Search Results (1,501)

Cancer is a major global health issue, with rising incidence rates highlighting the urgent need for more effective treatments. Despite advances in cancer therapy, challenges such as adverse effects and limitations of existing treatments remain. Immunotherapy, which harnesses the body’s immune system to target cancer cells, offers promising solutions. Gamma delta (γδ) T cells are noteworthy due to their potent ability to kill various cancer cells without needing conventional antigen presentation. Recent studies have focused on the role of γδ T cells in α-galactosylceramide (α-GalCer)-mediated immunity, opening new possibilities for cancer immunotherapy. We engineered humanized T cell receptor (HuTCR)-T1 γδ mice by replacing mouse sequences with human counterparts. This study investigates the cytotoxic activity of humanized γδ T cells against several human cancer cell lines (A431, HT-29, K562, and Daudi) in vitro, aiming to elucidate mechanisms underlying their anticancer efficacy. Human cancer cells were co-cultured with humanized γδ T cells, with and without α-GalCer, for 24 h. The humanized γδ T cells showed enhanced cytotoxicity across all tested cancer cell lines compared to wild-type γδ T cells. Additionally, γδ T cells from HuTCR-T1 mice exhibited higher levels of anticancer cytokines (IFN-γ, TNF-α, and IL-17) and Granzyme B, indicating their potential as potent mediators of anticancer immune responses. Blocking γδ T cells’ cytotoxicity confirmed their γδ-mediated function. These findings represent a significant step in preclinical development of γδ T cell-based cancer immunotherapies, providing insights into their mechanisms of action, optimization of therapeutic strategies, and identification of predictive biomarkers for clinical application. Full article

In this study, growth mechanisms are proposed to understand how banded dendritic crystal aggregates in poly(1,4-butylene adipate) (PBA) transform into straight dendrites upon dilution with a large quantity of poly(ethylene oxide) (PEO) (25–90 wt.%). In growth packing, crystal plates are deformed in numerous ways, such as bending, scrolling, and twisting in self-assembly, into final aggregated morphologies of periodic bands or straight dendrites. Diluting PBA with a significant amount of PEO uncovers intricate periodic banded assemblies, facilitating better structural analysis. Both circularly banded and straight dendritic PBA aggregates have similar basic lamellar patterns. In straight dendritic PBA spherulites, crystal plates can twist from edge-on to flat-on, similar to those in ring-banded spherulites. Therefore, twists—whether continuous or discontinuous—are not limited to the conventional models proposed for classical periodic-banded spherulites. Thus, it would not be universally accurate to claim that the periodic circular bands observed in polymers or small-molecule compounds are caused by continuous lamellar helix twists. Straight dendrites, which do not exhibit optical bands, may also involve alternate crystal twists or scrolls during growth. Iridescence tests are used to compare the differences in crystal assemblies of straight dendrites vs. circularly banded PBA crystals. Full article

Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed disease face poor long-term survival odds. Topoisomerase 1 (TOP1) inhibitors are commonly used therapeutics in ES relapse regimens. Methods: In this work, we used a genome-wide CRISPR knockout library screen to identify the deletion of the TOP1 gene as a mechanism for resistance to topoisomerase 1 inhibitors. Using isogenic cell line models, we performed a high-throughput small-molecule screen to discover a small molecule, GNF-7, which had an IC50 that was 10-fold lower in TOP1-deficient cells when compared to the wild-type cells. Results: The characterization of GNF-7 demonstrated the molecule was highly active in the inhibition of CSK, p38α, EphA2, Lyn, and ZAK and specifically downregulated genes induced by the EWS::FLI1 fusion oncoprotein. Conclusions: Together, these results suggest that GNF-7 or small molecules with a similar kinase profile could be effective treatments for ES patients in combination with TOP1 inhibitors or for those patients who have developed resistance to TOP1 inhibitors. Full article

The integration of unmanned aerial vehicle (UAV) remote sensing and deep learning has emerged as a highly effective strategy for inventorying forest resources. However, the spatiotemporal variability of forest environments and the scarcity of annotated data hinder the performance of conventional supervised deep-learning models. To overcome these challenges, this study has developed efficient tree (ET), a semi-supervised tree detector designed for forest scenes. ET employed an enhanced YOLO model (YOLO-Tree) as a base detector and incorporated a teacher–student semi-supervised learning (SSL) framework based on pseudo-labeling, effectively leveraging abundant unlabeled data to bolster model robustness. The results revealed that SSL significantly improved outcomes in scenarios with sparse labeled data, specifically when the annotation proportion was below 50%. Additionally, employing overlapping cropping as a data augmentation strategy mitigated instability during semi-supervised training under conditions of limited sample size. Notably, introducing unlabeled data from external sites enhances the accuracy and cross-site generalization of models trained on diverse datasets, achieving impressive results with F1, mAP50, and mAP50-95 scores of 0.979, 0.992, and 0.871, respectively. In conclusion, this study highlights the potential of combining UAV-based RGB imagery with SSL to advance tree species identification in heterogeneous forests. Full article

In 2022, consecutive sweeps of highly transmissible SARS-CoV-2 Omicron-derived lineages (B.1.1.529*) maintained viral transmission despite extensive antigen exposure from both vaccinations and infections. To better understand Omicron variant emergence in the context of the dynamic fitness landscape of 2022, we aimed to explore putative drivers behind SARS-CoV-2 lineage replacements. Variant fitness is determined through its ability to either outrun previously dominant lineages or more efficiently circumvent host immune responses to previous infections and vaccinations. By analyzing data collected through our local genomic surveillance program from Connecticut, USA, we compared emerging Omicron lineages’ growth rates, estimated infections, effective reproductive rates, average viral copy numbers, and likelihood for causing infections in recently vaccinated individuals. We find that newly emerging Omicron lineages outcompeted dominant lineages through a combination of enhanced viral shedding or advanced immune escape depending on the population-level exposure state. This analysis integrates individual-level sequencing data with demographic, vaccination, laboratory, and epidemiological data and provides further insights into host–pathogen dynamics beyond public aggregate data. Full article

Model-Based Systems Engineering (MBSE) has gained significant attention from both industry and academia as an effective approach to managing product complexity. Despite its progress, current MBSE concepts, tools, languages, and methodologies face notable challenges in industrial applications, particularly in addressing design variability, ensuring model consistency, and enhancing operational efficiency. Based on the authors’ industry observations and literature analysis, this paper identifies the primary limitations of traditional MBSE, and introduces MBSE 2.0, a next-generation evolution characterized by comprehensive, integrated, and intelligent features. Key enabling technologies, such as model governance, integrated design methods, and AI-enhanced system design, are explored in detail. Additionally, several preliminary explorations were introduced under the guidance of the MBSE 2.0 philosophy. This study introduces the MBSE 2.0 concept to stimulate discussion and guide future efforts in academia and industry, emphasizing key advancements and highlighting several key and pressing perspectives to alleviate current limitations in industrial practice. Full article

Chronic ethanol use can lead to alcoholic cardiomyopathy (ACM), while the impact on the molecular and cellular aspects of the myocardium is unclear. Accordingly, male Sprague-Dawley rats were exposed to an ethanol-containing diet for 16 weeks and compared with a control group that was fed an isocaloric diet. Histological measurements from H&E slides revealed no significant differences in cell size. A proteomic approach revealed that alcohol exposure leads to enhanced mitochondrial lipid metabolism, and electron microscopy revealed impairments in mitochondrial morphology/density. Cardiac myosin purified from the hearts of ethanol-exposed animals demonstrated a 15% reduction in high-salt ATPase activity, with no significant changes in the in vitro motility and low-salt ATPase or formation of the super-relaxed (SRX) state. A protein carbonyl assay indicated a 20% increase in carbonyl incorporation, suggesting that alcohol may impact cardiac myosin through oxidative stress mechanisms. In vitro oxidation of healthy cardiac myosin revealed a dramatic decline in ATPase activity and in vitro motility, demonstrating a link between myosin protein oxidation and myosin mechanochemistry. Collectively, this study suggests alcohol-induced metabolic remodeling may be the initial insult that eventually leads to defects in the contractile machinery in the myocardium of ACM hearts. Full article

Pulmonary embolism (PE) is an under-recognised yet serious complication in patients with acute ischaemic stroke (AIS), contributing significantly to morbidity and mortality. The interplay of traditional risk factors—such as immobility, endothelial dysfunction, and hypercoagulability—with AIS-specific conditions, including atrial fibrillation, malignancy, and reperfusion therapies, complicates both diagnosis and management. Despite available prophylactic strategies, including low-molecular-weight heparin and intermittent pneumatic compression, their use remains limited by bleeding concerns and a lack of tailored guidelines. This review synthesises the current evidence on the incidence, risk factors, pathophysiology, diagnostic approaches, and preventive strategies for PE in AIS, identifying critical gaps in risk stratification and clinical decision-making. We propose a novel mechanistic framework—the Brain–Lung Thromboinflammatory Axis Hypothesis—which posits that stroke-induced systemic inflammation, neutrophil extracellular trap (NET) formation, and pulmonary endothelial activation may drive in situ pulmonary thrombosis independent of deep vein thrombosis. This conceptual model highlights new diagnostic and therapeutic targets and underscores the need for stroke-specific VTE risk calculators, biomarker-guided prophylaxis, and prospective trials to optimise prevention and outcomes in this vulnerable population. Full article

With the ongoing development of lightweight automobiles, research on new aluminum alloys and welding technology has gained significant attention. Friction stir welding (FSW) is a solid-state joining technique for welding aluminum alloys without melting. In this study, novel squeeze-cast Al-Si-Mg-Fe-Zn alloys with different Zn contents (0, 3.4, 6.5, and 8.3 wt%) were friction stir welded (FSWed) at a translational speed of 200 mm/min and a rotational speed of 800 rpm. These parameters were chosen based on the observations of visually sound welds, defect-free and fine-grained microstructures, homogeneous secondary phase distribution, and low roughness. Zn can affect the microstructure of Al-Si-Mg-Fe-Zn alloys, including the grain size and the content of secondary phases, leading to different mechanical and corrosion behavior. Adding different Zn contents with Mg forms the various amount of MgZn₂, which has a significant strengthening effect on the alloys. Softening observed in the weld zones of the alloys with 0, 3.4, and 6.5 wt% Zn is primarily attributed to the reduction in Kernel Average Misorientation (KAM) and a decrease in the Si phase and MgZn₂. Consequently, the mechanical strengths of the FSWed joints are lower as compared to the base material. Conversely, the FSWed alloy with 8.3 wt% Zn exhibited enhanced mechanical properties, with hardness of 116.3 HV_0.2, yield strength (YS) of 184.4 MPa, ultimate tensile strength (UTS) of 226.9 MP, percent elongation (EL%) of 1.78%, and a strength coefficient exceeding 100%, indicating that the joint retains the strength of the as-cast one, due to refined grains and more uniformly dispersed secondary phases. The highest corrosion resistance of the FSWed alloy with 6.5%Zn is due to the smallest grain size and KAM, without MgZn₂ and the highest percentage of {111} texture (24.8%). Full article

Background/Objectives: Ketorolac is commonly used for pain management after orthopedic surgery, but concerns regarding its effects on postoperative complications remain. This study evaluates the impact of ketorolac use on short- and long-term outcomes in adult patients undergoing uncemented primary total hip arthroplasty (THA), where implant stability relies on biological fixation through bone ingrowth into a porous-coated prosthesis rather than bone cement. Methods: A retrospective cohort study was conducted using the TriNetX Research Network. Patients aged 18 years or older who underwent uncemented primary THA between 1 January 2004 and 1 January 2024 were included. Two cohorts were compared: those who received ketorolac on the day of or within one week of surgery and those who did not. Cohorts were propensity score-matched. Outcomes were assessed at 30 days, 1 year, and 5 years postoperatively. Results: At 30 days, ketorolac use was associated with significantly lower risks of transfusion (RR: 0.6, p < 0.01). However, it was linked to higher rates of acute posthemorrhagic anemia (RR: 1.2, p < 0.01) and periprosthetic fracture (RR: 1.4, p < 0.01). At 1 year, ketorolac use was associated with reduced risks of death (RR: 0.8, p < 0.01) and transfusion (RR: 0.7, p < 0.01), but increased risks of acute posthemorrhagic anemia (RR: 1.2, p < 0.01), deep surgical site infection (SSI) (RR: 1.8, p = 0.01), superficial SSI (RR: 1.9, p < 0.01), periprosthetic joint infection (RR: 1.1, p < 0.01), wound dehiscence (RR: 1.2, p < 0.01), periprosthetic mechanical complication (RR: 1.2, p < 0.01), and periprosthetic fracture (RR: 1.5, p < 0.01). Conclusions: Our findings highlight the complex risk profile of ketorolac in uncemented THA patients and suggest that clinicians should carefully consider individual patient factors and engage in shared decision-making when counseling patients on the use of ketorolac in the perioperative setting. Full article

Therapeutic plasma exchange (TPE) is a blood purification technique which functions to remove pathological plasma constituents such as autoantibodies, inflammatory cytokines, immune complexes, and extracellular vesicles (EVs) that contribute to a range of disease states. In this review, we examine current and emerging indications for TPE across cardiovascular, metabolic, neurological, inflammatory, and oncological diseases. We cover emerging preclinical animal models and new applications, emphasizing the roles of cellular signaling and EV biology in mediating plasma functions, and discuss unique therapeutic “windows of opportunity” offered by TPE. We conclude that TPE is underutilized in both preventative and precision medicine, and that next generation TPE therapies will involve personalized plasma biomarker and modulation feedback, with synergistic plasma infusion therapies to mitigate age associated disease and promote tissue rejuvenation. Full article

Objective: This study aims to investigate the feasibility of an online music therapy protocol for individuals previously diagnosed with COVID-19, focusing on their perceptions of their respiratory symptoms and the intervention’s impact on psychosocial measures. Methods: A within-subject experimental design was applied to examine an eight-week weekly online music therapy protocol, including singing, wind instrument playing, and music visualizations. All self-report data were collected bi-weekly throughout the 16-weeks study period, including baseline and post-tests. The measures for respiratory symptoms included the Medical Research Council’s Dyspnea Scale (MRC Dyspnea), Chronic Respiratory Questionnaire-Mastery Scores (CRQ Mastery), and Visual Analogue Scale for breathlessness. The measures for the secondary psychosocial outcomes were the Beck Depression Inventory-Short Form, the Generalized Anxiety Disorder 7-item, the Hospital Anxiety and Depression Scale, the Fatigue Severity Scale, the Epworth Sleepiness Scale, the EuroQol 5-Dimension 5-Level, and the Connor-Davidson Resilience Scale. Results: Twenty-four participants were enrolled. The participants perceived a reduction in respiratory symptoms, and shortness of breath (MRC Dyspnea). Planned comparisons showed significant decreases in MRC from baseline to post-treatment (p = 0.008). The mixed-effects model, including pre-baseline and post-treatment, was significant (p < 0.001). Significant changes in Breathing VAS were consistent with improvements in MRC Dyspnea, showing a significant baseline-to-post difference (p = 0.01). The CRQ Mastery showed significant improvements from baseline to Week 12 (p < 0.001). No significant changes were observed in other secondary measures. Conclusions: Our preliminary findings suggest that this protocol is feasible, and as a result, may help individuals previously diagnosed with COVID-19 to cope with lasting respiratory symptoms and improve their perception of shortness of breath. Live music-making, including playing accessible wind instruments and singing, may contribute to an increase sense of control over breathing. As this was a feasibility study, we conducted multiple uncorrected statistical comparisons to explore potential effects. While this approach may increase the risk of Type I error, the findings are intended to inform hypotheses for future confirmatory studies rather than to draw definitive conclusions. Full article

The neurobiology of chronic pain is complex and multifaceted, intertwining with the mesocorticolimbic system to regulate the behavioral and perceptional response to adverse stimuli. Specifically, the ventral tegmental area (VTA), the dopaminergic hub of the reward pathways located deep within the midbrain, is crucial for regulating the release of dopamine (DA) throughout the central nervous system (CNS). To better understand the nuances among chronic pain, VTA response, and therapeutics, implementing progressive approaches for mapping and visualizing the deep brain in real time during nociceptive stimulation is crucial. In this study, we utilize a fluorescence imaging platform with a genetically encoded calcium indicator (GCaMP6s) to directly visualize activity in the VTA during acute nociceptive stimulation in both healthy adult mice and adult mice with partial nerve ligation (PNL)-induced neuropathic pain. We also investigate the visualization of the analgesic properties of morphine. Deep brain imaging using our self-fabricated µ-complementary metal–oxide–semiconductor (CMOS) imaging device allows the tracking of the VTA’s response to adverse stimuli. Our findings show that nociceptive stimulation is associated with a reduction in VTA fluorescence activity, supporting the potential of this platform for visualizing pain-related responses in the central nervous system. Additionally, treatment with morphine significantly reduces the neuronal response caused by mechanical stimuli and is observable using the CMOS imaging platform, demonstrating a novel way to potentially assess and treat neuropathic pain. Full article

Background/Objectives: Cigarette smoking has been causally linked to 90% of all cases of lung cancer, contributing to its high mortality rate. Lung cancer screening centers offer low-dose computed tomography, the only recommended diagnostic screening tool for lung cancer detection. A previous Texas-based study found that centers with lung cancer screening programs failed to consistently provide evidence-based tobacco cessation and relapse prevention interventions recommended by clinical practice guidelines to their patients, who are primarily people who currently or previously smoked. This represents a missed opportunity to assist patients by providing evidence-based tobacco use care during a particularly relevant clinical encounter. Methods: To improve cigarette smoking cessation care delivery and relapse prevention in this setting, this protocol paper seeks to provide a framework for adapting Taking Texas Tobacco Free, a comprehensive, evidence-based tobacco-free workplace program, to lung cancer screening centers. The adapted program, Project SWITCH, will be developed through a formative evaluation process with center stakeholders to identify proactive adaptations to programming based on center-specific contexts. Project SWITCH is expected to be implemented in at least nine lung cancer screening centers in Texas and will be disseminated more broadly to centers statewide. Results: Quantitative and qualitative data will be collected from multiple stakeholders throughout the intervention using a convergent parallel mixed methods design to make additional program adaptations and comprehensively evaluate the achievement of the project’s implementation and dissemination goals. Conclusions: Results from this project’s implementation and dissemination phases are expected to reduce lung cancer morbidity and mortality in Texas by providing an evidence-based, sustainable framework for tobacco-free workplace programs in this specific setting that improves cancer prevention and control practices. Full article