Search Results (18,934)

Gastric-type cervical adenocarcinoma (GCA) is a rare and aggressive subtype of cervical adenocarcinoma. Despite its clinical significance, its molecular carcinogenesis and therapeutic targets remain poorly understood. This study aimed to compare the clinicopathological, immunohistochemical, and molecular profiles of GCA and usual-type cervical adenocarcinoma (UCA), exploring prognostic and therapeutic biomarkers in a Japanese population. A total of 110 cervical adenocarcinoma cases, including 16 GCA and 94 UCA cases, were retrospectively analyzed for clinicopathological features, and a panel of immunohistochemical markers was assessed. Sanger sequences were performed for the KRAS, PIK3CA, and BRAF genes, and survival and clinicopathological correlations were assessed using Kaplan–Meier and Cox regression analyses. GCA was significantly associated with more aggressive features than UCA, including lymph node involvement, advanced FIGO stages, increasing recurrence rate, and poor survival status. High ARID1B expression was observed in a subset of GCA cases and correlated with worse progression-free and overall survival. Additionally, PD-L1 expression was more frequent in GCA than UCA and was associated with unfavorable prognostic factors. Conversely, UCA cases showed strong p16 expression, supporting their HPV-driven pathogenesis. Molecular profiling revealed KRAS and PIK3CA mutations in both subtypes, while BRAF mutations were identified exclusively in GCA. These findings reveal distinct clinical and molecular profiles for both tumor types and underscore ARID1B and PD-L1 as predictive prognostic and therapeutic biomarkers in GCA, implicating the use of subtype-specific treatment strategies. Full article

Background: DEAD/H box 5 (DDX5) serves as a transcriptional coactivator for several transcription factors including E2F1, the primary target of the tumor suppressor pRB. E2F1 physiologically activated by growth stimulation activates growth-related genes and promotes cell proliferation. In contrast, upon loss of pRB function due to oncogenic changes, E2F1 is activated out of restraint by pRB (deregulated E2F1) and stimulates tumor suppressor genes such as ARF, which activates the tumor suppressor p53, to suppress tumorigenesis. We have recently reported that DDX5 augments deregulated E2F1 activity to induce tumor suppressor gene expression and apoptosis. During the analyses, we noted that over-expression of E2F1 increased DDX5 expression, suggesting a feed forward loop in E2F1 activation through DDX5. Objective: We thus examined whether the DDX5 gene is a target of deregulated E2F1. Method: For this purpose, we performed promoter analysis and ChIP assay. Result: The DDX5 promoter did not possess typical E2F binding consensus but contained several GC repeats observed in deregulated E2F1 targets. Insertion of point mutations in these GC repeats decreased responsiveness to deregulated E2F1 induced by over-expression of E2F1, but scarcely affected responsiveness to growth stimulation. ChIP assays showed that deregulated E2F1 induced by over-expression of E2F1 or expression of E1a, which binds pRB and releases E2F1, bound to the DDX5 gene, while physiological E2F1 induced by growth stimulation did not. Conclusions: These results suggest that the DDX5 gene is a target of deregulated E2F1, generating a feed forward loop mediating tumor suppressive E2F1 activity. Full article

Background/Objectives: Most snakebite incidents in Latin America are caused by species of the Bothrops genus. Their venom induces severe local effects, against which antivenom therapy has limited efficacy. Metabolites derived from Coffea arabica have demonstrated anti-inflammatory and anticoagulant properties, suggesting their potential as therapeutic agents to inhibit the local effects induced by B. asper venom. Methods: Three enzymatic assays were performed: inhibition of the procoagulant and amidolytic activities of snake venom serine proteinases (SVSPs); inhibition of the proteolytic activity of snake venom metalloproteinases (SVMPs); and inhibition of the catalytic activity of snake venom phospholipases A₂ (PLA_2s). Additionally, molecular docking studies were conducted to propose potential inhibitory mechanisms of the metabolites chlorogenic acid, caffeine, and caffeic acid. Results: Green and roasted coffee extracts partially inhibited the enzymatic activity of SVSPs and SVMPs. Notably, the green coffee extract, at a 1:20 ratio, effectively inhibited PLA₂ activity. Among the individual metabolites tested, partial inhibition of SVSP and PLA₂ activities was observed, whereas no significant inhibition of SVMP proteolytic activity was detected. Chlorogenic acid was the most effective metabolite, significantly prolonging plasma coagulation time and achieving up to 82% inhibition at a concentration of 62.5 μM. Molecular docking analysis revealed interactions between chlorogenic acid and key active site residues of SVSP and PLA₂ enzymes from B. asper venom. Conclusions: The roasted coffee extract demonstrated the highest inhibitory effect on venom toxins, potentially due to the formation of bioactive compounds during the Maillard reaction. Molecular modeling suggests that the tested inhibitors may bind to and occupy the substrate-binding clefts of the target enzymes. These findings support further in vivo research to explore the use of plant-derived polyphenols as adjuvant therapies in the treatment of snakebite envenoming. Full article

Background/Objectives: Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) function as effectors in the Hippo pathway and have attracted attention due to their association with tumor formation. Glucose transporter (GLUT) proteins also contribute to the proliferation of cancer cells. In this study, we investigated the effect of YAP/TAZ on GLUT1 expression in endometrial carcinoma, as well as the clinical relevance and prognostic value of YAP/TAZ. Methods: The effects of YAP and TAZ knockdown and YAP overexpression on GLUT1 expression in human endometrial carcinoma-derived HHUA and Ishikawa cells were evaluated using RT-qPCR. In addition, we performed immunohistochemical expression of 100 tissue samples of diagnosed endometrial carcinoma. Based on staining intensity and the percentage of positively stained tumor cells, the immunoreactivity score was calculated, which ranged from 0 to 12. Results: YAP/TAZ were identified as important factors in the regulation of GLUT1 expression in HHUA and Ishikawa cells. In addition, a significant correlation (progression-free survival p < 0.05) was observed between TAZ and GLUT1 expression in tissues from endometrial carcinoma patients, and nuclear expression of TAZ was associated with poor prognosis (p < 0.05). Conclusions: YAP/TAZ promote tumor growth via GLUT1. Therapeutic targeting of YAP/TAZ could therefore be useful in the development of future treatments. Full article

The effects of long-term adjustments in body weight on the lipid balance in patients with severe obesity are not well understood. This study aimed to evaluate a non-invasive lipidomic approach to identifying biomarkers that could help predict which patients may require additional therapies before and after weight loss. Using mass spectrometry, 275 lipid species were analysed in non-obese controls, patients with severe obesity, and patients one year after bariatric surgery. The results showed that severe obesity disrupts lipid pathways, contributing to lipotoxicity, inflammation, mitochondrial stress, and abnormal lipid metabolism. Although weight loss improved these disturbances, surgery did not fully normalise the lipid profiles of all patients. Outcomes varied depending on their baseline liver health and genetic differences. Persistent alterations in cholesterol handling, membrane composition, and mitochondrial function were observed in partial responders. Elevated levels of sterol lipids, glycerophospholipids, and sphingolipids emerged as markers of complete metabolic recovery, identifying candidates for targeted post-surgical interventions. These findings support the use of lipidomics to personalise obesity treatment and follow-up. Full article

Physical activity, particularly when practiced in natural settings, has well-established benefits for overall health, sleep, and body composition. These effects are especially important for postmenopausal women, although research specifically targeting this population remains limited. The study evaluated a 16-week multicomponent outdoor exercise program (cardiorespiratory, strength, balance, coordination, and flexibility training) in postmenopausal women, consisting of three 60 min sessions per week. Participants were non-randomly assigned to an experimental group (EG, n = 55) and a control group (CG, n = 20). Measurements were taken at baseline and after 16 weeks, including body composition, sleep (duration and quality), and connection with nature. No significant differences were observed between groups at baseline. After the intervention, the EG and CG presented significant differences (p ≤ 0.01) in the rates of change in body mass, fat mass (FM; −9.26% and −1.21%, respectively), and visceral fat level (VFL; −13.46 points and −3.80 points). These differences were also observed for the sleep fragmentation index (p ≤ 0.01), but not for connection with nature. A significant interaction effect (p < 0.01) of time × group was observed for %FM, VFL, and appendicular skeletal muscle mass. Exercise duration had an effect (p = 0.043) on participants’ personal and affective identification with nature, and the time × group × medication interaction significantly influenced sleep efficiency (p = 0.034). The exercise program proved effective in reducing total and central adiposity levels; however, it did not lead to improvements in sleep duration, sleep quality, or connection with nature. Full article

Introduction: Carbapenem-resistant Klebsiella pneumoniae (CRKP) represents a critical public health threat due to its rapid nosocomial dissemination, limited therapeutic options, and elevated mortality rates. This study aimed to characterize the epidemiology, carbapenemase profiles, and antimicrobial susceptibility patterns of CRKP isolates, as well as the clinical features and outcomes observed in infected or colonized patients. Materials and Methods: We conducted a retrospective analysis of clinical and microbiological data from patients with CRKP infections or colonization admitted between January 2023 and January 2024. Descriptive statistics were used to assess prevalence, resistance patterns, and patient outcomes. Two binary logistic regression models were applied to identify independent predictors of sepsis and in-hospital mortality. Results: Among 89 CRKP isolates, 45 underwent carbapenemase typing. More than half were metallo-β-lactamase (MBL) producers, with 44.4% co-harbouring NDM and OXA-48-like enzymes. Surgical intervention was associated with a significantly lower risk of sepsis (p < 0.01) and in-hospital mortality (p = 0.045), whereas intensive care unit (ICU) stay was a strong predictor of both outcomes. ICU admission conferred a 10-fold higher risk of sepsis (95%Cl 2.4–41.0) and a 40.8-fold higher risk of in-hospital death (95% Cl 3.5–473.3). Limitations: This single-center retrospective study included a limited number of isolates in certain groups. Additionally, cefiderocol (FDC) susceptibility was assessed by disk diffusion rather than by the broth microdilution method. Conclusions: Our study underscores the increasing prevalence of metallo-beta-lactamase-producing CRKP, particularly strains harbouring dual carbapenemases. Timely recognition of high-risk patients, combined with the implementation of targeted infection control measures and the integration of novel therapeutic options, is crucial to optimize clinical management and reduce mortality associated with CRKP. Full article

Background/Objectives: Cannabidiol (CBD) is a non-intoxicating cannabinoid touted for a variety of medical benefits, including alleviation of anxiety. While legalization of hemp-derived products in the United States (containing ≤0.3% delta-9-tetrahydrocannabinol [d9-THC] by weight) has led to a rapid increase in the commercialization of hemp-derived CBD products, most therapeutic claims have not been substantiated using clinical trials. This trial aimed to assess the impact of 6 weeks of treatment with a proprietary hemp-derived, full-spectrum, high-CBD sublingual solution similar to those available in the marketplace in patients with anxiety. Methods: An open-label pilot clinical trial (NCT04286594) was conducted in 12 patients with at least moderate levels of anxiety. Patients self-administered a hemp-derived, high-CBD sublingual solution twice daily during the 6-week trial (target daily dose: 30 mg/day CBD). Clinical change over time relative to baseline was assessed for anxiety, mood, sleep, and quality of life, as well as changes in cognitive performance on measures of executive function and memory. Safety and tolerability of the study product were also evaluated. Results: Patients reported significant reductions in anxiety symptoms over time. Concurrent improvements in mood, sleep, and relevant quality of life domains were also observed, along with stable or improved performance on all neurocognitive measures. Few side effects were reported, and no serious adverse events occurred. Conclusions: These pilot findings provide initial support for the efficacy and tolerability of the hemp-derived, high-CBD product in patients with moderate-to-severe levels of anxiety. Double-blind, placebo-controlled studies are indicated to obtain robust data regarding efficacy and tolerability of these types of products for anxiety. Full article

Fractional flow reserve (FFR) is a standard physiological index for guiding coronary revascularization, with a threshold of >0.80 typically used to defer intervention. However, due to its distinct anatomical and physiological features, the left anterior descending artery (LAD) often exhibits lower FFR values than non-LAD vessels for lesions of similar angiographic severity. These vessel-specific differences raise concerns about applying a uniform FFR cutoff across all coronary territories. Observational studies indicate that LAD lesions deferred at an FFR of 0.80 may have similar or better outcomes than non-LAD lesions do. LAD lesions also tend to show lower post-percutaneous coronary intervention FFR values, suggesting that vessel specific target thresholds may be more prognostically appropriate. Additionally, some evidence suggests that instantaneous wave-free ratio may offer greater prognostic value than FFR, specifically in LAD lesions, a trend not consistently seen in other arteries. In patients with acute myocardial infarction and multivessel disease, the prognostic relevance of non-culprit lesion FFR may vary by coronary territory, particularly in the LAD. This review outlines the physiological rationale and clinical evidence for vessel-specific interpretation of FFR, with a focus on the LAD, and explores its potential clinical implications and limitations. Full article

Functional recovery after traumatic brain injury (TBI) is hindered by progressive neurodegeneration resulting from neuroinflammation and other secondary injury processes. Dexamethasone (DX), a synthetic glucocorticoid, has been shown to reduce inflammation, but its systemic administration can cause a myriad of other medical issues. We aim to provide a local, sustained treatment of DX for TBI. Previously, we demonstrated that PEG-bis-AA/HA-DXM hydrogels composed of polyethyleneglycol-bis-(acryloyloxy acetate) (PEG-bis-AA) and dexamethasone-conjugated hyaluronic acid (HA-DXM) reduced secondary injury and improved motor functional recovery at 7 days post-injury (DPI) in a rat moderate controlled cortical impact (CCI) TBI model. In this study, we evaluated the effect of PEG-bis-AA/HA-DXM hydrogel on cognitive function and secondary injury at 14 DPI. Immediately after injury, hydrogel disks were placed on the surface of the injured cortex. Cognitive function was evaluated using the Morris Water Maze test, and secondary injury was evaluated by histological analysis. The hydrogel treatment group demonstrated significantly shorter latency to target, decreased distance to find the hidden target, increased number of target crossings, increased number of entries to the platform zone, and decreased latency to first entry of target zone compared to untreated TBI rats for probe test. We also observed reduced lesion volume, inflammatory response, and apoptosis in the hydrogel treatment group compared to the untreated TBI group. Full article

Background/Objectives: Bronchiolitis is the leading cause of hospitalization in infants under 12 months. While often self-limiting, a subset of cases evolves into severe disease requiring intensive care. This study aimed to identify risk factors for severe bronchiolitis in two consecutive respiratory syncytial virus (RSV) seasons (before and after the introduction of nirsevimab) in Southern Italy. Methods: A retrospective, multicenter cohort study was conducted on all infants ≤12 months hospitalized with bronchiolitis from October 2023 to March 2025. Patients were categorized by disease severity: those requiring Sub-Intensive or Intensive Care (IC group) and others (n-IC group). Demographic and clinical data, virological testing, and therapeutic interventions were analyzed. Multivariable logistic regression was used to identify independent risk factors for severe disease. Results: Among 1056 hospitalized infants, 10.5% required intensive care. RSV was detected in 73.5% of tested patients and was significantly associated with severe outcomes. Independent risk factors for IC admission included younger age (<3 months), comorbidities, and RSV infection. A 33% reduction in bronchiolitis admissions was observed in the second season (post-nirsevimab), although the rate of severe cases remained stable (about 10% in both seasons). Conclusions: Younger age, comorbidities, and RSV infection are significant predictors of severe bronchiolitis. Although overall admissions decreased post-nirsevimab, severe cases persisted. These findings underscore the need for targeted preventive strategies and highlight the potential role of intermediate care approaches in managing bronchiolitis severity. Full article

Over three decades of research has been undertaken on point cloud registration algorithms, resulting in mature theoretical frameworks and methodologies. However, among the numerous registration techniques used, the impact of point cloud scanning quality on registration outcomes has rarely been addressed. In most engineering and industrial measurement applications, the accuracy and density of LiDAR point clouds are highly dependent on laser scanners, leading to significant variability that critically affects registration quality. Key factors influencing point cloud accuracy include scanning distance, incidence angle, and the surface characteristics of the target. Notably, in short-range scanning scenarios, incidence angle emerges as the dominant error source. Building on this insight, this study systematically investigates the relationship between scanning incidence angles and point cloud quality. We propose an incident-angle-dependent weighting function for point cloud observations, and further develop an improved weighted Iterative Closest Point (ICP) registration algorithm. Experimental results demonstrate that the proposed method achieves approximately 30% higher registration accuracy compared to traditional ICP algorithms and a 10% improvement over Faro SCENE’s proprietary solution. Full article

Refining the land use structure can boost land utilization efficiency and curtail regional carbon emissions. Nevertheless, prior research has predominantly concentrated on static linear planning analysis. It has failed to account for how future dynamic alterations in driving factors (such as GDP and population) affect simulation outcomes and how the land use spatial configuration impacts the attainment of the carbon-neutrality goal. In this research, 1 km spatial resolution LULC products were employed to meticulously simulate multiple land use scenarios across China at the national level from 2030 to 2060. This was performed by taking into account the dynamic changes in driving factors. Subsequently, an analysis was carried out on the low-carbon land use spatial structure required to reach the carbon-neutrality target. The findings are as follows: (1) When employing the PLUS (Patch—based Land Use Simulation) model to conduct simulations of various land use scenarios in China by taking into account the dynamic alterations in driving factors, a high degree of precision was attained across diverse scenarios. The sustainable development scenario demonstrated the best performance, with kappa, OA, and FoM values of 0.9101, 93.15%, and 0.3895, respectively. This implies that the simulation approach based on dynamic factors is highly suitable for national-scale applications. (2) The simulation accuracy of the PLUS and GeoSOS-FLUS (Systems for Geographical Modeling and Optimization, Simulation of Future Land Utilization) models was validated for six scenarios by extrapolating the trends of influencing factors. Moreover, a set of scenarios was added to each model as a control group without extrapolation. The present research demonstrated that projecting the trends of factors having an impact notably improved the simulation precision of both the PLUS and GeoSOS-FLUS models. When contrasted with the GeoSOS-FLUS model, the PLUS model attained superior simulation accuracy across all six scenarios. The highest precision indicators were observed in the sustainable development scenario, with kappa, OA, and FoM values reaching 0.9101, 93.15%, and 0.3895, respectively. The precise simulation method of the PLUS model, which considers the dynamic changes in influencing factors, is highly applicable at the national scale. (3) Under the sustainable development scenario, it is anticipated that China’s land use carbon emissions will reach their peak in 2030 and achieve the carbon-neutrality target by 2060. Net carbon emissions are expected to decline by 14.36% compared to the 2020 levels. From the perspective of dynamic changes in influencing factors, the PLUS model was used to accurately simulate China’s future land use. Based on these simulations, multi-scenario predictions of future carbon emissions were made, and the results uncover the spatiotemporal evolution characteristics of China’s carbon emissions. This study aims to offer a solid scientific basis for policy-making related to China’s low-carbon economy and high-quality development. It also intends to present Chinese solutions and key paths for achieving carbon peak and carbon neutrality. Full article

Purpose: To present the findings of our preliminary experience using daily image-guided radiotherapy (IGRT) supported by implanted fiducial markers (FMs) in the radiotherapy of the vaginal cuff, in a cohort of post-surgery endometrial cancer patients. Methods: Patients with vaginal cuff cancer requiring adjuvant radiation with external beams were enrolled. Five patients underwent radiation therapy targeting the pelvic disease and positive lymph nodes, with doses of 50.4 Gy in twenty-eight fractions and a subsequent stereotactic boost on the vaginal vault at a dose of 5 Gy in a single fraction. One patient was administered 30 Gy in five fractions to the vaginal vault. These patients underwent external beam RT following the implantation of three 0.40 × 10 mm gold fiducial markers (FMs). Our IGRT strategy involved real-time 2D kV image-based monitoring of the fiducial markers during the treatment delivery as a surrogate of the vaginal cuff. To explore the potential role of FMs throughout the treatment process, we analyzed cine movies of the 2D kV-triggered images during delivery, as well as the image registration between pre- and post-treatment CBCT scans and the planning CT (pCT). Each CBCT used to trigger fraction delivery was segmented to define the rectum, bladder, and vaginal cuff. We calculated a standard metric to assess the similarity among the images (Dice index). Results: All the patients completed radiotherapy and experienced good tolerance without any reported acute or long-term toxicity. We did not observe any loss of FMs during or before treatment. A total of twenty CBCTs were analyzed across ten fractions. The observed trend showed a relatively emptier bladder compared to the simulation phase, with the bladder filling during the delivery. This resulted in a final median Dice similarity coefficient (DSC) of 0.90, indicating strong performance. The rectum reproducibility revealed greater variability, negatively affecting the quality of the delivery. Only in two patients, FMs showed intrafractional shift > 5 mm, probably associated with considerable rectal volume changes. Target coverage was preserved due to a safe CTV-to-PTV margin (10 mm). Conclusions: In our preliminary study, CBCT in combination with the use of fiducial markers to guide the delivery proved to be a feasible method for IGRT both before and during the treatment of post-operative gynecological cancer. In particular, this approach seems to be promising in selected patients to facilitate the use of SBRT instead of BRT (brachytherapy), thanks to margin reduction and adaptive strategies to optimize dose delivery while minimizing toxicity. A larger sample of patients is needed to confirm our results. Full article

Triple-negative breast cancer (TNBC) is a clinically and molecularly heterogeneous subtype defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression. In this study, tumor specimens from 104 TNBC patients were analyzed to characterize molecular and clinicopathological features and to assess the expression and therapeutic potential of four key surface markers: epidermal growth factor receptor (EGFR), epithelial cell adhesion molecule (EpCAM), tissue factor (TF), and trophoblast cell surface antigen (TROP2). Multiplex immunofluorescence (mIF) demonstrated elevated EGFR and TROP2 expression in the majority of samples. Significant positive correlations were observed between EGFR and TF, as well as between TROP2 and both TF and EpCAM. Expression analyses revealed increased EGFR and TF levels with advancing tumor stage, whereas EpCAM expression declined in advanced-stage tumors. TROP2 and TF expression were significantly elevated in higher-grade tumors. Additionally, EGFR and EpCAM levels were significantly higher in patients with elevated Ki-67 indices. Binding specificity assays using single-chain variable fragment (scFv-SNAP) fusion proteins confirmed robust targeting efficacy, particularly for EGFR and TROP2. These findings underscore the therapeutic relevance of EGFR and TROP2 as potential biomarkers and targets in TNBC. Full article