Patients with relapsed or refractory acute myeloid leukemia (AML) with mutations in the FMS-like tyrosine kinase 3 gene (
) infrequently have a response to salvage chemotherapy. Gilteritinib is an ...oral, potent, selective FLT3 inhibitor with single-agent activity in relapsed or refractory
-mutated AML.
In a phase 3 trial, we randomly assigned adults with relapsed or refractory
-mutated AML in a 2:1 ratio to receive either gilteritinib (at a dose of 120 mg per day) or salvage chemotherapy. The two primary end points were overall survival and the percentage of patients who had complete remission with full or partial hematologic recovery. Secondary end points included event-free survival (freedom from treatment failure i.e., relapse or lack of remission or death) and the percentage of patients who had complete remission.
Of 371 eligible patients, 247 were randomly assigned to the gilteritinib group and 124 to the salvage chemotherapy group. The median overall survival in the gilteritinib group was significantly longer than that in the chemotherapy group (9.3 months vs. 5.6 months; hazard ratio for death, 0.64; 95% confidence interval CI, 0.49 to 0.83; P<0.001). The median event-free survival was 2.8 months in the gilteritinib group and 0.7 months in the chemotherapy group (hazard ratio for treatment failure or death, 0.79; 95% CI, 0.58 to 1.09). The percentage of patients who had complete remission with full or partial hematologic recovery was 34.0% in the gilteritinib group and 15.3% in the chemotherapy group (risk difference, 18.6 percentage points; 95% CI, 9.8 to 27.4); the percentages with complete remission were 21.1% and 10.5%, respectively (risk difference, 10.6 percentage points; 95% CI, 2.8 to 18.4). In an analysis that was adjusted for therapy duration, adverse events of grade 3 or higher and serious adverse events occurred less frequently in the gilteritinib group than in the chemotherapy group; the most common adverse events of grade 3 or higher in the gilteritinib group were febrile neutropenia (45.9%), anemia (40.7%), and thrombocytopenia (22.8%).
Gilteritinib resulted in significantly longer survival and higher percentages of patients with remission than salvage chemotherapy among patients with relapsed or refractory
-mutated AML. (Funded by Astellas Pharma; ADMIRAL ClinicalTrials.gov number, NCT02421939.).
Accurate analysis of specific biomarkers in clinical serum is essential for early diagnosis and treatment of cancer. Here, a surface-enhanced Raman scattering (SERS)-based immunoassay, using magnetic ...beads and SERS nano tags, was developed for the determination of free to total (f/t) prostate specific antigen (PSA) ratio to improve the diagnostic performance of prostate cancer. To assess the clinical applicability of the proposed method, SERS-based assays for the simultaneous detection of dual PSA markers, free PSA (f-PSA) and complexed PSA (c-PSA), were performed for clinical samples in the gray zone between 4.0 and 10.0 ng/mL. Our assay results for f/t PSA ratio showed a good linear correlation with those measured using the electrochemiluminescence (ECL) system installed in the clinical laboratory of the University Hospital. In addition, the simultaneous assay provided better precision than parallel assays for the detection of f-PSA and c-PSA in 13 clinical serum samples. Therefore, our SERS-based assay for simultaneous detection of dual PSA markers in clinical fluids has strong potential for application in the accurate diagnosis of prostate cancer.
This study investigated the mechanical properties of ultra high performance fiber reinforced cementitious composites (UHPFRCC) with four different fiber volume fractions (Vf=1%, 2%, 3%, and 4%) ...within an identical mortar matrix. The higher amount of fiber resulted in an improvement of load carrying capacity and elastic modulus in compression up to 3vol.% of fibers. A higher pullout strength was obtained from the inclusion of fibers in the matrix, and 2vol.% of fibers provided the best performance in all aspects of fiber pullout behavior including average and equivalent bond strengths and pullout energy. The flexural strength was pseudo-linearly increased with increase in fiber volume fraction, despite an insignificant difference in the first cracking load. Furthermore, a bi-linear softening curve for UHPFRCC was suggested based on the result of inverse analysis, and it was verified through comparison with the experimental data.
•An open architecture agent-based modeling (ABM) is introduced to predict occupant behaviors.•Simulation coupling is used to accounts for multiple occupant behaviors.•Occupant behaviors impact both ...comfort and energy performances.•The simulation methodology is applicable to various climates and building typologies.
A new simulation methodology using agent-based modeling is presented to simulate multiple, occupant behaviors in a commercial building. The purpose of the agent-based modeling is to mimic a real-world occupant: an autonomous agent that interacts with both its environment and other agents, and makes behavior decisions based on the level of its thermal comfort. First, individual agent behaviors are simulated; second, the results are aggregated to explain the behavioral phenomena of the building as a whole. Using simulation coupling, the behavior impact on the thermal conditions and, energy use can be scrutinized. A simple simulation experiment was conducted to see (1) how an agent considers five behaviors (adjust clothing level, adjust activity level, window use, blind use, and space heater/personal fan use behaviors) to achieve its comfort goal, and (2) how an agent adapts to the dynamic thermal changes in the space to optimize both comfort and energy savings.
Core/shell upconverting nanoparticles (UCNPs) of NaGdF4:Er3+,Yb3+/NaGdF4 (see figure) are shown to serve as a multimodal imaging probe that works for both background‐free optical imaging and magnetic ...resonance imaging (MRI). The nonblinking and nonbleaching properties of UCNPs can contribute to minimization of possible artifacts in long‐term imaging experiments. Owing to Gd3+ ions in the host matrix, contrast is enhanced in T1‐weighted MRI.
We report a SERS-based competitive immunoassay technique for the early diagnosis of acute myocardial infarction (AMI). Simultaneous quantification of the dual cardiac markers, CK-MB and troponin I, ...was achieved by single wavelength excitation.
Acute kidney injury (AKI) after liver transplantation has been reported to be associated with increased mortality. Recently, machine learning approaches were reported to have better predictive ...ability than the classic statistical analysis. We compared the performance of machine learning approaches with that of logistic regression analysis to predict AKI after liver transplantation. We reviewed 1211 patients and preoperative and intraoperative anesthesia and surgery-related variables were obtained. The primary outcome was postoperative AKI defined by acute kidney injury network criteria. The following machine learning techniques were used: decision tree, random forest, gradient boosting machine, support vector machine, naïve Bayes, multilayer perceptron, and deep belief networks. These techniques were compared with logistic regression analysis regarding the area under the receiver-operating characteristic curve (AUROC). AKI developed in 365 patients (30.1%). The performance in terms of AUROC was best in gradient boosting machine among all analyses to predict AKI of all stages (0.90, 95% confidence interval CI 0.86⁻0.93) or stage 2 or 3 AKI. The AUROC of logistic regression analysis was 0.61 (95% CI 0.56⁻0.66). Decision tree and random forest techniques showed moderate performance (AUROC 0.86 and 0.85, respectively). The AUROC of support the vector machine, naïve Bayes, neural network, and deep belief network was smaller than that of the other models. In our comparison of seven machine learning approaches with logistic regression analysis, the gradient boosting machine showed the best performance with the highest AUROC. An internet-based risk estimator was developed based on our model of gradient boosting. However, prospective studies are required to validate our results.
Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections and hospitalization in infants and young children. Here, we analyzed the genetic diversity of RSV using ...partial G gene sequences in 84 RSV-A and 78 RSV- B positive samples collected in Seoul, South Korea, for 10 consecutive years, from 2010 to 2019. Our phylogenetic analysis revealed that RSV-A strains were classified into either the ON1 (80.9%) or NA1 (19.0%) genotypes. On the other hand, RSV-B strains demonstrated diversified clusters within the BA genotype. Notably, some sequences designated as BA-SE, BA-SE1, and BA-DIS did not cluster with previously identified BA genotypes in the phylogenetic trees. Despite this, they did not meet the criteria for the assignment of a new genotype based on recent classification methods. Selection pressure analysis identified three positive selection sites (amino acid positions 273, 274, and 298) in RSV-A, and one possible positive selection site (amino acid position 296) in RSV-B, respectively. The mean evolutionary rates of Korean RSV-A from 1999 to 2019 and RSV-B strains from 1991 and 2019 were estimated at 3.51 × 10-3 nucleotides (nt) substitutions/site/year and 3.32 × 10-3 nt substitutions/site/year, respectively. The population dynamics in the Bayesian skyline plot revealed fluctuations corresponding to the emergence of dominant strains, including a switch of the dominant genotype from NA1 to ON1. Our study on time-scaled cumulative evolutionary analysis contributes to a better understanding of RSV epidemiology at the local level in South Korea.
The use of porous three-dimensional (3D) composite scaffolds has attracted great attention in bone tissue engineering applications because they closely simulate the major features of the natural ...extracellular matrix (ECM) of bone. This study aimed to prepare biomimetic composite scaffolds via a simple 3D printing of gelatin/hyaluronic acid (HA)/hydroxyapatite (HAp) and subsequent biomineralization for improved bone tissue regeneration. The resulting scaffolds exhibited uniform structure and homogeneous pore distribution. In addition, the microstructures of the composite scaffolds showed an ECM-mimetic structure with a wrinkled internal surface and a porous hierarchical architecture. The results of bioactivity assays proved that the morphological characteristics and biomineralization of the composite scaffolds influenced cell proliferation and osteogenic differentiation. In particular, the biomineralized gelatin/HA/HAp composite scaffolds with double-layer staggered orthogonal (GEHA20-ZZS) and double-layer alternative structure (GEHA20-45S) showed higher bioactivity than other scaffolds. According to these results, biomineralization has a great influence on the biological activity of cells. Hence, the biomineralized composite scaffolds can be used as new bone scaffolds in bone regeneration.
Summary
Real‐world outcomes of daratumumab monotherapy (DM) for relapsed/refractory multiple myeloma (RRMM) have remained unclear. We conducted a multicentre retrospective study of 107 patients ...receiving DM for RRMM. The cohort included 64 trial‐unfit patients whose characteristics could not meet inclusion criteria in two previous clinical trials (GEN501 and SIRIUS). The overall response rate (ORR), and median first and second progression‐free survival (PFS1 and PFS2) and overall survival were 42·1%, and 3·6, 8·1 and 11·9 months, respectively. Refractoriness to carfilzomib and/or lenalidomide, and neutropenia (<1.0 × 109/l) resulted in poorer ORRs. An Eastern Cooperative Oncology Group Performance Status of ≥3, neutropenia (<1.0 × 109/l), thrombocytopenia (<75 × 109/l), and renal failure (glomerular filtration rate of <20 ml/min/1·73 m2) were associated with poor PFS1 and PFS2 in respective univariate analysis. The modified trial‐unfit group, based on the above factors, showed significantly negative impacts on PFS1 and PFS2 (hazard ratio 2·823 and 3·677, all P < 0·001) in multivariate analysis despite having a 34% ORR. Fatal infections occurred more often in the modified trial‐unfit group than in the others (16·1% vs. 4·3%; P = 0·099). Despite failure of DM, subsequent therapy with pomalidomide‐based therapy or carfilzomib‐dexamethasone provided a 66·6% ORR. Real‐world DM showed favourable efficacies for RRMM and, potentially, additional benefits with subsequent therapies. However, characteristics corresponding with trial‐unfitness might offset the efficacy of DM.
PDF
