There are few tools support postmastectomy radiotherapy (PMRT) decisions for triple-negative breast cancer (TNBC) patients. This study aimed to develop a whole slide image (WSI)-based risk score to identify PMRT beneficiaries. We analyzed 608 TNBC patients treated at West China Hospital, Sichuan University (WCH) and 182 patients from The Cancer Genome Atlas (TCGA), diagnosed between 2011 and 2019. Utilizing features extracted from hematoxylin and eosin-stained WSI and clinicopathological characteristics, an image score and a clinicopathological score for each patient were computed via eXtreme Gradient Boosting, combined into a comprehensive risk score. Multivariate Cox proportional hazards regression analyses revealed a higher image score strongly associated with worse 5-year invasive disease-free survival (iDFS) (HR = 8.80, P < 0.001), overall survival (OS) (HR = 9.02, P < 0.001), and locoregional recurrence-free survival (LRFS) (HR = 8.39, P = 0.003). The integrated risk score outperformed clinicopathological score in prognostic accuracy, as evidenced by the area under the curve (WCH validation cohort, iDFS: 0.805 vs. 0.756; OS: 0.874 vs. 0.807; LRFS: 0.957 vs. 0.870; TCGA cohort, iDFS: 0.683 vs. 0.598; OS: 0.685 vs. 0.617). Importantly, PMRT significantly improved OS in "high-risk" patients identified by the risk score, but not in "low-risk" patients in both WCH and TCGA cohorts. These findings suggest that the WSI-based risk score shows promise as a tool for prognostic assessment and guiding PMRT decision-making in TNBC patients.

Lenvatinib resistance significantly limits its clinical efficacy and application in the treatment of hepatocellular carcinoma (HCC). Mitofusin 2 (MFN2) is an important GTPase involved in mitochondrial fusion, energy balance and mitophagy. The role and regulatory mechanism of MFN2 in HCC progression and lenvatinib resistance remain unclear. Herein, we demonstrated that the family with sequence similarity 111 member B (FAM111B) regulated the stability of MFN2 and the sensitivity to lenvatinib in HCC. Mechanistically, FAM111B promoted MFN2 ubiquitination by recruiting RAN-binding protein 9 (RANBP9), a core subunit of the C-terminal to LisH (CTLH) E3 ligase complex. Targeting FAM111B generated hyperfused mitochondria, driving a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) and antagonising cytoprotective mitophagy. Clinically, FAM111B protein levels were inversely correlated with MFN2 expression in HCC samples, with patients who exhibited high FAM111B levels having a worse prognosis and reduced sensitivity to lenvatinib treatment. More importantly, we developed glypican-3 (GPC3)-targeted lipid nanoparticles for efficient delivery of siFAM111B, which demonstrated strong efficacy in combination with lenvatinib. Together, our findings uncover a novel regulatory mechanism for MFN2 posttranscriptional regulation and highlight the therapeutic potential of targeting FAM111B in HCC treatment.

Tumor-infiltrating lymphocyte (TIL)-therapy has received FDA approval for the treatment of advanced melanoma and shows potential for broader applications in solid tumors, including glioblastoma. In this study, tumor-reactive TILs (tr-TILs) are isolated and enriched for CD137 expression from cavitron ultrasonic aspirator (CUSA) emulsions of 161 adult patients diagnosed with diffuse gliomas. Tr-TILs are successfully expanded in 87 out of the 161 patients, reflecting an expansion rate of 54%. Notably, the presence of IDH1 mutation and the cumulative dose of steroids are identified as significant negative predictors of expansion efficacy. The expanded tr-TILs exhibit distinct phenotypic and molecular dysfunctional features yet show upregulated expression of progenitor/memory-like markers and polyclonal T-cell receptors. Importantly, these tr-TILs demonstrate specific antitumor reactivity against autologous tumor cells in both in vitro and in vivo xenograft models. These findings provide a compelling background for a personalized immunotherapeutic approach while tackling one of the most significant challenges in oncology.

Histone deacetylases (HDACs) are epigenetic regulators frequently altered in cancer. Here we report that overexpression of HDAC1/2 occurs in Hepatocellular Carcinoma (HCC) patients, correlating with poor prognosis. We show that romidepsin, a class-I HDAC inhibitor, elicits a combinatorial perturbation of distinct molecular processes in HCC cells, altering lipid composition, mitotic spindle machinery, and levels of cell cycle/survival signals. Collectively, these alterations lead HCC cells to a vulnerable state, conferring dependency to receptor tyrosine kinase (RTK) signalling support. The cytostatic effects of romidepsin alone is converted into cytotoxicity by the RTK inhibitor cabozantinib in HCC models. We document that romidepsin+cabozantibib confers an immune-stimulatory profile in Alb-R26Met mouse models, with direct effects on primary human dendritic cell maturation in vitro. Our findings put forward the intricate crosstalk between epigenetics, metabolism, and immune response in cancer. The broad action of romidepsin on distinct cellular functions highlights its therapeutic potential for HCC treatment.

The limited response rate to immune checkpoint inhibitors (ICIs) remains a significant challenge in the treatment of lung adenocarcinoma (LUAD). In our study, we identified a lactate-based chemical barrier surrounding FAP+ cancer-associated fibroblasts (CAFs) within the LUAD microenvironment (TME), which may hinder the infiltration and function of CD8+ T cells. Further investigation revealed that FAP+ CAFs specifically overexpress LINC01711, which drives lactate production by promoting FGFR1-mediated phosphorylation of lactic dehydrogenase A (LDHA) at the Y10 site and facilitating the formation of active LDHA tetramers. These FAP+ CAFs then export lactate into TME via the MCT4 transporter, thereby establishing a chemical barrier and fostering an immunosuppressive TME. Notably, we developed a small extracellular vesicle (sEV)-based in vivo self-assembled siRNA system for in vivo knockdown of LINC01711 and demonstrated its potential to enhance the response rate to ICIs in LUAD. Our findings underscore the pivotal role of FAP+ CAFs in driving resistance to ICIs and propose novel therapeutic strategies to overcome this obstacle.

Digital pathology has revolutionized cancer diagnosis through microscopic analysis, yet manual interpretation remains hindered by inefficiency and subjectivity. Existing deep models for osteosarcoma cell nucleus recognition suffer from the difficulty of capturing hierarchical relationships in single-dimensional attention mechanisms, leading to inaccurate edge recognition. Furthermore, the fixed receptive field of CNNs limits the aggregation of multi-scale information, hindering the differentiation of overlapping cells. This study introduces MACC-Net, a novel multi-attention based method designed to enhance the recognition accuracy of digital pathology images. By integrating channel, spatial, and pixel-level attention mechanisms, MACC-Net overcomes the limitations of traditional single-dimensional attention models, improving feature consistency and receptive field expansion. Experimental results demonstrate a Dice Similarity Coefficient (DSC) of 0.847, highlighting MACC-Net's potential as a reliable auxiliary diagnostic tool for pathologists. Code: https://github.com/GFF1228/MACCNet .

Intratumoral heterogeneity remains a major barrier to durable cancer therapies, largely driven by the persistence of cancer stem cells (CSCs). In this study, we employed an integrated, multi-scale approach to investigate how melanoma CSCs respond to siRNA-mediated silencing of three key regulatory genes: KLF4, SHH, and HIF1α. Using a combination of morphological, molecular, spectroscopic, and elemental analyses, we explored structural and biochemical consequences of gene knockdown. Gene silencing resulted in significant changes in cell shape and size, reduced F-actin organization, and decreased PFN1 expression, indicating a loss of stem-like properties. ATR-FTIR spectroscopy revealed shifts in biomolecular composition, notably a reduction in amide III intensity and an increase in lipid ester content. SEM-EDS point-based elemental analysis revealed SEM-EDS point-based elemental analysis revealed relative differences in carbon and nitrogen levels between selected central and peripheral regions of silenced and control cells, at the micron-scale working depth, reflecting broader elemental distribution trends rather than precise subcellular compartmentalization. XPS analysis further confirmed these differences, providing additional insights into the elemental composition of the cellular surface. The integration of FTIR spectroscopy into this study highlights the potential of infrared spectroscopy as a powerful tool in cancer research. These findings demonstrate that targeting critical regulatory pathways induces cytoskeletal and biochemical remodelling in melanoma CSCs, offering a multi-dimensional perspective on cellular plasticity.

Intrahepatic cholangiocarcinoma (ICC) is a rare but highly malignant liver cancer. Surgical resection provides the best long-term survival, yet poor prognosis requires improved treatments. Galectin-9 (GAL9) has gained attention for its role in tumor biology. This study investigated circulating galectin-9 (cGAL9) levels in ICC patients undergoing resection, along with tumor tissue characteristics.

Phosphatidylinositol glycan anchor biosynthesis class U (PIGU), a crucial subunit of the glycosylphosphatidylinositol transamidase (GPI-T) complex, is an oncogene in hepatocellular carcinoma. However, its role in esophageal squamous cell carcinoma (ESCC) remains poorly understood. This study aims to clarify PIGU's role and mechanisms in ESCC by analyzing its expression across pan-cancer datasets, clinical relevance in TCGA-ESCA samples, and effects on cell behavior (migration, invasion, proliferation) and signaling pathways, validated via immunohistochemistry. To examine cell behavior, we used Transwell, colony-formation, CCK-8, and wound-healing assays to assess migration, invasion, proliferation, and wound healing.The epithelial-mesenchymal transition marker levels were measured using Western blot analysis, and the cell cycle and apoptosis were assessed using flow cytometry in conjunction with western blotting. Furthermore, we used western blotting to examine proteins implicated in the PI3K/AKT signaling pathway.To further confirm PIGU's role in ESCC progression, a subcutaneous xenograft mouse model was employed. Our findings suggest that PIGU is highly expressed in ESCC and is strongly associated with tumor growth, lymphatic metastasis and poor prognosis, and is an independent prognostic factor for ESCC patients.PIGU knockdown not only arrested the cell cycle and induced apoptosis, but also significantly reduced migration, invasion, and proliferation in ESCC cells. Additionally, vimentin and N-cadherin were downregulated when PIGU expression was silenced, although E-cadherin expression was simultaneously increased.Moreover, PIGU knockdown decreased the amount of phosphorylated Akt and PI3K. In vivo, PIGU knockdown inhibited ESCC cell proliferation and promoted apoptosis. These findings imply that targeting PIGU may represent a promising therapeutic approach, and that PIGU could potentially serve as both a diagnostic and prognostic biomarker for esophageal squamous cell carcinoma (ESCC).

A tumor cell membrane (CM)-based biomimetic membrane tumor vaccine is an emerging prevention and treatment strategy in tumor immunotherapy. However, a single CM mostly has a weak immune-boosting effect. Here, a heterogenic fusion membrane tumor vaccine, EV-CM, was successfully constructed by fusing extracellular vesicles (EVs) from S. aureus and CM from B16F10 melanoma cells. Inheriting the advantages of parental components, the EV-CM combines tumor antigens with natural adjuvants that can be used for immunotherapy and can be easily synergistic with complementary therapies. In vivo vaccine tests have shown that EV-CM can activate immune antitumor responses and prevent tumorigenesis. To further enhance the immunotherapeutic and antimetastatic effects of EV-CM, Pt-porphyrin coordination polymer as an immunopotentiator (CPIP) was implanted into an EV-CM nanoplatform (CPIP@EV-CM), which combines localized sonodynamic/chemodynamic therapy-induced immunogenic cell death with heterogenic fusion membrane-mediated antigen-presenting functions. In vitro performance tests, cell experiments, and in vivo animal models have confirmed that the CPIP@EV-CM combined with US has better ROS production, tumor cell killing, and antimetastasis abilities. The heterogenic fusion membrane strategy and ultrasound-augmented nanoplatform present exciting prospects for designing tumor-immunogenic, self-adjuvant, and expandable vaccines, providing new ideas for exploring new melanoma immunotherapy and antimetastasis strategies, which is expected to be used as a safe and effective treatment in clinical practice.

Neuroblastomas encompass malignant cells with varying degrees of differentiation, ranging from adrenergic (adr) cells resembling the sympathoadrenal lineage to undifferentiated, stem-cell-like mesenchymal (mes) cancer cells. Relapsed neuroblastomas, which often have mesenchymal features, have a poor prognosis and respond less to anticancer therapies, necessitating the development of novel treatment strategies. To identify novel treatment options, we analyzed the sensitivity of 91 pediatric cell models, including patient-derived tumoroid cultures, to a drug library of 76 anti-cancer drugs at clinically relevant concentrations. This included 24 three-dimensionally cultured neuroblastoma cell lines representing the range of mesenchymal to adrenergic subtypes. High-throughput ATP-based luminescence measurements were compared to high-content confocal imaging. With machine learning-supported imaging analysis, we focused on changes in the lysosomal compartment as a marker for therapy-induced senescence and assessed the basal lysosomal levels in a subset of untreated mesenchymal versus adrenergic cells. We correlated these findings with pathway activity signatures based on bulk RNA and scRNAseq. Comprehensive image-based synergy screens with spheroid cultures validated the combined effects of selected drugs on proliferation and cytotoxicity. Mesenchymal models presented high basal lysosomal levels correlating with senescence-associated secretory phenotype (SASP) and sphingolipid metabolism pathways. Chemotherapy treatment further increased lysosome numbers, indicative of therapy-induced senescence. Furthermore, the mesenchymal subtypes correlated with MAPK activity and sensitivity to MAPK pathway inhibitors. Lysosomal and SASP signaling is druggable by inhibitors of lysosomal acid sphingomyelinase (SLMi) or senolytics, including BCL2-family inhibitors. Especially the sequential combination of MEK inhibitors (MEKi) with BCL2-family inhibitors was the most effective on relapsed neuroblastoma cell lines. Gene expression analysis of 223 patient samples, drug sensitivity profiling of five patient-derived fresh tissue cultures, and in vivo zebrafish embryo neuroblastoma xenograft models confirmed these findings. Inhibition of MAPK signaling in combination with BCL2-family inhibitors is a novel treatment option for patients suffering from relapsed neuroblastomas.

In pancreaticoduodenectomy, extensive involvement of the superior mesenteric vein (SMV) often complicates venous reconstruction, especially when artificial grafts are unavailable. In such cases, meso-caval shunt (MCS) emerges as a solution. This study aimed to evaluate the safety and efficacy of permanent MCS as both an emergency procedure and a planned surgical strategy.

There are multiple pathologic subtypes of papillary thyroid carcinoma (PTC), each with distinct clinical prognoses. However, the available data on the clinicopathologic risks associated with several common PTC subtypes are controversial and require more comprehensive evaluation. To address this, we conducted a systematic search of English-language databases, including PubMed, EMbase, Cochrane Library, and Web of Science, for studies on six PTC subtypes, including classic papillary thyroid carcinoma (CPTC), papillary thyroid microcarcinoma (PTMC), follicular variant of papillary thyroid carcinoma (FVPTC), tall cell variant of papillary thyroid carcinoma (TCVPTC), diffuse sclerosing variant of papillary thyroid carcinoma (DSVPTC), and columnar cell papillary thyroid carcinoma (CCVPTC). Our case-control study of clinicopathological prognostic analyses of six subtypes, with a search date of January 2000 to May 2024. Two researchers independently screened the literature, extracted data, and assessed quality and risk of bias according to set criteria. R software gemtc package, Stata 15.1 software were applied to perform reticulated Meta-analysis methods were applied to compare the clinicopathological features and prognostic assessment of classic papillary thyroid carcinoma and the other five subtypes in all the studies.The risk of distant metastasis was higher in patients with CCVPTC, TCVPTC, and DSVPTC than in CPTC.FVPTC and PTMC exhibit a lower risk of in situ tumor relapse compared to CPTC. The tumour size of TCVPTC was significantly larger than that of CPTC, while there was no significant difference in the tumour size of CCV, DSV, FVPTC, CPTC and PTMC. DSVPTC was significantly more multifocal than the other subtypes. This network meta-analysis confirms the aggressive biological behavior and poor prognosis associated with TCVPTC, DSVPTC, and CCVPTC. Therefore, these subtypes should be managed aggressively with total thyroidectomy and lymph node dissection if diagnosed preoperatively. In contrast, FVPTC and PTMC are less aggressive and have a better prognosis, suggesting that treatment and follow-up strategies for PTC should be tailored according to the histopathological subtype.

The prognosis of relapsed or refractory diffuse large B-cell lymphoma (DLBCL) is poor. Therefore, searching for new therapeutic agents is particularly important to improve therapeutic efficacy. Targeting the ubiquitin-proteasome system is a potential therapeutic strategy for treating DLBCL. In this study, we investigated the role of the deubiquitase inhibitor Spautin-1 in the treatment of DLBCL. Spautin-1 significantly inhibited the growth of DLBCL, including the growth of cells and transplanted tumors in mice. Notably, Spautin-1 showed enhanced tumor suppression in immune-competent versus immunodeficient mice models, mediated by CD8+ T cell infiltration and activation. Mechanistically, Spautin-1 promotes PANoptosis by inducing mitochondrial damage mediated by USP13-ACLY inhibition in DLBCL cells, which in turn induces the release of injury-related molecular patterns and cytokines. Moreover, high USP13 expression in DLBCL is associated with poor prognosis and blocks CD8+ T cell infiltration. In summary, Spautin-1 may inhibit the growth of DLBCL cells by promoting mitochondrial damage-mediated PANoptosis and anti-tumor immunity, providing a potential strategy for DLBCL therapy.

Nicotinamide N-methyltransferase (NNMT) is an S-adenosyl-l-methionine (SAM)-dependent cytosolic enzyme, and a growing body of evidence suggest that it plays an essential role in cancer progression. Recently, NNMT has a role in methylation metabolism and tumorigenesis and was associated with a poor prognosis against numerous cancers. In addition, it has been reported that NNMT has been overexpressed in the stroma of advanced high-grade serous carcinoma and may contribute to decreased survival. This study aimed to identify novel biomarkers to predict resistance and investigate their clinicopathologic significance in paclitaxel-resistant advanced or recurrent ovarian clear cell carcinoma (OCCC). Fluorescence-labeled two-dimensional differential gel electrophoresis (2D-DIGE), immunohistochemical, and MASCOT analyses allowed us to identify the cytoplasmic metabolic enzyme NNMT. In cultured cell studies, NNMT protein expression was higher in paclitaxel-resistant OVMANA and OVTOKO cells than in paclitaxel-sensitive KK and ES-2 cells. Furthermore, although analysis of clinical tissue samples showed no association with poor prognosis in 7 individuals with low NNMT expression in the cytoplasm of OCCC cells, high expression of NNMT in the cytoplasm of OCCC cells may be associated with low sensitivity to paclitaxel in OCCC and may have prognostic implications. Therefore, targeting therapy to reduce cytoplasmic NNMT expression levels may increase the sensitivity of OCCC to paclitaxel.

Acute myeloid leukemia is a highly heterogeneous hematopoietic malignancy, and we constructed a prognostic signature combining disulfidptosis-related genes and ferroptosis-related genes to predict the prognosis, immunotherapy response, and drug sensitivity of acute myeloid leukemia (AML) patients. The TCGA-LAML datasets underwent random partitioning into training and validation sets. Subsequently, a prognostic risk signature was formulated using the least absolute shrinkage and selection operator algorithm. Kaplan-Meier survival analysis and receiver operating characteristic curve analysis were employed to assess the clinical significance of the signature. The results of the immune infiltration difference analyses are displayed, and the drug sensitivity analyses were used to identify potentially effective drugs for AML patients. qPCR was employed to validate the expression levels of the signature genes and compared the signature with existing signatures and mutated genes. Univariate and multivariate Cox regression analyses have underscored the signature as an autonomous prognostic risk determinant. Scrutiny into immune infiltration has unveiled significant associations: the risk score exhibits a favorable correlation with monocyte and M2 macrophage counts but an adverse correlation with resting mast cell counts. The expression patterns of immune checkpoint genes diverge between the distinct risk cohorts. Patients categorized as high-risk demonstrate enhanced benefits from cyclopamine, 443654, and 770041, whereas those classified as low-risk exhibit more pronounced advantages from cytarabine and AZD6244. The risk signature demonstrates superior prognostic accuracy compared to established signatures and mutated genes. In summary, our study may provide potential prognostic biomarkers and individualized precision therapy for AML patients.

PurposeThis retrospective study aimed to compare the clinical outcomes, safety profiles, and postoperative recovery characteristics of conventional open surgery, ultrasound-guided minimally invasive rotary cutting, and microwave ablation in the treatment of benign breast tumors, using historical patient data.MethodsIn total, 164 patients with benign breast tumors treated at Haidian Hospital, Beijing, from January 2020 to January 2023 were selected as study participants. Based on the treatment received by the patients, they were divided into three groups: open surgery group (87 patients treated with conventional open excision surgery), rotary cutting group (65 patients treated with Micromotion minimally invasive rotary cutting under color Doppler ultrasound guidance), and ablation group (12 patients treated with microwave ablation). Subsequently, key indicators, including operation time, intraoperative blood loss, incision length, incision healing time, postoperative pain score, incidence of postoperative complications, and aesthetic outcome of the breast, were comprehensively compared and analyzed among the three groups.ResultsStatistical analysis revealed significant differences (P < 0.05) among the groups in terms of operation time, intraoperative blood loss, incision length, incision healing time, and postoperative pain scores at 24, 48, and 72 h. Specifically, the ablation group showed significantly lower values for these parameters compared with the rotary cutting and open surgery groups. The rotary cutting group exhibited better outcomes than the open surgery group across these metrics. In addition, the incidence of postoperative complications and aesthetic outcome of the breast in the ablation and rotary cutting groups were significantly better than those in the open surgery group (P < 0.05). However, no significant differences were observed in the incidence of postoperative complications and the aesthetic outcome of the breast between the ablation and rotary cutting groups (P > 0.05).ConclusionCompared with conventional open surgery, microwave ablation and Micromotion minimally invasive rotary cutting under color Doppler ultrasound guidance demonstrate superior surgical outcomes, lower postoperative pain levels, and reduced incidence of postoperative complications in the treatment of benign breast tumors. Microwave ablation offers shorter operation time, less intraoperative blood loss, faster postoperative recovery, and significantly greater pain relief while providing better aesthetic outcome of the breast.

Subcutaneous panniculitis-like T-cell lymphoma is a rare type of T-cell lymphoma that causes multiple painless subcutaneous nodules over the body. Patients with subcutaneous panniculitis-like T-cell lymphoma may develop facial lipoatrophy that causes disfigurement. We report the case of a 53-year-old female patient with subcutaneous panniculitis-like T-cell lymphoma and severe facial lipoatrophy who underwent three sessions of autologous fat grafting. During the 2-year follow-up, she regained a good facial contour after treatment.

N6-methyladenosine (m6A) is the most prevalent internal modification of eukaryotic mRNA, playing a crucial role in the regulation of gene expression. Methyltransferase-like 3 (METTL3), a key catalytic component of the m6A methyltransferase complex, is primarily responsible for the deposition of m6A on target RNA. Recent studies have revealed that METTL3 contributes to diverse pathological processes, particularly tumorigenesis, through both m6A-dependent and independent mechanisms. As a result, METTL3 has attracted increasing interest as a potential therapeutic target across various cancer types. This review summarizes recent advances in the discovery of small molecules targeting METTL3, including substrate-competitive inhibitors, allosteric inhibitors, and proteolysis-targeting chimeras (PROTACs). It also discusses the strategies in their discovery, the associated structural features, and the remaining challenges and future directions in this field. Overall, these efforts provide valuable insights into the design and discovery of METTL3-targeted therapeutics with potential clinical applications.

Ovarian cancer is a lethal gynecological health issue, that poses a serious threat to women's health worldwide. The objective of this study was to provide a literature overview of the application of fluorescent tracers during surgical ovarian cancer treatment.