High-grade glioma with pleomorphic and pseudopapillary features (HPAP) is a recently identified methylation cluster comprised of relatively circumscribed gliomas enriched for variants in TP53, RB1, NF1, NF2, BRAF and with a more favorable clinical outcome than IDH-wildtype glioblastoma. Here, we present two cases occurring in young adults, one of which occurred in the background of NF2-related schwannomatosis. Both cases demonstrated characteristic histologic features including ependymoma-like areas (Case #1) and an astroblastoma-like phenotype (Case #2), as well as archetypal pseudopapillary structures and pleomorphic tumor cells. High-grade features were present and pathogenic variants in RB1 and TP53 were detected. Cytogenetic analysis revealed aneuploidy involving multiple whole chromosomes, including copy neutral LOH in chromosome 13 (Case #1). Both cases were classified as "no match" using the Heidelberg Brain Tumor Classifier (v12.5 and 12.8). Results from a preliminary classification model ("Bethesda Classifier") were consistent with HPAP. Confirmatory dimensionality reduction (t-SNE) showed clustering within (Case #2) or near (Case #1) the HPAP group. Patient #1 is currently receiving maintenance temozolomide following concomitant chemo-radiotherapy, 10 months post-surgery. Patient #2, treated with temozolomide, remains disease-free at 42 months. Our study highlights additional clinical and pathologic insights into this proposed tumor type and may suggest an association with NF2-related schwannomatosis and evolution from low-grade precursors. These observations support the consideration of HPAP as a distinct clinicopathological entity.

According to the updated classification system, human epidermal growth factor receptor 2 (HER2) expression statuses are divided into the following three groups: HER2-over-expression, HER2-low-expression, and HER2-zero-expression. HER2-negative expression was reclassified into HER2-low-expression and HER2-zero-expression. This study aimed to identify three different HER2 expression statuses for breast cancer (BC) patients using PET/CT radiomics and clinicopathological characteristics.

Cancer cells achieve replicative immortality through telomere maintenance mechanisms (TMMs), primarily via telomerase activation or alternative lengthening of telomeres (ALT). Sarcomas frequently employ the ALT pathway, which traditionally correlates with adverse clinical outcomes. However, chondrosarcomas represent a unique context where the role and prognostic significance of ALT remain largely unexplored.

Brain metastases (BrM) arising from breast cancer (BC) are an increasing consequence of advanced disease, with up to half of patients with metastatic HER2 + or triple negative BC experiencing central nervous system (CNS) recurrence. The genomic alterations driving CNS recurrence, along with contributions of the immune microenvironment, particularly by intrinsic subtype, remain unclear.

Solanine has been shown to inhibit cancer by regulating the expression of apoptosis (Bax, Bcl-2) and metastasis (CDH-1, MMP2) genes in various cancer cell types. We synthesized optimized niosome NPs (NPs) with high solubility and capacity for solanine loading. In this study, the cytotoxic, cell cycle inhibitory and apoptotic effects of solanine-loaded niosome NPs (SN-NPs) on MCF-7 were investigated. Thin-layer hydration was used to generate SN-NPs and their features were validated. The pH-dependent solanine release pattern was also examined. Synthesized SN-NPs were evaluated for cytotoxicity against MCF-7 and MCF-10 cell lines using MTT. Primary and secondary apoptosis, necrosis, and cell cycle arrest were measured using flowcytometry. Lastly, q-PCR was used to assess the expression of genes. The NPs had an average size between 50 and 70 nm, with a polydispersity index (PDI) of 0.452. Solanine was effectively incorporated into noisome NPs, as shown by the high encapsulation efficiency of 82.3%±0.24%. After a quick burst at pH 7 and 5, SN-NPs released slowly and sustainedly. The IC50 of solanine-loaded niosomes against MCF-7 cells decreased from 40 mg/100 mL to 10 mg/100 mL (48 h) and 5 mg/100 mL (72 h). After 72 h, SN-NPs caused late apoptosis in 30% of MCF-7 cells and necrosis in 5.06% (p < 0.01). SN-NPs caused 81% of cells to arrest in the G0/G1 phase, with only 12% progressing to G2/M (p < 0.01). Solanine-loaded NPs significantly increased Bax and CDH-1 gene expression in malignant cells compared to free niosomes and free solanine (p < 0.0001). Bcl-2 and MMP2 expression significantly decreased in this group compared to free niosomes and free solanine (p < 0.001). Solanine-containing niosomes showed significant anticancer effects on MCF-7 breast cancer cells, which were supported by apoptosis, cell cycle arrest and regulation of gene expression. The regulated release and precise delivery of solanine using SN-NPs show considerable translational potential. This improved nanocarrier technology may increase the bioavailability and efficacy of solanine, potentially leading to improved clinical outcomes in breast cancer therapy.

The role of postoperative radiotherapy (PORT) for patients with completely resected stage III-pN2 non-small-cell lung cancer (NSCLC) remains controversial. PORT is not routinely recommended for patients with completely resected stage III-pN2 NSCLC. Therefore, identifying the population that could benefit from PORT is urgently needed.

One of the most common and prevalent cancers is laryngeal squamous cell carcinoma (LSCC), which poses a great threat to the life and health of the patient. Nonetheless, it has been demonstrated that ubiquitination is crucial for the development and course of LSCC. Therefore, it is particularly important to identify biomarkers for ubiquitination-related genes (UbRGs) in LSCC.

Cuproptosis, a novel form of regulatory cell death, was investigated in this study for its effects on cuproptosis-associated proteins during gliomas development, offering novel insights into the mechanism of copper ion-based antitumor drugs.

Transcriptomic and metabolic profiles of tumor cells and stromal cells in oral squamous cell carcinoma (OSCC)-derived from oral submucosal fibrosis (OSF) (ODSCC) have been reported. However, the complex intercellular regulatory network within the tumor immunosuppressive microenvironment (TISME) in ODSCC remains poorly elucidated. Here, we utilized single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) data from GEO database and multiple immunofluorescence staining (mIF) to reveal distinctive TISME of ODSCC. Results found that compared to OSCC without OSF history (NODSCC), OSCC derived from OSF (ODSCC) showed a significant increase in exhausted CD8+T and Treg cells (Ro/e > 1, p < 0.05) and a decrease in cytotoxic T (CTL) (Ro/e < 1). ODSCC enriched in more Inhibin subunit beta A+ Macrophages (INHBA+Mac) and Proinflammatory Cancer-associated Fibroblast (iCAF) versus NODSCC. INHBA+Mac possessed strongest immune-suppressive functions, evidenced by highest immune checkpoint scores, lowest MHC scores and highest expression of SPP1 among macrophages. Moreover, INHBA+Mac in ODSCC presented stronger immune-suppressive functions than that in NODSCC. iCAF differentially highly expressed INHBA and enriched in immune-related pathways and collagen/ECM pathways across CAF subsets, and possessed stronger immune-suppressive functions, as shown by up-regulated gene expression of TDO2, IDO1 and DUSP4 in ODSCC versus in NODSCC. Furthermore, INHBA expression was higher in ODSCC than in NODSCC (p < 0.01). The classic OSF-inducing molecule arecoline significantly increases the expression of INHBA (p < 0.0001) in vitro experiments stimulating THP-1 cells. ST analysis revealed a close co-location of INHBA+Mac, iCAF and Treg and SpaGene identified INHBA-ACVR1/ACVR2A/ACVR2B interaction regions overlapping with distribution of three types of cells. Collectively, ODSCC shows a more severe TISME and potentially poorer sensitivity to immunotherapy than NODSCC. The increased INHBA+Mac and iCAF in ODSCC are associated with the observed more severe TISME. The upregulated INHBA in ODSCC and its interaction with INHBA-ACVR1/ACVR2A/ACVR2B may mediate the modulation effect of INHBA+ Mac and iCAF on Treg differentiation and functionality.

This study assessed the safety and efficacy of rechallenging patients in advanced non-small cell lung cancer (NSCLC) without targetable driver mutations using a combination of immune checkpoint inhibitors (ICIs) and anlotinib following progression after prior immunotherapy.

The newly discovered histone methyltransferase KMT9 serves as an epigenetic regulator of carcinogenesis in various cancer entities. For the first time, we investigated the presence of KMT9α in cholangiocarcinoma, the association with histologic subtypes, and its impact on survival.

Chronic lymphocytic leukemia (CLL) is characterized by immune dysfunctions driven by miRNA deregulation and the activation of immune checkpoint pathways, which contribute to disease progression and secondary immunodeficiency (SID). This study examines the interplay between miRNA expression profiles, Epstein-Barr virus (EBV) reactivation, and immune checkpoint pathways in the context of small intestine disease (SID) development in chronic lymphocytic leukemia (CLL). Patients were stratified into groups based on the presence of SID and EBV reactivation. Comprehensive analyses included miRNA profiling, EBV infection markers, and the expression of PD-1, PD-L1, CTLA-4, CD200, and CD86 on CD4 + and CD8 + T cells, as well as CD19 + B cells. The results revealed significant suppression of tumor-suppressive miRNAs (e.g., miR-15a, miR-181a, and miR-29a) in the SID EBV + group, correlating with enhanced immunosuppression. The highest expression of exhaustion markers (PD-1, PD-L1, CTLA-4) and immunosuppressive molecules (CD200/CD200R) was observed in the SID EBV⁺ group compared to all other groups, including SID EBV⁻, which may reflect the enhanced mechanisms of immunosuppression and lymphocyte exhaustion accompanying EBV reactivation in the course of secondary immunodeficiencies. Correlation analyses underscored significant associations between miRNA levels, EBV reactivation markers, and immune checkpoint activation. These findings highlight the dual role of miRNA deregulation and immune checkpoint activation in the immunosuppressive microenvironment of CLL. The study underscores the diagnostic and therapeutic potential of miRNAs and immune checkpoints in managing SID and EBV-associated immune dysregulation in CLL.

An elevated extracellular matrix (ECM) and interstitial fluid pressure (IFP) in gastric cancer limits the targeting of HER2-expressing cells when radioimmunotherapy (RIT) with 64Cu-trastuzumab (64Cu-TRZ) is utilized. Here, we used Losartan (LOS) to downregulate ECM and IFP in gastric cancer mice model. In our study we treated the gastric cancer mice model with a dose of 40 mg/kg of LOS. We found that the LOS treatment increases a twofold higher Alexa-647-TRZ accumulation which significantly enhanced 64Cu-TRZ. We determined that the LOS-treated samples exhibited reduced mRNA and protein expression of SERPINE1, a gene associated with the ECM degradation. Additionally, LOS treatment resulted in the downregulated mRNA expression of the TGF-β1 and COL13A1, the genes involved in ECM deposition and an upregulated RNA expression of MMP2, a gene associated with the ECM degradation. There were no significant changes in metastatic markers of N-Cadherin and E-Cadherin. Moreover, our study demonstrates that silencing SERPINE1 increases the activity of the MMP2 and decreases COL13A1 with no effect on the N-cadherin and E-cadherin were observed. Our novel combinational therapy of using 64Cu-TRZ with LOS is attributed to the downregulation of SERPINE1 targeting ECM and IFP is highly effective for treatment of gastric cancer.

High-grade serous ovarian cancer (HGSOC) is the most common and aggressive subtype of epithelial ovarian cancer, often diagnosed at advanced stages with a poor prognosis. Paclitaxel (PTX), a standard chemotherapeutic agent for HGSOC, exerts cytotoxic effects on cancer cells and modulates the tumor microenvironment. This study aimed to elucidate the molecular mechanisms of PTX in HGSOC using bioinformatics, machine learning, network pharmacology, and molecular docking, to identify potential diagnostic biomarkers and therapeutic targets. We identified differentially expressed genes (DEGs) between HGSOC and normal ovarian tissues using the GSE54388 dataset from the Gene Expression Omnibus database. The intersection of these DEGs with PTX targets, identified from the Swiss Target Prediction database, yielded 15 overlapping genes. These genes were analyzed via protein-protein interaction (PPI) network analysis to identify significant interaction relationships. Kaplan-Meier survival analysis was then performed to assess the prognostic significance of these genes. Their protein expression patterns in HGSOC tissues were validated using the Human Protein Atlas (HPA) database. Functional enrichment analysis was conducted using Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes. A combined diagnostic model was developed using LASSO regression and validated in two independent external datasets (GSE26712 and GSE12470). Molecular docking experiments were conducted to confirm the binding affinity of PTX to key proteins. Immune infiltration analysis was performed to assess the tumor microenvironment, revealing significant differences in immune cell composition between normal and tumor tissues. A total of 2267 DEGs were identified, with 15 overlapping genes related to PTX targets. After PPI network analysis, Kaplan-Meier survival analysis, and HPA validation, five key genes (AURKA, CBX7, CCNA2, HSP90AA1, and TUBB3) were identified as associated with HGSOC progression. The combined diagnostic model demonstrated high accuracy in distinguishing HGSOC from normal tissues, with AUC values of 0.9892 and 0.9465 in the GSE26712 and GSE12470 validation datasets, respectively. Molecular docking confirmed stable binding of PTX to these key proteins, suggesting their role in PTX's therapeutic effects. Immune infiltration analysis revealed significant differences in immune cell composition between normal and tumor tissues, highlighting the potential impact of these genes on the tumor microenvironment. In summary, our findings provide a theoretical basis for improving clinical diagnosis and elucidating the underlying mechanisms of HGSOC.

Homologous recombination (HR) and mismatch repair (MMR) act as guardians of the human genome, and defects in HR or MMR are causative in at least a quarter of all malignant tumors. Although these DNA repair-deficient tumors are eligible for effective targeted therapies, fully reliable diagnostic strategies based on functional assay have yet to be established, potentially limiting safe and proper application of the molecular targeted drugs. Here we show that transient transfection of artificial DNA substrates enables ultrarapid detection of HR and MMR. This finding led us to develop a diagnostic strategy that can determine the cellular HR/MMR status within one day without the need for control cells or tissues. Notably, the accuracy of this method allowed the discovery of a pathogenic RAD51D mutation, which was missed by existing companion diagnostic tests. Our methods, termed HR eye and MMR eye, are applicable to frozen tumor tissues and roughly predict the response to therapy. Overall, the findings presented here could pave the way for accurately assessing malignant tumors with functional defects in HR or MMR, a step forward in accelerating precision medicine.

Fumarate hydratase-deficient renal cell carcinoma (FH-deficient RCC) is a rare yet highly lethal kidney cancer. To deepen our understanding of FH-deficient RCC, we conduct a comprehensive integrated genomic study. We analyze the association of FH alteration patterns with tumor heterogeneity and develop a CpG site-specific methylation signature for precise identification of FH-deficient RCC. Transcriptomic analysis unveils three distinctive molecular subtypes characterized by enrichment of immune/Angiogenic/Stromal (C1), WNT/Notch/MAPK (C2), and proliferation/stemness (C3) pathways, respectively. Tumors in C1 derive the most substantial survival benefit from a combination of immune checkpoint blockade (ICB) and anti-angiogenic therapy. Tumors in C2 display moderate response to this therapeutic approach. In contrast, tumors in C3 exhibit an unfavorable response to anti-angiogenic monotherapy and its combination with ICB. These findings contribute to a profound understanding of the aggressive nature of FH-deficient RCC, offering insights into potential precision medicine approaches for disease management.

In patients with hepatocellular carcinoma (HCC) meeting the Milan criteria, liver transplantation (LT) is an effective therapy. This study aims to define the survival-related molecular biological features helping precisely identifying the patients with HCC beyond the Milan criteria who have acceptable outcomes. In the derivation cohort, integrated analyses of tumor tissues are conducted using RNA sequencing (RNA-seq), proteomic landscape, and transposase-accessible chromatin sequencing (ATAC-seq). Based on transcriptomics, three subgroups that significantly differ in overall survival were identified in the derivation cohort, and these findings are validated in an independent cohort. In-depth bioinformatics analysis using RNA-seq and proteomics reveals that the promotion of cancer stemness by cancer-associated fibroblasts (CAFs) can be responsible for the negative biological characteristics observed in high-risk HCC patients. The ATAC-seq identifies key factors regulating transcription, which may bridge CAF infiltration and stemness. Finally, we demonstrate that the CAF-derived CXCL12 sustains the stemness of HCC cells by promoting XRCC5 through CXCR4.

Recent advancements in probe-based, full-transcriptome technologies for FFPE tissues, such as Visium CytAssist, Chromium Flex, and GeoMx DSP, enable analysis of archival samples, facilitating the generation of data from extensive cohorts. However, these methods can be labor-intensive and costly, requiring informed selection based on research objectives. We compare these methods on FFPE tumor samples in Breast, NSCLC and DLBCL showing 1) good-quality, highly reproducible data from all methods; 2) GeoMx data containing cell mixtures despite marker-based preselection; 3) Visium and Chromium outperform GeoMx in discovering tumor heterogeneity and potential drug targets. We recommend the use of Visium and Chromium for high-throughput and discovery projects, while the manually more challenging GeoMx platform with targeted regions remains valuable for specialized questions.

Polo-like kinase 1 (PLK1) signaling drives tumor malignancy and chemotherapy resistance, which is an unmet clinical need. Recruiting PLK1 to the central spindle during anaphase is necessary for its function in promoting cancer cell proliferation, which is achieved by binding to microtubule-associated protein regulating of cytokinesis (PRC1) located in the spindle. However, the role of PLK1/PRC1 signaling in chemotherapy resistance is unknown. In this study, we identified a small molecule B4 which inhibited PLK1/PRC1 signaling through disrupting the formation of PLK1/PRC1 protein complexes. In the presence of blocking PLK1/PRC1 signaling, enhanced sensitivity of drug-resistant tumors to traditional chemotherapy was found. Suppression of PLK1 activity by B4 inhibited disease progression in allograft models, and combination with cisplatin elicited dramatic regression of drug-resistant tumors. Our findings provide a promising strategy to target the PLK1 signaling cascade and demonstrate a potential modality to enhance sensitivity to chemotherapy in non-small cell lung cancer (NSCLC).

ROS1 gene rearrangement is an important target for NSCLC treatment. There is not yet sufficient real-world data on ROS1 diagnostic methods, treatment selection, and clinical outcomes in the Chinese population.