Immune exclusion inhibits antitumor immunity and response to immunotherapy, but its mechanisms remain poorly defined. In triple-negative breast cancer (TNBC), an aggressive and generally immune-rich subtype, an immune-cold microenvironment predicts poor prognosis due to a limited response to chemotherapy and immune checkpoint inhibitors. This study aimed to identify mechanisms regulating immune infiltration in TNBC.

Yan Leyfman, MD, reflected on resilience and hope in the face of cancer, recounting a 37-year-old diagnosed with stage IV colorectal cancer followed by HIV.

Soft tissue sarcomas (STS) are rare but aggressive tumors. Although surgery and radiotherapy are standard treatments for localized STS, the role of adjuvant chemotherapy, particularly doxorubicin, in high-grade STS is debated.

Immunotherapy combined with chemotherapy is a standard treatment for advanced non-small cell lung cancer (NSCLC). However, the comparative efficacy and safety of cost-efficient modified PD-1 inhibitors remain incompletely characterized. This study aimed to determine the optimal choice for the 3 most commonly used modified PD-1 inhibitors-tislelizumab, sintilimab, and camrelizumab-combined with chemotherapy in locally advanced or metastatic NSCLC.

Cellular water content governs the concentration of all biomolecules inside a cell, thereby influencing the physical and functional properties of the cell. However, measurements of water content in physiologically relevant cell culture models remain largely unavailable, particularly in three-dimensional (3D) models such as tumor spheroids and organoids. Here, we achieve such measurements using an industrial-grade capillary steel tube. The steel tube functions as a mechanical resonator that inertially senses the buoyant mass of particles. For microgram-scale particles ≥ 400 micrometers in diameter, we achieve <1% precision error in buoyant mass with a 5-minute acquisition interval. By sequentially measuring the buoyant mass of individual, patient-derived glioblastoma tumor spheroids derived from patients with glioblastoma in media of different densities and cell permeabilities, we determine the absolute and fractional (volume/volume) water content of the spheroids, along with their dry mass, volume, and density properties. We achieve ~0.5% precision error in fractional water content with a throughput of three spheroids per hour. This enables us to detect both interspheroid heterogeneity in fractional water content and acute responses to kinase inhibition. Overall, we establish a simple and accessible technique for quantifying water content in living 3D cell culture models, opening previously unexplored avenues for studying biophysical regulation in multicellular systems.

Metabolic dysfunction-associated steatohepatitis (MASH) and its progression to hepatocellular carcinoma remain major clinical challenges. Chronic endoplasmic reticulum (ER) stress, induced by sustained high-fat diet (HFD) intake, promotes hepatic inflammation, lipid accumulation, and hepatocellular dysfunction during MASH pathogenesis. While transcriptional responses are well characterized, the posttranscriptional mechanisms underlying hepatocyte adaptation to chronic ER stress remain poorly understood. Using an integrative approach combining transcriptomics, ribosome profiling, cytoplasmic polyadenylation analysis, and cis-regulatory mapping, we define the posttranscriptional landscape induced by chronic HFD exposure. To delineate the specific role of chronic ER stress, we use a hepatocyte-specific knockout of a key regulator of translational control under prolonged ER stress. We show that ~70% of HFD-induced gene expression changes are modulated at the translational level. A distinct subset of mRNAs, enriched in suboptimal codons and bearing short poly(A) tails under normal diet, becomes selectively activated upon HFD-induced poly(A) tail elongation. These transcripts, associated with cell cycle, immune response, fibrosis, and tissue remodeling, correlate with MASH severity in both murine models and human samples. Their regulation is mediated by cis-elements in the 3' UTR that coordinate polyadenylation and deadenylation. Loss of this adaptive response exacerbates liver damage and tumor burden in HFD-fed mice.

Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a dense desmoplastic stroma and an immunosuppressive tumor microenvironment that contribute to therapeutic resistance. Here, we identify plasminogen activator inhibitor 1 (PAI1) as a stroma-derived mediator of immune evasion and tumor progression in PDAC. PAI1 is predominantly produced and secreted by cancer-associated fibroblasts, and its genetic ablation in the stromal compartment impairs tumor growth. Mechanistically, hypoxia induces PAI1 expression in fibroblasts, which in turn shifts macrophages toward immunosuppressive phenotypes and suppresses CD8+ T cell infiltration and function. We further show that tissue plasminogen activator (tPA), a direct PAI1 target, is also secreted by fibroblasts and supports antitumor CD8+ T cell responses. Notably, elimination of stromal tPA promotes immunosuppressive macrophage phenotypes, reduces CD8+ T cell infiltration, and accelerates PDAC progression. These findings define a previously unrecognized PAI1-tPA regulatory axis within the tumor stroma that modulates antitumor immunity. Targeting this pathway may provide a therapeutic opportunity to overcome stroma-driven immune suppression in PDAC.

Systemic neoadjuvant chemotherapy, often combined with immunotherapy, is the standard of care for early-stage, non-breast cancer susceptibility gene (BRCA)-mutant triple negative breast cancer (TNBC). However, up to 70% of patients retain residual disease after treatment, which is linked to recurrence and mortality within 5 years. To define mechanisms of resistance, we performed single-cell RNA sequencing on orthotopic TNBC patient-derived xenografts during a cycle of treatment with doxorubicin and cyclophosphamide (AC). Clustering identified four tumor epithelial cell populations, with basal cells enriched in residual tumors. These basal cells up-regulated C15ORF48, a paralog of the mitochondrial cytochrome c oxidase associated subunit FA4 (NDUFA4), while exhibiting reciprocal down-regulation of NDUFA4. Functionally, C15ORF48 knockdown sensitized breast cancer cells to AC, increasing reactive oxygen species (ROS) and apoptosis. Thus, the up-regulation of C15ORF48 blunts ROS accumulation and induces resistance to chemotherapy in the basal cell subpopulations. Our findings identify C15ORF48 as a potential therapeutic target for overcoming AC resistance in TNBC.

Photodynamic therapy (PDT) is an anti-cancer therapy that employs a photosensitizer (PS) and an optimal wavelength of light, causing a photochemical reaction that releases reactive oxygen species, thereby inducing cancer cell death via oxidative stress. Because light irradiation is limited to the tumor site, PDT has minimal adverse effects. The cancer cell selectivity of the PS is important for reducing damage to the normal mucosa caused by scattered light. Antibody-drug conjugates (ADC) are novel anti-cancer therapies that combine a monoclonal tumor-surface-receptor-targeting antibody with a drug bonded through chemical linkers. ADCs enable the targeted delivery of a variety of drugs to cancer cells while minimizing their delivery to healthy tissues. One such tumor surface receptor is the human epidermal growth factor receptor 2 (HER2), which is of interest in the treatment of many cancers, including gastrointestinal cancer. To improve tumor selectivity and minimize damage to the mucosa surrounding the tumor in PDT, we established a novel PS glucose-linked chlorin e6-conjugated trastuzumab (G-Ce6-trastuzumab) that is conjugated to existing PS glucose-linked chlorin e6 (G-Ce6) and evaluated its anti-cancer effect compared to G-Ce6. The effect of PDT was evaluated using HER2-high-expression cells NCI-N87 and HER2-low-expression cells MKN-45. G-Ce6-trastuzumab is internalized by the intracellular organelles in cancer cells. Evaluation of cell death using the WST-8 assay also demonstrated a significantly higher cytotoxic effect of G-Ce6-trastuzumab in HER2-high-expression cells compared with conventional PS G-Ce6. Thereby, G-Ce6-trastuzumab may be an excellent novel PS for PDT because of its strong selectivity for HER2-high-expression cells.

The status of cervical lymph node metastasis(LNM) in Papillary thyroid carcinoma(PTC) can affect the patient's treatment plan and prognosis. This study aims to develop and validate the application value of Vision transformer (ViT) model in preoperatively predicting cervical LNM in PTC.

Cancer remains a leading cause of mortality worldwide and a significant barrier to improving quality of life across all populations. The protein kinase D family, including PRKD3, has been demonstrated to play a crucial role in cancer development through its involvement in regulating key cellular processes. Although growing evidence highlights the role of PRKD3 in the tumorigenesis of certain cancers, a comprehensive pan-cancer analysis of PRKD3 remains unavailable. To address this, we performed an integrative pan-cancer analysis of PRKD3 using multi-omics datasets from The Cancer Genome Atlas, the Genotype-Tissue Expression project, and cBioPortal. We examined PRKD3 expression, copy number variation, mutation, and DNA methylation, and evaluated their associations with clinicopathological features, patient survival, and diagnostic potential across 33 cancer types. Immune relevance was further assessed through correlations with immune infiltration, checkpoint gene expression, and immunotherapy response-related genomic biomarkers. Our results revealed that PRKD3 expression was highly heterogeneous, showing significant upregulation in liver cancer, gastric cancer, and adrenocortical carcinoma, and downregulation in others. Elevated expression was consistently associated with poor prognosis and increased stromal, neutrophil, and cancer-associated fibroblast infiltration in adrenocortical carcinoma, liver cancer, and stomach cancer, whereas paradoxical associations with favorable outcomes were observed in kidney clear cell carcinoma. PRKD3 expression also correlated with immune checkpoint molecules including PD-1, PD-L1, and CTLA-4, supporting an immunosuppressive role, while context-dependent associations with TMB and MSI highlighted its potential influence on tumor immunogenicity and responsiveness to immune checkpoint blockade. Collectively, these findings identify PRKD3 as a potential context-dependent modulator of tumor biology, prognosis, and immune interactions, underscoring its potential as a biomarker of diagnostic, prognostic, and therapeutic relevance in precision oncology.

Hepatocellular carcinoma (HCC) has a very significant mortality rate and is one of the most common cancers worldwide. Jacaranda mimosifolia is reported to have potential antitumor activities against various human cancers. However, the effects of J. mimosifolia on HCC are yet elusive. This study aimed to investigate the anti-HCC potential of methanolic extract of J. mimosifolia leaves using in vitro and in vivo studies and a network pharmacology approach. The effect of J. mimosifolia extract was assessed on Huh-7.5 cells using MTT assay, wound healing assay, and DNA fragmentation assay. These experiments found that J. mimosifolia extract significantly suppressed Huh-7.5 cell proliferation, impaired cell migration, and induced cell apoptosis. The real-time PCR validated the upregulation of p53 and Bax, alongside the downregulation of AFP and GPC3 in Huh-7.5 cells after treatment with J. mimosifolia extract. In vivo experiments confirmed the hepatoprotective effects of J. mimosifolia extract in mice models with CCl4-induced hepatic injury. In addition, through network pharmacological analysis, J. mimosifolia was found to play a critical role against HCC via targeting multiple potential targets and pathways. Docking analysis identified apigenin and kaempferol with the lowest binding energy against PTGS2 and EGFR, respectively, while flavonol glycoside showed the lowest binding energy against MMP9. However, detailed research is needed to isolate the potential phytochemicals from J. mimosifolia against HCC.

Revolution of chemo-immunotherapy (CT-IO) in the first-line treatment of metastatic non-small-cell lung cancers (NSCLC) without actionable genomic alterations (AGAs) has dramatically improved prognosis, providing long response in a subset of patients. Due to the highly heterogeneous nature of the disease, most of patients do not show long term benefit. Long axial field of view positron emission tomography (LAFOV-PET) scanner is a new emerging system allowing dynamic whole-body imaging with higher sensitivity, representing unique opportunity for oncological applications. The aim of this study is to determine whether 18F-fluorodeoxyglucose positron emission (18F-FDG) LAFOV-PET derived parameters might have prognostic and predictive potential for CT-IO outcomes in NSCLC.

Programmed death-ligand 1 (PD-L1) positivity is associated with a favorable response to immune checkpoint blockade (ICB) in urothelial bladder cancer (BLCA). However, the efficacy of ICB in BLCA exhibits considerable heterogeneity, leading to the need for complementary predictive biomarkers. Recent studies suggest that a high degree of plasma cell infiltration is correlated with improved benefit from ICB, but a specific plasma cell marker in BLCA has not been identified. The aim of this study was to evaluate tumor necrosis factor receptor superfamily member 17 (TNFRSF17) as a plasma cell-specific marker in BLCA and test its utility, combined with PD-L1, for patient stratification receiving ICB therapy.

Gastric cancer continues to be a worldwide health crisis because it results in many deaths. The protein Claudin 18.2 (CLDN18.2) exists at higher levels in gastric adenocarcinoma tumors which makes it a promising therapeutic target. This study evaluated CLDN18.2 protein levels in gastric cancer tissues and their relationship with patient and tumor characteristics. This retrospective cohort study analyzed 112 gastric adenocarcinoma patients together with 62 healthy controls. The research team used ELISA to determine CLDN18.2 concentrations in tumor tissue and adjacent normal tissue and control specimens. Patients were stratified based on their Helicobacter pylori infection status, tumor site, tumor grade, and presence of metastasis. Diagnostic performance was assessed using receiver operating characteristic analysis, and Cox regression analysis was performed to evaluate prognostic factors for survival. The cancer tissue contained elevated CLDN18.2 levels which measured at 2.385 ng/mL (median), whereas normal tissue and controls displayed 1.349 ng/mL and 1.260 ng/mL (median) respectively (P < .001). The receiver operating characteristic analysis for diagnosing gastric adenocarcinoma showed 92.4% sensitivity and 100% specificity at 1.675 ng/mL (area under the curve: 0.956). The study found that CLDN18.2 levels were higher in patients with Helicobacter pylori infection and in cases with poor tumor differentiation and metastasis. The risk of metastasis increased by 4.82 times for every 1 ng/mL rise in CLDN18.2 levels (P < .001). This study demonstrates that CLDN18.2 exhibits strong diagnostic performance for gastric adenocarcinoma and shows strong correlation with cancer progression. The Cox regression analysis established CLDN18.2 as an independent prognostic factor for patient survival outcomes.

This study aimed to determine the associations between pretreatment quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) pharmacokinetic (PK) parameters, post-neoadjuvant systemic therapy (NST) MRI features, and pathologic complete response (pCR) in patients with invasive ductal carcinoma (IDC). Twenty-eight consecutive IDC patients who received NST were retrospectively reviewed. All patients underwent MRI at 3 time points: before NST; after 2 cycles of NST; and before surgery. Continuous and categorical variables were compared between pCR and non-pCR groups using the Mann-Whitney U test and Fisher exact test, respectively, with HER2 status adjusted in PK parameter analyses. Partial correlation assessed associations between MRI features and pCR. Select PK parameters were further evaluated using Firth's penalized-likelihood regression, controlling for covariates. Receiver operating characteristic (ROC) analysis was performed to evaluate predictive performance. Significant differences were detected between groups regarding HER2-positive, luminal B subtype, Miller-Payne, and postoperative lymph node metastasis (P < .05). Pretreatment peritumoural extravascular extracellular volume (Ve), post-NST shrinkage pattern, and residual disease were significantly different between the groups (P < .05). Partial correlation analysis indicated a positive association between the peritumoural flux rate constant (Kep) and pCR (P < .05). Regression analysis identified the peritumoural Kep as a factor influencing the pCR with an area under the curve of 0.756 (95% CI = 0.564-0.947). Our preliminary findings suggested an association between the pCR and pretreatment peritumoural PK parameters, highlighting the potential value of the peritumoural region. These results require further validation in larger prospective studies.

Neoplastic diseases are among the most important conditions of morbidity and mortality in companion dogs worldwide. The research was conducted from October 2017 to May 2018 to determine the type and incidence of neoplasms in canines.

Conventional magnetic resonance imaging (MRI) exhibits notable limitations in the diagnosis, grading, and therapeutic assessment of gliomas, making it insufficient to meet the demands of precision medicine. As a chemical exchange saturation transfer MRI technique, amide proton transfer (APT) imaging enables molecular-level visualization by detecting the chemical exchange of amide protons in endogenous mobile proteins and peptides. Previous studies have demonstrated that APT imaging provides substantial advantages over conventional MRI in the diagnosis, grading, and treatment monitoring of gliomas. This review systematically summarizes the development of APT imaging technology, emphasizing its innovative clinical applications, including preoperative grading, differentiation of postoperative recurrence, and dynamic evaluation of radiotherapy and chemotherapy efficacy. Furthermore, it discusses current challenges and future directions for clinical implementation, aiming to offer new perspectives for advancing precision medicine in glioma management.

IntroductionImmunohistochemistry (IHC) plays a crucial role in breast cancer diagnosis, treatment selection, and research. However, manual scoring of IHC whole slide images (WSIs) is time-consuming and suffers from inter- and intra-observer variability.MethodsTo help address these challenges, we present and publicly release a fully automated, compartment-specific (ie, tumor and stroma) H-scoring framework for IHC analysis. The framework consists of three deep learning modules: tumor-stroma segmentation, nuclei segmentation, and H-score estimation for tumor and stroma. It processes WSIs in minutes, delivering consistent and reproducible H-scores with accuracy comparable to expert pathologists. The modular design also allows flexibility for use in other IHC tasks such as cellularity quantification, and supports configuration options to balance accuracy and computational efficiency.ResultsFine-tuned on 87 expert-annotated patches, the framework achieved a Spearman's rank correlation (ρ) in internal validation of 0.84 (95% confidence interval [CI]: 0.77-0.89) across 100 expert-annotated WSIs, outperforming state-of-the-art (ρ = 0.78, 95% CI: 0.68-0.85) and matching the inter-observer variability between two expert pathologists (ρ = 0.84, 95% CI: 0.63-0.94). In external validation, it achieved 86% accuracy in HER2 classification (0-3+) and a mean absolute error of 21 ± 10 (range: [5-46]) in CD73 scoring, where ground truth H-scores were all 0.ConclusionThe framework achieves agreement comparable to that of expert pathologists, underscoring its clinical utility in providing reproducible IHC scores that can reduce diagnostic variability and support consistent treatment decisions. The code is available at https://github.com/YinTuo/AutoIHC.

Thyroid carcinoma is characterized by significant heterogeneity and immune evasion, in which myeloid cells play a pivotal role in tumor microenvironment (TME) remodeling. However, the key regulatory genes and their underlying mechanisms are not yet fully elucidated.