A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapi...
详细信息
A major limiting factor in the success of chimeric antigen receptor (CAR) T cell therapy for the treatment of solid tumors is targeting tumor antigens also found on normal tissues. CAR T cells against GD2 induced rapid, fatal neurotoxicity because of CAR recognition of GD2+ normal mouse brain tissue. To improve the selectivity of the CAR T cell, we engineered a synthetic Notch receptor that selectively expresses the CAR upon binding to P-selectin, a cell adhesion protein overexpressed in tumor neovasculature. These tumor microenvironment actuated T (MEAT) cells ameliorated T cell infiltration in the brain, preventing fatal neurotoxicity while maintaining antitumor efficacy. We found that conditional CAR expression improved the persistence of tumor-infiltrating lymphocytes because of enhanced metabolic fitness of MEAT cells and the infusion of a less differentiated product. This approach increases the repertoire of targetable solid tumor antigens by restricting CAR expression and subsequent killing to cancer cells only and provides a proof-of-concept model for other targets.
BackgroundMobility disability (MD) manifests as walking dysfunction and postural instability in more than 90% of people with multiple sclerosis (MS) within 10 years of disease onset. Disease-modifying pharmacotherapie...
BackgroundMobility disability (MD) manifests as walking dysfunction and postural instability in more than 90% of people with multiple sclerosis (MS) within 10 years of disease onset. Disease-modifying pharmacotherapies reduce rates of relapses and new lesions and slow disease progression, but ongoing decline in MD can persist or result from secondary, symptomatic pharmacotherapies. This systematic review focuses on symptomatic pharmacotherapies that potentially impact markers of MD in ***/Medline, Google Scholar, and Scopus were searched between January 1990 and December 2024. Eligible studies were included on the basis of the following criteria: (1) randomized, placebo-controlled trials (RCTs);(2) confirmed MS diagnosis;(3) one MD-related outcome;and (4) one symptomatic pharmacotherapy;OR (5) multiple doses of a symptomatic pharmacotherapy. Results were uploaded to Rayyan: Intelligent Systematic Review software and screened by two blinded reviewers for eligibility. Risk of bias was assessed using the PEDRo Scale for quality *** review included 23 RCTs (all RCTs scored good-to-excellent on PEDRo Scale);13 RCTs examined fampridine (4-aminopyridine) for its direct effects on MD, and 10 RCTs assessed indirect effects of symptomatic pharmacotherapies, including cannabinoids (n = 9), and baclofen (n = 1) on MD. The MD outcomes included gait (25-foot walk [T25FW], kinetics, and kinematics), community mobility (12-item MS Walking Scale [MSWS-12]), endurance (6-min walk [6MW]), balance (Berg Balance Scale [BBS], Dynamic Gait Index [DGI], Six-Spot Step Test, posturography, and falls), and functional mobility (Timed Up and Go [TUG] and 5 Times Sit-to-Stand [5STS]). Fampridine significantly improved gait (T25FW, MSWS-12), endurance (6MW), and functional mobility (5STS, TUG), with the largest effect on gait speed;changes in balance were inconclusive. Indirect pharmacotherapies, specifically cannabinoids mainly reduced spasticity (Modified Ashwort
ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoan...
ObjectiveSystemic sclerosis (SSc) is a rare but severe autoimmune disease characterized by immune dysregulation, fibrosis, and vasculopathy. Although previous studies have highlighted the presence of functional autoantibodies targeting the angiotensin II receptor type 1 (AT1) and endothelin-1 type A receptor (ETAR), leading to autoantibody-mediated receptor stimulation and subsequent activation of endothelial cells (ECs), a comprehensive understanding of the direct interaction between these autoantibodies and their receptors is currently lacking. Moreover, existing data confirming the presence of these autoantibodies in SSc often rely on similar methodologies and assays. Our aim was to replicate previous findings and to investigate the functional effects of IgG derived from patients with SSc (SSc IgG) on AT1 and ETAR signaling, the downstream EC response, and the presence of AT1-binding autoantibodies in *** polymerase chain reaction and cytokine enzyme-linked immunosorbent assay, alongside a real-time cell analyzer, were used to assess receptor-specific functional characteristics of purified SSc IgG (n = 18). Additionally, a novel protein capture assay using solubilized epitope-tagged AT1 was developed to detect AT1-binding autoantibodies in plasma samples from patients with SSc (n = 28) and healthy donors (n = 14).ResultsNo evidence for EC activation in an AT1- or ETAR-dependent manner was revealed. Furthermore, stimulation with SSc IgG did not induce receptor activation or alter G protein-coupled receptor signaling on agonist stimulation in a model with receptor overexpression. Lastly, no AT1-binding autoantibodies were detected in plasma samples from patients with SSc when using epitope-tagged solubilized ***, our study did not provide evidence to support the presence of AT1- or ETAR-activating autoantibodies in purified SSc IgG or AT1-binding autoantibodies in the circulation of patients with SSc.
In this era of true wireless stereo, in-ear earphones have become widely used. Critical factors for determining the frequency response of earphones not only include the microspeaker and the design of the chamber, but ...
详细信息
ISBN:
(纸本)9781665491303
In this era of true wireless stereo, in-ear earphones have become widely used. Critical factors for determining the frequency response of earphones not only include the microspeaker and the design of the chamber, but also the ventilation material that is attached to the front and rear chamber vents. Therefore, accurately and effectively grasping the effects of ventilation materials on the acoustic characteristics of in-ear earphones are currently the focuses of acoustic design. In this paper, a prediction model of the acoustic characteristics of in-ear earphones was constructed using the commercial finite element method software, COMSOL Multiphysics, and the changes in frequency response between the front and rear vents with ventilation materials of different specific airflow resistances. Finally, simulations were conducted to complete the study on the influence of ventilation materials on acoustic performance. The results showed that by importing the parameters measured using ventilation material measurement equipment, designed in compliance with international standards, into the validated simulation model, the effects of ventilation materials of various specific airflow resistances on the sound pressure level (SPL) curve can be effectively predicted after their attachment to in-ear earphone. In particular, with the measurement system and prediction model used in this paper, the error of frequency shift was controlled at 2% and difference in sound pressure value was controlled to 9%. In addition, by attaching meshes of different specific airflow resistances to the front and rear vents, the effect of the ventilation material was influenced by the Helmholtz Resonator effect generated by the chamber structure, which led to changes in the curve. The contribution of this paper is not only in the facilitation of the selection of ventilation materials for in-ear earphones in future designs, but also the selection of different types of ventilation materials according to th
The dynamic substructuring design describes the dynamic responses in the modal, frequency and physical domains using coupling methods at joint nodes. This paper presents dynamic structuring methods to modify existing ...
详细信息
The dynamic substructuring design describes the dynamic responses in the modal, frequency and physical domains using coupling methods at joint nodes. This paper presents dynamic structuring methods to modify existing substructuring methods by merging the concept of interfacial forces in the satisfaction of compatibility conditions at joint nodes. The algorithms correspond to a type of model reduction approaches that use a few modes of substructures with the assumption of pseudo-masses at the joint nodes of the substructures. It was verified through numerical examples that the pseudo-masses rarely affected the dynamic responses of the synthesized structure. A frequency response function-based substructuring method was derived by applying interface forces at joint nodes to frequency response function (FRF). The proposed dynamic substructuring methods are expressed in explicit forms for synthesizing substructures without any numerical schemes. The validity of the proposed method was illustrated using two numerical examples. The limitations of this study are evaluated using numerical examples.
We report the in vitro characterization and in vivo evaluation of a novel Zr-89-labeled radioimmunoconjugate synthesized using a site-selective bioconjugation strategy based on the oxidation of tyrosinase residues exp...
详细信息
We report the in vitro characterization and in vivo evaluation of a novel Zr-89-labeled radioimmunoconjugate synthesized using a site-selective bioconjugation strategy based on the oxidation of tyrosinase residues exposed by the deglycosylation of the IgG and the subsequent strain-promoted oxidation-controlled 1,2-quinone cycloaddition between these amino acids and trans-cyclooctene-bearing cargoes. More specifically, we site-selectively modified a variant of the A33 antigen-targeting antibody huA33 with the chelator desferrioxamine (DFO), thereby producing an immunoconjugate (DFO-(SPOCQ)huA33) with equivalent antigen binding affinity to its parent immunoglobulin but attenuated affinity for the Fc gamma RI receptor. This construct was subsequently radiolabeled with [Zr-89]Zr4+ to create a radioimmunoconjugate - [Zr-89]Zr-DFO-(SPOCQ)huA33 - in high yield and specific activity that exhibited excellent in vivo behavior in two murine models of human colorectal carcinoma.
A theoretical study of the interaction between melamine and CO2 was carried out using density functional theory (DFT) with the B3LYP-D3-(BJ)/aug-cc-pVTZ level of theory. The presence of anions interacting with melamin...
详细信息
A theoretical study of the interaction between melamine and CO2 was carried out using density functional theory (DFT) with the B3LYP-D3-(BJ)/aug-cc-pVTZ level of theory. The presence of anions interacting with melamine transforms the weakly bonded tetrel complexes into adducts. Thus, melamine acts as an FLP (frustrated Lewis pair) with acid groups (NHs as hydrogen bond donors) and a base group (N of the triazine ring). The application of the relative energy gradient formalism (REG) along the reaction coordinate has demonstrated that the ability of the melamine-anion systems to capture CO2 is linked to its capacity to polarize the CO2 molecule. These results have been confirmed by placing the melamine:CO(2 )complex in a uniform electric field with different strengths.
Serious games offer a magnificent potential for developing future skills along with the 21st-century learning ecosystem. A close nexus between the design and effectiveness of serious games is still argued. In this reg...
详细信息
Serious games offer a magnificent potential for developing future skills along with the 21st-century learning ecosystem. A close nexus between the design and effectiveness of serious games is still argued. In this regard, the current study provides a systematic literature review on serious game design approaches with a special focus on future skill development. A systematic review protocol, including planning, conducting, and reporting stages, is followed to comprehensively interpret the existing studies. Applying quality controls, 32 serious game studies which include a practical serious game design approach are selected. For providing a more systematic analysis, these approaches are then categorized based on the intended outcome of the serious game that the approach aims to facilitate. It is found that 8 (25%) of these design approaches support at least one future skills, among which problem-solving as well as collaboration and teamwork are the most commonly supported ones. It is also discovered that clear goals and interactivity, used in 6 (75%) and 5 (63%) of the 8 design approaches respectively, are the most commonly implemented game design elements. Considering the significant literature gap on the implementation of serious games for future skills development, this study consequently provides valuable insights for the game designers, software developers, educational technology researchers, and engineering educators in various domains.
This paper analyzes the relationships between the circulation regimes of the 500-hPa height (z500) and 250-hPa zonal winds (u250) in the Pacific-North America region during boreal winter, and the 45-day Northern Hemis...
详细信息
This paper analyzes the relationships between the circulation regimes of the 500-hPa height (z500) and 250-hPa zonal winds (u250) in the Pacific-North America region during boreal winter, and the 45-day Northern Hemisphere oscillation in z500. The regimes were calculated using a k-means clustering applied to the leading 12 principal components of the combined z500-u250 anomaly fields. We divided the oscillation into eight arbitrary phases. The oscillation phase z500 composite maps are spatially well correlated with regime z500 composites: phases 1-2 are best correlated with the Arctic Low, phases 3-5 are best correlated with the Pacific Trough, phase 6 is best correlated with the Arctic High, and phases 7-8 are best correlated with the Alaskan Ridge. We found that these correlations are generally consistent with the regimes that tend to occur during the individ-ual oscillation phases: the Arctic Low occurs above significance in phases 1-2, the Pacific Trough occurs above significance in phase 3, and Alaskan Ridge occurs above significance in phases 7-8. Therefore, the oscillation has a preferred order with respect to the regimes. The regime transitions indicate a pattern that moves through the Pacific Wavetrain, a regime that appears for k 5 5 as a mean state. Transitions out of this regime into different regimes are preferred in different phases of the oscillation. These results imply a possible enhancement to regime prediction using the low-frequency oscillations in combination with *** STATEMENT: Subseasonal prediction, weather forecasting in the 2-4-week range, is important for many parts of society, e.g., water managers, emergency response units, and farmers. However, current prediction skill in this time range is low. This paper performs an initial analysis of a possible method to increase weather statistic prediction skill beyond 10 days in the winter for the Pacific-North America region. This is done by combining two ways of looking at large
暂无评论