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"Primary neuroendocrine breast carcinoma (NEBC) is an underdiagnosed subtype of breast cancer, which includes small cell (SCNEC) and large cell neuroendocrine carcinomas (LCNEC). Accurate diagnosis remains challenging given their low incidence; misclassification as invasive breast carcinoma of no special type (IBC-NST), invasive ductal carcinoma (IDC), or a metastatic neuroendocrine carcinoma may occur. Cases with any component of adenocarcinoma and well-differentiated neuroendocrine tumors were excluded. A search of the pathology database (2012-2024) revealed six female patients (27-85 years) with a final pathologic diagnosis of NEBC (stages IA-IV), including four diagnosed with LCNEC and two with SCNEC. Even though most NEBC cases (5 of 6; 83%) were of the luminal subtype, five of six patients (83%) developed distant metastases within 4 years of the initial diagnosis. Molecular profiling of six cases revealed common alterations in the FGF/FGFR and PI3K/AKT/mTOR pathways. In summary, primary neuroendocrine carcinomas of the breast display aggressive behavior. However, they are more likely to harbor certain alterations, such as activating Show less

Sciatica, often resulting from lumbar disc herniation or nerve compression, disrupts electrical signal transmission, leading to muscle atrophy, mitochondrial dysfunction, and impaired energy metabolism. This study explored the therapeutic effects of Fu's subcutaneous needling (FSN) in a chronic constriction injury (CCI) rat model, assessing its impact on neuropathic pain, muscle mass, and structural integrity. Histological and ultrastructural analyses demonstrated that FSN alleviated hypersensitivity, reduced muscle atrophy, preserved mitochondrial density, and maintained glycogen storage. Gene expression and pathway enrichment analyses revealed FSN's involvement in PI3K-Akt, MAPK signaling, oxidative phosphorylation, and mitophagy, suggesting its role in modulating energy metabolism and cellular repair. FSN also normalized energy-related proteins FGFR1, FGFR3 and phosphorylated FOXO3, highlighting their significance in muscle repair and regeneration. These findings provide novel insights into FSN's potential for counteracting neuropathy-induced muscle damage and improving mitochondrial function, supporting its clinical application. Additionally, FSN's role in muscle repair suggests a connection between growth factor signaling and nerve regeneration, offering a foundation for future research on muscle-neural recovery mechanisms. Show less

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide and is increasingly diagnosed in younger populations. Conventional biopsy techniques can be invasive and may not accurately capture tumor heterogeneity. Liquid biopsy, analyzing circulating tumor DNA (ctDNA), offers a minimally invasive and dynamic alternative for detecting genetic alterations critical to early diagnosis and personalized treatment strategies. We analyzed serum-derived ctDNA from 20 HCC patients to identify genetic variants using next-generation sequencing (NGS). Mutations in key oncogenes and tumor suppressor genes (eg, KIT, FGFR1, FGFR3, EGFR, BRAF, FBXW7) were evaluated for their association with clinical outcomes, including tumor size, metastasis, and overall survival. Statistical analyses were performed using SPSS (v.30), with survival curves assessed via the Kaplan-Meier method. Of the 20 patients (mean age 64.8±13.1 years), 35% had detectable ctDNA mutations. The most frequently observed alterations were in KIT (28.6% of ctDNA-positive patients), followed by FGFR1, FGFR3, EGFR, BRAF, and FBXW7. Patients harboring FGFR1 and FGFR3 mutations exhibited the poorest survival (3 and 7 months, respectively). Conversely, one patient with a BRAF mutation showed prolonged survival (60 months), and KIT mutations were linked to comparatively better outcomes. Overall, ctDNA-positive patients demonstrated shorter mean survival (22.5 months) than ctDNA-negative patients (35.7 months). Liquid biopsy-detected genetic alterations correlate with clinical outcomes in HCC, underscoring the prognostic value of ctDNA analysis. Mutations in FGFR1 and FGFR3 were associated with aggressive disease, suggesting these pathways as potential therapeutic targets. Integrating liquid biopsy with other diagnostic modalities may enhance personalized management and improve prognosis for patients with HCC. Show less

Lupus nephritis is recognized as a common and severe complication of systemic lupus erythematosus, without an optimal therapeutic strategy currently available. While mesenchymal stem cells (MSCs) hold therapeutic promise, their efficacy varies substantially, likely due to their plasticity and capacity to adopt pro-inflammatory (MSC1) or anti-inflammatory (MSC2) functional states in response to different microenvironments. Here, we report for the first time that IL-27, via JAK1-STAT1 signaling, up-regulates indoleamine 2,3-dioxygenase (IDO) in MSCs, driving MSC differentiation toward an IDO-positive MSC2 phenotype with low immunogenicity. These IDO-positive MSC2 cells produce kynurenine and kynurenic acid, the metabolites of tryptophan, which bind to the intracellular aryl hydrocarbon receptor. This interaction stimulates an increase in the anti-inflammatory factor TSG-6 and induces the differentiation of regulatory T cells. Notably, IL-27-conditioned MSC2 demonstrated superior therapeutic efficacy compared to conventional MSCs in a murine lupus nephritis model. In conclusion, this study revealed that IL-27 is a critical modulator of MSC immune plasticity and presented a novel therapeutic strategy utilizing IL-27-enhanced MSC2 for autoimmune diseases. Show less

Cranial neural crest cells (CNCs) play a critical role in craniofacial bone morphogenesis, engaging in intricate interactions with various molecular signals to ensure proper development, yet the molecular scaffolds coordinating these processes remain incompletely defined. Here, we identify neurofibromin 2 (Nf2) as a critical regulator to direct CNC-derived skull morphogenesis. Genetic ablation of Nf2 in murine CNCs causes severe craniofacial anomalies, featuring declined proliferation and increased apoptosis in osteoprogenitors, impaired type I collagen biosynthesis and trafficking, and aberrant osteogenic mineralization. Mechanistically, we uncover that Nf2 serves as a molecular linker that individually interacts with FGF receptor 1 (FGFR1) and Akt through spatially segregated phosphor-sites, and structural modeling and mutagenesis identified Ser10 and Thr230 as essential residues, with Thr230 mutation selectively ablating Akt binding while preserving FGFR1 association. Strikingly, Akt inhibition phenocopied Nf2 deficiency, reducing collagen production and Nf2 phosphorylation, whereas phospho-mimetic Nf2 (T230D) rescued CNC-derived osteogenic defects in Nf2-mutant animals. Our findings underscore the physiological significance of Nf2 as a phosphorylation-operated scaffold licensing the FGFR1/AKT axis to regulate collagen type I biogenesis and trafficking, ensuring normal CNC-derived osteogenesis and craniofacial bone development, thus exposing the Nf2/FGFR1/AKT signaling axis as a therapeutic target and promising advancements in treatment of craniofacial anomalies. Show less

Gastric cancer (GC) remains a leading cause of cancer-related mortality worldwide, with significant racial and ethnic disparities in incidence, molecular characteristics, and patient outcomes. However, genomic studies focusing on Hispanic/Latino (H/L) populations remain scarce, limiting our understanding of ethnicity-specific molecular alterations. This study aims to characterize pathway-specific mutations in TP53, WNT, PI3K, TGF-Beta and RTK/RAS signaling pathways in GC and compare mutation frequencies between H/L and Non-Hispanic White (NHW) patients. Additionally, we evaluate the impact of these alterations on overall survival using publicly available datasets. We conducted a bioinformatics analysis using publicly available GC datasets to assess mutation frequencies in TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway genes. A total of 800 patients were included in the analysis, comprising 83 H/L patients and 717 NHW patients. Patients were stratified by ethnicity (H/L vs. NHW) to evaluate differences in mutation prevalence. Chi-squared tests were performed to compare mutation rates between groups, and Kaplan-Meier survival analysis was used to assess overall survival differences based on pathway alterations among both H/L and NHW patients. Significant differences were observed in the TP53 pathway and related genes when comparing GC in H/L patients to NHW patients. TP53 mutations were less prevalent in H/L patients (9.6% vs. 19%, p = 0.03). Borderline significant differences were noted in the WNT pathway when comparing GC in H/L patients to NHW GC patients, with WNT alterations more frequent in H/L GC (8.4% vs. 4%, p = 0.08), and APC mutations significantly higher (3.6% vs. 0.8%, p = 0.05). Although alterations in PI3K, TGF-Beta and RTK/RAS pathways were not statistically significant, borderline significance was observed in genes related to these pathways, including EGFR (p = 0.07), FGFR1 (p = 0.05), FGFR2 (p = 0.05), and PTPN11 (p = 0.05) in the PI3K pathway, and SMAD4 (p = 0.08) in the TGF-Beta pathway. Survival analysis revealed no significant differences among H/L patients. However, NHW patients with TP53 and PI3K pathway alterations exhibited significant differences in overall survival, while those without TGF-Beta pathway alterations also showed a significant survival impact. In contrast, WNT pathway alterations were not associated with significant survival differences. These findings suggest that TP53, PI3K, and TGF-Beta pathway disruptions may have distinct prognostic implications in NHW GC patients. This study provides one of the first ethnicity-focused analyses of TP53, WNT, PI3K, TGF-Beta and RTK/RAS pathway alterations in GC, revealing significant racial/ethnic differences in pathway dysregulation. The findings suggest that TP53 and WNT alterations may play a critical role in GC among H/L patients, while PI3K and TGF-Beta alterations may have greater prognostic significance in NHW patients. These insights emphasize the need for precision medicine approaches that account for genetic heterogeneity and ethnicity-specific pathway alterations to improve cancer care and outcomes for underrepresented populations. Show less

Fel d1, the major cat allergen responsible for over 90% of human IgE-mediated allergies, has an incompletely defined physiological role. To explore its function and assess the feasibility of producing hypoallergenic cats, we knocked out the CH2 domain of Fel d1 using CRISPR/Cas9 in feline skin cells. An optimized sgRNA introduced a frameshift mutation, with knockout efficiency validated by sequencing, qRT-PCR, and Western blot. Transcriptomic alterations were profiled by RNA-seq, and functional consequences were investigated via GO, KEGG, and GSEA analyses. Key findings were confirmed by qPCR, and phenotypes were assessed using CCK-8, EdU, and flow cytometry. The approach successfully generated a three-base insertion, resulting in near-complete loss of CH2 mRNA and Fel d1 protein. RNA-seq identified 3,469 differentially expressed genes (DEGs), with significant enrichment in pathways for hypertrophic cardiomyopathy (HCM) and rheumatoid arthritis (RA). Key genes in these pathways (e.g., Show less

Anxiety is significantly correlated with levels of physical activity in university students. This research assessed the effects of anxiety on engagement in physical activity and explored the potential mediating function of psychological resilience. Additionally, latent profile analysis (LPA) was employed to identify distinct subtypes based on anxiety and resilience levels, and to explore their associations with physical activity. Utilizing a non-probability convenience sampling approach, this cross-sectional study recruited a total of 1,436 collegiate participants from multiple universities. Data collection was carried out with the Generalized Anxiety Disorder Scale (GAD-7), the abbreviated Connor-Davidson Resilience Scale (CD-RISC-10), and the Physical Activity Rating Scale (PARS-3). Data analysis included mediation effect analysis via Bootstrap methods (Model 4) and latent profile analysis (LPA). Anxiety demonstrated a significant negative association with physical activity ( Results demonstrated that anxiety affects physical activity both directly and indirectly, with the latter effect occurring through the channel of psychological resilience. Latent profile analysis identified three distinct profiles among college students based on anxiety and psychological resilience: High Anxiety-Low Psychological Resilience, Moderate Anxiety-Moderate Psychological Resilience, and Low Anxiety-High Psychological Resilience. Marked variations in physical activity levels were observed among these subgroups. The results underscore the complex relationships among mental health indicators and health behaviors within the collegiate population. The delineation of distinct profiles offers practical implications for designing tailored intervention strategies. Show less

Bone morphogenetic proteins (BMPs) and the fibroblast growth factor receptor 1 (FGFR1) gene play essential roles in the development and maintenance of the skeletal system. Brachydactyly is a genetic condition characterized by shortened or missing bones in the hands and feet. Several types of brachydactyly have been identified, each associated with different genetic mutations. However, some cases do not fit into existing classifications, necessitating further genetic investigation. A 34-year-old female patient with an absent middle phalanx in the second digit of her left foot and her 13-year-old son, who presented with absent or malformed middle and distal phalanx in all ten toes, are evaluated. Whole Genome Sequencing (WGS) analysis identifies a missense variant (c.1073A >T; p.K358M) in the BMP8A gene and a novel missense variant (c.1787C >T, p.Ser596Phe) in the FGFR1 gene. Functional protein association network analysis demonstrates a strong association of BMP8A and FGFR1 with other brachydactyly disease-causing genes. Given that these mutations have not been previously linked to any recognized brachydactyly subtype, they likely define a distinct genetic condition. The findings suggest a novel form of brachydactyly, which naming is proposed as brachydactyly type AB. Show less

Dyslipidemia and oxidative stress are key components in the pathophysiology of gestational diabetes mellitus (GDM), yet the contribution of genetic factors to these metabolic disturbances remains unclear. This study aimed to investigate the relationship between two lipid-related genetic polymorphisms, apolipoprotein C1 (apoC1) gene -317H1/H2 (rs1568822) and rs4420638, with GDM risk and lipid profiles and oxidative stress markers in Chinese populations. The apoC1 -317H1/H2 and rs4420638 polymorphisms were genotyped in 734 GDM patients and 1,102 control subjects. Genetic association with GDM risk and related traits were also analyzed. The distribution of genotype and allele in both polymorphisms were similar between the two groups. However, the combined H1H1/AG+GG genotype was significantly more frequent in women with GDM than in the control group. GDM patients who carried H1H1/AG+GG genotype were 1.97-fold increased risk to develop GDM (95% CI: 1.140-3.414, ApoC1 gene polymorphisms associate with GDM risk and affect the lipid profile. The combined H1H1/AG+GG genotype of the apoC1 gene polymorphisms appears to augment the propensity to develop GDM, while the rs4420638 polymorphism links to adverse lipid components in the patients. Further genetic studies to add information beyond the traditional risk factors in GDM and to identify risk genotypes will help in early prediction and identification of at-risk patients. Show less

Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase that catalyzes the trimethylation of histone H3 at lysine 27 (H3K27me3), has been implicated in promoting renal fibrogenesis. Nevertheless, its precise role and underlying mechanisms remain incompletely defined. To investigate the role of EZH2 in partial epithelial-mesenchymal transition (pEMT) and renal fibrosis, we utilized a mouse model with renal tubular cell-specific EZH2 deletion and administered gambogic acid (GA), a selective EZH2 degrader, following unilateral ureteral obstruction (UUO). In vitro, mouse renal epithelial cells were stimulated with TGF-β1 and treated with either EZH2-specific siRNA or GA to assess the effects on EMT and Notch1/3 signaling. In addition, chromatin immunoprecipitation (ChIP) assays were conducted to evaluate the binding of EZH2 and H3K27me3 to the promoters of Notch1 and Notch3. Compared with wild-type controls, mice with tubular cell-specific EZH2 deletion exhibited significantly reduced renal fibrosis, characterized by decreased expression of fibronectin, collagen III, vimentin, and Snail, while preserving E-cadherin levels in injured kidneys. Pharmacological degradation of EZH2 with GA produced comparable antifibrotic effects. UUO injury markedly upregulated Notch1, Notch3, the Notch intracellular domain, Hes1, Hey2, and Jagged-1; these increases were significantly suppressed by either EZH2 deletion or GA treatment. Similarly, in vitro, GA or EZH2-specific siRNA inhibited the expression of Notch signaling molecules in TGF-β1-treated renal epithelial cells. Chromatin immunoprecipitation analyses revealed direct binding of EZH2 and H3K27me3 to the Notch1 and Notch3 promoters. UUO injury enhanced EZH2 binding while reducing H3K27me3 enrichment at these sites, effects reversed by GA treatment. These findings demonstrate that epithelial EZH2 contributes to pEMT in renal tubular cells and promotes renal fibrosis, at least in part through activation of Notch signaling. Targeting EZH2 may hold potential as a therapeutic approach for chronic kidney disease. Show less

The integration of serum biomarkers and gene polymorphisms may enhance early prognostic assessment in sepsis. Early and accurate prediction of outcomes is crucial for optimizing treatment strategies and improving survival. However, the clinical utility of combining genetic markers with conventional inflammatory indicators remains insufficiently validated. In this retrospective cohort ( 6 predictors were retained - PCT, CRP, lactate (LAC), lactate clearance rate (LCR), TLR4 rs4986790, and PPARγ rs1801282. The nomogram achieved AUC 0.885 (95% CI 0.812-0.943) with sensitivity 88.6% and specificity 73.9%; calibration was good (H - L χ This integrative biomarker-genotype model demonstrated strong internal performance and potential clinical utility for individualized risk stratification in sepsis. The results support combining genetic susceptibility and inflammatory biomarkers for enhanced prognostic precision, although external and multi-ethnic validation remains warranted before widespread adoption. Show less

Primary hypobetalipoproteinemia (HBL) is mostly due to a polygenic origin or to monogenic disorders including loss of function (LOF) variants in APOB, much less frequently Angiopoietin-like 3 gene (ANGPTL3). A new heterozygous variant of uncertain significance (VUS), p.H343R missense variant in ANGPTL3 cosegregated with HBL in a family. The aim of the present study was to assess in vitro the functionality of this variant and to establish its causality in this family. Targeted next-generation sequencing was performed in the proband to assess monogenic and polygenic origins using an LDL-C-dedicated polygenic risk score (PRS All 8 HBL subjects had PRS This study shows that the novel ANGPTL3-p.H343R variant decreases ANGPTL3 secretion in vitro and can now be considered as a LOF variant. The lipid phenotype in this family results from a synergistic combination of the p.H343R ANGPTL3 variant and a polygenic HBL predisposition. Show less

Lipoprotein lipase (LPL) is the rate-limiting enzyme responsible for hydrolyzing triglycerides in circulating lipoproteins. Reduced LPL activity contributes to hypertriglyceridemia, a major cardiovascular risk factor. LPL activity is thought to depend on the conformation of the lid domain, the lipid pore, N- and C-terminal domains (NTD, CTD), and stabilization of these domains by endogenous activators such as apolipoprotein C-II (ApoC-II). Despite major clinical significance, the structure-function relationship of LPL's functional domains and cofactors remain incompletely understood. To address this, we performed the longest known (1-μs) molecular dynamics simulations of LPL independently and in complex with an ApoC-II mimetic peptide (ApoC-II-P). For the first time, we show that LPL's flexible lid can adopt multiple orientations, transitioning between open and closed states that regulate lipid pore access and catalytic activity. We also observed 'flipping' of ~180° by the CTD, a unique characteristic that dictates LPL activity when not in a closed lid state. Furthermore, ApoC-II-P stabilizes LPL by bridging its NTD and CTD, while maintaining an optimal lid orientation. Biochemical and cellular assays corroborate these findings, demonstrating that ApoC-II-P enhances LPL hydrolysis and supports noncanonical LPL functions. Together, these insights reveal previously unrecognized mechanisms governing LPL regulation and activity dynamics. Show less

Familial hypercholesterolemia (FH) is characterized by lifelong elevated LDL-C levels and increased cardiovascular risk. PCSK9 inhibitors (PCSK9i) reduce LDL-C and Lp(a), however, the effect of dual lipid reduction on mechanical vascular function remains unclear. The aim of this study was to evaluate the efficacy of PCSK9i in reducing LDL-C and Lp(a) and to assess the relationship between the dual lipid reduction and the mechanical vascular profile improvement in FH subjects. This prospective observational study included 301 genetically confirmed FH subjects treated with PCSK9i added to high-intensity statins and ezetimibe. Biochemical and PWV measurements were performed at baseline and after six months. Subjects were stratified into four groups based on median values of ΔLDL-C and ΔLp(a). After six months of add-on PCSK9i, 44.9% of FH subjects achieved their LDL-C targets. Reductions were observed in LDL-C (− 49.8%, Dual lipid reduction with PCSK9i was associated with a pronounced mechanical vascular profile improvement in FH subjects; however, an intensive Lp(a) reduction may be needed to achieve a greater mechanical vascular benefit. Show less

Renal cell carcinoma (RCC) is a prevalent malignancy characterized by a rising incidence and significant mortality. Interleukins (ILs) are crucial in regulating immune cell trafficking and exhibit anti-tumor properties. However, limited research has explored the expression levels and prognostic significance of interleukins in RCC. In this comprehensive study, we performed a detailed analysis of interleukins in RCC patients using multiple bioinformatics tools, including Oncomine, UALCAN, GEPIA, Kaplan-Meier plotter, cBioPortal, GeneMANIA, TRRUST, STRING, and Linked Omics. Our analysis demonstrated a significant upregulation in the transcriptional levels of IL4, IL7, IL15, IL16, IL23A, IL26, and IL32 were significantly upregulated in RCC tissues, indicating their potential involvement in the pathogenesis of this malignancy. In contrast, IL1A, IL11, and IL27 were downregulated, indicating their potential function as tumor suppressors. Significant correlations were identified between the expression levels of IL11, IL23A, IL27, IL32, and the pathological stage of RCC patients. The expression levels of IL1A, IL4, IL11, IL15, IL16, IL23A, IL26, IL27, and IL32 were significantly correlated with improved prognosis. The differentially expressed interleukins primarily function in cytokine-cytokine receptor interactions and immune response-regulating signaling pathways. homeobox A10 (HOXA10), v-myb myeloblastosis viral oncogene homolog (avian) (MYB), v-rel reticuloendotheliosis viral oncogene homolog A (avian) (RELA), and nuclear factor of kappa light polypeptide gene enhancer in B-cells 1(NFKB1) are key transcription factors for ILs, while LCK proto-oncogene (LCK), LYN proto-oncogene (LYN), spleen associated tyrosine kinase (SYK), Janus kinase 3 (JAK3), and FER tyrosine kinase (FER) are IL targets. IL expression significantly correlated with the infiltration of six distinct immune cell types. IL1A potentially exerts an anti-tumor effect in RCC prognosis by inducing neutrophil extracellular traps (NETs). Additionally, NFKB1 may positively regulate IL1A, providing a rationale for further In conclusion, our study demonstrates the potential role of IL 1A in the prognosis of RCC and establishes a theoretical foundation for subsequent Show less

Sepsis, a life-threatening organ dysfunction caused by dysregulated host responses to infection, has emerged as a leading cause of mortality in ICU patients. Macrophages, crucial effector cells in innate immunity, play pivotal regulatory roles in sepsis pathogenesis. While Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, is traditionally believed to exert immunosuppressive effects through membrane anchoring, its involvement in macrophage polarization during sepsis remains unclear. This study investigated the spatial distribution of PD-L1 in macrophages and its regulatory effects on inflammatory responses during sepsis. This study investigated PD-L1’s regulatory role in macrophage polarization through RNA sequencing, Immunoprecipitation-mass spectrometry, molecular docking, and site-directed mutagenesis, with preliminary validation in C57BL/6 mice. Using GEO database analysis combined with qRT-PCR and Western blotting, we confirmed elevated PD-L1 expression in sepsis and M1-polarized macrophages. Laser scanning confocal microscopy demonstrated dual localization of PD-L1, appearing both on the plasma membrane and intracellularly within M1 macrophages. RNA sequencing revealed PD-L1’s promotion of M1 polarization through enhanced AIM2 expression in the NOD-like receptor pathway. Integrated analyses employing mass spectrometry, molecular docking, site-directed mutagenesis, and Western blotting demonstrated PD-L1 binding to AIM2, which augmented expression of downstream effector molecules (IL-18 and IFN-γ) and potentiated STAT1 activation. Silencing AIM2 by siRNA or IL-18 antagonism reversed PD-L1-induced M1 markers (IL-27, IL-6, iNOS/NO). PD-L1 was further shown to exacerbate pathological progression in septic mouse models. Our study demonstrated that sepsis-induced PD-L1 overexpression in macrophages exacerbates pathological progression by upregulating AIM2 expression, binding to AIM2 to enhance IL-18 production, which activates STAT1 to drive M1 polarization. The online version contains supplementary material available at 10.1186/s12964-025-02578-1. Show less

Malignant gliomas (MG) are the most common primary brain malignancies and are considered universally fatal. Oncolytic HSVs (oHSV) are promising immunotherapeutics capable of selectively lysing cancer cells, eliciting anti-tumor immunity, and providing local delivery of immune-activating transgenes. IL-27 is a pleiotropic cytokine capable of enhancing tumor-reactive cytotoxic T cell (CTL) function while also possessing neuroprotective properties. We hypothesized that IL-27 expression by oHSV would enhance CTL function and improve anti-glioma therapeutic activity. We developed an oncolytic herpes simplex virus (oHSV) that expresses IL-27 (C027). The anti-glioma efficacy of C027 was tested in three syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (SB28, KR158) glioma lines. Spectral flow cytometry was used to assess immunophenotypic and functional changes in the tumor infiltrates and systemically. To further investigate the C027-related CTL activity, we employed C027 significantly prolonged survival in syngeneic orthotopic glioma models derived from both chemical (CT-2A) and genetic (KR158, SB28) glioma lines. In the CT-2A model, IL-27-expressing oHSV treatment was associated with increased intratumoral multifunctional effector cytotoxic T lymphocytes (CTL) and functional T cell populations systemically. Mechanistically, both CD8 T cells and IL-27 were required for the C027 survival benefit Our findings demonstrate that IL-27 expression by oHSV significantly improves anti-glioma therapeutic efficacy, enhances CTL effector function, and induces durable immune memory. Thus, IL-27-oHSV may provide a promising therapeutic approach for malignant gliomas. Show less

Carbohydrate-responsive element binding protein (ChREBP) and Max-like protein X (MLX) are key Mondo Family Proteins (MFPs) acting as transcription factors. They are known to couple intracellular sugar levels with carbohydrate and lipid metabolism by regulating glucose-responsive gene expression. MondoA regulates lipid metabolism and insulin signaling in addition to controlling glucose uptake, whereas ChREBP primarily regulates Show less

The present case report presents the diagnostic challenges of pediatric diffuse low-grade glioma (pDLGG) with oligodendroglioma-like features. The patient, an 11-year-old girl, presented with refractory epilepsy and brain imaging did not provide a clear diagnosis. Intraoperatively, the tumor appeared gray-yellow to gray-red, with moderate texture and unclear borders, consistent with LGG. Postoperative pathology showed diffuse infiltrative growth of the tumor, with pleomorphic cell morphology and oligodendroglioma-like gliocyte proliferation. Staining was positive for markers such as glial fibrillary acidic protein and Olig-2. Genomic analysis revealed BRAF V600E, fibroblast growth factor receptor (FGFR)1 and FGFR4 mutations, but no IDH mutations or other related mutations. The final diagnosis was pDLGG with alterations in the MAPK pathway. The present case underscores the importance of molecular and histological features in the diagnosis of pDLGG, especially when clinical and imaging characteristics are atypical, as molecular diagnostics provide key insights for disease classification. Show less

Protein arginine methyltransferase 5 (PRMT5) complexes with methylosome protein 50 (MEP50) play crucial roles in tumor progress. However, the regulatory mechanism of governing the PRMT5-MEP50 hetero-octameric complex remains unclear. Here, we demonstrate that C6orf223, to our knowledge an uncharacterized protein, facilitates PRMT5-MEP50 multiprotein complex assembling, thereby promoting colorectal cancer (CRC) growth and metastasis. C6orf223 forms dimers through disulfide bonds, with its N-terminal arginine-enriched region binding to the C-terminal negatively charged groove of PRMT5, thus stabilizing PRMT5-MEP50 multiprotein and enhancing PRMT5 methyltransferase activity. Consequently, PRMT5-mediated H4R3me2s substantially decreases the expression of the tumor suppressor GATA5, leading to the upregulation of multiple oncogenic target genes including WWTR1, FGFR1, and CLU. Targeting C6orf223 using siRNAs encapsulated in ferritin protein shells effectively suppresses CRC tumor growth and metastasis. Collectively, our findings characterize the role of C6orf223 in facilitating PRMT5-MEP50 hetero-octameric complex assembling and suggest that C6orf223 could serve as a potential therapeutic target for CRC. Show less

CNS tumors are a significant cause of death in the adolescent and young adult (AYA; age 15-39 years) population; however, these patients often lack standardized treatments. In Canada, we have established national multidisciplinary virtual AYA CNS tumor board rounds (national rounds) to improve and standardize care. From November 2021 to June 2024, 185 AYA patients with CNS tumors were presented from centers nationwide, including 138 patients with glioma. Before case presentation, 5.1% of patients with glioma were taking targeted agents or were enrolled in clinical trials. However, after national rounds, 72.6% of patients with pediatric-type glioma and 45.9% of patients with adult-type glioma were recommended clinical trials and/or targeted agents. Among the 44 patients with glioma who had received radiation therapy before national rounds, only 14 were recommended further radiation. Cumulatively, 68.9% of patients analyzed received a treatment recommendation that represented a change in clinical management compared with their previous treatments. Concurrently, we performed molecular review of 174 AYA CNS tumors during the study time frame. Using TruSight, we identified gene fusions involving Our results suggest that national rounds with centralized molecular review can direct AYA patients with CNS tumors toward targeted agents and clinical trials, while deferring radiation therapy. Taken together, our work details an ongoing effort to improve and standardize care of AYA patients with CNS tumors in Canada. Show less

Hepatocellular carcinoma (HCC) arises from various etiologies, including viral hepatitis and non-viral liver diseases. Although comprehensive genomic profiling (CGP) is increasingly applied in oncology, the influence of disease etiology on the genomic landscape of HCC and biomarker applicability remains insufficiently characterized. CGP data from 551 patients with HCC, registered in the National Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database, were analyzed after excluding cases with undefined etiology. We characterized the mutational landscape, compared mutation frequencies among HBV-, HCV-, and non-viral, non-cholestatic (nBnC)-related HCC, assessed the association between homologous recombination repair (HRR)-related gene alterations and tumor mutation burden (TMB), and evaluated the detection rates of actionable mutations in tissue- versus liquid-based CGP. Telomerase reverse transcriptase splice site mutations were the most common genomic alteration and were consistently observed across all etiologic groups. Although mutations in AXIN1 and DDR2 genes showed modest enrichment in HCV- and HBV-related HCC, respectively, the overall mutational profiles remained largely conserved across etiologies. TMB was significantly lower in nBnC-HCC compared to HCV-related HCC but showed no association with HRR-related mutations. The detection rates of targetable mutations were similar between tissue and liquid biopsies; however, only a small proportion of patients received matched therapies. Real-world data indicate a conserved genomic architecture in HCC regardless of etiology, supporting unified therapeutic approaches. The absence of a relationship between HRR alterations and TMB suggests distinct biological mechanisms. Liquid biopsy remains a reliable option when tissues are unavailable in managing patients with HCC. Show less

Schiff bases derived from 3-acetyl-4-hydroxycoumarin represent a promising yet underexplored scaffold in medicinal chemistry. Here, we report the efficient synthesis of a series of bisimine derivatives (3a-j) through condensation with structurally diverse amines, achieving yields of 68-95%. Spectroscopic characterization (NMR, IR, MS) confirmed their unique architectures, with 3j emerging as a standout candidate exhibiting anticancer activity comparable to doxorubicin but with superior selectivity against MCF-7 and A549 cell lines. Among the tested derivatives, compound 3a exhibited the most potent antibacterial activity, with the lowest MIC values observed against Gram-positive strains. Notably, 3f (a thiourea analog) demonstrated broad-spectrum antifungal efficacy (MICs: 1.95-31.25 µg/mL), while 3c surpassed ascorbic acid in radical scavenging (96.7% DPPH inhibition). Molecular docking revealed robust interactions between lead compounds (3b, 3c, 3j) and key therapeutic targets (FGFR1, cIAP1-BIR3), suggesting a dual inhibitory mechanism. These findings underscore the potential of coumarin bisimines as versatile platforms for addressing antibiotic resistance and oxidative stress-related pathologies. Show less

Management of advanced hormone receptor-positive, HER2-negative breast cancer after progression on endocrine therapy plus CDK4/6 inhibitors is challenging due to mutational heterogeneity. Current therapies yield limited efficacy, achieving 4-6 months PFS. FGFR signaling is implicated in resistance to endocrine plus CDK4/6 inhibitors, but FGFR inhibitors have shown limited activity in unselected populations. Co-clinical trials bridge preclinical and clinical findings, optimize resources, and enable biomarker identification. Using patient-derived organoids (PDOs), we demonstrated that FGFR-amplified PDOs respond to fulvestrant, palbociclib, and rogaratinib only when PIK3CA and ESR1 are wild-type. In a dose-escalation trial pre-screening 66 patients with FGFR1/2-amplification (FISH) and/or overexpression (RNAScope) patients, >40% harbored FGFR alterations. Nine patients were enrolled; the combination showed activity specifically in PIK3CA- and ESR1-wild type patients (9.1 vs. 1.9 months PFS; P = 0.0005). Toxicity was manageable and consistent with prior data. Our findings highlight biomarker-driven approaches as essential for refining FGFR-targeted strategies in this resistant population. Show less

Limited identification of insulin resistance-associated loci hinders understanding of its role in cardiometabolic health, impeding therapeutic strategies. We apply three multivariate genome-wide association study approaches on homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and ratio of triglycerides to high-density lipoprotein cholesterol from MAGIC and UK Biobank to develop a comprehensive phenotype ('mvIR'), and identify 217 independent loci, including 24 novel loci. The mvIR is causally associated with higher risks of 17 cardiometabolic diseases and five aging phenotypes, independent of adiposity and sarcopenia. We outline 21 of 2644 druggable genes for insulin resistance by Mendelian randomization and colocalization, where six genes (AKT1, ERBB3, FCGR1A, FGFR1, LPL, NR1H3) encode targets for approved drugs with consistent directions in alleviating insulin resistance, with no significant side effects revealed by phenome-wide association study. This study uncovers novel loci and therapeutic targets to inform strategies promoting insulin resistance-centered cardiometabolic health and longevity. Show less

Sepsis, defined as a dysregulated host response to infection, is one of the leading causes of mortality worldwide. It unleashes in the organism a cascade of molecules, cytokines, and proteins which leads to an inflammatory storm. If this response to infection is uncontrolled, any organ is susceptible to damage. Acute kidney injury (AKI) is one of the most frequent organ dysfunctions in septic patients, and while it can be reversible, its presence leads to a higher burden of morbidity and mortality. While serum creatinine is essential in evaluating kidney function, the pathophysiology of AKI is not completely elucidated, and a plethora of novel biomarkers have been studied in the hope of an early diagnosis and fast treatment. While the liver is not as affected by sepsis, it plays an important role as a guardian by providing acute-phase proteins, activating neutrophils, and controlling iron balance. Acute liver failure (ALF) could impair the organism's capacity to contain and eliminate pathogens. Some molecules have been associated with either AKI or ALF, although biomarkers specific for organ dysfunction are difficult to validate. The aim of this review is to understand the role of several molecules in the pathophysiology of sepsis and their clinical ability for diagnosing or predicting sepsis-induced hepato-renal dysfunction. Show less

Tumor fibrosis is recognized as a malignant hallmark in various solid tumors; however, the clinical importance and associated molecular characteristics of tumor fibrosis in liver metastases (LM) from colorectal cancer (CRLM) remain poorly understood. Here we show that patients with CRLM whose liver metastases (LM) exhibited tumor fibrosis (Fibrosis+ LM) had significantly worse progression-free survival (P = 0.025) and overall survival (P = 0.008). Single-cell RNA sequencing revealed that the tumor microenvironment of the Fibrosis+ LM was characterized by T cells with an exhausted phenotype, macrophages displaying a profibrotic and suppressive phenotype and fibrosis-promoting fibroblasts. Further investigation highlighted the pivotal role of VCAN_eCAF in remodeling the tumor fibrosis in the tumor microenvironment of Fibrosis+ LM, emphasizing potential targetable interactions such as FGF23 or FGF3-FGFR1. Validation through multiplex immunohistochemistry/immunofluorescence and spatial transcriptomics supported these findings. Here we present a comprehensive single-cell atlas of tumor fibrosis in LM, revealing the intricate multicellular environment and molecular features associated with it. These insights deepen our understanding of tumor fibrosis mechanisms and inform improved clinical diagnosis and treatment strategies. Show less

Breast cancer (BC) is the most common malignancy among women, with an increasing incidence correlated with age and diverse subtypes exhibiting distinct prognoses. The tumor microenvironment (TME) in BC is complicated. It is now believed that BC may acquire invasive characteristics and even extra proliferative ability from the TME through various mechanisms. However, most studies predominantly focus on the heterogeneity of tumor cells in BC, lacking a comprehensive depiction of intercellular communication within BC. Therefore, the present study aimed to elucidate cellular communication in the TME by integrated bioinformatic analysis of bulk mRNA and single-cell mRNA sequencing, combined with certain validation in clinical samples. We first utilized single-cell sequencing data from GSE176078 to find out the most important cell communication pairs for the tumor microenvironment in BC then we conducted bulk-sequencing analysis to identify the differential expressed genes. Through correlation analysis, we sort out the top five most relevant genes to the most important cell communication pairs. We then validated the expression of the key genes of the aforementioned cell communication pairs and the five differentially expressed genes by qPCR on clinical samples. Furthermore, we analyzed the immunological relevance of these genes via a novel approach at single-cell resolution. The results of single-cell analysis indicated that the CXC12-CXCR4 ligand-receptor pair in the CXCL pathway and the FGF7-FGFR1 ligand-receptor pair in the FGF pathway are the most important cell communication pairs of the TME in BC. Subsequent bulk sequencing analysis showed that CHRDL1, SCARA5, LYVE1, PI16, and SAA2 were the most important differentially expressed genes linked to these cell communication pairs. In addition, we validated the expression of the key genes of the two cell communication pairs and the five genes in clinical samples, observing that the trends fitted the computational results. Finally, we studied the association of these genes with immune cell infiltration at single-cell level and had it cross-validated in bulk sequencing data, finding out that there were significant connections. In the tumor microenvironment of breast cancer, intercellular communication pairs of different cell types and molecules can exacerbate the development of breast cancer. among them, through the present study, we found that CXCL12-CXCR4 and FGF7-FGFR1 are the most important. Also, most significantly differentially expressed genes including CHRDL1, SCARA5, LYVE1, PI16, and SAA2 seemed to play a critical role in these mechanisms and immune cell infiltration, shaping the TME of BC. Show less