BACKGROUND: Psoriasis is an immune-mediated inflammatory skin disease with variable biologic therapy response. Current treatment selection lacks reliable predictive biomarkers for personalized decisions. OBJECTIVES: To identify distinct immunological patient subgroups based on peripheral blood immune cells and evaluate their association with biologic therapy efficacy. METHODS: This retrospective cohort study included 329 plaque psoriasis patients initiating first-time biologic therapy and 169 healthy controls. Peripheral blood flow cytometry data were analyzed using hierarchical clustering. Kaplan-Meier analysis assessed time to PASI90 achievement among subgroups. RESULTS: Psoriasis patients showed significantly elevated lymphocyte populations. Three distinct immunological clusters were identified: Cluster 1 (57.8%) with moderate T cells and low NK cells; Cluster 2 (27.7%) with decreased T cells and increased NK cells; and Cluster 3 (14.6%) with increased total lymphocytes. Cluster 1 patients achieved PASI90 significantly faster with both IL-17 and IL-23 inhibitors ( < 0.001). CONCLUSION: Peripheral blood flow cytometry identified distinct psoriasis immunophenotypes with significant differences in biologic therapy response, offering potential biomarkers for treatment selection and personalized medicine approaches.

The cGAS-STING1 pathway is essential for innate immunity, while its functions beyond immune activation have emerged as a key research topic. Recent studies have revealed the non-canonical roles of this pathway in autophagy. However, whether it participates in organelle quality control through selective autophagy processes such as mitophagy remains largely unexplored. In our study, we identify the cGAS-STING1 pathway as an essential upstream regulator of PINK1-PRKN-dependent mitophagy. We demonstrate that upon mitochondrial damage, STING1 is recruited to damaged mitochondria in a process requiring PINK1- and VCP/p97-mediated degradation of outer mitochondrial membrane proteins. STING1 at damaged mitochondria then activates TBK1, which phosphorylates the mitophagy receptor OPTN at Ser177, enhancing its recruitment to damaged mitochondria and driving efficient mitophagy. Disruption of the STING1-TBK1-OPTN axis impairs mitophagy and shifts the cellular response from pro-survival mitophagy to apoptosis. Our findings therefore uncover a non-canonical, pro-survival function of the cGAS-STING1 pathway in mitophagy, extending its role beyond innate immunity to the regulation of selective autophagy and cell fate decisions. Abbreviations: BafA1: bafilomycin A1; cGAS: cyclic GMP‑AMP synthase; ER: endoplasmic reticulum; GABARAP: GABA type A receptor-associated protein; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MQC: mitochondrial quality control; mtDNA: mitochondrial DNA; NAC: N-Acetylcysteine; Nec-1: Necrostatin-1; OMM: outer mitochondrial membrane; OPTN: optineurin; PINK1: PTEN induced kinase 1; PRKN: parkin RBR E3 ubiquitin protein ligase; RIPK1: receptor interacting serine/threonine kinase 1; ROS: reactive oxygen species; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; VCP/p97: valosin containing protein; Z-VAD-FMK: benzyloxycarbony (Cbz)-l-ValAla-Asp (OMe)-fluoromethylketone.

Characterizing protein-drug interactions at the atomic level is challenging partly because small molecules can be difficult to detect within large biomolecular complexes. We have developed a strategy to introduce NMR-active isotopic N labels into derivatives of bevirimat (BVM), a triterpenoid inhibitor of HIV-1 maturation. Isotopically labeled compounds were synthesized through concise and efficient routes using commercially available, isotopically enriched building blocks. Three N-labeled BVM derivatives were prepared to be used as molecular probes to investigate HIV-1 protein interactions. These labeled compounds enable site-specific N detection of the inhibitor in both solution and solid-state NMR experiments, which will be useful to obtain molecular-level insight into the interactions between BVM derivatives and its target HIV-1 Gag protein. Synthetic incorporation of NMR-active isotopes produces chemical probes for atomic-level analysis of next-generation HIV-1 therapeutics derived from BVM and can be applied to other derivatives of betulinic acid with various medical applications.

BACKGROUND: Cervical cancer harbors a profoundly immunosuppressive tumor microenvironment (TME) that impairs innate and adaptive antitumor immunity and, critically, limits the efficacy of emerging radioimmunotherapy strategies. The NKG2D receptor-ligand axis-comprising the stress-inducible ligands MICA and MICB-constitutes a pivotal innate immune recognition interface whose surface expression on tumor cells determines susceptibility to NKG2D-armed effector cells and, by extension, dictates the targetability of radiolabeled NKG2D-directed probes for precision radionuclide therapy (RNT). Yet the mechanistic basis for NKG2D ligand dysregulation and its implications for radionuclide theranostics in cervical cancer remain poorly defined. This study integrated single-cell RNA sequencing (scRNA-seq) and experimental validation to comprehensively map the NKG2D-axis immune escape landscape in cervical carcinogenesis and to delineate its translational significance for precision RNT target selection and patient stratification. METHODS: scRNA-seq datasets (GSM1551311 and GSM1551411) were processed using Seurat and Harmony for cell-type annotation, immune landscape characterization, and radionuclide target density profiling. Louvain clustering was performed at a resolution of 0.8 after evaluating multiple resolution parameters (0.4-1.2) using the clustree package to ensure stable cluster assignments. The top 20 principal components were retained for Uniform Manifold Approximation and Projection (UMAP) embedding based on elbow plot analysis. Harmony integration used default parameters (θ = 2 and λ = 1) with convergence assessed over 20 iterations. Doublet detection was performed using DoubletFinder (v2.0.3) with an estimated doublet rate of 4.0%; additionally, cells with >40% ribosomal protein gene reads were excluded. Batch correction quality was validated using the Local Inverse Simpson's Index, Adjusted Rand Index, and silhouette coefficient metrics. Real-time quantitative PCR and enzyme-linked immunosorbent assay (ELISA) quantified expression of four candidate RNT-relevant genes-MICA, MICB (NKG2D ligands; primary radionuclide targeting molecules), SUSD1 (immunosuppressive upregulator; potential RNT resistance mediator), and STAG3L1-in HeLa, SiHa, and normal HCerEpiC cell lines. Five independent biological replicates were performed per cell line, each with three technical replicates, following Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Shapiro-Wilk normality testing and Levene's test for homogeneity of variance were applied prior to all parametric analyses. RESULTS: Cervical cancer scRNA-seq profiles revealed significantly depleted cluster of differentiation 8 (CD8)+ T cells (mean difference: -0.12; 95% CI: [-0.16, -0.08]; Cohen's d = 1.45) and natural killer (NK) cells (Cohen's d = 1.12), with increased CD25+ regulatory T cells (+0.08; 95% CI: [+0.05, +0.11]), establishing an RNT-unfavorable immunosuppressive TME. Comparative benchmarking against RNT-responsive tumor types, neuroendocrine tumors and prostate-specific membrane antigen (PSMA) positive prostate cancer, confirmed that cervical cancer exhibits a combination of reduced target surface density, depleted NKG2D-effector populations, and enriched immunosuppressive subsets collectively predictive of attenuated RNT efficacy. Experimental validation confirmed dramatic downregulation of MICA (HeLa: 0.44 ± 0.07 relative expression, < 0.001, = 5) and MICB (HeLa: 0.51 ± 0.09, < 0.05), translating to markedly reduced MICA protein secretion (124.3 ± 18.5 pg/mL in HeLa versus 285.4 ± 31.2 pg/mL in controls, < 0.01). Concurrently, SUSD1 was markedly upregulated (HeLa: 2.28 ± 0.25-fold; protein 3.42 ± 0.45 ng/mg, < 0.001, = 5). Strong mRNA-protein correlations, r = 0.78-0.92, < 0.001; computed from five independent biological replicates per cell line; coefficient of variation (CV) < 15% for all measurements, validated transcriptomic profiling as a reliable proxy for theranostic target protein density estimation. CONCLUSIONS: This integrative study reveals that MICA/MICB downregulation and SUSD1 upregulation converge to suppress NKG2D-mediated antitumor immunity in cervical cancer, creating an immune-cold TME that limits current immunotherapy and radionuclide targeting efficacy. The NKG2D ligand expression landscape mapped here delineates a precision RNT strategy: scRNA-seq-guided patient stratification, radiolabeled anti-MICA/MICB nanobody theranostic imaging to confirm surface target density, and combination radioimmunotherapy integrating MICA/MICB re-expression induction with targeted radionuclide delivery to selectively irradiate the NKG2D-ligand-negative tumor cell population.

PURPOSE: Non-Hodgkin lymphoma (NHL) is a heterogeneous group of cancers. Published recommendations and guidelines for fertility preservation are very general and heterogeneous. Therefore, a very first meta-analysis analyzing the worldwide-published data on the risk of infertility after treatment of NHL is required to better counsel patients regarding fertility issues and to develop further strategies to evaluate the gonadotoxicity of treatments in NHL. METHODS: A systematic literature search was conducted using Medline, Embase, and Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials (CENTRAL), including articles published since 2000. Exclusion criteria were cases with disease relapse, follow-up of <1 year, testicular NHL, studies with <40% reproductive markers, and case reports. A total of 4602 records were identified. For the systematic review, 58 studies met the inclusion criteria. In this meta-analysis, 51 studies were included. RESULTS: The prevalence of expected infertility is 27% (95% confidence interval [CI] 0.20-0.37) overall, 23% (95% CI: 0.14-0.35) in females, and 35% (95% CI: 0.27-0.44) in males. It is highest after chemotherapy and radiotherapy to the pelvis and testis ± bone marrow transplantation, 43% (95% CI: 0.20-0.69) in females and 57% (95% CI: 0.21-0.86) in males. After alkylating agents in females, it is 24% (95% CI: 0.17-0.34). CONCLUSION: The results of this review and meta-analysis indicate a broad heterogeneity of data regarding the risk of infertility. Therefore, fertility counseling and, if necessary, fertility preservation measures are mandatory before oncologic treatment for NHL. Prospective studies stratified by chemotherapy regimen and including new treatment regimens are urgently needed.

The Australian Magnetic Resonance Imaging (MRI) Linear Accelerator program (MRI linac) was a major research project that aimed to build and test a unique MRI linac prototype for cancer treatment. It aimed to improve radiotherapy anatomical targeting and explore physiological targeting. The purpose of this report is to summarise the development and achievements of the program so as to provide an example of a successful large-scale research project in Australian radiation oncology. The project involved six Australian universities and international collaborators. We developed and built a unique MRI linac configuration comprising a 1 T magnetic field and a 6 MV accelerator, with the beam delivered in line with B and the patient placed across B in the split between the two halves of the magnet. The broad research domains were personalised disease targeting, medical device innovation, and biodiscovery. Specific projects included Artificial Intelligence image enhancement, radiation dosimetry in high magnetic fields, MRI characterisation of cancer heterogeneity in human tumours, and animal and human studies. Over $27 million was obtained to support the program from competitive sources. The program published over 120 papers and supported 25 PhD completions. The learnings from the Australian MRI linac program are that Australia has world-class radiotherapy research in physics and engineering, that major projects need a lot of time and a lot of collaboration, and that large, novel radiotherapy projects can attract significant funding and produce significant results.

OBJECTIVES: This study aimed to compare the efficacy of administering carbetocin before versus after placental delivery in preventing PPH in low-risk vaginal deliveries. METHODS: The randomized controlled trial was conducted at Kartal City Hospital, Istanbul, Turkey. A total of 160 primiparous women with uncomplicated pregnancies who underwent vaginal delivery were enrolled. Participants were randomly assigned to receive 100 mcg of carbetocin either before or after placental delivery. The primary outcome was the incidence of PPH. Secondary outcomes included the need for additional uterotonics, manual removal of the placenta with consequent antibiotic administration, blood transfusions, maternal adverse events, and changes in hemoglobin levels at baseline and 24 h postpartum. RESULTS: The incidence of PPH was significantly lower in the carbetocin-before group than in the carbetocin-after group (p=0.015). The carbetocin-before group had a significantly lower mean hemoglobin drop compared to the carbetocin-after group (p<0.001). The need for additional uterotonics was significantly higher in the carbetocin-after group (p<0.001). Manual placenta removal and the need for antibiotics were more frequent in the carbetocin-before group (p=0.017). No significant differences in adverse maternal events were observed between the groups. CONCLUSIONS: Administering carbetocin before placental delivery significantly reduces the incidence of PPH, blood loss, and the need for additional uterotonics. However, the increased rate of manual placenta removal necessitates individualized risk-benefit assessment; pre-placental administration may be most advantageous in women at elevated risk for PPH, in whom the hemorrhagic benefit outweighs the risks associated with manual extraction.

BACKGROUND: Readmission is considered as a surgical quality indicator. More data regarding predictors of readmission and outcomes after surgery for colorectal liver metastasis are needed. Using a propensity score match to create a 1:2 match of cases:controls for 90-day. Readmission, the matching variables used for balance included age, tumor size, estimated blood loss, and type of resection (minor or major). T-tests were used for continuous measures, Fisher's exact test was used for categorical data, and the Kaplan-Meier method was used to estimate survival. p < 0.05 was considered significant. METHODS: Retrospectively examined 935 patients with CLM from 2000 to 2018. Using a propensity score match to create a 1:2 match of cases:controls for 90-day. Readmission, the matching variables used for balance included age, tumor size, estimated blood loss, and type of resection (minor or major). T-tests were used for continuous measures, Fisher's exact test was used for categorical data, and the Kaplan-Meier method was used to estimate survival. p < 0.05 was considered significant. RESULTS: 935 patients were included in the initial sample with 896 eligible for inclusion in the propensity matching. The average age of the population was 59% and 59% male. Overall readmission rate was 8.0%. Median time to readmission was 14 days. In the propensity score matched sample, readmitted patients had higher rates of organ space infection (28% vs 2% and p < 0.0001), bile leak (26% vs 1% and p < 0.0001), and liver failure (9% vs 2% and p = 0.042). There was no difference in LOS (7 days versus six days and p = 0.40), overall survival (median 39.7 vs 41.0 months and p = 0.79), or rate of adjuvant therapy (68% for both and p > 0.99). CONCLUSION: Patients readmitted for intermediate and late complications after surgery for CLM can recover and receive adjuvant therapy with no adverse effect on overall survival. Organ space infection, bile leak, and liver failure are highly associated with readmission.

PURPOSE OF REVIEW: Drug-induced anaphylaxis during pregnancy, although uncommon, represent potentially serious clinical situation with significant maternal-fetal impact and relevant therapeutic implications. This topic is particularly timely given the need for guidance of health professionals dealing with this challenge and correct labelling patients with drug allergy/hypersensitivity. RECENT FINDINGS: Recent studies report a high prevalence of self-reported β-lactam allergy during pregnancy, with poor correlation with true allergy, underscoring the value of structured, safe, and effective diagnostic evaluation for appropriate delabeling. SUMMARY: These findings highlight the need for a systematic approach to drug-induced anaphylaxis in pregnancy, including accurate diagnosis and protocol-based management. Incorporating allergological evaluation into prenatal care can reduce unnecessary risks, optimize maternal and fetal outcomes, and promote rational medication use. Important knowledge gaps remain, emphasizing the need for prospective studies with standardized methodologies and expanded immunological assessment.

INTRODUCTION: Male infertility is increasingly recognized as a systemic condition associated with impaired long-term health, yet clinically applicable frameworks linking reproductive dysfunction to comorbidity burden remain limited. Here, we investigated whether a composite immuno-metabolic signature could capture comorbidity burden and reduced reproductive capacity in men with primary male factor infertility (MFI). METHODS AND MATERIALS: In a cross-sectional cohort of 2953 men, metabolic and inflammatory variables were systematically screened for directional and independent associations with comorbidity burden, defined by the Charlson Comorbidity Index (CCI) ≥1, and impaired reproductive capacity, assessed by total motile sperm count (TMSC) <5 million. Three variables-LDL cholesterol, waist circumference, and C-reactive protein (CRP)-met selection criteria and were integrated into an unweighted standardized score. RESULTS: Three variables met selection criteria: LDL cholesterol, waist circumference, and C-reactive protein. Higher immuno-metabolic scores were observed in men with comorbidity burden (0.20 ± 0.73 vs. -0.02 ± 0.62, p < 0.001) and in those with TMSC <5M (0.13 ± 0.64 vs. -0.07 ± 0.62, p < 0.001). Each unit increase in the score was independently associated with comorbidity burden (OR 1.50, 95% CI 1.23-1.82, p < 0.001) and TMSC <5M (OR 1.67, 95% CI 1.48-1.89, p < 0.001). Predicted probabilities rose across the score range from 2% to 40% for comorbidity and from 12% to 75% for reduced reproductive capacity. CONCLUSION: These findings identify a biologically coherent immuno-metabolic signature linking spermatogenic impairment with systemic comorbidity in men with primary MFI and support a model in which male infertility reflects broader immuno-metabolic vulnerability. Prospective external validation is warranted before clinical implementation.

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely used to treat patients with malignant and nonmalignant hematologic disorders. The development of secondary malignancies is recognized, especially secondary oral squamous cell carcinoma (OSCC). This study aimed to evaluate and summarize the risk factors for secondary OSCC after allo-HSCT. STUDY DESIGN: The search was conducted in 3 electronic databases for studies published up to May 2025. The quality of the identified studies was evaluated using the Newcastle-Ottawa Quality Assessment Scale for nonrandomized studies. The results were presented as risk ratios (RRs) with corresponding 95% confidence intervals (95% CI). RESULTS: Overall, 15 924 patients from 16 studies were included in the systematic review. The results show that, among many factors involved in HSCT, chronic graft-versus-host disease (cGVHD; RR = 4.01, 95% CI = 1.91-8.39, p = 0.0002), malignant primary diagnosis (RR = 0.40, 95% CI = 0.19-0.84, p = 0.02), and intensity of conditioning myeloablative therapy (RR = 0.41, CI = 0.17-0.98, p = 0.04) were found to be risk factors for secondary OSCC after allo-HSCT. CONCLUSION: Patients with cGVHD, with a primary diagnosis of malignant disease, or myeloablative intensity of conditioning are more likely to develop secondary OSCC. Our analysis of the literature shows patients after allo-HSCT that required close follow-up, especially examining oral mucosa regularly.

Siglec-15 has emerged as a therapeutic target in cancer, yet the glycan determinants and protein scaffolds that mediate engagement between Siglec-15-expressing myeloid cells and tumor cells remain incompletely defined. Here, we investigated the molecular basis of Siglec-15 recognition of cancer cells and examined transcriptional as well as functional programs associated with Siglec-15 expression in tumor-associated myeloid populations. Using immunoprecipitation-mass spectrometry in the pancreatic cancer cell line AsPC-1, we identified multiple mucin-domain glycoproteins enriched in Siglec-15 pulldowns. Disruption of glycan structures demonstrated that both complex N-glycans and extended mucin-type O-glycans contribute to optimal Siglec-15 binding. To define the myeloid population associated with Siglec-15 in human tumors, we interrogated publicly available single-cell RNA sequencing datasets and found that SIGLEC15 expression is enriched within a subset of tumor-associated myeloid cells exhibiting transcriptional features linked to osteoclast differentiation and extracellular matrix remodeling. Finally, in a THP-1 coculture model, Siglec-15 was further associated with DAP12-dependent tumor-induced expression of the osteoclast markers ACP5 and MMP9, together with increased release of IL-1β and IL-6. Collectively, these findings identify glycan and glycoprotein features that support Siglec-15 binding to malignant cells and associate SIGLEC15 expression with osteoclast-like and matrix-remodeling myeloid programs in human cancers, providing a framework for mechanistic studies of this glyco-immune checkpoint.

Chronic systemic inflammation is a key driver of disease progression in rheumatoid arthritis and chronic kidney disease (CKD), particularly in patients undergoing long-term hemodialysis. Persistent elevation of proinflammatory cytokines contributes to pain, anemia, endothelial dysfunction, and increased cardiovascular risk, while therapeutic options are often limited by comorbidities and drug intolerance. Mesenchymal stem cells (MSCs) possess immunomodulatory properties that may offer an alternative strategy for systemic inflammatory control. We report on the case of a 56-year-old woman with juvenile-onset rheumatoid arthritis and dialysis-dependent CKD who received three consecutive systemic administrations of MSCs. Baseline evaluation demonstrated elevated inflammatory markers, including C-reactive protein, interleukin-6, and tumor necrosis factor-α. Following treatment, inflammatory parameters were consistently reduced, which was accompanied by improvement in hemoglobin levels and favorable trends in renal function markers. Additionally, pain assessment scores (Western Ontario and McMaster Universities Arthritis Index, Knee Injury and Osteoarthritis Outcome Score, Visual Analogue Scale) showed clinically significant improvement. The patient also reported significant subjective pain relief and improved overall well-being. Although limited by its single-case design, this report supports the biological plausibility of systemic MSC therapy as a potential immunomodulatory approach in patients with overlapping autoimmune and uremia-associated chronic inflammation. Further controlled studies are warranted.

Chemotherapy-induced intestinal mucositis is a frequent and dose-limiting toxicity that compromises cancer treatment outcomes and lacks effective targeted interventions. Here, we investigate the mechanisms by which the nonabsorbable antibiotic rifaximin mitigates chemotherapy-induced intestinal injury, focusing on microbiota-mediated preservation of epithelial barrier integrity. In a murine model of 5-fluorouracil (5-FU)-induced intestinal injury, rifaximin pretreatment reduced mucosal inflammation and tissue damage, preserved epithelial and mucus barrier integrity, and limited systemic endotoxemia. Importantly, rifaximin did not impair the antitumor efficacy of 5-FU in ApcC3arKO mice. To assess translational relevance, we employed a human intestinal organ culture system (EVOC) and found that rifaximin preserved mucosal architecture, mucus balance, and tight junction integrity following inflammatory challenge. Microbiome profiling revealed that rifaximin reshaped the intestinal microbial community, preventing the depletion of health-associated taxa, including and . Functional experiments demonstrated that supplementation alone attenuated 5-FU-induced injury, reproducing key protective features of rifaximin treatment. Together, these findings identify as a microbial contributor to rifaximin's protective effects, supporting its potential role as a safe adjunctive strategy to improve gastrointestinal tolerability of cancer treatment.

Cytokinins (CKs) are adenine-derived metabolites traditionally characterized as plant hormones, yet their origin, distribution, and functions in mammalian systems remain largely undefined. Using integrated metabolomics, microbiome, and metagenomics approaches, we provide a systematic characterization of CK occurrence and potential sources in mammals. Serum profiling across five animal species revealed consistent detection of multiple CK derivatives, with concentrations markedly lower than in plant tissue. The CK storage form, zeatin-O-glucoside, predominated in mammalian sera, followed by trans-zeatin and kinetin, indicating a CK composition distinct from that in plants. Species-specific differences, such as reduced trans-zeatin in mice and lower kinetin in humans, further suggest divergent regulatory patterns. In mice, CKs were present in vascular tissues of the kidney, heart, and liver, demonstrating systemic distribution. Dietary manipulation showed that starvation significantly reduced CK abundance in serum, colon, feces, and urine, confirming that diet is a major contributor to the mammalian CK pool. Meta-omics analysis of gut microbiomes identified CK-related genes across multiple microbial taxa, with the highest representation in human microbiomes, followed by those of mouse and pig. Germ-free mouse experiments showed substantially lower CK levels than conventionally raised counterparts, establishing a microbiome-dependent contribution. Collectively, our findings identify CKs as diet and microbiome modulated metabolites in mammals, warranting future investigation to elucidate their physiological significance in mammalian biology.

BACKGROUND: There are few objective tools to quantify lymphatic disease changes in anatomy and physiology of affected tissues. Tissue sodium could be a relevant physiological indicator of lymphatic disease. However, the importance of sodium to lymphatic physiology in humans has not been well-characterized nor exploited for clinical applications due to a lack of imaging methods to observe sodium and lymphatics together . The purpose of this study was to apply Na-MRI to measure tissue sodium content (TSC) in human subjects with or without lower extremity lymphedema (LEL) and investigate the relationship between lymphatic dysfunction and tissue sodium. METHODS AND RESULTS: A prospective, cross-sectional observational clinical trial enrolled participants with LEL and controls without lymphedema. Na-MRI measured standardized TSC in the mid-calf. For each leg with lymphedema, clinical stage was determined by a licensed clinician, and lymphedema severity was determined by radiology assessment of noncontrast hydrogen (H)-magnetic resonance lymphangiography (MRL). Linear mixed-effects models determined differences in TSC between cases and controls and measured the association of TSC with clinical stage and lymphedema severity. Image subregions were analyzed to observe spatial patterns of TSC involvement. Results found that TSC was nearly 50% higher in lymphedema ( = 52 legs) in the skin (1.51-fold) and adipose tissue (1.47-fold) compared with controls ( = 31 legs; < 0.001) and was directly related to both clinical stage and lymphedema severity by H-MRL in the skin ( < 0.001) and adipose tissue ( < 0.001). TSC accumulated in patterns in the anterior subcutaneous adipose tissue, increasing with disease severity. CONCLUSION: Na-MRI demonstrates that standardized TSC is distinctly elevated in lymphedema, sensitive to lymphedema disease severity, and a potential objective imaging tool for evaluating lymphedema in future clinical trials.

Pyroptosis has emerged as a promising antitumor strategy offering unique advantages in overcoming apoptosis resistance and activating antitumor immunity. However, the development of drugs capable of achieving spatiotemporally controlled pyroptosis remains a challenge. Herein, we engineered a folate-targeted liposomal nanoplatform to deliver a Ru(II) complex photosensitizer (Ru-Thi@Lipo-FA) for pyroptosis-mediated photodynamic therapy. The Ru(II) complex (Ru-Thi), acting as a photosensitizer, can produce singlet oxygen and superoxide anions and facilitate the photocatalytic oxidation of NADH through multiple mechanisms to kill tumor cells under white light irradiation. Additionally, we encapsulated the complex within folic acid-modified liposomes, which markedly boosted cellular uptake efficiency and tumor targeting, leading to improved therapeutic effects. Mechanistic investigations demonstrated that light-triggered reactive oxygen species generation activates the caspase-3/GSDME-mediated pyroptosis pathway. This study demonstrated a rationally designed, targeted nanoplatform that utilizes a multifunctional Ru(II)-based photosensitizer and induces pyroptosis, providing a viable approach to improve the efficacy of tumor photodynamic therapy.

BACKGROUND: Oxidative stress plays a pivotal role in the pathogenesis of heart failure and is closely linked to myocardial remodeling, which includes myocardial hypertrophy and fibrosis. Chrysin (CHR) has multiple medicinal effects such as antioxidant, anti-inflammatory, and anti-apoptosis. This research seeks to investigate whether CHR can protect against pressure overload-induced myocardial remodeling and to explore the underlying mechanism. METHODS: Transverse aortic constriction (TAC) surgery was conducted to establish a model of cardiac hypertrophy on male C57BL/6J mice. A model of cardiomyocyte hypertrophy in H9C2 cells induced by angiotensin II (Ang II) was also established. RESULTS: The results showed that CHR significantly improved survival and cardiac function, reduced myocardial hypertrophy and fibrosis, inhibited the expression of inflammatory mediators TNF-α and IL-1β, suppressed cell apoptosis rate, downregulated the levels of Bcl-2 Associated X protein (BAX) and Cleaved-Caspase-3, and upregulated B-cell lymphoma/leukemia 2 (BCL-2) expression in TAC surgical mice or Ang II-treated H9C2 cells. CHR could also upregulate the levels of antioxidant enzymes SOD1 and HO-1 by mediating the nuclear translocation and expression of NRF2 to counteract oxidative stress response. The further mechanism investigation utilizing bioinformatics analysis and western blot revealed that the disease of heart failure is associated with the phosphatidylinositol‑3‑kinase (PI3K)/serine/threonine-protein kinase B (AKT) signaling pathway. CONCLUSIONS: Collectively, our findings demonstrated that CHR might exert the improvement effects on pressure overload-induced myocardial remodeling with hypertrophy and fibrosis through regulating the PI3K/AKT/NRF2 pathway-mediated oxidative stress response to alleviate myocardial cell inflammation and apoptosis, suggesting that CHR may be a promising therapeutic agent for cardiac diseases induced by pressure overload.

Apatinib combined with CAPTEM (capecitabine plus temozolomide) has demonstrated preliminary activity in neuroendocrine tumours, yet head-to-head comparative efficacy data against standard-of-care sunitinib remain lacking. This study aims to evaluate the efficacy and safety of both regimens in advanced GEP-NETs using real-world data. This retrospective analysis examined patients with advanced GEP-NETs treated with either apatinib plus CAPTEM or sunitinib.Baseline characteristics (e.g. pathological grade, hepatic tumour burden) were balanced between groups using 1:1 propensity score matching (PSM). The primary endpoint was progression-free survival (PFS), with secondary endpoints including overall survival (OS), objective response rate (ORR), and safety. A total of 150 patients were included in the analysis, with 52 patients in each group after PSM. Following matching, the median PFS was significantly longer in the apatinib plus CAPTEM group compared with the sunitinib group (not reached [NR] [95% CI: 36.6-NR] vs 17.9 months [95% CI: 8.0-18.0]; hazard ratio [HR] = 0.17, 95% CI: 0.08-0.36;  < 0.001). The combination therapy group also demonstrated a significant OS benefit (52.0 months [95% CI: 48.1-58.0] vs 16.4 months [95% CI: 12.7-22.1]; HR = 0.10, 95% CI: 0.05-0.22;  < 0.001). The ORR was numerically higher in the combination group than in the sunitinib group (65.4% vs 50.0%,  = 0.164). Regarding safety, the sunitinib group exhibited higher rates of hand-foot syndrome and diarrhoea, whilst the combination group did not experience any unexpected severe toxicities. In a PSM-matched cohort of advanced GEP-NETs, apatinib combined with CAPTEM was associated with improved PFS and OS, together with a numerically elevated ORR. Given the retrospective design and the potential for residual confounding, these findings should be considered hypothesis-generating and warrant prospective validation.

BACKGROUND: Treatment of laryngeal squamous cell carcinoma (SCC) requires specialized expertise. While high-volume facilities demonstrate superior outcomes, the relationship between facility volume and travel distance on survival remains poorly understood. METHODS: Retrospective cohort study using the National Cancer Database (2004-2022) of adults with laryngeal SCC receiving definitive treatment. Risk-adjusted restricted cubic splines characterized non-linear survival relationships, guiding development of multivariable Cox-proportional hazards regression models. RESULTS: Among 106 700 patients, an inflection point was identified at 10 cases/year. Below this threshold, volume had no effect (HR 1.00 [95% CI: 0.97-1.03]); above it, each doubling was associated with an 11% mortality reduction (HR 0.89 [0.84-0.94]). Travel distance showed a paradoxical protective effect (HR 0.97 [0.96-0.99]), but only in advanced-stage disease (HR 0.96 [0.94-0.97]), with no effect in early-stage disease. CONCLUSIONS: A 10-case/year threshold exists for laryngeal SCC care. Early-stage disease can be treated at facilities meeting this, while advanced-stage disease may warrant referral to higher-volume centers.

Neutropenic sepsis remains a life-threatening complication in patients undergoing cytotoxic chemotherapy or haematopoietic stem cell transplantation. A comprehensive literature search was conducted across PubMed, Embase, and the Cochrane Library through December 2025, focusing on clinical trials, observational studies, and population PK analyses involving neutropenic or febrile neutropenic patients in both adult and paediatric haematology and oncology populations. Pathophysiological changes in neutropenic sepsis-including augmented renal clearance, increased volume of distribution, and hypoalbuminemia-lead to substantial PK variability and frequent target non-attainment with standard dosing. Animal models consistently demonstrate that higher PK/PD targets are required in the absence of neutrophils. PK/PD-guided dose optimisation appears highly beneficial in neutropenic sepsis, although prospective randomised evidence specifically in this population remains limited. Integration of TDM, population PK modelling, and Bayesian dose adaptation into routine clinical practice represents a promising avenue towards improved outcomes, recognising that implementation will depend on locally available laboratory and pharmacy resources.

BACKGROUND: IDH2 mutations occur in a small subset of intrahepatic cholangiocarcinoma and currently lack approved targeted therapies. CASE PRESENTATION: We report a post-transplant patient with IDH2-mutant intrahepatic cholangiocarcinoma who developed recurrent disease following multiple treatments for hepatocellular carcinoma and subsequent liver transplantation. Comprehensive genomic profiling revealed an IDH2 p. R172K mutation. Given limited treatment options and contraindications to immunotherapy, off-label treatment with the dual IDH1/2 inhibitor vorasidenib was initiated. RESULTS: The patient achieved a durable radiographic and molecular response, with reduction in circulating tumor DNA and partial response by RECIST criteria sustained for approximately one year. CONCLUSION: This case highlights the potential clinical relevance of IDH-directed therapy in IDH2-mutant cholangiocarcinoma and demonstrates feasibility in an immunosuppressed post-transplant setting. These findings are hypothesis-generating and support further evaluation of IDH inhibition in this population.

BACKGROUND: Hand-foot syndrome (HFS) is a complication of many anticancer therapies and negatively affects patients' quality of life (QoL). Currently, little data are available on using non-pharmacological skin products as standard therapy for HFS. AIM: This study aims to investigate whether a specific set of cosmetic products is effective for managing HFS skin side effects in cancer patients. MATERIAL AND METHODS: This single-arm study involved 53 cancer patients with grade 1 of HFS undergoing chemotherapy, targeted, or hormonal treatments at the European Institute of Oncology (IEO). The study included a baseline visit and a follow-up visit 45 days later. All enrolled patients were prescribed a set of four cosmetic products for skin treatment. Patients underwent instrumental measurement to evaluate skin hydration and erythema while their QoL was assessed using the Skindex-16 self-questionnaire. Additionally, physicians clinically evaluated the HFS severity, using the CTCAE (Common Terminology Criteria for Adverse Events) scale and by comparing patient photographs. RESULTS: No patients worsened. After 45 days, the application of the cosmetic set increases skin hydration by 33% (p < 0.0001), while skin erythema decreases by 82,9% (p < 0.0001). Patients also showed a significantly lower mean Skindex-16 score at 45 days (-35.5%, p < 0.0001) compared to baseline. These findings were associated with clinical improvement in HFS-related skin symptoms in 58.5% of patients. CONCLUSIONS: These results show that a set of cosmetic products specific for cancer skin care can effectively manage HFS-related symptoms, resulting in improved QoL for patients, regardless of the anticancer treatment received.