Background: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor with limited treatment options. Tumors harboring the BRAFV600E mutation exhibit aggressive behavior and present therapeutic challenges. Although dabrafenib/trametinib (D+T) target the BRAF/MAPK pathway and show efficacy in BRAFV600E mutant melanoma, their effectiveness against GBM remains unclear. RES demonstrates anti-GBM activity through the inhibition of multiple signaling pathways. This study evaluated the therapeutic potential of RES either in monotherapy or in combination with D+T in GBM cells with and without the BRAFV600E mutation. Methods: BRAFV600E mutational status was confirmed in LN428 and U251 GBM cell lines using Sanger sequencing. Cell proliferation and viability was assessed by CCK-8, EdU assay and Calcein AM/PI staining, cell morphology by H&E staining, cell migration by Transwell assay, and apoptosis by TUNEL assay. The protein expressions of BRAF, pERK, and pSTAT3 were analyzed by Western blot, immunocytochemistry (ICC), and immunofluorescence (IF) following treatment with RES, D+T, or their combination. Statistical significance was determined using one-way ANOVA followed by Dunnett’s post hoc test with p < 0.05. Results: Sanger sequencing confirmed the presence of the BRAFV600E mutation in the LN428 cells and its absence in the U251 cells. In the BRAFV600E mutant LN428 cells, neither RES, D+T, nor their combination inhibited cell proliferation or migration, nor did they induce apoptosis. In contrast, RES monotherapy significantly suppressed proliferation, reduced migration, and induced apoptosis in the wild-type U251 cells, while D+T showed minimal inhibitory effects in both cell lines. Western blotting, ICC, and IF analyses revealed that RES significantly downregulated both pERK and pSTAT3 expression in the U251 cells but failed to produce similar effects in the LN428 cells. Notably, D+T treatment induced marked upregulation of pSTAT3 in both cell lines, which was effectively reversed by RES treatment in the U251 cells but not in the LN428 cells. Conclusions: RES selectively suppressed the MAPK and STAT3 signaling pathway in the BRAF wild-type U251 cells, while demonstrating no significant inhibitory effects in the BRAF mutant LN428 cells. This differential response indicates that mutational background governs MAPK/STAT3 pathway regulation, positioning RES as a promising dual-pathway inhibitor in mutation-stratified GBM therapeutics.

Coronavirus Disease 2019 (COVID-19) and other lower respiratory tract diseases (LRTDs), including bacterial pneumonia and acute respiratory distress syndrome, share overlapping clinical features but arise from distinct pathophysiological mechanisms. The molecular signatures that distinguish these diseases remain insufficiently characterized in African populations, where genetic background, endemic infections, and environmental exposures may substantially shape immune responses. We integrated spatially resolved single-cell transcriptomic profiles from lung autopsy specimens of 30 Malawian patients, including 10 with COVID-19, 12 with other LRTDs, and 8 non-LRTD controls. In total, 61,391 cells representing 15 cell types and 36,602 gene expression features were analyzed. Using an integrated machine learning framework that combined nine feature-ranking algorithms with incremental feature selection, we identified potential molecular signatures that could discriminate among disease states within this cohort. The optimal classification models achieved weighted F1 scores greater than 0.94, demonstrating a robust capacity to differentiate COVID-19 from other LRTDs in our dataset. Notably, the macrophage-associated state in COVID-19 was dominated by an IFN-γ response with upregulation of CD163 and HLA-DQA2, contrasting sharply with the type I/III interferon signature reported in European cohorts. In addition, we observed cell-type-specific COVID-19 signatures, including downregulation of CAV1 in AT1 cells, consistent with epithelial damage; dysregulation of SFTPC in AT2 cells, suggesting surfactant dysfunction; and upregulation of NFKBIA in neutrophils, indicating altered inflammatory regulation. Gene Ontology enrichment further revealed universal disruption of protein synthesis machinery, along with cell-type-specific alterations in immune activation, epithelial repair, and inflammatory signaling pathways.

This systematic review and meta-analysis evaluate the comparative diagnostic efficacy and safety of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and transbronchial mediastinal cryobiopsy (EBUS-TBMC) for sampling mediastinal and hilar lymph nodes. Following the PRISMA 2020 guidelines, 20 studies published between January 2020 and July 2025 were analysed to provide a comprehensive performance overview. The results demonstrate that EBUS-TBMC offers a significantly higher overall diagnostic efficacy compared to EBUS-TBNA, with a pooled risk difference (RD) of 0.30 (95% CI: 0.17–0.44, p < 0.001). The subgroup analyses revealed a trend toward a superior yield for EBUS-TBMC in lymphoma (RD 0.11, p = 0.05) and sarcoidosis (RD 0.03, p = 0.077), while no significant differences were found for lung cancer subtypes. Safety profiles remained comparable, with no significant differences in the risk of pneumothorax (RD 0.00, p = 1.00) or bleeding (RD 0.00, p = 0.965). In conclusion, these findings support integrating EBUS-TBMC into diagnostic algorithms when preserved tissue architecture is critical, such as for lymphoproliferative disorders, granulomatous diseases, and advanced molecular profiling, providing a safe and more effective alternative to conventional needle aspiration.

Keloids are pathological scars originating from connective tissue characterized by excessive growth that extends beyond the original edges of the wound. They occur significantly more often in skin areas exposed to increased mechanical tension during the wound-healing process and up to fifteen times more frequently in individuals with darker skin pigmentation. The underlying mechanism of keloid formation is driven by an inflammatory response triggered by skin injury extending into the reticular dermis, leading to fibroblast accumulation and neovascularization. The management of keloids remains challenging, as the recurrence rate is high when surgical excision is performed as a standalone treatment. Evidence indicates that combining surgical resection with adjunctive modalities results in superior clinical outcomes and may significantly lower recurrence rates compared with monotherapy. Adjuvant radiotherapy plays a key role in this approach, as it has been shown to reduce recurrence rates to below 10%, primarily through suppression of inflammation and inhibition of fibroblast activity. This systematic review adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. A systematic search of the PubMed and Web of Science databases identified 22 studies comprising more than 2219 patients treated with surgical excision followed by postoperative radiotherapy. Reported recurrence rates ranged from 1.6% to 55.2% and were influenced by total radiation dose, fractionation schedule, radiotherapy technique, and duration of follow-up. Despite its proven effectiveness when combined with surgery, radiotherapy has certain limitations, including the lack of standardized guidelines regarding dose, fractionation, and timing of administration. Most reported adverse effects were mild to moderate and localized to the treated area, while a direct causal relationship between postoperative radiotherapy and secondary malignancy development could not be established. The variability in treatment protocols highlights the need for further studies to support more effective, evidence-based decision-making in the treatment of keloids.

Background: Headache is a frequent but often underestimated complaint in patients with sarcoidosis. In clinical practice, headache is commonly interpreted as secondary to neurosarcoidosis, potentially overlooking the presence of primary headache disorders, particularly migraine. The prevalence and clinical relevance of migraine in sarcoidosis remain insufficiently characterized. Objective: To investigate the prevalence and clinical characteristics of migraine in patients with sarcoidosis and to explore its association with pulmonary functional outcomes. Methods: The OUtcome and Clinical characteristics of primary Headache in patients with Sarcoidosis (OUCH!) Study is a multicenter, retrospective, observational study including adult patients evaluated at pulmonology outpatient clinics and headache centers between January 2019 and January 2021. Demographic, clinical, radiological, and pulmonary function data were collected. Patients were stratified according to the presence or absence of migraine. Pulmonary function parameters were compared using non-parametric statistical tests. Results: Seventy-two patients with sarcoidosis were included; 21 (29.2%) were diagnosed with migraine. Migraine prevalence was higher than expected for the general population. Pulmonary involvement was the most frequent disease manifestation. Patients with migraine showed significantly lower DLCO values compared with those without migraine (median ( IQR): 55 (40–70) vs. 78 (65–90); p = 0.0009). No significant differences were observed in spirometric parameters or radiological patterns between groups. Conclusions: Migraine is a common comorbidity in sarcoidosis and is associated with reduced DLCO, suggesting a link with greater functional disease burden rather than structural lung damage. Migraine should be recognized as a primary headache disorder in this population, rather than automatically attributed to neurosarcoidosis. These findings support a multidisciplinary, patient-centered approach and warrant prospective studies to clarify shared inflammatory, vascular, and neuroimmune mechanisms.

Nasopharyngeal carcinoma (NPC) presents unique clinical and biological characteristics that distinguish it from other head and neck malignancies. It poses a great therapeutic challenge for many specialists. It is associated with Epstein–Barr virus (EBV) infection, genetic predisposition, and environmental risk factors. With advancements in radiotherapy and systemic therapy, new treatment options have emerged. We want to focus on contemporary therapeutic strategies for NPC, emphasizing breakthroughs in intensity-modulated radiotherapy (IMRT), chemoradiotherapy, targeted therapy, immunotherapy, and emerging cellular therapies. By integrating recent discoveries with clinical evidence, we aim to provide state-of-the-art information, along with a comprehensive understanding of current best practices, emerging treatments, and critical prognostic determinants in NPC.

Traditional cardiovascular assessment has historically focused on the isolated evaluation of either atrial or ventricular structure and function. However, the left atrioventricular coupling index (LACI) represents a paradigm shift by moving beyond single-chamber metrics to quantify the dynamic interaction between the left atrium and left ventricle. Defined as the ratio of left atrial end-diastolic volume to left ventricular end-diastolic volume, LACI integrates structural and functional aspects of cardiac performance. This comprehensive review examines the physiological basis of how the left atrium and ventricle operate as an integrated hemodynamic unit. We detail current measurement methodologies, including two- and three-dimensional echocardiography, cardiac computed tomography, and cardiac magnetic resonance imaging, which serves as the reference standard. Furthermore, the review explores the pathophysiological mechanisms driving atrioventricular uncoupling, specifically mechanical dysfunction, electromechanical desynchrony, and hemodynamic alterations. Extensive clinical evidence demonstrates LACI’s robust independent prognostic value across diverse cardiovascular conditions, such as heart failure, myocardial infarction, cardiomyopathies, and atrial fibrillation. Observational data suggest that LACI provides a promising prognostic value beyond established risk assessment tools by combining the assessment of both chambers’ interdependence. Finally, we outline future directions for clinical translation, highlighting the necessity for standardized measurement protocols, the integration of artificial intelligence, and the potential of LACI as a target for personalized therapeutic strategies.

Mitochondrial dysfunctions contribute to the pathogenesis of tauopathies, a group of neurodegenerative diseases with abnormal accumulation of microtubule-associated protein tau. The combination of 5-aminolevulinic acid (5-ALA) and sodium ferrous citrate (SFC) is known to improve mitochondrial functions. Here, we report that 5-ALA combined with SFC (5-ALA/SFC) improves mitochondrial functions and mitigates neurodegeneration in transgenic Drosophila expressing human tau. We found that tau reduces ATP levels, decreases mitochondrial distribution to neurites, and increases mitochondrial reactive oxygen species (ROS). Expression of oxidative phosphorylation (OXPHOS) genes was upregulated, and activities of complexes I and IV were elevated. Feeding 5-ALA/SFC to tau flies lowers oxidative damage without correcting OXPHOS activities or mitochondrial distribution. 5-ALA/SFC treatment suppressed pathological tau phosphorylation and mitigated tau-induced neurodegeneration. These results suggest that 5-ALA/SFC attenuates a neurodegenerative pathway involving tau, mitochondria, and ROS.

Background: Therapeutic drug monitoring (TDM) of anti-TNF biologics may help optimise treatment in rheumatoid arthritis (RA), but current therapeutic ranges do not always reflect clinical response in routine practice. Methods: We conducted a retrospective observational study including 224 adults with RA treated with infliximab (IFX), adalimumab (ADL), or etanercept (ETN) during the maintenance phase at Hospital Universitario Puerto Real between May 2016 and May 2023. Drug and anti-drug antibody levels were measured by sandwich ELISA and analysed against clinical response using DAS28. Demographic and clinical variables, associations between drug levels and response, the effect of antibodies, correlations between serum concentrations and DAS28, and the performance of current and proposed therapeutic ranges were evaluated. Results: The cohort was mainly female (62.1%), with a mean age of 57.7 years, BMI of 28.5 kg/m2, and mean DAS28 of 3.33. ETN was most frequently used (62.5%), followed by ADL (21.9%) and IFX (15.6%). Drug levels were significantly associated with response (p < 0.001). Anti-drug antibodies were strongly linked to non-response, especially with IFX and ADL. Serum drug levels correlated inversely with disease activity for IFX and ADL, but not for ETN. Current therapeutic ranges showed low sensitivity, while lower proposed ranges improved sensitivity considerably. Conclusions: Current anti-TNF therapeutic ranges have limited ability to identify responders in real-world RA. Lowering the lower bound improves sensitivity and supports more individualised TDM, particularly for IFX and ADL, pending prospective validation.

Background: Bloodstream infections (BSIs) represent a severe complication among patients with solid tumors (STs), contributing substantially to morbidity and mortality, especially in the context of increasing antimicrobial resistance (AMR). Evidence in STs remains limited compared to hematologic malignancies. Methods: We conducted a two-center observational study including 282 hospitalized adults with solid malignancies and documented infections; 66 patients (23.4%) had confirmed BSIs. Clinical characteristics, microbiological profiles, resistance patterns, and outcomes were evaluated. Results: Patients had a mean age of 66.4 ± 11.8 years, and 63.6% were male. The majority (84.8%) had stage IV disease and were receiving chemotherapy (95.5%). Gram-negative bacteria predominated (51.5%), mainly Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Multidrug resistance (MDR) was detected in 45.5% of isolates, while 28.8% of BSIs were polymicrobial; both were associated with worse outcomes and increased infection-related mortality (p = 0.041 and p = 0.032, respectively). Overall infection-related mortality reached 28.8%. In multivariable analysis, poor functional status (ECOG PS ≥ 2), prior hospitalization, and concurrent radiotherapy were independently associated with unfavorable outcomes. Conclusions: BSIs remain a significant cause of morbidity and mortality in patients with STs. The high burden of Gram-negative and MDR pathogens, along with the impact of polymicrobial infections and impaired performance status, highlights the need for early risk stratification and locally adapted empirical antimicrobial strategies. Prospective multicenter studies are warranted to validate these findings and optimize management strategies in this vulnerable population.