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Colorectal cancer (CRC) is among the most common malignancies with limited treatments other than surgery. The tumor microenvironment (TME) profiling enables the discovery of potential therapeutic targets. Here, we profile 54,103 cells from tumor and adjacent tissues to characterize cellular composition and elucidate the potential origin and regulation of tumor-enriched cell types in CRC. We demonstrate that the tumor-specific FAP + fibroblasts and SPP1 + macrophages were positively correlated in 14 independent CRC cohorts containing 2550 samples and validate their close localization by immuno-fluorescent staining and spatial transcriptomics. This interaction might be regulated by chemerin, TGF-β, and interleukin-1, which would stimulate the formation of immune-excluded desmoplasic structure and limit the T cell infiltration. Furthermore, we find patients with high FAP or SPP1 expression achieved less therapeutic benefit from an anti-PD-L1 therapy cohort. Our results provide a potential therapeutic strategy by disrupting FAP + fibroblasts and SPP1 + macrophages interaction to improve immunotherapy. Tumour microenvironment profiling during colorectal cancer progression may enable the discovery of therapeutic targets. Here, single cell and spatial RNA sequencing of tumour and adjacent normal tissues reveals an interaction between FAP + fibroblasts and SPP1 + macrophages that could be disrupted as an immunotherapy strategy.

Head and neck squamous cell carcinoma (HNSCC) remains a major health burden, with abnormal activation of phosphatidylinositol 3-kinase alpha (PI3Kα) strongly implicated in its pathogenesis. Targeting PI3Kα represents a promising therapeutic strategy. In this study, we employed structure-based virtual screening to identify natural small-molecule inhibitors of PI3Kα. A total of 12,800 molecules were screened, and five compounds were selected for further evaluation based on binding affinity and interaction patterns. Pharmacokinetic properties were assessed using ADMET predictions, and molecular dynamics (MD) simulations were conducted to validate the binding stability. Among the candidates, Apigetrin demonstrated favorable ADMET properties, a high safety profile, and stable binding within the ATP-binding pocket of PI3Kα. These findings suggest that Apigetrin is a promising natural PI3Kα inhibitor with potential therapeutic relevance for HNSCC.

Drug resistance strikingly limits the therapeutic effect of temozolomide (TMZ) (a common drug for glioma). Long non-coding RNA (lncRNA) RMRP has been found to be implicated in glioma progression. However, the effect of RMRP on TMZ resistance along with related molecular mechanisms is poorly defined in glioma. In the present study, RMRP, ZNRF3, and IGF2BP3 were screened out by bioinformatics analysis. The expression levels of lncRNAs and mRNAs were measured by RT-qPCR assay. Protein levels of genes were detected by western blot and immunofluorescence assays. ZNRF3 mRNA stability was analyzed using Actinomycin D assay. Cell proliferative ability and survival rate were determined by CCK-8 assay. Cell apoptotic pattern was estimated by flow cytometry. The effect of RMRP knockdown on the growth of TMZ-treated glioma xenograft tumors was explored in vivo. The relationships of IGF2BP3, RMRP, and ZNRF3 were explored by bioinformatics prediction analysis, RNA immunoprecipitation, luciferase, and RNA pull-down, and chromatin immunoprecipitation assays. The results showed that RMRP was highly expressed in glioma. RMRP knockdown curbed cell proliferation, facilitated cell apoptosis and reduced TMZ resistance in glioma cells, and hindered the growth of TMZ-treated glioma xenograft tumors. RMRP exerted its functions by down-regulating ZNRF3 in glioma cells. IGF2BP3 interacted with RMRP and ZNRF3 mRNA. IGF2BP3 knockdown weakened the interaction of Argonaute 2 (Ago2) and ZNRF3. RMRP reduced ZNRF3 expression and mRNA stability by IGF2BP3. RMRP knockdown inhibited β-catenin expression by up-regulating ZNRF3. The inhibition of Wnt/β-catenin signaling pathway by XAV-939 weakened RMRP-mediated TMZ resistance in glioma cells. β-catenin promoted RMRP expression by TCF4 in glioma cells. In conclusion, RMRP/ZNRF3 axis and Wnt/β-catenin signaling formed a positive feedback loop to regulate TMZ resistance in glioma. The sustained activation of Wnt/β-catenin signaling by RMRP might contribute to the better management of cancers.

Phosphatidylinositol 3-kinase alpha (PI3Kα) is frequently mutated in head and neck squamous cell carcinoma (HNSCC), leading to the constitutive activation of the PI3K/Akt pathway, which promotes tumor cell proliferation, survival, and metastasis. PI3Kα allosteric inhibitors demonstrate therapeutic potential as both monotherapy and combination therapy, particularly in patients with PIK3CA mutations or resistance to immunotherapy, through the precise targeting of mutant PI3Kα. Compared to ATP-competitive PI3Kα inhibitors such as Alpelisib, the allosteric inhibitor RLY-2608 exhibits enhanced selectivity for mutant PI3Kα while minimizing the inhibition of wild-type PI3Kα, thereby reducing side effects such as hyperglycemia. To date, no allosteric PI3Kα inhibitors have been approved for clinical use. To develop novel PI3Kα inhibitors with improved safety and efficacy, we employed a scaffold hopping approach to structurally modify RLY-2608 and constructed a compound library. Based on the structural information of the PI3Kα allosteric site, we conducted the systematic virtual screening of 11,550 molecules from databases to identify lead compounds. Through integrated approaches, including molecular docking studies, target validation, druggability evaluation, molecular dynamics simulations, and metabolic pathway and metabolite analyses, we successfully identified a promising novel allosteric PI3Kα inhibitor, H-18 (3-(2-chloro-5-fluorophenyl)isoindolin-1-one). H-18 has not been previously reported as a PI3Kα inhibitor, and provides an excellent foundation for subsequent lead optimization, offering a significant starting point for the development of more potent PI3Kα allosteric inhibitors.

Spinal ependymomas are the most common spinal cord tumors in adults, but their intratumoral cellular heterogeneity has been less studied, and how spinal microglia are involved in tumor progression is still unknown. Here, our single-cell RNA-sequencing analyses of three spinal ependymoma subtypes dissect the microenvironmental landscape of spinal ependymomas and reveal tumor-associated macrophage (TAM) subsets with distinct functional phenotypes. CCL2 + TAMs are related to the immune response and exhibit a high capacity for apoptosis, while CD44 + TAMs are associated with tumor angiogenesis. By combining these results with those of single-cell ATAC-sequencing data analysis, we reveal that TEAD1 and EGR3 play roles in regulating the functional diversity of TAMs. We further identify diverse characteristics of both malignant cells and TAMs that might underlie the different malignant degrees of each subtype. Finally, assessment of cell-cell interactions reveal that stromal cells act as extracellular factors that mediate TAM diversity. Overall, our results reveal dual functions of TAMs in tumor progression, providing valuable insights for TAM-targeting immunotherapy. The intratumoural heterogeneity of spinal ependymomas and the role of microglia in tumour progression remain underexplored. Here, the authors perform single-cell RNA- and ATAC-sequencing data analysis of three subtypes and reveal tumour-associated macrophage subsets with distinct functional phenotypes.

Although tree peony ( Paeonia ostii ) is widely cultivated in China, it has not been fully utilized as an arable resource. To investigate the suitability of tree peony in intercropping systems, we examined the allelopathic effects of aqueous extracts from the leaves and roots of P. ostii ‘Fengdan’ on the seed germination, growth, and physiological responses of tatsoi, spinach, and bok choy. Among these vegetables, tatsoi exhibited the best seed germination and seedling growth. Lower concentrations of aqueous extracts of ‘Fengdan’ roots (5–10 g L −1 for tatsoi and 5 g L −1 for spinach and bok choy) promoted seed germination, biomass, chlorophyll content, root activity, photosynthetic rate, intercellular CO 2 concentration, stomatal conductance, and antioxidant enzyme activity. However, high concentrations of the leaf extract (40 g L −1 for tatsoi and 20–40 g L −1 for spinach and bok choy) significantly increased levels of malondialdehyde and reduced seed germination, dry weight, chlorophyll content, root activity, and antioxidant enzyme activity. These deleterious effects increased with higher extract concentrations. The allelopathic effect of the leaf extract was greater than that of the root extract. The order of the allelopathic effect of tree peonies on the three vegetables was bok choy, spinach, and tatsoi. Therefore, tatsoi is the most suitable vegetable for interplanting with tree peonies.

IntroductionPostoperative pain is particularly pronounced in spinal surgery. Inadequate management of acute postoperative pain not only reduces patient satisfaction and delays recovery but also increases the risk of developing chronic pain. Local infiltration analgesia (LIA) is a widely used technique for perioperative pain management. However, even with the use of long-acting local anaesthetics, such as ropivacaine, postoperative analgesia often remains insufficient. Preliminary evidence suggests that combining diprospan, a mixture of betamethasone disodium phosphate and betamethasone dipropionate, with ropivacaine can significantly reduce analgesic requirements in the immediate postoperative period. However, concerns about steroid-related complications, including hyperglycaemia and surgical site infections, highlight the need to identify the minimum diprospan concentration to achieve a balance between efficacy and safety. This randomised, controlled, evaluator-blinded trial aims to investigate the dose-response relationship of diprospan as an adjunct to ropivacaine for LIA in spinal surgery to determine the minimum effective dose for effective and safe pain management.Methods and analysisThis is a single-centre, randomised, evaluator-blinded, controlled, dose-mapping study in which subjects will be randomised in a 1:1:1:1:1 ratio to the control group or to receive diprospan at concentrations of 0.003%, 0.006%, 0.009% or 0.012%. Patients will receive either 0.5% ropivacaine alone or a corresponding dose of diprospan combined with 0.5% ropivacaine for LIA. All participants will be followed for a duration of 3 months. The primary outcome measure will be cumulative sufentanil consumption within the first 48 hours postsurgery. Secondary outcomes will include additional assessments of analgesia, steroid-related adverse events and other complications within the 3-month follow-up period.Ethics and disseminationThis study protocol was approved by the Institutional Review Board of Beijing Tiantan Hospital (KY2024-365-02-1). Written informed consent will be obtained from all participants. The results will be submitted for publication in a peer-reviewed journal.Trial registration numberNCT06785350.

The relation between angiogenesis and immune response was revealed at the gene and transcriptomic level.Kurmyshkina et al.have focused on the difference in transcriptomic landscapes between early-stage invasive cervical carcinoma (CeCa) and cervical intraepithelial neoplastic lesions (CIN). The high-risk group showed a higher level of tumor mutation burden (TMB), higher mutation rate of tumor suppressor genes, and higher level of immune escape, suggesting a poor response to immunotherapy at the same time. Conflict of interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Colorectal cancer (CRC) is one of the most common cancers worldwide. Current therapies such as surgery, chemotherapy, and radiotherapy encounter obstacles in preventing metastasis of CRC even when applied in combination. Immune checkpoint inhibitors depict limited effects due to the limited cases of CRC patients with high microsatellite instability (MSI-H). Cancer vaccines are designed to trigger the elevation of tumor-infiltrated lymphocytes, resulting in the intense response of the immune system to tumor antigens. This review briefly summarizes different categories of CRC vaccines, demonstrates the current outcomes of relevant clinical trials, and provides particular focus on recent advances on nanovaccines and neoantigen vaccines, representing the trend and emphasis of CRC vaccine development.

Background Tyrosine kinase inhibitors (TKIs) are crucial in the targeted treatment of advanced colorectal cancer (CRC). Anlotinib, a multi-target TKI, has previously been demonstrated to offer therapeutic benefits in previous studies. Circular RNAs (circRNAs) have been implicated in CRC progression and their unique structural stability serves as promising biomarkers. The detailed molecular mechanisms and specific biomarkers related to circRNAs in the era of targeted therapies, however, remain obscure. Methods The whole transcriptome RNA sequencing and function experiments were conducted to identify candidate anlotinib-regulated circRNAs, whose mechanism was confirmed by molecular biology experiments. CircHAS2 was profiled in a library of patient-derived CRC organoids ( n  = 22) and patient-derived CRC tumors in mice. Furthermore, a prospective phase II clinical study of 14 advanced CRC patients with anlotinib-based therapy was commenced to verify drug sensitivity (ClinicalTrials.gov identifier: NCT05262335). Results Anlotinib inhibits tumor growth in vitro and in vivo by downregulating circHAS2. CircHAS2 modulates CCNE2 activation by acting as a sponge for miR-1244, and binding to USP10 to facilitate p53 nuclear export as well as degradation. In parallel, circHAS2 serves as a potent biomarker predictive of anlotinib sensitivity, both in patient-derived organoids and xenograft models. Moreover, the efficacy of anlotinib inclusion into the treatment regimen yields meaningful clinical responses in patients with high levels of circHAS2. Our findings offer a promising targeted strategy for approximately 52.9% of advanced CRC patients who have high circHAS2 levels. Conclusions CircHAS2 promotes cell proliferation via the miR-1244/CCNE2 and USP10/p53/CCNE2 bidirectional axes. Patient-derived organoids and xenograft models are employed to validate the sensitivity to anlotinib. Furthermore, our preliminary Phase II clinical study, involving advanced CRC patients treated with anlotinib, confirmed circHAS2 as a potential sensitivity marker.