Macrophages are heterogeneous tissue-resident immune cells distributed throughout the body. The majority of tissue-resident macrophages are seeded in the peripheral tissues during embryogenesis, and these embryonic precursors form tissue-specific macrophages dependent on their specific microenvironment. The skin is the first line of immune defence and contains various uniquely differentiated tissue-resident macrophage populations, including Langerhans cells in the epidermis, perivascular and sensory nerve-associated macrophages in the dermis, and LYVE1 + and CD169 + macrophages in the hypodermis. Cutaneous melanoma is the most aggressive skin cancer, and macrophages are abundant immune cells found in these tumours. Due to the diversity of macrophage subsets in the skin, macrophages have highly heterogeneous roles in melanoma lesions, including exerting both tumour-suppressing and promoting functions. Additionally, macrophage subsets in the tumour-draining lymph node play important roles in tumour immunity and progression. A comprehensive understanding of the different macrophage subsets in both tumour and tumour-draining lymph nodes may lead to improved therapeutic outcomes for cutaneous melanoma.

Marjolin's ulcer is a rare but aggressive malignant transformation arising in chronic wounds or scars. We report the case of a man in his 60s who developed a large, non-healing ulcer at the site of a previous traumatic injury and reconstructive surgery performed three decades earlier. Clinical suspicion of malignancy led to wide local excision with sentinel lymph node biopsy, followed by staged reconstruction. Negative pressure wound therapy (NPWT) was used to optimise the wound bed, which was complicated by a local infection requiring targeted antibiotic therapy. Subsequent split-thickness skin grafting achieved complete graft take and satisfactory functional outcome. Histopathology confirmed well-differentiated squamous cell carcinoma with clear surgical margins. This case highlights the importance of early biopsy of chronic ulcers, multidisciplinary management and the role of NPWT in facilitating successful reconstruction after oncological resection.

Retaliatory aggression may be influenced not only by cognitive-control processes but also by counter-empathic pleasantness in response to an offender's suffering. In this randomized, double-blind, sham-controlled study, 42 healthy young adults were randomized to real or sham Fpz-centered high-definition transcranial direct current stimulation (HD-tDCS). One participant per group withdrew, leaving 20 per group for analysis. Real stimulation was delivered at 2mA for 25min, whereas sham current was applied only during the first 60s. Before and after stimulation, participants rated the pleasantness of seeing fair or unfair targets receive electric shocks and selected the final shock intensity ostensibly delivered to each target. Compared with sham stimulation, real HD-tDCS produced larger reductions in selected shock intensity for both fair and unfair targets. Counter-empathic pleasantness also decreased overall; at lower initial shock intensities, the reduction was not clearly condition-specific, whereas at higher initial intensities it was mainly observed for unfair targets. Mediation analyses showed a significant indirect effect through pleasantness overall and in the insufficient-punishment condition, but not in the expected-punishment condition. Reductions in frontal N2 and parietal LPP event-related potential (ERP) amplitudes following real HD-tDCS did not differ significantly between fair and unfair contexts. Behavioral, ERP, and mediation analyses were hypothesis-driven, whereas phase transfer entropy was exploratory. Together, these findings indicate that single-session Fpz-centered HD-tDCS can alter immediate laboratory shock-selection behavior in healthy young adults and that changes in counter-empathic pleasantness may partly account for this effect, providing behavioral and electrophysiological evidence linking Fpz-centered neuromodulation to retaliatory punishment.

Triple-negative breast cancer (TNBC) is a highly aggressive breast cancer subtype with limited targeted therapies, leading to higher mortality compared with other breast cancer subtypes. In our previous study we identified N-acyl sphingosine amidohydrolase 1 (ASAH1) to be overexpressed in TNBC cells and demonstrated its role in promoting TNBC growth and progression. ASAH1 is a metabolic enzyme that converts ceramide into sphingosine and free fatty acids, thereby creating a favorable environment for tumor growth. To gain a more comprehensive understanding of the metabolic alterations associated with ASAH1 inhibition, we performed a large-scale metabolomic analysis of TNBC cells expressing ASAH1 shRNAs. Our analysis revealed a significant increase in carnosine levels following ASAH1 inhibition. Subsequent studies demonstrated that exogenous treatment of TNBC cells with carnosine inhibited their growth. Moreover, combining carnosine with ASAH1 inhibitors (carmofur or ceranib-2) resulted in potent synergistic inhibition of TNBC growth. Mechanistically, the combined treatment led to a greater reduction in mitochondrial membrane potential, increased mitochondrial superoxide production and further increased apoptosis. Collectively, these results identify a new metabolism-based combination therapeutic strategy for the effective treatment of TNBC.

Hypopharyngeal carcinoma (HPC) is an aggressive malignancy that is often diagnosed at an advanced stage. Advances in narrowband imaging have increased the early detection rate of HPC. Definitive radiotherapy (RT) is a noninvasive, organ-preserving option recommended for early stage (T1-2N0M0) disease; however, its clinical outcomes remain limited. This study retrospectively evaluated the clinical outcomes of definitive RT for early stage HPC. We retrospectively analyzed 55 patients with early stage HPC who were treated with RT between 2013 and 2023. Treatments included volumetric-modulated arc therapy or three-dimensional conformal radiotherapy with elective nodal irradiation. Chemoradiotherapy was administered to selected patients with stage T2 disease. Survival outcomes were assessed using Kaplan-Meier and Cox models. Median follow-up was 43 months. The 5-year overall survival (OS), progression-free survival, and cancer-specific survival rates were 65%, 57%, and 82%, respectively. Local control, locoregional control and laryngeal preservation rate at 5 years were 79%, 74%, and 91%, respectively. Initial recurrences were locoregional, with local recurrence in 10 of 55 patients (18%) and regional lymph node recurrence in three of 55 patients (5.4%). In univariate analysis, older age (≧71 years) and a history of esophageal cancer were associated with significantly worse OS. The multivariate analysis confirmed that older age and a history of esophageal cancer were independent predictors of OS. RT for early stage HPC provides favorable oncological outcomes and high rates of laryngeal preservation. However, OS was strongly influenced by age and a history of esophageal cancer, highlighting the need for treatment selection and follow-up, including surveillance for second primary esophageal cancer.

Clinical-grade RAS inhibitors raise an unresolved question about whether KRAS alleles impose constraints on adaptive resistance that can be exploited therapeutically. Using daraxonrasib (RMC-6236), a multiselective RAS(ON) inhibitor, we compared resistance mechanisms between KRASG12D and KRASG12R, mutants with fundamentally different RAS network dynamics. Daraxonrasib inhibited mutant KRAS primarily through steric occlusion of effector binding while engaging wild-type RAS (RASWT) only modestly (∼20%). KRASG12R was marked by its inability to transactivate RASWT, and daraxonrasib-resistant KRASG12R pancreatic ductal adenocarcinoma (PDAC) cells utilized EGFR/RASWT-GTP signaling as the dominant adaptive route. In contrast, KRASG12D resistance arose through retained KRASG12D-GTP signaling, with a decrease in cyclophilin A (CypA) protein, the binding partner required for daraxonrasib activity. The shift from KRASG12R dependence to EGFR/RASWT dependence conferred sensitivity to trametinib. As clinical confirmation, a patient with KRASG12R PDAC who progressed after 10 months on daraxonrasib showed intratumoral EGFR/RASWT activation, and rapid 3D-bioprinted patient-derived tumoroid modeling predicted sensitivity to trametinib-based combination therapy. Despite the aggressive disease trajectory and lack of response to the two immediately preceding lines of therapy, sixth-line trametinib-based combination therapy achieved approximately 5 months of disease control, and this patient ultimately achieved 40 months of overall survival, far exceeding the 8 to 12 months median for metastatic PDAC. Collectively, these data establish a framework in which allele-specific RAS network topology dictates the adaptive resistance landscape, enabling rational selection of targeted therapies with meaningful clinical benefit in metastatic PDAC.

Polymer modification shows potential for improving the performance of clays in geotechnical applications. This includes its use as a filler in clay liners under challenging geotechnical and environmental conditions (e.g., exposure to aggressive leachates and intensive drying), as well as applications in soil stabilisation and as supporting fluids for mechanised tunneling and diaphragm wall construction. However, due to the organic nature of most commonly used polymers, they may serve as a substrate for microbial metabolism. The limited understanding of polymer biodegradation and its influence on bentonite behaviour raises concerns regarding the long-term stability of polymer-enhanced clays. This study investigates potential biological degradation of cationic (PAA+) and anionic (PAA-) polyacrylamide-modified bentonite under saturated conditions. Bentonite MX80 was modified via solution intercalation and subjected to 32 weeks of permeation testing. The outflow was analysed chemically and microbiologically. Following permeameter testing, the hydraulic conductivity, rheological behaviour and microbial community composition of the soil material were determined, and initial and post-test microbial communities were compared. Based on the analysis a conceptual degradation model was developed and discussed. Polymer degradation was found to depend on the presence and persistence of specific polymer-degrading microorganisms, with Pseudomonas species identified as key contributors. Although PAA+ modified MX80 exhibited higher microbial degradation activity, the long-term performance of polymer-modified bentonite was governed primarily by the charge-dependent polymer-clay binding mechanism rather than by the extent of polymer loss. Surface-bound PAA+ showed greater robustness than bridging-dominated PAA- systems, as confirmed by hydraulic and rheological analyses.

Genome-scale personalized metabolic modeling relies on objective functions to simulate intracellular flux phenotypes, yet the optimal formulation for characterizing complex human diseases remains unknown. We ask which combination of objective function, biological resolution, and feature-selection strategy yields the most reliable diagnostic signal, treating machine-learning architecture as a controlled factor. We benchmarked these choices across 57 600 experimental configurations spanning six diverse pathologies, from oncology to neurodegeneration. Within this benchmark, pathway-level minimum reaction flux was the best-performing representation, indicating that diagnostic signals are more strongly associated with rate-limiting metabolic bottlenecks than with aggregate pathway activity. Under a leakage-free evaluation, diagnostic accuracy was largely insensitive to feature density (mean $F_{1}$-score varying by <0.003 between the top-10% subset and the full feature space), so aggressive feature selection was not required. Among classifiers, only Logistic Regression lost accuracy at full density, whereas SVM was essentially unaffected and tree-based ensembles were resilient. Statistical regularization (robust_sigma) ensured consistent generalization, while topological objectives (local_k) were highly sensitive to metabolic noise, excelling only in specific high-signal cohorts. Finally, integrating objective function values as competitive features recovered the regulatory context lost during pathway aggregation. Accurate metabolic phenotyping was best captured by isolating restrictive bottleneck reactions. Predictive accuracy was largely insensitive to feature density; tree-based architectures tolerated dense omics data, while feature selection benefited mainly Logistic Regression. Overall, this benchmark offers systematic, evidence-based guidance for personalized metabolic modeling, complementing heuristic parameter tuning with quantitative comparison.

Methylthioadenosine phosphorylase (MTAP) deficiency is prevalent in pancreatic ductal adenocarcinoma (PDAC). Herein, we reveal that MTAP loss in PDAC induces a branched-chain amino acid (BCAA) dependency by upregulating the expression of BCAA transaminase 1 (BCAT1) through DNA demethylation. We establish that BCAT1 upregulation promotes cell proliferation and migration in PDAC by fueling the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) via BCAA consumption. Moreover, the BCAA dependency contributes to a more aggressive phenotype via activation of cancer-associated pathways. In addition, the BCAT1 inhibitor BAY-069 demonstrates remarkable therapeutic efficacy in MTAP-deficient PDAC by diminishing the BCAA-facilitated OXPHOS. Finally, clinical analysis reveals an inverse correlation between MTAP and BCAT1 expression in PDAC, and high BCAT1 expression is associated with poor prognosis in patients with PDAC. Collectively, these findings identify the role of BCAT1 as a key regulator mediating metabolic reprogramming in MTAP-deficient PDAC and support BCAT1 as a potential therapeutic target.

Gliomas are diffusely infiltrative, requiring accurate and sensitive diagnostic tools during surgical resection. Mutations in isocitrate dehydrogenase enzyme (IDH) alter its normal activity and result in accumulation of a unique oncometabolite, 2-hydroxyglutarate (2HG), in tumor cells. However, IDH-wild-type (IDH-wt) gliomas are more common and typically more aggressive. Here, 86 human brain samples were analyzed by syringe touch spray mass spectrometry to evaluate molecular alterations in gliomas. Tandem mass spectrometry (MS/MS) experiments were performed to minimize isobaric and isomeric interferences, and a ratiometric approach (using only signals for endogenous compounds) was employed to improve reliability of the measurements. Multiple ratios for pairs of metabolite signal intensities were found to differentiate tumor samples from nontumor tissue and they stratified glioma subtypes by IDH mutation status and by tumor grade, with several ratios showing 100% agreement with independent clinical assignments (P < 0.0001, Mann-Whitney U test). Increased carnitine relative abundances were found across all glioma subtypes. Importantly, α-aminoadipate was significantly elevated in grade 4 glioma, which may correlate with increased tumor malignancy. Grade 3 gliomas showed markedly higher 2HG abundance than grade 4 samples. In addition, a selection of ratios showed a linear trend with varying tumor cell percentage. Overall, the multiple metabolic ratio alterations indicate a high degree of heterogeneity among glioma subtypes. Furthermore, there are metabolites that can differentiate glioma from nontumor tissue and this measurement can be made by a simple ratiometric method which has potential to be used intraoperatively for margin assessment without diverging from standard of care.

Primary central nervous system lymphoma (PCNSL) is an uncommon and aggressive extranodal non-Hodgkin lymphoma confined to the central nervous system, including the brain, leptomeninges, spinal cord, and eyes. Although high-dose methotrexate-based induction remains the backbone of first-line therapy, long-term disease control remains challenging, particularly in older or frail patients and in those with relapsed or refractory disease. Recent genomic and multi-omics studies have reshaped the biological understanding of PCNSL by identifying recurrent alterations in MYD88, CD79B, PIM1, PRDM1, CDKN2A/B, HLA-related genes, B2M, CIITA, and immune checkpoint loci, which converge on B-cell receptor/Toll-like receptor signaling, NF-κB activation, immune evasion, and microenvironmental adaptation. These molecular insights have accelerated minimally invasive diagnostics, including targeted mutation assays, multigene circulating tumor DNA profiling, methylation-based approaches, and cytokine analysis in cerebrospinal fluid, vitreous humor, and aqueous humor. Targeted and immune-based therapies, including Bruton tyrosine kinase inhibitors, immunomodulatory agents, immune checkpoint inhibitors, mTOR inhibitors, and CD19-directed chimeric antigen receptor T-cell therapy, have shown variable degrees of clinical activity, particularly in relapsed or refractory disease. However, most evidence remains derived from early-phase trials, single-arm studies, retrospective cohorts, or small series, and treatment selection is not yet routinely biomarker-defined. This review summarizes current advances in molecular taxonomy, pathogenesis, diagnostic work-up, liquid biopsy, prognostic stratification, and therapeutic management of PCNSL, emphasizing how molecular and longitudinal biomarker data may inform individualized treatment and future clinical trial design.