Search Results (270,423)

Osteosarcoma (OS) is the most common primary bone malignancy in children and adolescents, which is also considered an aggressive disease due to its rapid growth rate, ability to metastasize early, and complex and heterogeneous tumor microenvironment (TME). Although we are developing improved surgical and chemotherapeutic approaches, the presence of metastatic or recurrent disease is still detrimental to the patient’s outcome. Major advances in understanding the molecular mechanisms of OS are needed to substantially improve outcomes for patients being treated for OS. This review integrates new data on the molecular biology, pathophysiology, and immune landscape of OS, as well as introducing salient areas of tumorigenesis underpinning these findings, such as chromothripsis; kataegis; cancer stem cell dynamics; and updated genetic, epigenetic, and glycosylation modifiers. In addition, we review promising biomarkers, diagnostic platforms, and treatments, including immunotherapy, targeted small molecule inhibitors, and nanomedicine. Using genomic techniques, we have defined OS for its significant genomic instability due to TP53 and RB1 mutations, chromosomal rearrangements, and aberrant glycosylation. The TME is also characterized as immunosuppressive and populated by tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, ultimately inhibiting immune checkpoint inhibitors. Emerging fields such as glycomics and epigenetics, as well as stem cell biology, have defined promising biomarkers and targets. Preclinical studies have identified that glycan-directed CAR therapies could be possible, as well as metabolic inhibitors and 3D tumor models, which presented some preclinical success and could allow for tumoral specificity and enhanced efficacy. OS is a biologically and clinically complex disease; however, advances in exploring the molecular and immunologic landscape of OS present new opportunities in biomarkers and the development of new treatment options with adjunctive care. Successful treatments in the future will require personalized, multi-targeted approaches to account for tumor heterogeneity and immune evasion. This will help us turn the corner in providing improved outcomes for patients with this resilient malignancy. Full article

Background/Objectives: The breast cancer susceptibility gene 1 (BRCA1) is a tumor suppressor gene whose mutations are associated with increased susceptibility to develop breast or ovarian cancer. BRCA1 mainly exerts its protective effects through DNA double-strand break repair. Although not itself a transcriptional factor, BRCA1, through its multiple protein interaction domains, exerts transcriptional coregulation. In addition, BRCA1 expression alters cellular metabolism including inhibition of de novo fatty acid synthesis, changes in cellular bioenergetics, and activation of antioxidant defenses. Some of these actions may contribute to its global oncosuppressive effects. However, the breadth of metabolic pathways reprogrammed by BRCA1 is not fully elucidated. Methods: Breast cancer cells expressing BRCA1 were investigated by multiplatform metabolomics, metabolism-related transcriptomics, and joint metabolomics/transcriptomics data processing techniques, namely two-way orthogonal partial least squares and pathway analysis. Results: Joint analyses revealed the most important metabolites, genes, and pathways of metabolic reprogramming in BRCA1-expressing breast cancer cells. The breadth of metabolic reprogramming included fatty acid synthesis, bioenergetics, HIF-1 signaling pathway, antioxidation, nucleic acid synthesis, and other pathways. Among them, rewiring of glycerophospholipid (including phosphatidylcholine, -serine and -inositol) metabolism and increased arginine metabolism have not been reported yet. Conclusions: Rewired glycerophospholipid and arginine metabolism were identified as components of BRCA1-induced metabolic reprogramming in breast cancer cells. The study helps to identify metabolites that are candidate biomarkers of the BRCA1 genotype and metabolic pathways that can be exploited in targeted therapies. Full article

Background/Objectives: The whole cell pertussis vaccine was introduced in the United States in the 1940s and switched to the acellular pertussis vaccine partially in 1992 and completely in 1997. This study examines the relationship between the resurgence of pertussis in the United States and the change in the type of pertussis vaccines. Methods: Pertussis cases from 1922 to 2024 were obtained from the CDC’s national notifiable disease surveillance system, and vaccination coverage was obtained from the WHO. A trend analysis and Pearson’s correlation test were conducted between the incidence of cases and the coverage of the third and fourth doses of the pertussis vaccine. An ANOVA test and multivariable linear regression were performed to assess the association between the type of vaccine and the number of pertussis cases. Results: The number of cases increased from 4083 in 1992 to 35,435 in 2024, with cyclical outbreaks in 2010, 2012–2014, and 2024. The third and fourth doses of pertussis vaccine coverage had mild and moderate correlations with the number of pertussis cases. The vaccine type had a significant association with the number of pertussis cases and stayed significant after adjusting for vaccination coverage. Conclusions: The switch in pertussis vaccine has impacted the epidemiology of pertussis outbreaks in the United States. A combination of factors, such as different types of immune response to vaccines, waning of immunity, and selection of non-vaccine bacterial strains, may explain the observed results. Further research on newer, improved vaccinations or alternative schedules in children needs to be conducted to address the resurgence of pertussis in this study. Full article

Soybean (Glycine max (L.) Merrill) is a major oilseed crop rich in phytosterols and tocopherols, compounds associated with functional and nutritional properties of vegetable oils. This study aimed to apply, for the first time, Independent Component Analysis (ICA) to discriminate the composition of phytosterols (β-sitosterol, campesterol, stigmasterol) and tocopherols (α, β, γ, δ) in 20 soybean genotypes—14 non-transgenic and six transgenic—cultivated in two major producing regions of Paraná state, Brazil (Londrina and Ponta Grossa). Lipophilic compounds were extracted from soybean seeds, quantified via gas chromatography and HPLC, and statistically analyzed using ICA with the JADE algorithm. The extracted independent components successfully differentiated soybean varieties based on phytochemical profiles. Notably, transgenic cultivars from Ponta Grossa exhibited higher levels of total tocopherols, including α- and β-tocopherol, while conventional cultivars from both regions showed elevated phytosterol content, particularly campesterol and stigmasterol. ICA proved to be a powerful unsupervised method for visualizing patterns in complex compositional data. These findings highlight the significant influence of genotype and growing region on the nutraceutical potential of soybean, and support the use of multivariate analysis as a strategic tool for cultivar selection aimed at enhancing functional quality in food applications. Full article

Background/Objectives: Mild Cognitive Impairment (MCI), a condition between normal aging and dementia, is characterized by cognitive changes that do not significantly affect instrumental activities of daily living. The Memory Support System (MSS), an evidence-based behavioral intervention developed by the Mayo Clinic, has been shown to aid those living with MCI and their support partners in coping with cognitive challenges. However, the MSS has not been offered clinically within the Canadian context. Therefore, we conducted a study assessing the feasibility of the MSS from the perspectives of individuals living with MCI and their support partners. Methods: Participants from an institutional registry of research participants, patients, and support partners at a memory clinic, as well as members of a local Dementia Society, were approached to complete an online or paper version of a survey assessing feasibility dimensions. Responses were compared between and within groups for differences in mean scores and associations between linked binary choice response questions. Results: A total of 77 responses were received; 39 surveys were completed by participants with MCI, and 38 by support partners. Respondents found the MSS to be acceptable and practical. On average, participants thought it would be more difficult to train in using the MSS than support partners. Both groups expressed interest in the intervention. On average, participants with MCI and support partners preferred virtual MSS training to in-person and indicated more interest in participating in training over six weeks as compared to two weeks. Conclusions: Flexibility in duration and format when offering the MSS are important considerations when offering the intervention as part of a clinical program. Future research should evaluate cost-effectiveness (e.g., financial, staff resources, etc.) of the MSS approach if it were to be institutionalized in the Ontario healthcare system. Full article

Head and neck squamous cell carcinoma (HNSCC) is a highly aggressive malignancy characterized by complex interactions within the tumor microenvironment (TME) that facilitate immune evasion and tumor progression. The TME consists of diverse cellular components, including cancer-associated fibroblasts, immune and endothelial cells, and extracellular matrix elements, that collectively modulate tumor growth, metastasis, and resistance to therapy. Immune evasion in HNSCC is orchestrated through multiple mechanisms, including the suppression of cytotoxic T lymphocytes, recruitment of immunosuppressive cells, such as regulatory T and myeloid-derived suppressor cells, and upregulation of immune checkpoint molecules (e.g., PD-1/PD-L1 and CTLA-4). Natural killer (NK) cells, which play a crucial role in anti-tumor immunity, are often dysfunctional within the HNSCC TME due to inhibitory signaling and metabolic constraints. Additionally, endothelial cells contribute to tumor angiogenesis and immune suppression, further exacerbating disease progression. Recent advancements in immunotherapy, particularly immune checkpoint inhibitors and NK cell-based strategies, have shown promise in restoring anti-tumor immunity. Moreover, TP53 mutations, frequently observed in HNSCC, influence tumor behavior and therapeutic responses, highlighting the need for personalized treatment approaches. This review provides a comprehensive analysis of the molecular and cellular mechanisms governing immune evasion in HNSCC with a focus on novel therapeutic strategies aimed at improving patient outcomes. Full article

Virtual AI-driven streamers have been gradually used in live commerce, and they may affect consumer impulsive purchase intention. Drawing on the stimulus–organism–response (S-O-R) model, this research examined consumer impulsive purchase intention in virtual AI streaming. Based on survey data from 411 predominantly young and educated virtual AI streaming users recruited through snowball sampling, we found that perceived responsiveness, perceived likeability, perceived expertise, and perceived anthropomorphism of virtual AI streamers are associated with trust and flow experience, both of which predict consumers’ impulsive purchase intentions. The fsQCA identified two paths that lead to impulsive purchase intention. The results imply that live streaming platforms need to engender consumers’ trust and flow experience in order to increase their impulsive purchase intention. Full article

This study demonstrates how Structural Topic Modeling (STM) can be used to analyze qualitative student comments in conjunction with quantitative student evaluation of teaching (SET) scores, providing a scalable framework for interpreting student evaluations of teaching. Drawing on 286,203 open-ended comments collected over fourteen years at a large U.S. research university, we identify eleven latent topics that characterize how students describe instructional experiences. Unlike traditional topic modeling methods, STM allows us to examine how topic prevalence varies with course and instructor attributes, including instructor gender, course discipline, enrollment size, and numeric SET scores. To illustrate the utility of the model, we show that topic prevalence aligns with SET ratings in expected ways and that students associate specific teaching attributes with instructor gender, though the effects are relatively small. Importantly, the direction and strength of topic–SET correlations are consistent across male and female instructors, suggesting shared student perceptions of effective teaching practices. Our findings underscore the potential of STM to contextualize qualitative feedback, support fairer teaching evaluations, inform institutional decision-making, and examine the relationship between qualitative student comments and numeric SET ratings. Full article

Background/Objectives: Anterior redisplacement, defined as a postoperative anterior shift of the distal fragment despite intraoperative reduction, is occasionally observed after cephalomedullary nailing for trochanteric femoral fractures. However, its incidence and associated risk factors remain unclear. This study aimed to determine the incidence of anterior redisplacement following intramedullary nail fixation in geriatric trochanteric fractures, and to identify independent risk factors. Methods: This study retrospectively reviewed data from 598 consecutive hips in 577 patients (aged ≥ 65 years) who underwent intramedullary nail fixation for trochanteric fractures at a single center (2012–2023). Sagittal reduction on the lateral radiographic view was classified as posterior, anatomical, or anterior according to the position of the distal fragment, and was recorded preoperatively and postoperatively. Anterior redisplacement, the primary outcome, was defined as a change in alignment from a posterior or anatomical position postoperatively to an anterior position on any subsequent follow-up radiograph. Independent risk factors were identified by logistic regression. Results: Among the 543 hips reduced posteriorly (n = 204) or anatomically (n = 339), anterior redisplacement occurred in 73 (13.4%). The incidence of anterior redisplacement was significantly higher following anatomical compared to posterior reduction (19.5% vs. 3.4%; p < 0.001), and also higher in fractures that were anteriorly aligned preoperatively (18.0%) compared to anatomical (8.5%; p < 0.01) and posterior (6.2%; p < 0.01) alignment. Multivariate analysis revealed two independent predictors: preoperative anterior alignment (odds ratio [OR] 1.87, 95% confidence interval [CI] 1.24–2.81; p = 0.003) and postoperative anatomical (vs. posterior) reduction (OR 6.49, 95% CI 2.92–14.44; p < 0.001). Age, sex, Arbeitsgemeinschaft für Osteosynthesefragen/Orthopaedic Trauma Association classification, Evans–Jensen classification, nail length, and canal-filling ratio were not associated with redisplacement. No lag‑screw cutout occurred during the follow-up. Conclusions: Anterior redisplacement occurred in one of seven geriatric trochanteric fractures despite apparently satisfactory fixation. An anatomical sagittal reduction—traditionally considered “ideal”—increases the risk more than sixfold, whereas a deliberate posterior-buttress is protective. Unlike patient-related risk factors, sagittal reduction is under the surgeon’s control. The study findings provide evidence that choosing a slight posterior bias can significantly improve stability. Full article

This paper introduces a first approach to miscomputations for data-driven systems. First, we establish an ontology for data-driven learning systems and categorize various computational errors based on the Levels of Abstraction ontology. Next, we consider computational errors which are associated with users’ evaluation and requirements and consider the user level ontology, identifying two additional types of miscomputation. Full article

Pregnane X receptor (PXR) is an important nuclear receptor that regulates diverse physiological functions, including drug metabolism. Although PXR activation is potentially involved in adverse events, the full scope of its impact has yet to be elucidated. In this study, we developed a machine learning model to predict the activity of PXR agonists and applied the model to drugs listed in the US Food and Drug Administration Adverse Event Reporting System database. Analysis of the predicted agonist–active drug interactions and adverse event reports revealed statistically significant risks (lnROR > 1 and −logp > 1.3) for multiple cardiac disorders. These findings suggest that PXR activity is involved in cardiovascular adverse effects and may contribute to drug safety through the early identification of risks. Full article

Despite extensive research on early childhood education (ECE) quality at the preschool level, toddler settings remain comparatively understudied, particularly in Chile and Latin America. Research suggests that quality ECE strengthens child development, while low-quality services can be harmful. ECE quality comprises structural features like ratios and classroom resources, and process features related to interactions within classrooms. This study examines how process and structural quality indicators are related in nurseries serving disadvantaged backgrounds. Data were collected from 51 Chilean urban classrooms serving children aged 12–24 months. Classrooms were evaluated using the Classroom Assessment Scoring System (CLASS) for toddlers, questionnaires, and checklists. Latent Profile Analysis identified process quality patterns, while multinomial regression examined associations with structural quality indicators. The results revealed low-to-moderate process quality across classrooms (M = 4.78 for Emotional and Behavioral Support; M = 2.35 for Engaged Support for Learning), with three distinct quality clusters emerging. Marginally significant differences were found between high- and low-performing clusters regarding classroom space (p = 0.06), number of toys (p = 0.08), and staff educational credentials (p = 0.01–0.07). No significant differences emerged for group sizes or adult-to-child ratios, which are heavily regulated in Chile. These findings underscore the need to strengthen quality assurance mechanisms ensuring all children access quality ECE. Full article

Introduction: A validated clinical decision tool predictive of favorable functional outcomes following endovascular thrombectomy (EVT) in acute ischemic stroke (AIS) remains elusive. We performed a retrospective case series of patients at our regional Comprehensive Stroke Center, over a four-year period, who have undergone EVT to elucidate patient characteristics and factors associated with a favorable functional outcome after EVT. Methods: We reviewed all cases of EVT at our institution between February 2018 and February 2022 in the extended time window from 6–24 h. Demographic, clinical, imaging, and procedure co-variates were included. A favorable clinical outcome was defined as a modified Rankin scale of 0–2. We included patients with M1 or internal carotid artery occlusion treated with EVT within 6–24 h after symptom onset. We used a univariate and multivariate logistic regression analysis to identify patient factors associated with a favorable clinical outcome at 90 days. Results: Our study included evaluation of 121 patients who underwent EVT at our comprehensive stroke center. Our analysis demonstrates that a higher recanalization score based on the modified Thrombolysis In Cerebral Infarction (mTICI) scale (2B-3) was a strong indicator of a favorable outcome (OR 7.33; CI 2.06–26.07; p = 0.0021). Our data also showed that a higher baseline National Institutes of Health Stroke Scale (NIHSS) score (p = 0.0095) and the presence of pre-existing hypertension (p = 0.0035) may also be predictors of an unfavorable outcome (mRS > 2) per our multivariate analysis. Conclusion: Patients without pre-existing hypertension had more favorable outcomes following EVT in the expanded time window. This is consistent with other multicenter data in the expanded time window that demonstrates greater odds of a poor outcome with elevated pre-, peri-, and post-endovascular-treatment blood pressure. Our data also demonstrate that the mTICI score is a strong predictor of favorable outcome, even after controlling for other variables. A lower baseline NIHSS at the time of thrombectomy may also indicate a favorable outcome. Furthermore, the presence of clinical or radiographic mismatch based on the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) and NIHSS per DAWN and DEFUSE-3 criteria did not emerge as a predictor of favorable outcome, which is congruent with recent randomized controlled trials and meta-analyses. Full article

Background/Objectives: Curcumin (CUR) is well known for its therapeutic properties, particularly attributed to its antioxidant and anti-inflammatory effects in managing chronic diseases such as arthritis. While CUR application for biomedical purposes is well known, the phytochemical has several restrictions given its poor water solubility, physicochemical instability, and low bioavailability. These limitations have led to innovative formulations, with nanocarriers emerging as a promising alternative. For this reason, this study aimed to address the potential advantages of associating CUR with nanocarrier systems in managing arthritis through a scoping review. Methods: A systematic literature search of preclinical (in vivo) and clinical studies was performed in PubMed, Scopus, and Web of Science (December 2024). General inclusion criteria include using CUR or natural derivatives in nano-based formulations for arthritis treatment. These elements lead to the question: “What is the impact of the association of CUR or derivatives in nanocarriers in treating arthritis?”. Results: From an initial 536 articles, 34 were selected for further analysis (31 preclinical investigations and three randomized clinical trials). Most studies used pure CUR (25/34), associated with organic (30/34) nanocarrier systems. Remarkably, nanoparticles (16/34) and nanoemulsions (5/34) were emphasized. The formulations were primarily presented in liquid form (23/34) and were generally administered to animal models through intra-articular injection (11/31). Complete Freund’s Adjuvant (CFA) was the most frequently utilized among the various models to induce arthritis-like joint damage. The findings indicate that associating CUR or its derivatives with nanocarrier systems enhances its pharmacological efficacy through controlled release and enhanced solubility, bioavailability, and stability. Moreover, the encapsulation of CUR showed better results in most cases than in its free form. Nonetheless, most studies were restricted to the preclinical model, not providing direct evidence in humans. Additionally, inadequate information and clarity presented considerable challenges for preclinical evidence, which was confirmed by SYRCLE’s bias detection tools. Conclusions: Hence, this scoping review highlights the anti-arthritic effects of CUR nanocarriers as a promising alternative for improved treatment. Full article

Background/Objectives: We aimed to identify questionnaire items associated with an increased risk of developing hepatic steatosis in the general population. Methods: A total of 15,063 individuals aged ≥20 years who underwent general health checkups and had no hepatic steatosis at baseline were included. The relationship between questionnaire data at baseline and hepatic steatosis incidence over a median 4.2-year follow-up was investigated across body mass index (BMI) categories. Results: Among 15,063 individuals (mean [SD] age, 47.1 [10.2] years; 6769 [44.9%] male; mean [SD] BMI, 21.4 [2.6] kg/m²), 1889 individuals (12.5%) developed hepatic steatosis during follow-up. After adjusting for age, sex, and factors related to metabolic diseases and liver injury, the strongest questionnaire-based risk factor for hepatic steatosis was self-reported weight gain of 10 kg or more after the age of 20 across all BMI categories: total population (hazard ratio [HR], 2.11; 95% confidence interval [CI], 1.90–2.34; p < 0.001), Category 1 (BMI < 22) (HR, 2.33; 95% CI, 1.86–2.91; p < 0.001), Category 2 (BMI 22 to <25) (HR, 1.43; 95% CI, 1.25–1.63; p < 0.001), and Category 3 (BMI ≥ 25) (HR, 1.41; 95% CI, 1.12–1.77; p = 0.003). Conclusions: In this cohort study, self-reported weight gain of 10 kg or more after the age of 20 was associated with an increased risk of hepatic steatosis, independent of baseline BMI. Questionnaires capturing weight gain history may support universal screening efforts to identify individuals at elevated risk. Full article