Search Results (2,028)

Melanoma is a highly immunogenic cancer, and immunotherapy is the first-line treatment for patients with advanced disease. However, CD155 overexpression in melanoma has been associated with resistance to immunotherapy. Whether CD155 can be transferred from tumour cells via extracellular vesicles (EVs), and how this transfer affects immune responses in melanoma, remains unclear. To investigate melanoma cell transfer of CD155 in vivo, B16F10-WT and B16F10-CD155KO melanoma cells were subcutaneously injected into CD155^−/− mice. We show that CD155 is transferred from melanoma cells to several immune cell populations infiltrating the tumour, at least partly through EV secretion and uptake. DNAM-1 expression was significantly reduced on natural killer (NK) cells in B16F10-WT tumours compared with B16F10-CD155KO tumours. We also found that CD155 was enclosed and enriched in different melanoma EV subtypes. Finally, incubation of NK cells with CD155⁺ melanoma EVs increased cellular CD155 levels and led to downregulation of DNAM-1. In summary, melanoma-derived CD155 is enriched in melanoma EVs and transferred to immune cells, especially NK cells. Moreover, cancer-derived CD155⁺ EVs increase CD155 expression on NK cells and are associated with reduced DNAM-1 expression. Full article

Background/objective: Urinary continence recovery after robot-assisted radical prostatectomy remains variable despite technical refinements intended to preserve function. We describe Total en bloc Urethra Preservation at Robot-assisted Prostatectomy (ToP-RAP), a technique that preserves the entire intraprostatic urethra and avoids urethral transection, and report short-term functional and oncological outcomes. Methods: Patients with PSA ≤ 15 ng/mL, prostate volume ≤ 80 mL, biopsy ISUP grade ≤ 3, and predefined selection criteria underwent surgery in this single-arm, two-center, IDEAL stage 1–2a development study (ClinicalTrials.gov NCT07678489). Surgical, perioperative safety, continence, and oncological outcomes based on PSA, imaging, and secondary treatment were assessed descriptively. Results: The first 16 consecutive patients were treated between 02/2024 and 05/2025. Median age was 66 years (IQR 62–71), PSA was 6.7 ng/mL (IQR 4.7–9.6), and prostate volume was 33 mL (IQR 29–46). Biopsy ISUP grades 1, 2, 3 were in 19%, 44%, and 38% of patients, respectively. On MRI, 38% of patients had multifocal bilateral lesions. Urethral repair of ≤1 cm was required in 13% of patients. All patients underwent at least interfascial nerve sparing. One posterolateral positive surgical margin and one perioperative complication (fascial dehiscence) occurred, no further complications were observed within 90 days. Median follow-up was 7.2 months (IQR 6.1–10.7). No patient had PSA persistence, biochemical recurrence, or secondary treatment. Overall, 15 of 16 patients (94%) recovered urinary continence, and 94% did so within 5 days. Limitations include the small cohort and short follow-up. Conclusions: Early findings support the feasibility and short-term safety of ToP-RAP. The observed early continence recovery warrants evaluation in larger cohorts with longer follow-up. Full article

Background: The manner of breathing affects the autonomic nervous system (ANS) and corresponding processes in the body. Most studies focus on techniques prolonging breathing. Nevertheless, there are also techniques aimed at accelerating or changing other aspects of the breath. The variety of concepts suggests that different breathing techniques could have different effects on the ANS. This study intended to investigate differential effects of four yogic breathing techniques on heart-rate variability: (1) Ujjayi—relaxation through slowing down the breath; (2) Paced Breathing—enhancement of concentration by following a precise protocol of slowdown breathing; (3) Kapalabhati—raising wakefulness by mild hyperventilation; and (4) Alternate Nostril Breathing—balancing the autonomic nervous system by alternating breath between the nostrils. We hypothesized that there would be (1) differences in the impact on baseline measures after the training weeks, (2) differences between baseline and practice, (3) higher impact with longer performance of the breathing technique, and (4) differences between techniques. Methods: This study was conducted with 36 participants who learned each technique in group sessions and practiced them daily for two weeks of an eight-week program. After practicing each technique, participants performed the breathing technique while HRV, breathing frequency and other psychological variables were recorded; rMSSD was calculated for to interpret the HRV. Results: We found significant differences between calming and accelerating breathing techniques on HRV and breathing frequency, and different effects of the four breathing techniques compared to their baseline and over practice time. Conclusions: Because breathing is such an easily accessible tool for regulation, it seems important to see which breathing technique helps people regulate quickly and effectively in everyday life. Full article

Background/Objectives: Caprine coccidiosis caused by Eimeria spp. is an important parasitic disease affecting goat health and production, with current control strategies relying mainly on anticoccidial drugs. The emergence of drug resistance and the need for sustainable alternatives highlight the importance of developing effective immunoprophylactic approaches. This study aimed to evaluate the immunoprotective effect of X-ray-attenuated Eimeria oocysts against caprine coccidiosis under field conditions and to determine the influence of vaccination on parasite burden, clinical outcomes, and productive performance. Methods: A field study was conducted using attenuated oocysts obtained from naturally infected goats from the same farm. The main Eimeria species identified were E. christenseni, E. arloingi, and E. ninakohlyakimovae. Three sequential trials were performed to optimize vaccination protocols. Goat kids aged 1–6 weeks received different immunization treatments consisting of doses ranging from 5 × 10³ to 6 × 10⁴ sporulated oocysts attenuated by X-ray irradiation at 10–30 kRad (100–300 Gy). Animals were monitored weekly through the evaluation of body weight, faecal consistency, health status, faecal oocyst shedding, and Eimeria species composition. Results: Vaccination with radiation-attenuated oocysts reduced parasite replication and faecal oocyst shedding, particularly affecting highly pathogenic species such as E. ninakohlyakimovae, while maintaining overall Eimeria species diversity. Clinical protection was mainly reflected in reduced parasite pressure rather than the complete prevention of mild diarrhoea. Productive parameters were not markedly improved, suggesting that the main benefit of vaccination was improved parasite control and reduced environmental contamination. Conclusions: Early administration of X-ray-attenuated Eimeria oocysts represents a promising strategy for controlling caprine coccidiosis. Vaccine efficacy depends on appropriate timing and optimization of attenuation conditions. Further studies investigating immune mechanisms, species-specific protection, and performance under commercial farming conditions are required to support the development of sustainable vaccines for goat production. Full article

The use of Recirculating Aquaculture Systems (RASs) in fish farms reduces water consumption and the emission of polluted effluents into the environment. The microbial community in a RAS biofilter is crucial for effective water purification. This study aims to investigate the biocontrol activity of two bacterial strains obtained from a RAS biofilter. Several heterotrophic strains were isolated and selected based on their metabolic profiles and antagonistic effects against bacterial pathogens. Two selected candidates, namely Serratia oryzae (R5) and Bacillus thuringiensis (R28), had a phenotypic profile potentially suitable for conditions commonly found in freshwater RAS biofilters, as well as an in vitro antagonistic effect against several pathogens. S. oryzae and B. thuringiensis were tested in a small-scale simulated biofilter for their effectiveness in controlling the growth of the Escherichia coli. Both strains successfully colonized the biofilter systems, but only S. oryzae maintained lower E. coli cell densities. Therefore, S. oryzae could be an interesting strain for its future applicability as an enrichment culture and biocontrol agent. Further studies could test the strain in situ for using as an environmentally friendly and biosecure alternative for improving biofiltration processes and preventing disease in RAS. Full article

Introduction: Scientific Competence (SC) is a central objective in medical education, but its conceptualization remains insufficiently differentiated, particularly regarding the relationship between evidence use and participation in scientific knowledge generation. Objective: This study reconstructs how physiology educators conceptualized SC and related different forms of scientific engagement within their professional orientation frameworks. Methods: Three group discussions were conducted in 2015–2016 with physiology educators from two German medical faculties and a didactic workshop of the German Physiological Society (n = 30). Bohnsack’s documentary method was used to reconstruct shared and contrasting professional orientation frameworks. Results: SC encompassed scientific thinking, scientific practices, and scientific agency. Critical appraisal, methodological understanding, and evidence-informed medical practice were consistently constructed as relevant to future physicians. Autonomous participation in knowledge generation was also valued, but its curricular positioning varied: participants differed in whether authentic inquiry should be expected of all students or whether more sustained independent research participation should primarily be associated with research-oriented trajectories. Conclusions: This historically situated reconstruction suggests that the central curricular question is not simply whether SC should be developed, but which forms of scientific participation should be expected of all physicians and which remain more closely associated with research-oriented trajectories. The findings offer conceptual hypotheses for examining this distinction in contemporary medical education. Full article

Liposomal drug-delivery systems can improve the formulation performance of poorly soluble compounds by enhancing aqueous dispersion, protecting encapsulated agents, and modifying release behavior. Co-encapsulation of pharmacologically distinct compounds may provide a formulation strategy for comparing combined delivery with a single agent nanoliposomal system. This study aimed to develop and characterize atorvastatin–rutin co-loaded nanoliposomes and to compare their antioxidant, anti-inflammatory, and SRB-based cytotoxic activity with the corresponding free-drug and single-loaded nanoliposomal formulations. Nanoliposomes were prepared by thin-film hydration and characterized by particle size, polydispersity index, zeta potential, encapsulation efficiency, lyophilization-associated retention of encapsulation efficiency, morphology, and in vitro release. A reverse-phase HPLC method was validated for simultaneous atorvastatin and rutin quantification, and lyophilized formulations were evaluated for retention of encapsulation efficiency. In vitro assays included DPPH radical scavenging, nitrite inhibition in LPS-stimulated RAW 264.7 macrophages, and SRB-based cytotoxicity screening across human cancer cell lines and normal periodontal ligament fibroblasts. The co-loaded nanoliposomes achieved encapsulation efficiencies of 88.46% for atorvastatin and 81.74% for rutin; after lyophilization, encapsulation efficiency decreased to 72.31% for atorvastatin and 76.63% for rutin. The nanoliposomal formulations showed measurable DPPH radical-scavenging activity, nitrite-inhibition activity in LPS-stimulated macrophages, and SRB-based antiproliferative activity in several cancer cell lines, while showing no detectable cytotoxicity toward PDL fibroblasts within the tested concentration range. With exquisite similarity to apoptogenic Anti-VEGF antiangiogenesis chemotherapeutic efficacies ofcisplatin; nanoliposomal atorvastatin and co-loaded atorvastatin with rutin were remarkably comparable (in descending order of human VEGF mitigations) in mammary T47D> uterine cervix HeLa> lung A549 adherent monolayers post 72 h incubations. These findings support further investigation of atorvastatin–rutin co-loaded nanoliposomes as an in vitro formulation platform; however, formal synergy analysis, cellular uptake studies, mechanistic assays, pharmacokinetic evaluation, and in vivo safety testing remain necessary. Further in vivo studies are required to determine pharmacokinetic behavior, tissue distribution, therapeutic relevance, and systemic safety. Full article

Background/Objectives: Obsessive–compulsive disorder (OCD) is a chronic and disabling condition. Despite first-line treatment with cognitive behavioral therapy (CBT) including exposure and response prevention (ERP) and selective serotonin reuptake inhibitors (SSRIs), many patients remain severely symptomatic. This highlights the need for further research into innovative multimodal treatment strategies for OCD. We report two inpatients with severe OCD, comorbid depressive symptoms, and insufficient response to previous pharmacological and psychotherapeutic treatments. Methods: Both patients completed 30 multimodal treatment units over six weeks consisting of sequential multi-target repetitive transcranial magnetic stimulation (rTMS) targeting the left dorsolateral prefrontal cortex (DLPFC), right DLPFC, and supplementary motor area (SMA), combined with a modified, largely self-administered, clinician-supervised exposure and response prevention protocol. Results: Both patients demonstrated large observed reductions in OCD symptom severity. Y-BOCS total scores decreased from 29 to 11 in Patient 1 and from 29 to 10 in Patient 2, corresponding to reductions of 62.1% and 65.5%, respectively, with improvements apparent after approximately four weeks and largely maintained at follow-up. Depressive symptoms also improved, and no clinically relevant adverse effects were observed. Conclusions: These cases provide an initial description of the feasibility and tolerability of this specific protocol architecture but do not establish efficacy, long-term durability, or the contribution of individual components. The protocol-level novelty lies in integrating a repeated three-target TBS schedule with a response-limited, cue-terminated exposure procedure, a combination not previously described in the OCD neuromodulation literature. Full article

Triple-negative breast cancer (TNBC) is an aggressive and clinically heterogeneous breast cancer subtype characterized by the absence of estrogen receptor, progesterone receptor, and HER2 overexpression, limited targeted treatment options, early relapse, and frequent development of therapy resistance. Although TNBC often shows initial sensitivity to chemotherapy, durable responses are commonly undermined by the emergence of adaptive resistant cell states rather than solely by fixed genetic mutations. This review synthesizes the role of epigenetic plasticity as a central mechanism that enables TNBC cells to dynamically reprogram transcriptional identity, survive therapeutic stress, and transition between epithelial, mesenchymal, stem-like, immune-evasive, and drug-tolerant persister phenotypes. Key epigenetic mechanisms include aberrant DNA methylation, histone acetylation and methylation, BET/BRD4-dependent transcriptional regulation, EZH2-mediated repression, SWI/SNF-dependent chromatin remodeling, non-coding RNA networks, and three-dimensional genome reorganization. These processes regulate tumor suppressor silencing, DNA-damage repair, epithelial–mesenchymal plasticity, cancer stem-cell maintenance, metabolic adaptation, immune-checkpoint regulation, and minimal residual disease. The review also highlights the translational relevance of epigenetic biomarkers, including DNA methylation signatures, circulating epigenetic markers, chromatin-accessibility profiles, and single-cell epigenomic approaches for diagnosis, prognosis, therapy prediction, and monitoring resistance evolution. Finally, therapeutic strategies targeting epigenetic plasticity are discussed, including DNMT, HDAC, BET, EZH2, KDM, and LSD1 inhibitors, with emphasis on rational combination approaches involving chemotherapy, PARP inhibitors, immunotherapy, and metabolic targeting. Overall, epigenetic plasticity represents both a major driver of TNBC resistance and a therapeutically exploitable vulnerability, provided those future strategies account for tumor heterogeneity, adaptive cell-state transitions, biomarker-guided patient selection, and combination-based treatment design. Full article

Background/Objectives: Traumatic intracranial hemorrhage (tICH) in older adults following low-energy falls (LEF) represents a common yet diagnostically challenging condition in the emergency department (ED), where predicting injury prior to computed tomography (CT) remains difficult. Machine learning (ML) has been proposed to support CT decision-making, but its feasibility using routinely available pre-CT clinical variables in this specific population remains unclear. This study presents a systematic exploratory benchmarking of ML pipeline configurations for pre-CT tICH prediction in a well-defined retrospective cohort of older emergency patients following LEF. Methods: We performed a secondary analysis from a retrospective observational bicentric study from two university hospital EDs, including 2250 patients aged ≥65 years presenting after an LEF and undergoing cranial CT. Clinical data were extracted manually from electronic health records (EHRs). Eighteen pre-CT clinical features retrieved from electronic health records were selected based on routine availability and ≤10% missingness. Overall, 1224 valid ML pipeline configurations, combining nine classification algorithms, six imputation strategies, four class-balancing approaches, and optional hyperparameter tuning, were evaluated using 10-fold stratified cross-validation on a training set. The 20 highest-ranked configurations by cross-validation AUC were then assessed on a previously inspected exploratory hold-out test set (n = 563); training-derived rule-out operating points were evaluable for 17 of these 20, as three tuned SVM configurations lacked stored out-of-fold predictions. Results: tICH prevalence was 7.0% (n = 158). Across the 20 highest-ranked configurations, hold-out AUC ranged from 0.517 to 0.585, with Matthews correlation coefficient near zero and balanced accuracy of approximately 50% throughout, indicating differences in operating point rather than in discriminative ability. Some of these top-ranked pipelines reached higher cross-validation AUC (up to 0.679) but detected no cases at the default 0.5 threshold—an effect of the decision threshold under class imbalance rather than of the models’ rank-order discrimination, which was itself limited (hold-out AUC of 0.517–0.585). Conclusions: Despite comprehensive exploratory benchmarking across 1224 ML pipelines, routinely available pre-CT clinical features did not provide sufficient discriminatory signal to develop a clinically useful tICH prediction model in this cohort of CT-imaged older adults following LEF. These findings indicate that none of the evaluated configurations produced clinically adequate performance; this near-chance result persisted across all pipelines and most plausibly reflects a combination of limited feature signal, low outcome prevalence, and a sample size below the level required for reliable model development at this event rate. Future studies should target substantially larger prospective multicenter cohorts and evaluate additional feature domains, including structured clinical examination findings, point-of-care biomarkers, and imaging features. Full article

Background: Oral cavity cancer is a clinically relevant subgroup of head and neck malignancies and is associated with substantial treatment burden and healthcare utilization. Hospital length of stay (LOS) is an important indicator of inpatient resource use and complexity of care, yet large multicenter data from Germany are limited. Methods: This retrospective multicenter analysis used anonymized inpatient administrative data from 49 German hospitals; eligible oral cavity cancer hospitalizations were contributed by 34 of these hospitals. Adult inpatient hospitalizations (≥18 years) with malignant neoplasms of the oral cavity, defined using ICD-10-GM codes C00–C06, recorded between January 1 2019 and 31 December 2024 were included. The primary outcome was hospital LOS in days. Multimorbidity was quantified using the van Walraven-weighted Elixhauser Comorbidity Score. Prolonged hospitalization was defined as LOS ≥ 7 days and LOS ≥ 14 days. Associations between demographic, clinical, and treatment-related variables and LOS were examined using multivariable Poisson regression models. Because overdispersion was present, a negative binomial mixed model was additionally fitted as a sensitivity analysis. To account for inter-hospital variability, hospital was included as a random intercept in all multivariable models. Associations with prolonged LOS were analyzed using multivariable logistic regression models. All analyses were performed at the hospitalization level. Results: A total of 3957 inpatient hospitalizations for oral cavity cancer were included. Mean age was 65.6 years, and 66.2% of hospitalizations involved male patients. The median LOS was 6 days (interquartile range [IQR] 3–13; mean 10.2 days, standard deviation 11.8). Overall, 49.4% of hospitalizations had an LOS ≥ 7 days and 23.5% had an LOS ≥ 14 days. Older age, particularly >80 years, and higher comorbidity burden were associated with longer LOS (adjusted Poisson rate ratio [RR] for age > 80 years 1.17, 95% CI 1.13–1.21; high comorbidity burden RR 1.58, 95% CI 1.54–1.63). Several treatment-related variables, including surgical procedures in the oral and facial region, lymphatic system operations, blood transfusions, and complex intensive care treatment, were associated with prolonged hospitalization (e.g., blood transfusion RR 1.80, 95% CI 1.76–1.85; complex intensive care RR 1.70, 95% CI 1.65–1.75). Chemotherapy-related hospitalizations were associated with shorter LOS. Conclusions: LOS varied substantially across inpatient hospitalizations for oral cavity cancer in Germany. Older age, higher comorbidity burden, and markers of more complex inpatient treatment were associated with extended hospital stay. These findings may help identify hospitalizations at increased risk of prolonged LOS and inform inpatient planning and resource allocation. Full article

Swine Inflammation and Necrosis Syndrome (SINS) is characterized by multifocal inflammatory lesions in pigs of different ages and has been associated with systemic inflammatory processes. Therefore, the objective of the present study was to characterize associations between SINS expression and systemic inflammatory, hematological, and metabolic biomarkers in pigs from two farm cooperatives within the same commercial production system. In this exploratory study, 45 undocked piglets were assessed during the suckling and weaner stages. Clinical lesions were quantified across multiple body regions, and clinical-chemical and hematological parameters were analyzed in weaners. LASSO regression identified Pig major acute phase protein (PigMAP) as the biomarker most strongly associated with SINS-related traits, showing positive associations with tail base bristle loss and teat redness, whereas heel swelling and tail tip reddening were negatively associated or showed no association. Additional findings included decreased creatinine and urea under more favorable environmental conditions, and differences in bilirubin, creatine kinase (CK), lactate dehydrogenase (LDH), and glutamate dehydrogenase (GLDH) under less favorable conditions, indicating distinct patterns of clinical-chemical parameters associated with SINS. Platelet counts were lower in piglets with SINS status 2, i.e., piglets showing clinical signs of SINS during both the suckling and nursery periods, with statistically significant differences in the respective comparisons. These findings are consistent with the concept of SINS as a systemic inflammatory condition accompanied by measurable hematological and metabolic alterations. Together, these findings broaden the biological characterization of SINS and provide a foundation for future longitudinal studies investigating the temporal relationships between clinical manifestations and systemic biomarkers. Full article

Background/Objectives: Pediatric nasopharyngeal carcinoma (NPC) is a very rare childhood cancer strongly associated with Epstein–Barr virus (EBV) infection. We investigated the prognostic value of EBV DNA on staging and outcome in pediatric NPC from two large study centers, the Children’s Oncology Group (COG) in North America and the German Society of Pediatric Oncology and Hematology (GPOH) in Europe. Methods: Samples collected from NPC patients treated on the COG study ARAR0331 between 2006 and 2012 and the GPOH NPC protocol between 2003 and 2021 were retrospectively analyzed for the level of available plasma (P-EBV) or whole-blood EBV DNA (WB-EBV), both pre-treatment and post-induction chemotherapy. Patients were dichotomized into high and low groups based on the median pre-treatment EBV value. Results: Pre-treatment EBV DNA levels from 102 patients (50 and 23 P-EBV DNA from the COG and GPOH, respectively, and 29 WB-EBV from GPOH) and post-induction EBV DNA levels from 61 patients (31 and 12 P-EBV DNA from the COG and GPOH, respectively, and 18 WB-EBV DNA from GPOH) were evaluated. Patient characteristics, including age and disease stage, were not associated with high and low P-EBV values in any cohort. Disease stage correlated with high EBV levels in the WB-EBV GPOH cohort (p = 0.014). Pre-treatment P-EBV and WB-EBV levels showed no significant association with 5-year event-free survival (EFS: COG p = 0.65, GPOH P-EBV: p = 0.08, GPOH WB-EBV: p = 0.75) or 5-year overall survival (OS: COG p = 0.90, GPOH P-EBV p = 0.17, GPOH WB-EBV p = 0.19). Conclusions: Our study could not establish a significant correlation between outcome and pre-treatment EBV DNA in pediatric NPC patients from non-endemic areas. Full article