Search Results (1,337)

Background and Objectives: Cholangiocarcinoma (CCA) is an aggressive tumor that originates in the biliary tract and is subdivided anatomically into intrahepatic (iCCA) and extrahepatic (perihilar-pCCA and distal-dCCA). Diagnosis remains challenging, particularly for extrahepatic forms (pCCA and dCCA). We aimed to assess the relation between systemic inflammatory markers—specifically lymphocyte-related ratios—and tumor characteristics in a Romanian cholangiocarcinoma cohort. Methods: We conducted an exploratory single-center study including adult patients with a confirmed CCA histopathological diagnosis. We excluded patients with an uncertain diagnosis or tumors of the ampulla of Vater or gallbladder. Demographic and clinical data were retrospectively collected from medical records. Results: Tumor localization was the strongest predictor of metastatic disease. The odd of metastasis was 7.3 times higher for iCCA than dCCA and 4.5 times higher for iCCA than pCCA. Although several evaluated inflammatory biomarkers showed statistically significant associations, their clinical relevance was limited. The odds ratios for these biomarkers were characterized by lower bounds near the null value and wide confidence intervals, reflecting considerable patient heterogeneity, model instability, and inconclusive effect sizes. Conclusions: Our findings suggest a potential biological link between systemic inflammation, metastatic spread, and tumor differentiation grade that deserves further investigation using more accurate systemic inflammation biomarkers than those routinely collected. Full article

Climate-induced ocean warming poses a major threat to marine invertebrate reproduction, including the sea urchin Paracentrotus lividus, a species of considerable ecological, economic, and scientific interest. Its gonads, highly valued as a culinary delicacy, support local fisheries and aquaculture industries, making reproductive health a critical factor for both conservation and commercial viability. The present study reported the effects of elevated seawater temperatures, mimicking marine heatwave (MHW) conditions, on gonadal maturation and fertilization success on P. lividus. Here, adult specimens at the mature stage of gametogenesis were exposed to control (18 °C) and elevated temperature regimes (24 °C) over a six-week period, and key reproductive metrics were assessed, including histological analysis. Morphological analysis showed very evident gonadal retraction, nearly devoid of germ cells, both for males and females, with a significant decrease in the gonadal index. In addition, histological analysis revealed consistent damage to the gonads, with a significantly increase in histopathological index in specimens kept at 24 °C. These findings reinforce the temperature sensitivity of P. lividus reproduction, suggesting that recurrent heatwaves could severely impair its reproductive output and population dynamics with potential cascading effects on benthic community structure in a long-term ocean warming predicted to intensify. Full article

Breast cancer (BC) is increasingly recognized as a heterogeneous disease, with complexity that extends beyond the classical luminal A/B, HER2-enriched, and triple-negative framework. Advances in molecular and functional profiling have uncovered emerging subpopulations, including HER2-low, claudin-low, BRCA-deficient (“BRCAness”), and refined TNBC subsets, such as luminal AR (LAR) and basal-like immune variants, that extend beyond traditional taxonomies. These novel classifications provide additional resolutions, offering both prognostic insight and therapeutic opportunities. In this comprehensive review, we integrate evidence from genomic, epigenetic, proteomic, immune-related, and liquid biopsy biomarkers, underscoring how they define the biology of these subgroups and predict responses to targeted therapies, such as antibody–drug conjugates, PARP inhibitors, and immune checkpoint blockade. We further highlight the role of the tumor microenvironment (TME) and intratumoral heterogeneity in shaping these entities. Collectively, recognition of emerging subtypes as clinically actionable groups represents a paradigm shift from static receptor-based models to dynamic, biomarker-driven frameworks that refine prognosis, enable patient stratification, and support precision oncology in aggressive BC. Full article

The current study aimed to fortify fresh pasta with red onion peels in the form of powder (OPP). For this aim, three concentrations were used (3%, 6%, and 9% w/w) and properly added to the dough. A control sample was also prepared for comparison (CTRL). Raw and cooked pasta samples were assessed for sensory acceptability and technological properties. Fibre content, total polyphenols, and antioxidant activity (by ABTS and FRAP) were assessed in raw materials and pasta samples. The glycaemic index was also predicted. Results from sensory evaluation and technological analyses demonstrated that with increasing OPP, some defects were perceived to provoke a complete unacceptance with the highest fortification level (9% score < 5). However, these effects were counterbalanced by a significant functional quality increase in fibre content, total polyphenols, and antioxidant activity, justified by the presence of the new onion-based ingredient. Therefore, to better balance benefits and drawbacks of onion peel recycling, a global quality index (GQI) was calculated, which accounted for nutritional improvements and sensory worsening. The most interesting GQI values were found for both 3% and 6% levels of fortification (52.58 vs. 51.86). Considering that these values are very comparable, the 6% can be considered the optimal concentration because it represents the highest concentration to give a fortified and sensorially friendly product. Full article

Background/Objectives: Sepsis-associated liver injury (SALI) is a critical and often early complication of sepsis, defined by distinct hyper-inflammatory and immunosuppressive phases that shape patient phenotypes. Methods: Characterizing these phases establishes a foundation for immunomodulation strategies tailored to individual immune responses, as discussed subsequently. Results: The initial inflammatory response activates pathways such as NF-κB and the NLRP3 inflammasome, leading to a cytokine storm that damages hepatocytes and is frequently associated with higher SOFA scores and a higher risk of 28-day mortality. Kupffer cells and infiltrating neutrophils exacerbate hepatic injury by releasing proinflammatory cytokines and reactive oxygen species, thereby causing cellular damage and prolonging ICU stays. During the subsequent immunosuppressive phase, impaired infection control and tissue repair can result in recurrent hospital-acquired infections and a poorer prognosis. Concurrently, hepatocytes undergo significant metabolic disturbances, notably impaired fatty acid oxidation due to downregulation of transcription factors such as PPARα and HNF4α. This metabolic alteration corresponds with worsening liver function tests, which may reflect the severity of liver failure in clinical practice. Mitochondrial dysfunction, driven by oxidative stress and defective autophagic quality control, impairs cellular energy production and induces hepatocyte death, which is closely linked to declining liver function and increased mortality. The gut-liver axis plays a central role in SALI pathogenesis, as sepsis-induced gut dysbiosis and increased intestinal permeability allow bacterial products, including lipopolysaccharides, to enter the portal circulation and further inflame the liver. This process is associated with sepsis-related liver failure and greater reliance on vasopressor support. Protective microbial metabolites, such as indole-3-propionic acid (IPA), decrease significantly during sepsis, removing key anti-inflammatory signals and potentially prolonging recovery. Clinically, SALI most commonly presents as septic cholestasis with elevated bilirubin and mild transaminase changes, although conventional liver function tests are insufficiently sensitive for early detection. Novel biomarkers, including protein panels and non-coding RNAs, as well as dynamic liver function tests such as LiMAx (currently in phase II diagnostics) and ICG-PDR, offer promise for improved diagnosis and prognostication. Specifying the developmental stage of these biomarkers, such as identifying LiMAx as phase II, informs investment priorities and translational readiness. Current management is primarily supportive, emphasizing infection control and organ support. Investigational therapies include immunomodulation tailored to immune phenotypes, metabolic and mitochondrial-targeted agents such as pemafibrate and dichloroacetate, and interventions to restore gut microbiota balance, including probiotics and fecal microbiota transplantation. However, translational challenges remain due to limitations of animal models and patient heterogeneity. Conclusion: Future research should focus on developing representative models, validating biomarkers, and conducting clinical trials to enable personalized therapies that modulate inflammation, restore metabolism, and repair the gut-liver axis, with the goal of improving outcomes in SALI. Full article

Objective: We aimed to provide real-world insights into the management of non-small cell lung cancer stage III (NSCLC-SIII) in Spain. Methods: The GOECP-SEOR group conducted an observational, retrospective, multicenter study in which data from patients diagnosed with NSCLC-SIII treated in Spanish radiotherapy departments (RTDs) were collected. Results: A total of 1505 NSCLC-SIII patients from 35 RTDs from 2018 to 2021 were recruited. A total of 871 patients (57.9%) received concurrent chemoradiotherapy (cCRT), and 390 patients (25.91%) received maintenance durvalumab. The immunotherapy (IT) was well tolerated, with Common Terminology Criteria for Adverse Events (CTCAE) Grade 0–2 toxicity observed in 85% of the patients (295 patients). The median overall survival (OS) was 26 months (95% CI 9.4-Not Reached NR). There was a statistically significant difference when patients were stratified by IT, with a median OS of 40 months (95% CI 22.1-NR) in the IT maintenance cohort compared with 19.4 months (95% CI 7.1–58.1) in the non-IT cohort. Differences were also noted in progression-free survival (PFS), with a median PFS of 20.8 months (95% CI 9.6-NR) in the IT cohort versus 8.4 months (95% CI 3.1–25.1) in the non-IT cohort. These differences remained significant according to the multivariate model (OS: HR 0.45 [95% CI 0.36–0.56], p < 0.001; PFS: HR 0.5 [95% CI 0.42–0.59], p < 0.001). Conclusions: The management of NSCLC-SIII patients can vary, leading to differences in treatment outcomes. The treatment of lung cancer in NSCLC-SIII patients in RTDs across Spain aligns with international guidelines and expert recommendations. Full article

Being a crucial barometer of labour market stability, employment successfully predicts changes in business cycles, becoming a relevant indicator to policymakers and economists worldwide. The scope of this paper is to investigate the impact of socioeconomic and demographic factors on the employment rate in the European Union through a spatial approach, as well as to compare pre- and post-pandemic characteristics of European labour markets. A persistent North–South divide in employment was observed among the main findings, with Southern regions having lower employment rates and being more vulnerable to the pandemic shocks than Northern regions. Furthermore, the comparison between the spatial econometric models estimated for 2019 and 2022 showed a significant change in the influences of regional employment performance. These discoveries could be of interest to both governments and corporate decision-makers in order to elaborate knowledgeable policies and strategies regarding the labour force. Full article

Background: Diet is a crucial factor in both physical and mental health. Several studies in adult populations report that a healthy diet is negatively associated with depression; however, data among adolescents are scarce. Aim: The investigation of the correlation between the consumption of plant foods and depressive symptoms among adolescents. Materials and Methods: A systematic review of articles published over the last decade was conducted across five databases: PubMed, Cochrane, Embase, Scopus, and Google Scholar. Results: Fourteen studies were included in the analysis. Twelve studies reported a negative correlation between symptoms of depression in adolescents and consumption of certain plant foods. Two studies did not report significant correlations, while one study reported a weak positive correlation. Conclusions: Studies report that the consumption of plant foods and specific nutrients included in them is negatively associated with symptoms of depression in adolescents. Further research is needed to explore the relationship and the possible biological mechanisms between plant food consumption and depressive symptoms. Full article

(1) Background: We propose that cfDNA levels may serve as a valuable biomarker for monitoring the progress of liver transplant recipients, reflecting the quality of the donated organ, and predicting patient prognosis and survival. Thus, we analyzed the relationship between total cfDNA levels during the first 48 h post-transplantation, ischemia–reperfusion injury, and patient outcomes. (2) Methods: cfDNA quantification was applied to 115 liver transplant patients using real-time quantitative PCR at the time of transplantation (during reperfusion) and throughout the first month post-transplantation. (3) Results: Significantly higher early cfDNA levels were observed in patients who suffered liver damage or post-transplantation complications during the first month. High cfDNA levels were also associated with prolonged ICU stays and reduced survival. Kaplan–Meier analysis revealed a significantly lower survival rate in patients with elevated cfDNA. CRP levels were elevated and significantly correlated with cfDNA values. Regarding organ preservation prior to transplantation, prolonged cold and warm ischemia times were significantly associated with high cfDNA levels in the early hours post-transplantation. (4) Conclusions: Elevated cfDNA levels in the early hours following liver transplantation are associated with poorer patient outcomes. Therefore, determining total cfDNA levels post-transplantation may be a valuable tool for patient management and early intervention. Full article

Vasculogenic mimicry is the capacity of growing cancer cells to overcome the lack of normal capillaries and hypoxia by forming networks of sinuses lacking endothelial cells. The formation of vasculogenic mimicry by melanoma cells is coupled with the upregulation of the genes involved in ribosome biogenesis, the downregulation of hundreds of developmental genes, and strong changes in the inter-chromosomal contacts of developmental genes with rDNA clusters. The epigenetic mechanism driving the regulatory role of inter-chromosomal contacts of genes with nucleoli is not yet known. This study aimed to determine whether these contacts are associated with either the silencing or the activation of the expression of developmental genes. Here, two different sets of developmental genes are subjected to silencing either by increasing or decreasing their contacts with nucleoli. Our data indicate that one set of developmental genes mainly associated with system development is silenced by the contacts, while another set of genes involved mainly in the generation of neurons is silenced by the loss of contacts with the nucleoli. We conclude that mechanisms of silencing of these sets of developmental genes lead to the loss of the established differentiated state of melanoma cells and to the formation of more aggressive cancer cells. The data also indicate the important role of the nucleoli in the global regulation of gene expression during differentiation and cancer. Full article

Estrogens are cholesterol-derived hormones, with four endogenous estrogens being presented in the scientific literature, namely, estradiol, estrone, estriol, and estetrol. In this study, we aim to obtain a complete thermoanalytical profile for the three most important endogenous estrogens: estradiol, estriol, and estrone. To achieve this, the TG/DTG were registered in non-isothermal conditions at five different heating rates (β = 2, 4, 6, 8, and 10 °C min⁻¹). To describe the mechanisms of the degradation processes, a complex kinetic analysis was performed by applying a preliminary method (ASTM E698), two isoconversional methods (Flynn–Wall–Ozawa and Friedman), and the non-parametric kinetic method. The results indicate that estradiol undergoes a single-step degradation process, while estriol and estrone present a complex degradation process. The determination of the shelf life of pharmaceutical products represents a critical factor in ensuring their safety and efficacy. This parameter can be estimated from the activation energy derived from non-isothermal experiments through the application of the Arrhenius equation and appropriate kinetic models. Full article

Background: Knee osteoarthritis (OA) is a prevalent musculoskeletal condition associated with pain, functional limitation, and reduced quality of life. Telerehabilitation has emerged as a scalable intervention, yet many platforms lack neuromuscular feedback or objective-monitoring capabilities. The KneE-PAD system uniquely integrates electromyographic and inertial sensing to provide personalized feedback and remote performance tracking. Objective: To evaluate the clinical effectiveness of a sensor-augmented telerehabilitation system (KneE-PAD) compared to conventional face-to-face physiotherapy in older adults with mild-to-moderate knee OA. Methods: In this single-blind randomized controlled trial, 42 older adults (mean age 68.4 ± 5.7 years) were randomly assigned to either KneE-PAD telerehabilitation or conventional physiotherapy for eight weeks. KneE-PAD sessions incorporated real-time electromyographic and motion feedback, while physiotherapists remotely supervised training. Assessments were performed at baseline, post-intervention, and 12-week follow-up. Primary outcomes included quadriceps strength, neuromuscular activation, and WOMAC scores. Secondary outcomes covered functional mobility, psychological distress, self-efficacy, and fear of movement. Results: The telerehabilitation group demonstrated notable improvements in neuromuscular activation, quadriceps strength, and functional capacity, all exceeding clinically meaningful thresholds. Functional mobility and pain outcomes showed substantial gains compared with the control group, while psychological indicators (self-efficacy and depressive symptoms) exhibited modest but positive trends. Between-group comparisons consistently favored KneE-PAD, with effects maintained at the 12-week follow-up, confirming both clinical and functional robustness. Conclusions: Sensor-augmented telerehabilitation using the KneE-PAD platform appears to be a feasible and potentially effective alternative to conventional physiotherapy for knee OA. By combining real-time feedback, motor learning reinforcement, and remote monitoring, the system may enhance neuromuscular and functional recovery. These findings should be confirmed in larger and longer-term trials. Trial Registration: ClinicalTrials.gov: NCT06416332. Full article

Recently, significant attention has been paid to the use of multirole materials in additive manufacturing (AM). Polyvinylidene fluoride (PVDF) is an ideal candidate material that has been selected for examination because of its unique characteristics. This study establishes a correlation between the macroscopic mechanical behavior and microscopic structural mechanisms, enabling the utilization of the deformation rate in tailoring the mechanical response of printed PVDF components. This research focuses on testing AM PVDF samples under different strain rates (10–300 mm/min), aiming to report their behavior under loading conditions compatible with the stochastic nature of real-life applications. The thermal (thermogravimetric analysis and differential scanning calorimetry) and rheological (viscosity and melt flow rate) properties were investigated along with their morphological characteristics (scanning electron microscopy). The response under combined dynamic and thermal loading was investigated through dynamic mechanical analysis, and the structural characteristics were investigated using spectroscopic techniques (Raman and energy-dispersive spectroscopy). The properties examined were the ultimate and yield strengths, modulus of elasticity, and toughness. Sensitivity index data are also provided. For completeness, the flexural strength, Charpy impact strength, and Vickers hardness were also evaluated, suggesting that the AM PVDF samples exhibit a resilient nature even when subjected to extremes regarding their strain rate versus their overall mechanical characteristics. PVDF exhibited a strain-hardening response with an increase in its strength of up to ~25% (300 mm/min) and a stiffness of ~15% (100 mm/min) as the loading speed of testing increased. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a biologically and clinically heterogeneous malignancy with variable outcomes. Accurate risk prediction at diagnosis remains essential to guide treatment and follow-up strategies. In this retrospective study we aimed to assess the performance of multiple modeling approaches to predict death by 26 months of follow-up in patients with DLBCL using data available in the diagnostic stage. Methods: In this study we included 412 patients with DLBCL who were evaluated, treated, and followed-up at the Regional Institute of Oncology in Iasi, Romania, between 2015 and 2023. Clinical and paraclinical data determined at baseline examination was used to train and test six machine learning models (logistic regression, random forest—RF, support vector machine with a radial-basis kernel—SVM-RBF, multilayer perceptron neural network—MLP, random survival forest—RSF, and extreme gradient boosting—XGBoost) and to compare their performance to the Cox proportional hazards model. Results: Among the models, RF achieved the highest discrimination (AUC = 0.9060), with balanced performance (accuracy = 0.833; F1 = 0.902), followed by XGBoost (AUC = 0.8335) and MLP (AUC = 0.7861; accuracy = 0.849). RF and logistic regression demonstrated the best calibration (Brier = 0.360 and 0.377). The Cox model achieved moderate discrimination (time-dependent AUC = 0.5561; C-index = 0.55). Conclusions: Our findings align with contemporary reports showing that machine learning frameworks can outperform classical prediction approaches. Full article

Recombinant Bacillus subtilis endospores are promising bacterial expression platforms for oral protein delivery, such as oral vaccines. A simple and effective spore inactivation method that preserves protein functionality, however, is needed to prevent potential shedding into the environment. This study evaluated iron or copper combined with EDTA and ethanol as sporicidal solutions for the inactivation of recombinant spores expressing the 1PR82 gene. Immunoblot and immunofluorescence (IF) assay confirmed the presence of antigenic proteins post-treatment, while electron microscopy (SEM/TEM) assessed spore morphology. Mice immunization tested immunogenicity, and fecal analysis monitored gastrointestinal persistence. Iron ethanol treatment completely inactivated the spores while maintaining recombinant protein detection using antibody-based assays. SEM/TEM revealed morphological damage, yet antigenicity was preserved, as evidenced by robust IgG responses in immunized mice. Fecal analysis showed no prolonged spore shedding, confirming effective inactivation. These findings demonstrate that iron ethanol efficiently inactivates recombinant B. subtilis spores without compromising protein antigenicity. Despite structural damage, the recombinant protein remained immunogenic, and inactivated spores posed no environmental persistence risk. This inactivation method supports the safe use of Bacillus subtilis recombinant spores for oral delivery applications, balancing inactivation efficacy with functional protein preservation. Further research could optimize this approach for clinical or industrial applications. Full article