Objective: To investigate the clinicopathological characteristics and genetic alterations of undifferentiated embryonal sarcoma of the liver (UESL). Methods: Three cases of UESL diagnosed in the Department of Pathology, the Third Affiliated Hospital of Sun Yat-sen University from 2020 to 2023 were retrospectively collected. The clinical, histomorphological, immunohistochemical, and genetic profiles were reviewed and analyzed. Results: The cohort comprised of three patients, including one male and two females, aged 7, 9, and 15 years, respectively. Tumor locations were in the right lobe of the liver in two cases, and in both the right and left lobes in one case. One case exhibited tumor rupture with hemorrhage. Gross examination revealed solid tumors in gray-red fleshy appearance, with areas of hemorrhage and necrosis. Microscopically, the tumor was composed of irregularly shaped spindle and polygonal cells arranged in bundles or sheets with varying density, scattered within a myxoid matrix containing giant tumor cells and eosinophilic globules. The tumor cells were positive for Vimentin, CD56, CD68, and bcl-2, with a Ki-67 index of 30%-80%. INI1 expression was retained, while p53 exhibited a mutant pattern. CKpan, CK7, CK19, EMA, HepPar-1, Arginase-1, AFP, CD34, S-100, Myogenin, and MyoD1 were negative. All three cases harbored TP53 missense mutations. Case 1 also showed MDM2 copy number amplification (class Ⅰ mutation), and case 2 exhibited a frameshift mutation in exon 10 of TSC2 (class Ⅱ mutation). Additionally, several class Ⅲ mutations were identified in all three cases. Germline testing for tumor-related genetic variants in case 2 revealed a missense mutation in exon 12 of DICER1, an in-frame insertion mutation in exon 8 of MSH2, and a missense mutation in exon 30 of TSC2. Conclusion: UESL is a rare malignant mesenchymal tumor of the liver, predominantly affecting children, with distinctive clinicopathological features and genetic alterations. TP53 mutations may play a key role in the pathogenesis of this tumor.

In the past decade, breast pathology in China has made significant progress in diagnostic standards, technological applications, scientific research, and discipline development. The histopathological diagnostic system has been continuously refined, with the implementation of relevant guidelines and expert consensus enhancing standardization and reproducibility of diagnostic results. Immunohistochemistry and molecular testing technologies have become increasingly sophisticated, with emerging biomarkers such as low HER2 expression and PIK3CA mutations gradually integrated into clinical decision-making, promoting the advancement of precision therapy. The application of digital pathology and image-assisted analysis has steadily expanded, providing new tools to improve diagnostic efficiency and consistency. The national breast pathology group has actively advanced the development of tiered diagnostic systems, workforce training, and public education, effectively strengthening diagnostic capabilities at the grassroots level. Looking ahead, the integration of multidimensional data, optimization of auxiliary diagnostic systems, and interdisciplinary collaboration are expected to drive the continued development of breast pathology in China.

Pediatric tumors differ significantly from adult cancers, possessing unique developmental origins, histological features, and molecular genetic changes. With the rapid advancement of multi-omics technologies, such as genomics, transcriptomics, proteomics, and epigenetic analyses, the molecular characteristics of pediatric tumors have been extensively revealed, providing new possibilities for precision medicine. Concurrently, the integration of artificial intelligence and digital pathology has effectively enhanced diagnostic accuracy, presenting a broad scope for future development. While this progress positively impacts the pathological diagnosis of pediatric tumors, it also presents challenges related to data complexity, technology integration, and the promotion of clinical applications. This article aims to discuss the influence of molecular and artificial intelligence, as well as multimodal integrated pathological models on diagnosis and prognostic prediction of pediatric tumor, with the goal of fostering further exploration and in-depth research.

Breast cancer (BC) represents a major contributor to cancer-associated deaths among women, underscoring the need for novel therapeutic approaches. This study explores the role of miR-155-5p as an oncogenic driver in BC progression through a multi-omics approach. Elevated miR-155-5p expression was observed in serum exosomes and tumor tissues, with its upregulation correlating with advanced pathological stages, lymph node metastasis, and unfavorable clinical outcomes. Functional experiments demonstrated that miR-155-5p enhances cellular proliferation, motility, and invasive capacity while inhibiting apoptosis in BC. Mechanistically, miR-155-5p exerts its effects by directly suppressing Nedd4 Family Interacting Protein 1 (NDFIP1), thereby initiating activation of the NF-κB axis. This activation was characterized by increased nuclear translocation of NF-κB p65 and enhanced secretion of inflammatory cytokines, including IL-6 and TNF-α. In vivo, knockdown of miR-155-5p effectively suppressed tumor growth and metastasis, with these effects reversed by silencing NDFIP1. These results highlight the miR-155-5p/NDFIP1/NF-κB axis as a critical pathway in BC progression, providing new insights into its molecular mechanisms. miR-155-5p emerges as a promising diagnostic marker and therapeutic candidate, suggesting the feasibility of miRNA-based interventions in BC treatment. This study highlights the pivotal role of integrative omics technologies in uncovering cancer-related regulatory networks.

HMGA1, an architectural transcription factor that plays a crucial role in tumorigenesis, chemotherapy resistance and cancer stem cell transformation in many human cancers, is intrinsically disordered and cannot be targeted by conventional small molecule drug therapy. While HMGA1 is required and essential for normal growth and development, HMGA1 expression occurs at very low levels in normal healthy adult cells. In contrast, HMGA1 is expressed at very high levels in many different types of human cancer cells. Since HMGA1 cannot be targeted using conventional small molecule drug therapy, alternative approaches are needed to target HMGA1 in new cancer therapies. Here, we explored the use of serotype 5 adenoviruses (Ad5) engineered 1) to sequester overexpressed HMGA1 in cancer cells using an HMGA1 hyper binding site (HBS) inserted into the Ad5 genome and 2) to suppress HMGA1 synthesis in cancer cells by incorporating exogenous genes into the Ad5 genome that encode an artificial HMGA1 cis-antisense transcript (AAT) and that encode a gene to express an HMGA1-targeted shRNA transcript (shRNA). The three engineered Ad5s were tested in MiaPaCa-2, PANC-1 and BxPC-3 human pancreatic cancer cell lines and in the ZR-75 human breast cancer cell line. Cancer cell viabilities and cell migration capability decreased by ~50-75% with HBS viruses and by 25-50% for shRNA and AAT viruses. Anchorage-independent migration capacity decreased by 60-70% with all three HBS, shRNA and AAT viruses. HMGA1 mRNA transcripts levels varied from 100 to 300 copies per cell in untreated cells and these levels were not significantly affected by treatment with the HBS and shRNA viruses, however the HMGA1 mRNA levels increased by ~3-fold upon AAT virus treatment. HMGA1 protein levels decreased in the range of 40, 50 and 70% with shRNA, AAT and HBS viruses, respectively. The HBS virus designed to sequester HMGA1 proved most effective overall in suppressing HMGA1 oncogenic activity in these in vitro cell-based studies compared to the AAT and shRNA viruses.

Chemoresistance in breast cancer therapy, especially for triple negative breast cancer (TNBC) remains a significant challenge. Recent studies showed that overexpression of lipolysis-stimulated lipoprotein receptor (LSR), known as a tricellular tight-junction protein, was detected in TNBC and MDR1 was among LSR upregulated genes in a screening assay but its functional impact has not been studied. This study aimed to characterize LSR overexpression-induced regulation of MDR1 in TNBC cells focusing on chemoresistance. LSR was overexpressed in MDA-MB-231 cells and knocked-out via CRISPR/Cas9 in MDA-MB-468 cells for functional studies. Chemoresistance of individual cell lines was evaluated with doxorubicin treatment, followed by cell proliferation, invasion, colony formation and apoptosis assays. Modulated protein and mRNA levels of specific genes were assessed with Western blotting and RT-qPCR. MDR1 inhibitor verapamil and MDR1-targeted siRNA were used to evaluate the functional impact of LSR-induced MDR1. Overexpression of LSR not only promotes cell proliferation and invasion in MDA-MB-231 cells, but also renders the cells resistant to doxorubicin. LSR induces MDR1 expression at both mRNA and protein levels. Moreover, inhibition of MDR1 with specific inhibitor verapamil or MDR1 knockdown reversed cellular resistance to doxorubicin in LSR-overexpressing MDA-MB-231 cells. In contrast, knockout of LSR expression in MDA-MB-468 cells, which express higher levels of LSR, significantly sensitized the cells to doxorubicin-induced growth inhibition and apoptosis. Our data demonstrated that LSR overexpression promotes TNBC cell proliferation and invasion, and upregulation of MDR1 in these cells renders them resistant to doxorubicin, suggesting that targeting LSR could be a useful strategy to overcome chemoresistance in TNBC.

FMS-like tyrosine kinase 3 (FLT3), a class III receptor tyrosine kinase, exhibits a mutation frequency of approximately 30% in acute myeloid leukemia (AML) patients and constitutes a critical therapeutic target. As representative type I and type II FLT3 inhibitors, respectively, gilteritinib and Quizartinib (AC220) are clinically employed in FLT3-mutant AML management. Gilteritinib inhibits both activated and inactivated FLT3 proteins, with additional inhibition of AXL targets to help overcome resistance. AC220 inhibits activated FLT3. The comet assay was systematically employed to quantify and compare DNA damage patterns induced by type I versus type II FLT3 inhibitors in mutant cells. The experimental results revealed that the DNA damage caused by AC220 was significantly higher than that caused by Gilteritinib. For strong DNA damage, FLT3 inhibitors can be combined with DNA damage repair inhibitors to target DNA repair defects. The results provide experimental support for the rational combination strategy of DNA damage-targeting drugs.

As the foremost endocrine system cancer, thyroid carcinoma exhibits an accelerating epidemiological trend across populations. Despite advances in treatment modalities, recurrence and metastasis remain challenges. The long non-coding RNA PVT1 (lncPVT1) has emerged as a conserved oncogenic regulator in multiple cancer types, yet its specific function in TC requires further exploration. Our research focused on examining how lncPVT1 affects glycolysis under both normoxic and hypoxic conditions using TC cell lines TPC-1 and K1. Overexpression of lncPVT1 significantly enhanced glucose consumption and lactate production under hypoxia, corroborating its ability to augment glycolysis. Further, lncPVT1 upregulated key glycolytic genes such as GLUT1, HK1, HK2, and PGK1, and facilitated TC cell proliferation. Mechanistically, lncPVT1 stabilized hypoxia-inducible factor 1α (HIF-1α) by impeding its degradation and leading to its accumulation. This accumulated HIF-1α then bound to specific regulatory sequences that control the expression of genes involved in glycolysis, ultimately activating these genes and boosting glycolytic activity. Our findings demonstrate that lncPVT1 regulates HIF-1α stability and glycolytic gene expression, advancing our understanding of TC metabolism and potentially revealing novel therapeutic targets.

The development of spatial transcriptomics (ST) technologies has enabled researchers to better understand cells' spatial organization and functional heterogeneity within their native tissue context. Spatial domain identification plays a crucial role in ST data analysis. However, most existing spatial domain identification methods do not fully exploit spatial information, and often fail to adequately integrate both local and global features, resulting in suboptimal spatial domain identification. We propose SLGCA, a novel method based on cross-level graph contrastive learning to address these challenges. SLGCA adopts a dual-channel learning mechanism, combining local-level contrastive learning based on spatial neighborhood information and global information contrastive learning across views, thereby significantly enhancing the accuracy of spatial domain identification. SLGCA can integrate multiple tissue sections without needing pre-alignment or external tools, eliminating batch effects and accurately identifying spatial domains across multiple slices. Experimental results show that SLGCA significantly outperforms the benchmark methods in spatial domain identification accuracy on ST data generated by multiple techniques. Moreover, SLGCA enables accurate dissection of tumor heterogeneity in human breast cancer datasets and effectively uncovers the heterogeneous tumor microenvironment in liver cancer, revealing two distinct fibroblast subtypes.

The high recurrence rate of tumor limits the growth of precision medicine, whereas the exploration of correlations in multimodal data enables mining of features linked to tumor recurrence, ultimately identifying prospective biomarkers. Nevertheless, existing multimodal approaches centered on genetic molecular data inadequately leveraged data structure and ignored the involvement of genes in the pathway or biological processes, thereby hampering interpretability of association models. In this study, a novel joint similarity nonnegative matrix factorization (JSNMF) model based on data-driven idea was proposed by adding pathway scoring data based on utilizing pathological images of tumor, gene expression data. The similarity network fusion model was applied to calculate the fusion matrices of the three-modality data with tumor recurrence as the label. Additionally, the prior information was calculated using the principal component analysis method, which was then applied to the joint nonnegative matrix factorization model with network regularization constraints. The solving efficiency of JSNMF model was enhanced by incorporating sparse orthogonality constraints on objective function. Experimental results demonstrate that incorporating prior knowledge enhances the search efficiency for joint patterns across multimodal data. The model identified recurrence-related common modules, including cellular features, genes, and pathways. Bioinformatics analysis indicated that the model can identify potential biomarkers associated with immune cell infiltration levels for recurrence diagnosis. Furthermore, the proposed method provides a new perspective for mining task-specific associations in multimodal data. This study also improves understanding of association patterns among genetic molecular features linked to tumor recurrence.

Alkylating agent-based chemotherapy is one of the main treatment options for patients with metastatic pancreatic neuroendocrine tumors (PanNETs).However, it favors the acquisition of a hypermutator phenotype, suggesting a potential benefit of immunotherapy.We aimed to describe the efficacy of immunotherapy in an international retrospective cohort of patients with metastatic well-differentiated PanNETs pretreated with alkylating therapy. The primary endpoint was progression-free survival (PFS) and the main secondary endpoint was the radiological objective response rate (ORR). We explored the impact of tumor mutation burden (TMB) and mismatch repair deficiency (MMRd), and evaluated variables associated with PFS.We included 64 patients with heavily pretreated PanNETs (median Ki-67 28%). Among 51 PanNETs with mutational profiling, 37 (73%) were TMBhigh (median 35 mut/Mb). Among 46 PanNETs with available MMR status, 18 (39%) were MMRd, representing 49% of all TMBhigh PanNETs. Immunotherapy consisted of a single (31%) or a dual (69%) immune checkpoint inhibitor. Median PFS was 3.2 months (95% CI, 1.3-5.0.3.0) and the ORR was 17%. Patients with TMBhigh PanNETs had longer PFS (median 3.8 vs. 2.3 months, p = 0.015) and higher ORR (30% vs. 0%, p = 0.002) compared with TMBlow/unk cases. Patients with MMRd PanNETs had longer PFS (median 8.9 vs. 2.7 months, p = 0.003) and higher ORR (44% vs. 7%, p < 0.001) compared with MMRp/unk. On multivariable analyses, MMRd predicted longer PFS (HR 0.42, 95% CI [0.20-0.82], p = 0.015).Overall, immunotherapy may be effective against alkylating-pretreated metastatic PanNETs exhibiting TMBhigh and MMRd. MMR immunohistochemistry and TMB assessment could be implemented in the routine assessment of alkylating-pretreated metastatic PanNETs.

CD40 is a T-cell co-stimulatory receptor targeted by next-generation immunotherapies. We conducted a pan-cancer transcriptome analysis of CD40, its ligand, and related immune markers to evaluate co-expression patterns and clinical outcomes.

Thyroid cancer is the most common endocrine malignancy, with an increasing incidence, particularly driven by differentiated thyroid cancers (DTC), including papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC). Although DTC generally have excellent prognosis, dedifferentiated forms such as poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC) exhibit aggressive progression and poor outcomes. Understanding the tumor microenvironment (TME) is crucial for developing novel therapeutic strategies.

Lung adenocarcinoma (LUAD) treatment remains a substantial clinical challenge, warranting a thorough investigation of the molecular mechanisms underlying tumor progression. In our study, the expression patterns and clinical implications of the macrophage M1 related gene, membrane spanning 4-domains A1 (MS4A1) were assessed using quantitative real-time PCR (RT-qPCR), western blotting, and immunohistochemistry in LUAD. A co-culture system involving LUAD cells and macrophages assessed macrophage polarization and recruitment using RT-qPCR, flow cytometry, immunofluorescence, and macrophage chemotaxis assay. Additionally, transcriptome sequencing, tube formation, and co-immunoprecipitation assays demonstrated the roles and mechanisms underlying MS4A1 in HIPPO pathway and angiogenesis in cancer progression and M1 polarization. Furthermore, the efficacy of antagonists against angiogenesis and HIPPO pathway including ivonescimab and verteporfin was assessed in MS4A1 low tumor-bearing mouse receiving immunotherapy. Results showed that the significant prognostic association of MS4A1 expression was specific to LUAD. Furthermore, MS4A1 facilitated the malignant progression of LUAD by modulating macrophage M1 polarization, migration, and angiogenesis. Mechanistically, MS4A1 interacted with Yes-associated protein to regulate macrophage polarization and cancer progression through the HIPPO pathway. In vivo experiments also demonstrated that verteporfin inhibited the in-situ tumor progression and ivonescimab enhanced the efficacy of immunotherapy in MS4A1 low tumor-bearing mouse. The MS4A1/M1 macrophage axis was identified as a crucial regulator of malignancy in LUAD, indicating MS4A1 as a promising novel therapeutic target for advanced LUAD treatment.

While mismatch repair-deficient (dMMR) colorectal cancers (CRCs) exhibit strong immunogenicity and better response to immune checkpoint inhibitors, the more prevalent mismatch repair-proficient (pMMR) CRCs typically show poor T- cell infiltration and inferior outcomes. Profiling the limited tumor-infiltrating CD8+ T cells helps identify responders and guides new strategies to enhance their infiltration and function in pMMR CRC tumors. Our study reveals that the proportion and number of CD103-CD8+ T (CD103N) cells are significantly increased in pMMR CRC tissue compared to adjacent non-tumor tissue. Distinguish from CD103+CD8+ T (CD103P) cells with elevated TEX markers, these CD103N cells display a precursor exhausted T cells (TPEX) phenotype with elevated stemness properties, reduced exhaustion markers, and retained functional capacity to secrete anti-tumor mediators. Moreover, CD103N cells in pMMR CRC shared a substantial number of identical TCR clonotypes with both CD103P cells in tumor and CD103N cell in peripheral blood. In dMMR CRC patients, enrichment of TPEX-like CD103N cells is associated with a favorable prognosis following anti-PD-1 therapy, suggesting their association with clinical outcome. Our findings identify an expanded population of CD103N cells exhibiting a TPEX phenotype with anti-tumor potential in pMMR CRC, highlighting their promise as therapeutic targets for recruitment into the tumor microenvironment to enhance the efficacy of immunotherapy.

Diffuse large B-cell lymphoma (DLBCL) patients with co-expression of MYC (≥ 40%) and BCL2 (≥ 50%), classified as double-expressor DLBCL (DE-DLBCL), consistently exhibit poor prognosis with traditional first-line therapies. In order to address the unmet therapeutic needs in this high-risk population, this real-world study retrospectively reviewd 46 newly diagnosed DE-DLBCL patients from two centers to evaluate the efficacy and safety of zanubrutinib-based regimens. Key outcomes included complete response rate (CRR), objective response rates (ORR), progression-free survival (PFS), overall survival (OS) and adverse events. Univariate analysis was conducted to evaluate the impact of various prognostic factors on complete response. The median age was 57.8 years (range:20-81), with 45.65% of patients over 60 years old and 17.39% over 75 years old. Advanced-stage (III/IV) disease was present in 60.87% of patients at diagnosis, 78.26% had a non-germinal center B-cell (non-GCB) subtype, and 41.3% exhibited an International Prognostic Index score ≥ 3. The best CRR was 73.90% (95% CI, 58.90%-85.70%), and the best ORR was 95.70% (95% CI, 85.20%-99.50%). At a median follow-up of 15.7 months, the 3-year PFS and OS was 86.27% (95% CI, 75.37%-98.75%) and 89.79% (95% CI, 78.40%-100%) respectively. Multivariate analysis revealed that zanubrutinib-based chemotherapy regimen significantly improved CRR. Significant differences in PFS were observed across age, bulky disease, IPI score, and extranodal involvement stratification. Adverse events were mainly hematologic toxicities and fatigue. These findings suggest that zanubrutinib may serve as an effective component of first-line therapy for this population, with favorable tolerability.

Gastric cancer (GC), a malignant and highly proliferative disease, has profoundly impacts a substantial global population and is associated with several variables, including genetic, epigenetic, and environmental impacts. Global variance is associated with Helicobacter pylori infection and dietary factors.

Bladder cancer is a significant malignancy, for which prognostic prediction and understanding of the tumor immune microenvironment are crucial. B cells play a key regulatory role in this environment, making their study essential for advancing bladder cancer research.

Bisphenol A (BPA) is an endocrine-disrupting chemical that may contribute to cancer development. However, its role in lung adenocarcinoma (LUAD) remains poorly understood. This study aimed to investigate how BPA affects LUAD development by examining key genes involved in tumor progression and the immune microenvironment.

Epithelial ovarian cancer (EOC) remains a lethal epithelial malignancy. Immune-checkpoint inhibitors have entered management for recurrent/metastatic disease; yet durable benefit is confined to a subset, reflecting TGF-β-conditioned stromal barriers and organised T-cell exclusion. In this review we summarise advances from single-cell RNA and ATAC profiling and spatial transcriptomics that resolve fibroblast, tumour and immune programmes linked to TGF-β signalling, and appraise translational opportunities spanning selective pathway modulation, checkpoint combinations and spatial biomarkers. We also discuss enduring challenges-including site-specific heterogeneity across adnexal, omental and peritoneal niches, limited assay standardisation and a scarcity of predictive metrics-that temper implementation. By integrating TGF-β-informed readouts (e.g., INHBA+ cancer-associated fibroblast burden, periostin/fibronectin indices, MHC-I status and CD8-tumour distances) with PD-1-based regimens and TGF-β-axis agents (ALK5 inhibitors, Activin A neutralisation, NOX4-directed reprogramming), emerging strategies aim to restore antigen presentation, improve lymphocyte access and remodel tumour-stroma interfaces. Our synthesis provides an appraisal of the evolving landscape of TGF-β-informed precision immuno-oncology in ovarian cancer and outlines pragmatic standards and avenues for clinical translation. We hope these insights will assist researchers and clinicians as they endeavour to implement more effective, individualised regimens.