disease progression toward the fibrotic phase in murine models and in patient stroma and plasma. Tasquinimod, a small-molecule inhibiting S100A8/S100A9 signaling, significantly ameliorated the MPN phenotype and fibrosis in JAK2V617F-mutated murine models, highlighting that S100A8/S100A9 is an attractive therapeutic target in MPNs.
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•Mesenchymal progenitor cells are fibrosis-driving cells in the bone marrow•Inflammation in the stroma characterizes pre-fibrosis and TGF-β signaling fibrosis•Stromal S100A8/S100A9 marks disease progression in MPN patients•Tasquinimod, inhibiting S100A8/S100A9 signaling, ameliorates the MPN phenotype
Leimkühler and colleagues demonstrate that mesenchymal stromal progenitor cells are fibrosis-driving cells in mice and patients, that inflammation in the bone-marrow stroma precedes TGF-β signaling-driven fibrosis, and that the alarmin heterocomplex S100A8/S100A9 holds promise as MPN progression marker and therapeutic target.
Power quality of power systems affects all connected electrical and electronic equipment. Power quality is a measure of deviations in voltage and frequency of the particular supply system. In recent ...years, there has been a considerable increase in nonlinear loads; in particular distributed loads, such as computers, TV monitors and lighting. These draw harmonic currents which, when distorted, have detrimental effects including interference, loss of reliability, increased operating costs, equipment overheating, motor failures, capacitor failure and inaccurate power metering. This subject is pertinent to engineers involved with electric power systems, electronic equipment, computers and manufacturing equipment. This book shows readers to understand the causes and effects of power quality problems such as non-sinusoidal wave shapes, voltage outages, losses due to poor power quality, and origins of single-time events such as voltage dips, voltage reductions and outages, along with techniques to mitigate these problems.
To ascertain the most appropriate treatment for chronic, stable, coronary artery disease (CAD) in patients submitted to elective coronary angiography.
A total of 814 patients included in the ...prospective cohort study were referred for elective coronary angiography and were followed up on average for 6±1.9 years. Main outcomes were all-cause death, cardiovascular death, non-fatal myocardial infarction (MI) and stroke and late revascularization and their combinations as major adverse cardiac and cerebral events (MACCE): MACCE-1 included cardiovascular death, nonfatal MI, and stroke; MACCE-2 was MACCE-1 plus late revascularization. Survival curves and adjusted Cox proportional hazard models were used to explore the association between the type of treatment and outcomes.
All-cause death was lower in participants submitted to percutaneous coronary intervention (PCI) (0.41, 0.16-1.03, P=0.057) compared to medical treatment (MT). Coronary-artery bypass grafting (CABG) had an overall trend for poorer outcomes: cardiovascular death 2.53 (0.42-15.10), combined cardiovascular death, nonfatal MI, and stroke 2.15 (0.73-6.31) and these events plus late revascularization (2.17, 0.86-5.49). The corresponding numbers for PCI were 0.27 (0.05-1.43) for cardiovascular death, 0.77 (0.32-1.84) for combined cardiovascular death, nonfatal MI, and stroke and 2.35 (1.16-4.77) with the addition of late revascularization. These trends were not influenced by baseline blood pressure, left ventricular ejection fraction and previous MI. Patients with diabetes mellitus had a significantly higher risk of recurrent revascularization when submitted to PCI than CABG.
Patients with confirmed CAD in elective coronary angiography do not have a better prognosis when submitted to CABG comparatively to medical treatment. Patients treated with PCI had a trend for the lower incidence of combined cardiovascular events, at the expense of additional revascularization procedures. Patients without significant CAD had a similar prognosis than CAD patients treated with medical therapy.
Resumo Fundamento A prevenção secundária é recomendada a pacientes com evidência de doença arterial coronariana (DAC) independentemente da indicação de tratamento por cirurgia de bypass da artéria ...coronária (CABG) ou intervenção coronária percutânea (ICP). Objetivos Este estudo avaliou se o tratamento clínico, a ICP ou o CABG teve influência na adesão à prevenção secundária farmacológica em pacientes com DAC estável. Métodos Esta coorte incluiu pacientes com idade ≥40 anos com DAC estável confirmada por angiografia coronária estável. A decisão por tratamento clínico isolado, ou combinado com ICP ou CABG foi feita por médicos assistentes. A adesão às drogas prescritas recomendadas pelas diretrizes de prevenção secundária (tratamento farmacológico ótimo), incluindo agentes antiplaquetários, drogas hipolipemianetes, betabloqueadores, e bloqueadores do sistema angiotensina aldosterona, foi avaliada no acompanhamento. Diferenças com valores de p < 0,05 foram consideradas estatisticamente significativas. Resultados Dos 928 pacientes incluídos inicialmente, 415 apresentaram DAC leve e 66 apresentaram DAC leve a moderada. O período médio de seguimento foi 5,2 ± 1,5 anos. Os pacientes submetidos ao CABG apresentaram maior probabilidade de receberem tratamento farmacológico ótimo que aqueles submetidos à ICP ou tratamento clínico (63,5% versus 39,1% versus 45,7% respectivamente, p=0,003). Fatores basais independentemente associados com maior probabilidade de prescrição de tratamento ótimo foram CABG 39% maior (6% - 83%, p=0,017) em comparação a outros tratamentos e diabetes 25% maior (1% - 56%), p=0,042 em comparação à ausência de diabetes. Conclusões Pacientes com DAC submetidos ao CABG são mais frequentemente tratados com prevenção secundária farmacológica ótima que pacientes tratados com ICP ou exclusivamente com tratamento clínico.
Understanding drop size distribution (DSD) variability has important implications for remote sensing and numerical modeling applications. Twelve disdrometer datasets across three latitude bands are ...analyzed in this study, spanning a broad range of precipitation regimes: light rain, orographic, deep convective, organized midlatitude, and tropical oceanic. Principal component analysis (PCA) is used to reveal comprehensive modes of global DSD spatial and temporal variability. Although the locations contain different distributions of individual DSD parameters, all locations are found to have the same modes of variability. Based on PCA, six groups of points with unique DSD characteristics emerge. The physical processes that underpin these groups are revealed through supporting radar observations. Group 1 (group 2) is characterized by high (low) liquid water content (LWC), broad (narrow) distribution widths, and large (small) median drop diameters D
0
. Radar analysis identifies group 1 (group 2) as convective (stratiform) rainfall. Group 3 is characterized by weak, shallow radar echoes and large concentrations of small drops, indicative of warm rain showers. Group 4 identifies heavy stratiform precipitation. The low latitudes exhibit distinct bimodal distributions of the normalized intercept parameter N
w
, LWC, and D
0
and are found to have a clustering of points (group 5) with high rain rates, large N
w
, and moderate D
0
, a signature of robust warm rain processes. A distinct group associated with ice-based convection (group 6) emerges in the midlatitudes. Although all locations exhibit the same covariance of parameters associated with these groups, it is likely that the physical processes responsible for shaping the DSDs vary as a function of location.
We demonstrate direct coupling between phonons and diamond nitrogen-vacancy (NV) center spins by driving spin transitions with mechanically generated harmonic strain at room temperature. The ...amplitude of the mechanically driven spin signal varies with the spatial periodicity of the stress standing wave within the diamond substrate, verifying that we drive NV center spins mechanically. These spin-phonon interactions could offer a route to quantum spin control of magnetically forbidden transitions, which would enhance NV-based quantum metrology, grant access to direct transitions between all of the spin-1 quantum states of the NV center, and provide a platform to study spin-phonon interactions at the level of a few interacting spins.
This double-blind, phase 3 study assessed the efficacy and safety of ganitumab plus gemcitabine as first-line treatment of metastatic pancreatic cancer. The study was stopped after a preplanned ...futility analysis indicated a positive outcome was unlikely at primary analysis. Ganitumab plus gemcitabine had manageable toxicity but did not improve OS versus gemcitabine alone in unselected patients.
This double-blind, phase 3 study assessed the efficacy and safety of ganitumab combined with gemcitabine as first-line treatment of metastatic pancreatic cancer.
Patients with previously untreated metastatic pancreatic adenocarcinoma were randomly assigned 2 : 2 : 1 to receive intravenous gemcitabine 1000 mg/m2 (days 1, 8, and 15 of each 28-day cycle) plus placebo, ganitumab 12 mg/kg, or ganitumab 20 mg/kg (days 1 and 15 of each cycle). The primary end point was overall survival (OS). Secondary end points included progression-free survival (PFS), safety, and efficacy by levels of circulating biomarkers.
Overall, 322 patients were randomly assigned to placebo, 318 to ganitumab 12 mg/kg, and 160 to ganitumab 20 mg/kg. The study was stopped based on results from a preplanned futility analysis; the final results are reported. Median OS was 7.2 months 95% confidence interval (CI), 6.3-8.2 in the placebo arm, 7.0 months (95% CI, 6.2-8.5) in the ganitumab 12-mg/kg arm hazard ratio (HR), 1.00; 95% CI, 0.82-1.21; P = 0.494, and 7.1 months (95% CI, 6.4-8.5) in the ganitumab 20-mg/kg arm (HR, 0.97; 95% CI, 0.76-1.23; P = 0.397). Median PFS was 3.7, 3.6 (HR, 1.00; 95% CI, 0.84-1.20; P = 0.520), and 3.7 months (HR, 0.97; 95% CI, 0.77–1.22; P = 0.403), respectively. No unexpected toxicity was observed with ganitumab plus gemcitabine. The circulating biomarkers assessed insulin-like growth factor-1 (IGF-1), IGF-binding protein-2, and -3 were not associated with a treatment effect on OS or PFS by ganitumab.
Ganitumab combined with gemcitabine had manageable toxicity but did not improve OS, compared with gemcitabine alone in unselected patients with metastatic pancreatic cancer.
ClinicalTrials.gov NCT01231347.
Background: Upon activation, neutrophils can release nuclear material known as neutrophil extracellular traps (NETs), which were initially described as a part of antimicrobial defense. Extracellular ...chromatin was recently reported to be prothrombotic in vitro and to accumulate in plasma and thrombi of baboons with experimental deep vein thrombosis (DVT). Objective: To explore the source and role of extracellular chromatin in DVT. Methods: We used an established murine model of DVT induced by flow restriction (stenosis) in the inferior vena cava (IVC). Results: We demonstrate that the levels of extracellular DNA increase in plasma after 6 h IVC stenosis, compared with sham‐operated mice. Immunohistochemical staining revealed the presence of Gr‐1‐positive neutrophils in both red (RBC‐rich) and white (platelet‐rich) parts of thrombi. Citrullinated histone H3 (CitH3), an element of NETs’ structure, was present only in the red part of thrombi and was frequently associated with the Gr‐1 antigen. Immunofluorescent staining of thrombi showed proximity of extracellular CitH3 and von Willebrand factor (VWF), a platelet adhesion molecule crucial for thrombus development in this model. Infusion of Deoxyribonuclease 1 (DNase 1) protected mice from DVT after 6 h and also 48 h IVC stenosis. Infusion of an unfractionated mixture of calf thymus histones increased plasma VWF and promoted DVT early after stenosis application. Conclusions: Extracellular chromatin, likely originating from neutrophils, is a structural part of a venous thrombus and both the DNA scaffold and histones appear to contribute to the pathogenesis of DVT in mice. NETs may provide new targets for DVT drug development.
Because studies have evidenced variations in nutrient intake, further investigation of the interaction between demographic characteristics and the seasons is necessary. We aimed to test the ...differences in food intake throughout the seasons and the interaction between the seasons and sex and age.
This study included 273 individuals. Food intake was evaluated with 24-hour dietary recalls, and the reported food items were sorted into food groups. We performed the test on the differences in intake of food groups throughout the seasons with repeated measures and on the interaction effect by using the Generalized Estimate Equation.
Intake of fruits and natural fruit juices and sweetened beverages was lower, whereas that of grains and derivatives was higher in the winter. The intake of leafy vegetables and fish and seafood was lower in the autumn. The consumption of coffee and eggs was higher in the spring. Intake of chocolate powder and sugar, salt and lean poultry was higher in the winter. The variation in consumption of grains and derivatives, eggs, fatty poultry and processed meat over the seasons was more likely to be modified by sex. Age interacted with the seasons for leafy vegetables, beans and lentils, lean beef, lean poultry, low fat milk and light yogurt, vegetable oil and unsalted margarine, chocolate powder and sugar and processed meat.
This study shows that food intake may change seasonally and that seasonal variation depends on sex and age, which might aggregate a specific co-variation component.
This paper presents a new genetic algorithm (GA)-based approach for the simultaneous power quality improvement and optimal placement and sizing of fixed capacitor banks in radial distribution ...networks in the presence of voltage and current harmonics. The objective function includes the cost of power losses, energy losses and that of the capacitor banks. Constraints include voltage limits, number/size and locations of installed capacitors (at each bus and the entire feeder) and the power quality limits of standard IEEE-519. Candidate buses for capacitor placement are selected based on an initial generation of chromosomes. Using a proposed fitness function, a suitable combination of objective and constraints is defined as a criterion to select (among the candidates) the most suitable buses for capacitor placement. A genetic algorithm computes improved generations of chromosomes and candidate buses until the solution is obtained. Simulation results for two IEEE distorted networks are presented and solutions of the genetic algorithm are compared with those of the maximum-sensitivities-selection (MSS), the maximum sensitivities selection-local variations (MSS-LV), and the fuzzy set algorithms. The main contribution of this paper is the computation of the near global solution, with weak dependency on initial conditions.
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