An earlier analysis of this phase 3 trial showed that the addition of a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor to endocrine therapy provided a greater benefit with regard to ...progression-free survival than endocrine therapy alone in premenopausal or perimenopausal patients with advanced hormone-receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Here we report the results of a protocol-specified interim analysis of the key secondary end point of overall survival.
We randomly assigned patients to receive either ribociclib or placebo in addition to endocrine therapy (goserelin and either a nonsteroidal aromatase inhibitor or tamoxifen). Overall survival was evaluated with the use of a stratified log-rank test and summarized with the use of Kaplan-Meier methods.
A total of 672 patients were included in the intention-to-treat population. There were 83 deaths among 335 patients (24.8%) in the ribociclib group and 109 deaths among 337 patients (32.3%) in the placebo group. The addition of ribociclib to endocrine therapy resulted in significantly longer overall survival than endocrine therapy alone. The estimated overall survival at 42 months was 70.2% (95% confidence interval CI, 63.5 to 76.0) in the ribociclib group and 46.0% (95% CI, 32.0 to 58.9) in the placebo group (hazard ratio for death, 0.71; 95% CI, 0.54 to 0.95; P = 0.00973 by log-rank test). The survival benefit seen in the subgroup of 495 patients who received an aromatase inhibitor was consistent with that in the overall intention-to-treat population (hazard ratio for death, 0.70; 95% CI, 0.50 to 0.98). The percentage of patients who received subsequent antineoplastic therapy was balanced between the groups (68.9% in the ribociclib group and 73.2% in the placebo group). The time from randomization to disease progression during receipt of second-line therapy or to death was also longer in the ribociclib group than in the placebo group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.55 to 0.87).
This trial showed significantly longer overall survival with a CDK4/6 inhibitor plus endocrine therapy than with endocrine therapy alone among patients with advanced hormone-receptor-positive, HER2-negative breast cancer. No new concerns regarding toxic effects emerged with longer follow-up. (Funded by Novartis; MONALEESA-7 ClinicalTrials.gov number, NCT02278120.).
As an alternative strategy for phosphate removal, biochar (black carbon) has characteristics superior to those of widely used adsorptive media, from both economic and environmental points of view. In ...this study, various types of biochar derived from oak wood, bamboo wood, maize residue, soybean stover, and peanut shell were tested for evaluation of phosphate removal. After 24 h of reaction time, the phosphate removal was limited (2.0–9.4 %) in case of general adsorptive media. However, interestingly, among various biochars, peanut shell-derived biochar (PSB) exhibited the best performance, showing the highest phosphate removal rate, 61.3 % (3.8 mg PO
4−
P g PSB
−1
). We attribute this high value to the proper structural properties of PSB, such as BET-specific surface area of 348.96 m
2
g
−1
and mineral/phosphorus ratio (Mg/P = 3.46 and Ca/P = 47.6). Adsorption equilibrium and kinetics of phosphate at different temperature (10, 20, and 30 °C) were well explained in the whole experimental region by Langmuir isotherm and pseudo-second-order kinetic models, respectively. The maximum adsorption capacity of PSB was 6.79 mg g
−1
for phosphate at 30 °C. These findings suggest that PSB has great potential as an alternative and renewable adsorptive media for phosphate removal.
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•Mesoporous ZIF-8 showed the highest adsorption capacity for p-arsanilic acid.•Adsorption kinetics and adsorbed amount were improved with mesoporosity.•Facile regeneration and little ...effect of external ions were confirmed.•Adsorption mechanism could be explained by electrostatic interactions.
The adsorptive removal of p-arsanilic acid (ASA) from water using zeolitic imidazolate framework-8 (ZIF-8) materials was investigated for the first time. The adsorption kinetics and adsorbed amount of ASA were improved by introducing mesoporosity into the pristine ZIF-8 structure. The high adsorption capacity of mesoporous ZIF-8 for ASA and facile regeneration of the used adsorbent show that mesoporous ZIF-8 has potential applications in the adsorptive removal of organoarsenic compounds such as ASA. Based on the adsorption results at various pH values and the surface charges on ZIF-8s, the adsorption mechanism of ASA on ZIF-8s can be explained by electrostatic interactions between the positively charged ZIF-8 surface and the anionic forms of ASA.
Aims
The leucine‐rich repeat kinase 2 (LRRK2) G2019S mutation is the most common genetic cause of Parkinson's disease (PD). There is compelling evidence that PD is not only a brain disease but also a ...gastrointestinal disorder; nonetheless, its pathogenesis remains unclear. We aimed to develop human neural and intestinal tissue models of PD patients harbouring an LRRK2 mutation to understand the link between LRRK2 and PD pathology by investigating the gene expression signature.
Methods
We generated PD patient‐specific induced pluripotent stem cells (iPSCs) carrying an LRRK2 G2019S mutation (LK2GS) and then differentiated into three‐dimensional (3D) human neuroectodermal spheres (hNESs) and human intestinal organoids (hIOs). To unravel the gene and signalling networks associated with LK2GS, we analysed differentially expressed genes in the microarray data by functional clustering, gene ontology (GO) and pathway analyses.
Results
The expression profiles of LK2GS were distinct from those of wild‐type controls in hNESs and hIOs. The most represented GO biological process in hNESs and hIOs was synaptic transmission, specifically synaptic vesicle trafficking, some defects of which are known to be related to PD. The results were further validated in four independent PD‐specific hNESs and hIOs by microarray and qRT‐PCR analysis.
Conclusion
We provide the first evidence that LK2GS also causes significant changes in gene expression in the intestinal cells. These hNES and hIO models from the same genetic background of PD patients could be invaluable resources for understanding PD pathophysiology and for advancing the complexity of in vitro models with 3D expandable organoids.
Using three dimensional neural and intestinal organoids derived from induced pluripotent stem cells carrying a LRRK2 G2019S mutation and wild‐type controls has demonstrated differential gene expression implicating several cellular pathways in the pathogenesis of Parkinson's disease.
Background and purpose
We investigated the effect of celecoxib, a selective inhibitor of cyclo‐oxygenase 2, in patients with intracerebral hemorrhage (ICH).
Methods
We conducted a multicenter, ...randomized, controlled, and open with blinded end‐point trial of 44 Korean patients 18 years or older with ICH within 24 h of onset. The intervention group (n = 20) received celecoxib (400 mg twice a day) for 14 days. The control group (n = 24) received the standard medical treatment for ICH. The primary end‐point was the number of patients with a change in the volume of perihematomal edema (PHE) from the 1st to the 7th ± 1 day (cut‐off value, 20%).
Results
The time from onset to computed tomography scan slightly differed between groups (177 ± 160 min for control vs. 297 ± 305 min for the celecoxib group; P = 0.10). In the primary end‐point analysis using cut‐off values, there was a significant shift to reduced expansion of PHE in the celecoxib group (P = 0.005). With respect to the secondary end‐points, there was also a significant shift to reduced expansion of ICH in the celecoxib group (P = 0.046). In addition, the expansion rate of PHE at follow‐up tended to be higher in the control group than in the celecoxib group (90.6 ± 91.7% vs. 44.4 ± 64.9%; P = 0.058).
Conclusions
In our small, pilot trial, administration of celecoxib in the acute stage of ICH was associated with a smaller expansion of PHE than that observed in controls.
Hematopoietic stem and progenitor cells (HSPCs) are responsible for lifelong maintenance of hematopoiesis through self-renewal and differentiation into mature blood cell lineages. Traditional models ...hold that HSPCs guard homeostatic function and adapt to regenerative demand by integrating cell-autonomous, intrinsic programs with extrinsic cues from the niche. Despite the biologic significance, little is known about the active roles HSPCs partake in reciprocally shaping the function of their microenvironment. Here, we review evidence of signals emerging from HSPCs through secreted autocrine or paracrine factors, including extracellular vesicles, and via direct contact within the niche. We also discuss the functional impact of direct cellular interactions between hematopoietic elements on niche occupancy in the context of leukemic infiltration. The aggregate data support a model whereby HSPCs are active participants in the dynamic adaptation of the stem cell niche unit during development and homeostasis, and under inflammatory stress, malignancy, or transplantation.
There is growing interest in using routinely collected data from health care databases to study the safety and effectiveness of therapies in “real‐world” conditions, as it can provide complementary ...evidence to that of randomized controlled trials. Causal inference from health care databases is challenging because the data are typically noisy, high dimensional, and most importantly, observational. It requires methods that can estimate heterogeneous treatment effects while controlling for confounding in high dimensions. Bayesian additive regression trees, causal forests, causal boosting, and causal multivariate adaptive regression splines are off‐the‐shelf methods that have shown good performance for estimation of heterogeneous treatment effects in observational studies of continuous outcomes. However, it is not clear how these methods would perform in health care database studies where outcomes are often binary and rare and data structures are complex. In this study, we evaluate these methods in simulation studies that recapitulate key characteristics of comparative effectiveness studies. We focus on the conditional average effect of a binary treatment on a binary outcome using the conditional risk difference as an estimand. To emulate health care database studies, we propose a simulation design where real covariate and treatment assignment data are used and only outcomes are simulated based on nonparametric models of the real outcomes. We apply this design to 4 published observational studies that used records from 2 major health care databases in the United States. Our results suggest that Bayesian additive regression trees and causal boosting consistently provide low bias in conditional risk difference estimates in the context of health care database studies.
A high-performance H
gas sensor system based on capacitive electrodes and a volumetric analysis technique were developed. Coaxial capacitive electrodes were fabricated by placing a thin copper rod in ...the center and by adhering a transparent conductive film on the exterior surface of a graduated cylinder. Thus, H
from a polymer specimen lowered the water level in the cylinder between the two electrodes, producing measurable changes in capacitance that allowed for the measurement of the H
concentration emitted from the specimen enriched by H
under high-pressure conditions. The sensing system detected diffused/permeated hydrogen gas from a specimen and hydrogen gas leaks caused by imperfect sealing. The hydrogen gas sensor responded almost instantly at 1 s and measured hydrogen concentrations ranging from 0.15 to 1500 ppm with controllable sensitivity and a measurable range. In addition, performance tests with polymer specimens used in hydrogen infrastructure verified that the sensor system was reliable; additionally, it had a broad measurement range to four decimal places. The sensor system developed in this study could be applied to detect and characterize pure gases (He, N
, O
and Ar) by real time measurement.
Microglia, the immune cells of the brain, can have a beneficial effect in Alzheimer's disease by phagocytosing amyloid-β. Two-photon in vivo imaging of neuron loss in the intact brain of living ...Alzheimer's disease mice revealed an involvement of microglia in neuron elimination, indicated by locally increased number and migration velocity of microglia around lost neurons. Knockout of the microglial chemokine receptor Cx3cr1, which is critical in neuron-microglia communication, prevented neuron loss.
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