This experimental research investigates the mechanical properties and shrinkage of ultra high performance concrete (UHPC) incorporating coarser fine aggregates with maximum particle size of 5 mm. To ...adequately design UHPC mixtures using various sizes of solid constituents, particle packing theory was adopted. UHPC mixtures containing either dolomite or basalt, and four fiber volume fractions up to two volume percent were investigated. Uniaxial tension test was performed to evaluate the first cracking tensile strength, ultimate tensile strength, tensile strain capacity and cracking pattern. The UHPC mixtures with dolomite and steel fibers with more than one volume percent achieved more than 150 MPa of compressive strength at the age of 56 days, and showed strain hardening behavior and limited decrease in tensile strength compared to typical UHPC without coarser fine aggregates. The experimental results highlight the potential of dolomite used as coarser fine aggregate in UHPC.
Drug candidates often cause an unwanted blockage of the potassium ion channel of the human ether-a-go-go-related gene (hERG). The blockage leads to long QT syndrome (LQTS), which is a severe ...life-threatening cardiac side effect. Therefore, a virtual screening method to predict drug-induced hERG-related cardiotoxicity could facilitate drug discovery by filtering out toxic drug candidates.
In this study, we generated a reliable hERG-related cardiotoxicity dataset composed of 2130 compounds, which were carried out under constant conditions. Based on our dataset, we developed a computational hERG-related cardiotoxicity prediction model. The neural network model achieved an area under the receiver operating characteristic curve (AUC) of 0.764, with an accuracy of 90.1%, a Matthews correlation coefficient (MCC) of 0.368, a sensitivity of 0.321, and a specificity of 0.967, when ten-fold cross-validation was performed. The model was further evaluated using ten drug compounds tested on guinea pigs and showed an accuracy of 80.0%, an MCC of 0.655, a sensitivity of 0.600, and a specificity of 1.000, which were better than the performances of existing hERG-toxicity prediction models.
The neural network model can predict hERG-related cardiotoxicity of chemical compounds with a high accuracy. Therefore, the model can be applied to virtual high-throughput screening for drug candidates that do not cause cardiotoxicity. The prediction tool is available as a web-tool at http://ssbio.cau.ac.kr/CardPred .
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Metal halide perovskites (MHPs) exhibit optoelectronic properties that are dependent on their ionic composition, and the feasible exploitation of these properties for device applications requires the ...ability to control the ionic composition integrated with the patterning process. Herein, the halide exchange process of MHP thin films directly combined with the patterning process via a vapor transport method is demonstrated. Specifically, the patterned arrays of CH3NH3PbBr3 (MAPbBr3) are obtained by stepwise conversion from polymer‐templated PbI2 thin films to CH3NH3PbI3 (MAPbI3), followed by halide exchange via precursor switching from CH3NH3I to CH3NH3Br. It is confirmed that the phase transformation from MAPbI3 patterns to MAPbBr3 shows time‐ and position‐dependences on the substrate during halide exchange following the solid‐solution model with Avrami kinetics. The photodetectors fabricated from the completely exchanged MAPbBr3 patterns display exceptional air stability and reversible detectivity from “apparent death” upon removing the adsorbed impurities, thereby suggesting the superior structural stability of perovskite patterns prepared through vapor‐phase halide exchange. The results demonstrate the potential of chemical vapor deposition patterning of MHP materials in multicomponent optoelectronic device systems.
An in situ vapor‐based halide exchange of the metal halide perovskite thin film patterns is demonstrated via stepwise conversion from PbI2 patterns to CH3NH3PbI3, directly followed by halide exchange via precursor switching (CH3NH3I → CH3NH3Br). Photodetector devices prepared from the completely exchanged CH3NH3PbBr3 exhibit remarkable stability to air exposure and reversible performance via Br passivation of grain boundaries.
•RA could be used as an internal curing agent for an AAS.•RA could reduce autogenous shrinkage.•Pore structure of RA influenced to internal curing efficiency.•Strength of AAS was not degraded by RA.
...This study aims to investigate the feasibility of recycled aggregates (RA) as an internal curing agent for an alkali activated slag (AAS) system. The physical and chemical characteristics of the aggregates were studied through various analytical techniques including X-ray diffraction, thermogravimetry, mercury intrusion porosimetry, and indirect alkalinity measurements. The compressive strength, degree of hydration, and autogenous and dry shrinkages of AAS generated with RA were measured and compared with those of AAS made using artificial lightweight aggregates. The use of RA can reduce the autogenous shrinkage of an AAS system without a decrease in compressive strength. The degree of hydration for AAS mortar was not increased by the addition of RA owing to the dilution effect of the alkali activator, which was caused by the additional water supplied from internal curing materials.
Non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (
) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, ...an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site.
CHRYSALIS is a phase I, open-label, dose-escalation, and dose-expansion study, which included a population with
Exon20ins NSCLC. The primary end points were dose-limiting toxicity and overall response rate. We report findings from the postplatinum
Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, ≥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5.
In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively.
Amivantamab, via its novel mechanism of action, yielded robust and durable responses with tolerable safety in patients with
Exon20ins mutations after progression on platinum-based chemotherapy.
In CheckMate 227, nivolumab plus ipilimumab prolonged overall survival (OS) versus chemotherapy in patients with tumor programmed death-ligand 1 (PD-L1) greater than or equal to 1% (primary end ...point) or less than 1% (prespecified descriptive analysis). We report results with minimum 4 years' follow-up.
Adults with previously untreated stage IV or recurrent NSCLC were randomized (1:1:1) to nivolumab plus ipilimumab, nivolumab, or chemotherapy (PD-L1 ≥1%); or to nivolumab plus ipilimumab, nivolumab plus chemotherapy, or chemotherapy (PD-L1 <1%). Efficacy included OS and other measures. Safety included timing and management of immune-mediated adverse events (AEs). A post hoc analysis evaluated efficacy in patients who discontinued nivolumab plus ipilimumab due to treatment-related AEs (TRAEs).
After 54.8 months' median follow-up, OS remained longer with nivolumab plus ipilimumab versus chemotherapy in patients with PD-L1 greater than or equal to 1% (hazard ratio = 0.76; 95% confidence interval: 0.65–0.90) and PD-L1 less than 1% (0.64; 0.51–0.81); 4-year OS rate with nivolumab plus ipilimumab versus chemotherapy was 29% versus 18% (PD-L1 ≥1%); and 24% versus 10% (PD-L1 <1%). Benefits were observed in both squamous and nonsquamous histologies. In a descriptive analysis, efficacy was improved with nivolumab plus ipilimumab relative to nivolumab (PD-L1 ≥1%) and nivolumab plus chemotherapy (PD-L1 <1%). Safety was consistent with previous reports. The most common immune-mediated AE with nivolumab plus ipilimumab, nivolumab, and nivolumab plus chemotherapy was rash; most immune-mediated AEs (except endocrine events) occurred within 6 months from start of treatment and resolved within 3 months after, mainly with systemic corticosteroids. Patients who discontinued nivolumab plus ipilimumab due to TRAEs had long-term OS benefits, as seen in the all randomized population.
At more than 4 years' minimum follow-up, with all patients off immunotherapy treatment for at least 2 years, first-line nivolumab plus ipilimumab continued to demonstrate durable long-term efficacy in patients with advanced NSCLC. No new safety signals were identified. Immune-mediated AEs occurred early and resolved quickly with guideline-based management. Discontinuation of nivolumab plus ipilimumab due to TRAEs did not have a negative impact on the long-term benefits seen in all randomized patients.
Brigatinib, a next-generation anaplastic lymphoma kinase (ALK) inhibitor, demonstrated superior progression-free survival (PFS) and improved health-related quality of life (QoL) versus crizotinib in ...advanced ALK inhibitor-naive ALK-positive non-small cell lung cancer (NSCLC) at first interim analysis (99 events; median brigatinib follow-up, 11.0 months) in the open-label, phase III ALTA-1L trial (ClinicalTrials.gov identifier: NCT02737501). We report results of the second prespecified interim analysis (150 events).
Patients with ALK inhibitor-naive advanced ALK-positive NSCLC were randomly assigned 1:1 to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. The primary end point was PFS as assessed by blinded independent review committee (BIRC). Investigator-assessed efficacy, blood samples for pharmacokinetic assessments, and patient-reported outcomes were also collected.
Two hundred seventy-five patients were randomly assigned (brigatinib, n = 137; crizotinib, n = 138). With median follow-up of 24.9 months for brigatinib (150 PFS events), brigatinib showed consistent superiority in BIRC-assessed PFS versus crizotinib (hazard ratio HR, 0.49 95% CI, 0.35 to 0.68; log-rank
< .0001; median, 24.0
11.0 months). Investigator-assessed PFS HR was 0.43 (95% CI, 0.31 to 0.61; median, 29.4
9.2 months). No new safety concerns emerged. Brigatinib delayed median time to worsening of global health status/QoL scores compared with crizotinib (HR, 0.70 95% CI, 0.49 to 1.00; log-rank
= .049). Brigatinib daily area under the plasma concentration-time curve was not a predictor of PFS (HR, 1.005 95% CI, 0.98 to 1.031;
= .69).
Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and QoL over crizotinib, making it a promising first-line treatment of ALK-positive NSCLC.
The LUX-Lung 3 study investigated the efficacy of chemotherapy compared with afatinib, a selective, orally bioavailable ErbB family blocker that irreversibly blocks signaling from epidermal growth ...factor receptor (EGFR/ErbB1), human epidermal growth factor receptor 2 (HER2/ErbB2), and ErbB4 and has wide-spectrum preclinical activity against EGFR mutations. A phase II study of afatinib in EGFR mutation-positive lung adenocarcinoma demonstrated high response rates and progression-free survival (PFS).
In this phase III study, eligible patients with stage IIIB/IV lung adenocarcinoma were screened for EGFR mutations. Mutation-positive patients were stratified by mutation type (exon 19 deletion, L858R, or other) and race (Asian or non-Asian) before two-to-one random assignment to 40 mg afatinib per day or up to six cycles of cisplatin plus pemetrexed chemotherapy at standard doses every 21 days. The primary end point was PFS by independent review. Secondary end points included tumor response, overall survival, adverse events, and patient-reported outcomes (PROs).
A total of 1,269 patients were screened, and 345 were randomly assigned to treatment. Median PFS was 11.1 months for afatinib and 6.9 months for chemotherapy (hazard ratio HR, 0.58; 95% CI, 0.43 to 0.78; P = .001). Median PFS among those with exon 19 deletions and L858R EGFR mutations (n = 308) was 13.6 months for afatinib and 6.9 months for chemotherapy (HR, 0.47; 95% CI, 0.34 to 0.65; P = .001). The most common treatment-related adverse events were diarrhea, rash/acne, and stomatitis for afatinib and nausea, fatigue, and decreased appetite for chemotherapy. PROs favored afatinib, with better control of cough, dyspnea, and pain.
Afatinib is associated with prolongation of PFS when compared with standard doublet chemotherapy in patients with advanced lung adenocarcinoma and EGFR mutations.
•Flowability and electrical properties of CNT/cement composites was compared.•Mechanical dispersion of CNTs was influenced by type of CNTs and flowability of mixture.•100–101 Ω·m for cement ...composites was obtained with 0.3 wt.%/cement of CNT.•Intuitive model of CNT dispersion on the resistance of cement composites was conducted.
The present study aims to understand the relationship between flowability and electrical properties of cement composites with mechanical dispersion of carbon nanotube (CNT) and to establish a guideline of mix proportioning for the CNT/cement composites with suitable workability and high electrical conductivity. In this study, mixtures composed of different mix proportions and CNT types were designed, and their flow diameter, electrical resistivity, basic mechanical properties in terms of strength and elastic modulus, and microscopic morphology were measured and evaluated. Intuitive and simple modeling was performed to quantitatively assess the effect of CNT dispersibility on conductivity. The results indicated that the flowability and resistivity of cement composites were significantly affected by the dispersibility of CNTs.
Here, we studied the triboelectric properties of structurally controlled laser-induced graphene (LIG) to clarify the key factors for improving the energy harvesting performance. With a facile ...defocusing method, the LIG morphology was modulated in porous LIG, in short carbon fiber combined LIG (SF-LIG) and in long carbon fiber-dominant LIG (LF-LIG). Through correlation analysis of the triboelectrification characteristic according to the material properties of LIG, it was found that asymmetric defects as well as the graphitic-N configuration within the fibrous LIG structure can significantly improve the triboelectric effectiveness by supplying trap sites and lowering the work function, respectively. The vertically aligned fibrous structure also increases the structural contact area, contributing to the improvement in the charge transfer efficiency. As a result, it was demonstrated that the long carbon fiber structure of LF-LIG can improve the performance by 130 times (512 mW m
−2
) compared with porous LIG-based triboelectric nanogenerators (TENGs) (3.9 mW m
−2
). As a feasible application, all LIG-based flexible triboelectric touch sensors are fabricated, which are composed of LF-LIG active matrices (4 × 4) and LIG electrodes through a one-step laser writing process. The demonstrated touch sensor independently addressed each pixel for tracking the location of the human touch, showing self-powering capabilities. This work presents a facile strategy for surface morphology modification of LIGs and investigates their triboelectric charging effect, which might promote the development of practical flexible TENGs for wearable electronic devices.
Here, we studied the triboelectric properties of structurally controlled laser-induced graphene (LIG) to clarify the key factors for improving the energy harvesting performance.
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