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Targeting the Glucose-Insulin Link in Head and Neck Squamous Cell Carcinoma Induces Cytotoxic Oxidative Stress and Inhibits Cancer Growth
No full textHead and neck squamous cell carcinoma (HNSCC) remains a clinically challenging malignancy with limited targeted therapy options and poor patient outcomes. Thus, identifying unique dependencies, including HNSCC-specific metabolic reprogramming, is imperative for improving treatment strategies for this disease. In this study, we show that HNSCC relies on elevated glucose transporter 1 (GLUT1)-mediated glucose uptake to support redox homeostasis and tumor growth. Analyses of GLUT1 expression data in tumors and cancer cell lines reveal significant upregulation of GLUT1 in HNSCC relative to both normal tissue and other cancer subtypes and that high GLUT1 expression correlates with poorer clinical outcomes. Using a basal epithelial layer-specific GLUT1-knockout mouse model, we demonstrate that GLUT1 ablation in HNSCC cells of origin markedly attenuates tumor initiation and progression, implicating the necessity of GLUT1 in HNSCC tumorigenesis. Building on this observation, combining pharmacologic inhibition of GLUT1 with pro-oxidants such as vitamin C and auranofin induces potent cytotoxicity in vitro and in vivo, partly by precipitating oxidative stress. We further observe that insulin signaling is required to sustain glucose uptake and redox homeostasis, as insulin receptor knockdown decreases proliferation and increases reactive oxygen species levels. Together, these results suggest that although GLUT1 overexpression is a key driver of glucose uptake, insulin signaling also contributes to the metabolic and oncogenic pathways underlying HNSCC progression. Consequently, strategies that co-target GLUT1 and insulin signaling to restrict glucose flux may synergize with pro-oxidant therapies, offering a promising therapeutic avenue for HNSCC. SIGNIFICANCE: Enhanced GLUT1 expression and oncogenic insulin signaling drive elevated glucose uptake in HNSCC, which contribute to the maintenance of redox homeostasis and tumor growth. Disrupting both glucose uptake and redox balance may offer a promising therapeutic approach
Detrimental influence of Arginase-1 in infiltrating macrophages on poststroke functional recovery and inflammatory milieu
No full textPoststroke inflammation critically influences functional outcomes following ischemic stroke. Arginase-1 (Arg1) is considered a marker for anti-inflammatory macrophages, associated with the resolution of inflammation and promotion of tissue repair in various pathological conditions. However, its specific role in poststroke recovery remains to be elucidated. This study investigates the functional impact of Arg1 expressed in macrophages on poststroke recovery and inflammatory milieu. We observed a time-dependent increase in Arg1 expression, peaking at 7 d after photothrombotic stroke in mice. Cellular mapping analysis revealed that Arg1 was predominantly expressed in LysM-positive infiltrating macrophages. Using a conditional knockout (cKO) mouse model, we examined the role of Arg1 expressed in infiltrating macrophages. Contrary to its presumed beneficial effects, Arg1 cKO in LysM-positive macrophages significantly improved skilled forelimb motor function recovery after stroke. Mechanistically, Arg1 cKO attenuated fibrotic scar formation, enhanced peri-infarct remyelination, and increased synaptic density while reducing microglial synaptic elimination in the peri-infarct cortex. Gene expression analysis of fluorescence-activated single cell sorting (FACS)-sorted CD45(low) microglia revealed decreased transforming growth factor-beta (TGF-beta) signaling and proinflammatory cytokine activity in peri-infarct microglia from Arg1 cKO animals. In vitro coculture experiments demonstrated that Arg1 activity in macrophages modulates microglial synaptic phagocytosis, providing evidence for macrophage-microglia interaction. These findings present unique insights into the function of Arg1 in central nervous system injury and highlight an interaction between infiltrating macrophages and resident microglia in shaping the poststroke inflammatory milieu. Our study identifies Arg1 in macrophages as a potential therapeutic target for modulating poststroke inflammation and improving functional recovery
Risk of aortic aneurysm or dissection following use of fluoroquinolones: a retrospective multinational network cohort study
No full textBACKGROUND: Fluoroquinolones (FQs) are commonly used to treat urinary tract infections (UTIs), but some studies have suggested they may increase the risk of aortic aneurysm or dissection (AA/AD). However, no large-scale international study has thoroughly assessed this risk. METHODS: A retrospective cohort study was conducted using a large, distributed network analysis across 14 databases from 5 countries (United States, South Korea, Japan, Taiwan, and Australia). The study included 13,588,837 patients aged 35 or older who initiated systemic fluoroquinolones (FQs) or comparable antibiotics (trimethoprim with or without sulfamethoxazole [TMP] or cephalosporins [CPHs]) for UTI treatment in the outpatient setting between JAN 01, 2010 and DEC 31, 2019. Patients were included if at the index date they had at least 365 days of prior observation and were not hospitalised for any reason on or within 7 days prior to the index date. The primary outcome was AA/AD occurrence within 60 days of exposure, with secondary outcomes examining AA and AD separately. Cox proportional hazards models with 1:1 propensity score (PS) matching were used to estimate the risk, with results calibrated using negative control outcomes. Analyses were subjected to pre-defined study diagnostics, and only those passing all diagnostics were reported. Hazard ratios (HRs) were pooled using Bayesian random-effects meta-analysis. FINDINGS: Among analyses that passed diagnostics there were 1,954,798 and 1,195,962 propensity-matched pairs for the FQ versus TMP and FQ versus CPH comparisons respectively. For the 60-day follow-up there was no difference in risk of AA/AD between FQ and TMP (absolute rate difference [ARD], 0.21 per 1000 person-year; calibrated HR, 0.91 [95% CI 0.73-1.10]). There was no significant difference in risk for FQ versus CPH (ARD, 0.11 per 1000 person-year; calibrated HR, 1.01 [95% CI 0.82-1.25]). INTERPRETATION: This large-scale study used a rigorous design with objective diagnostics to address bias and confounding. There was no increased risk of AA/AD associated with FQ compared to TMP or CPH in patients treated for UTI in the outpatient setting. As we only examined FQ used to treat UTIs in the outpatient setting, the results may not be generalisable to other indications with different severity. FUNDING: Yonsei University College of Medicine, Government-wide R&D Fund project for infectious disease research (GFID), Republic of Korea, National Health and Medical Research Council (NHMRC) Australian Government. Department of Veterans Affairs (VA) Informatics and Computing Infrastructure (VINCI), Department of Veterans Affairs, the United States Government
Predicting orthognathic surgery results as postoperative lateral cephalograms using graph neural networks and diffusion models
No full textOrthognathic surgery, or corrective jaw surgery, is performed to correct severe dentofacial deformities and is increasingly sought for cosmetic purposes. Accurate prediction of surgical outcomes is essential for selecting the optimal treatment plan and ensuring patient satisfaction. Here, we present GPOSC-Net, a generative prediction model for orthognathic surgery that synthesizes post-operative lateral cephalograms from pre-operative data. GPOSC-Net consists of two key components: a landmark prediction model that estimates post-surgical cephalometric changes and a latent diffusion model that generates realistic synthesizes post-operative lateral cephalograms images based on predicted landmarks and segmented profile lines. We validated our model using diverse patient datasets, a visual Turing test, and a simulation study. Our results demonstrate that GPOSC-Net can accurately predict cephalometric landmark positions and generate high-fidelity synthesized post-operative lateral cephalogram images, providing a valuable tool for surgical planning. By enhancing predictive accuracy and visualization, our model has the potential to improve clinical decision-making and patient communication
Effectiveness of room-of-error interventions for healthcare providers: a systematic review
No full textBACKGROUND: Patient safety incidents are recognized as significant contributors to patient mortality, thus demanding immediate attention and strategic interventions in healthcare systems. The room-of-error education program serves as a solution, as it provides a case-based learning platform allowing nursing students to identify and resolve medical errors within a controlled environment systematically. This study aimed to identify the context, mechanisms, and outcomes of room-of-error training programs. METHODS: This study adopted a systematic review methodology aligning with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Comprehensive searches were conducted across key databases, including OvidMEDLINE, Embase, Cochrane, and CINAHL, by utilizing specific terms related to healthcare providers, nursing students, room-of-error education, medical errors, simulation training, and virtual intervention. Included studies focused on healthcare providers or students, error recognition, RFE-related training, and randomized or quasi-experimental trials, while exclusion criteria were non-English/Korean studies, non-original articles, abstracts, and qualitative studies. Risk of bias in the selected studies was assessed using the Risk Of Bias In Non-randomized Studies version 2.0 tool. RESULTS: The search strategy yielded 2,447 articles, with eight studies meeting the inclusion criteria. Predominantly quasi-experimental in design, these eight studies primarily focused on nurses as the target population. Simulations were found to be widely integrated into room-of-error programs, emphasizing skill performance and critical thinking. Half of the studies provided preparation time, 37.5% included feedback, and 62.5% covered medication errors, with 87.5% using offline delivery, 62.5% offering individual education, and program durations ranging from 4 to 35 min, with 25% having no time limit for error inspection. Diverse content, including topics such as medication errors and infection control, was found to be delivered through offline or virtual formats and group-based or individual education. CONCLUSIONS: The findings provide valuable insights into the characteristics and outcomes of room-of-error training programs for healthcare professionals and students. This study emphasizes the significance of practical, case-based approaches in nursing education to augment knowledge, confidence, and competencies, thereby enhancing patient safety in clinical practice
Exploring the impact of dosiomics features on DQA results in breast radiotherapy using TomoDirect
No full textThis study investigates the correlation between dosiomics features and Delivery Quality Assurance (DQA) results in TomoDirect radiotherapy treatments, aiming to enhance DQA accuracy and efficiency. Dosiomics features, such as shape characteristics, statistical properties, and texture metrics (e.g., GLCM, GLSZM), were extracted from RT Dose DICOM files of patients treated with TomoDirect on the Radixact X9 system. Regions of interest (ROI), such as the planning target volume (PTV), were used to isolate dose values for feature extraction. The DQA results were classified using gamma analysis (3%/3mm criteria), and statistical methods like correlation, group comparison, and regression analysis were applied to assess the relationship between these features and DQA outcomes. The analysis identified several key predictors of DQA success. Shape features, including surface area and object size, along with texture features like GLCM autocorrelation and GLDM high gray-level emphasis, showed significant correlations with DQA pass rates. The multivariate regression model explained 79.7% of the variance in DQA outcomes, emphasizing the potential of dosiomics features to predict DQA results. In addition, features related to dose uniformity and complexity, such as firstorder_10th Percentile and GLCM contrast, significantly impacted gamma pass rates. This study demonstrates that dosiomics can enhance the predictability of DQA outcomes in TomoDirect treatments. The identified features can support the development of predictive models to streamline DQA processes, improve treatment accuracy, and reduce manual verification efforts. Future research should explore integrating additional parameters and expanding these methods to other radiotherapy techniques and machines for broader applicability
Adverse Impacts of Corticosteroid Treatment on Osteoporosis/Osteopenia in Adult Asthmatics: A Retrospective ICARUS Cohort Study
No full textBACKGROUND: Inhaled corticosteroid (ICS) and oral corticosteroid (OCS) are often used in asthma management. OBJECTIVE: To evaluate the long-term effect of ICS/OCS on osteoporosis, osteopenia, fractures, and bone metabolism in adult patients with asthma in real-world clinical practice. METHODS: This is a retrospective study investigating deidentified electronic health records from Ajou University Medical Center (Korea). Adult patients with asthma receiving maintenance ICS with/without OCS for at least 1 year were enrolled. They were classified into the high/low-dose of ICS or OCS group. Primary outcomes (incidences of osteoporosis, osteopenia, and fractures) and secondary outcomes (drug prescription and laboratory values related to bone metabolism including albumin and alkaline phosphatase) were compared after 5 years of follow-up. RESULTS: After propensity score matching, both high- and low-dose OCS groups included 468 patients, and high/low-dose ICS groups each comprised 1252 patients. The risk of osteoporosis/major fracture was higher (hazard ratio [95% CI], 2.00 [1.15-3.57]/3.03 [1.04-11.11]) in the high-dose OCS group (especially in females aged >/=50 years) than in the low-dose group, although the ICS groups showed no significant differences. The high-dose ICS group showed a higher risk of osteopenia (1.92 [1.05-3.70]) than the low-dose ICS group. The linear mixed model of laboratory values showed significantly decreased serum albumin and increased alkaline phosphatase in the high-dose OCS group than in the low-dose OCS group. CONCLUSIONS: The results of this study suggest that long-term use of OCS can increase the risk of osteoporosis and osteoporosis-related fractures, whereas long-term use of ICS may increase the risk of osteopenia in adult patients with asthma
Age-related eye diseases and subsequent risk of mental disorders in older adults: A real-world multicenter study
No full textBACKGROUND: The relationship between age-related eye diseases and the subsequent risk of dementia and depressive disorders remains inconsistent. Furthermore, the effects on anxiety disorders and sleep disorders have been underexplored. This study aims to comprehensively examine the impact of age-related eye diseases on common mental disorders in older adults, thereby enhancing our understanding of the mental health implications in these conditions. METHODS: The electronic health records of 1,522,036 patients aged over 60 from ten institutions in South Korea were analyzed. Patients with and without age-related eye diseases were identified, and 1:4 propensity score matching (PSM) was implemented. A 10-year longitudinal analysis was conducted using the Cox proportional hazards model to calculate the hazard ratios (HR). A meta-analysis was performed to combine the results from different institutions. Subgroup analyses were conducted to explore the impact of specific age-related eye diseases (cataract, glaucoma, age-related macular degeneration) on mental disorders. RESULTS: A total of 41,637 patients with age-related eye disease were matched with 134,908 patients without such conditions. Patients with age-related eye disease showed a significantly higher risk of mental disorders (dementia, HR: 1.21 [95 % CI: 1.14-1.27]; depressive disorders, HR: 1.28 [95 % CI: 1.20-1.36]; anxiety disorders, HR: 1.31 [95 % CI: 1.22-1.41]; sleep disorders, HR: 1.29 [95 % CI: 1.22-1.37]). In subgroup analyses, each of the three age-related eye diseases was significantly associated with an increased risk of mental disorders. (cataract, HR: 1.25-1.33; glaucoma, HR: 1.15-1.49; age-related macular degeneration, HR: 1.18-1.37). CONCLUSION: Age-related eye diseases increase the risk of developing mental disorders in older adults, highlighting the need for a multidisciplinary approach to patient care in these conditions
