A rare prenylated isoflavone-quinone from the roots of Flemingia philippinensis.

In order to make more rational use of Flemingia Philippinensis, a systematic separation from the roots of F. philippinensis was performed in the current study. The investigation of chemical constituents resulted in the isolation of a rare prenylated isoflavone-quinone, fleminquinone A (1), together with four known analogues (2-5). Their structures were established by extensive physical and spectroscopic data analysis. Anti-inflammatory activities of the isolated compounds were evaluated in lipopolysaccharide induced mouse mononuclear macrophage leukemia cells RAW 264.7 model. Compound 1 exhibited significant inhibitory effects on LPS-induced NO production and COX-2. Compound 1 also significantly affected the levels of inflammatory cytokines.

A novel hollow iron nanoparticle system loading PEG-Fe3O4 with C5a receptor antagonist for breast cancer treatment.

Breast cancer is the most diagnosed malignancy and major cause of cancer death among women population in the worldwide. Ferroptosis is a recently discovered iron-dependent regulated cell death involved in tumor progression and therapeutic response. Moreover, increasing studies have implied that ferroptosis is a promising approach to eliminating cancer cells like developing iron nanoparticles as a therapeutic agent. However, resistance to ferroptosis is a vital distinctive hallmark of cancer. Therefore, further investigation of the mechanism of ferroptosis resistance to enhance its tumor sensitivity is essential for ferroptosis-target breast cancer therapy. Our results revealed that the activation of C5a/C5aR pathway can drive resistance to ferroptosis and reshaping breast cancer immune microenvironment. Accordingly, loading PEG-Fe3O4 with C5aRA significantly improved the anti-tumor effect of PEG- Fe3O4 by inhibiting ferroptosis resistance and increasing macrophage polarization toward M1 phenotype. Our findings presented a novel cancer therapy strategy that combined cancer cell metal metabolism regulation and immunotherapy. The study also provided support for further evaluation of PEG- Fe3O4@C5aRA as a novel therapeutic strategy for breast cancer in clinical trials.

Effect of acidification pretreatment on two-phase anaerobic digestion of acidified food waste.

Acidified food waste significantly disrupts anaerobic digestion, highlighting the need for effective solutions to mitigate its impact. This study presents a method that utilizes acidified sludge to pretreat acidified food waste, thereby significantly improving the efficiency of hydrolysis and acidogenesis. After acidification pretreatment, hydrolysis efficiency improved from 64.54 % to 96.51 %, while acidogenesis efficiency increased from 34.82 % to 49.95 %. Additionally, the concentration of short-chain fatty acids and hydrogen production in the acidification pretreatment group increased by 45.89 % and 48.67 %, respectively. The pretreatment group exhibited a biochemical methane potential of 512.84 ± 13.73 mL/(g volatile suspended solids), which was 35.77 % higher than that of the control group. Mechanism analysis revealed that the higher abundance of genes associated with lactate dehydrogenase in the acidified sludge facilitated the rapid degradation of lactic acid. Moreover, the abundant Clostridium butyricum in the acidified sludge promoted the targeted conversion of lactic acid and other organic matter into butyric acid within the food waste system. This efficient butyric acid fermentation improved the fermentation environment and provided abundant substrates for methane production. This study introduces a promising bio-based strategy to improve the anaerobic digestion efficiency of acidified food waste.

Rnf111 has a pivotal role in regulating development of definitive hematopoietic stem and progenitor cells through the Smad2/3-Gcsfr/NO axis in zebrafish.

The ubiquitination or SUMOylation of hematopoietic related factors plays pivotal roles in hematopoiesis. RNF111, known as a ubiquitin ligase (Ubl), is a newly discovered SUMO-targeted ubiquitin ligase (STUbl) involved in multiple signaling pathways mediated by TGF-ß family members. However, its role in hematopoiesis remains unclear. Herein, a heritable Rnf111 mutant zebrafish line was generated by CRISPR/Cas9-mediated genome editing. Impaired hematopoietic stem and progenitor cells (HSPC) of definitive hematopoiesis was found in Rnf111 deficient mutants. Ablation of Rnf111 resulted in decreased phosphorylation of Smad2/3 in HSPC. Definitive endoderm 2 inducer (IDE2), which specifically activates TGF-ß signaling and downstream Smad2 phosphorylation, can restore the definitive hematopoiesis in Rnf111-deficient embryos. Further molecular mechanism studies revealed that Gcsfr/NO signaling was an important target pathway of Smad2/3 involved in Rnf111-mediated HSPC development. In conclusion, our study demonstrated that Rnf111 contributes to the development of HSPC by maintaining Smad2/3 phosphorylation and the Gcsfr/NO signaling pathway activation. Keywords: Rnf111, Ubiquitin ligase (UbL), HSPC, Smad2/3, Gcsfr/NO.

Penisimplinoids A-K, highly oxygenated andrastin-type meroterpenoids with diverse activities from the marine-derived fungus Penicillium simplicissimum.

Penisimplinoid A (1), the first andrastin-type meroterpenoid with an unprecedented 6/6/3/6/5/5 polycyclic systems, together with ten highly oxygenated andrastin-type meroterpenoids (2-11) and one known analogue (12), were co-isolated from the marine-derived fungus Penicillium simplicissimum. Their absolute configurations were determined by single-crystal X-ray diffraction analysis (Cu Kα), DP4+ probability analyses, and ECD quantum chemistry calculations. Biological evaluation revealed that 7 and 12 showed anti-inflammatory activities in the zebrafish assay, 6 exhibited cytotoxic activity against NCI-H446 tumor cells with an IC50 value of 6.49 µM, 7 and 11 exhibited significant promoting angio-genesis activities.

Immobilization of Membrane-Associated Protein Complexes on SERS-Active Nanomaterials for Structural and Dynamic Characterization.

Exploring the structural basis of membrane proteins is significant for a deeper understanding of protein functions. In situ analysis of membrane proteins and their dynamics, however, still challenges conventional techniques. Here we report the first attempt to immobilize membrane protein complexes on surface-enhanced Raman scattering (SERS)-active supports, titanium dioxide-coated silver (Ag@TiO2) nanoparticles. Biocompatible immobilization of microsomal monooxygenase complexes is achieved through lipid fission and fusion. SERS activity of the Ag@TiO2 nanoparticles enables in situ monitoring of protein-protein electron transfer and enzyme catalysis in real time. Through SERS fingerprints of the monooxygenase redox centers, the correlations between these protein-ligand interactions and reactive oxygen species generation are revealed, providing novel insights into the molecular mechanisms underlying monooxygenase-mediated apoptotic regulation. This study offers a novel strategy to explore structure-function relationships of membrane protein complexes and has the potential to advance the development of novel reactive oxygen species-inducing drugs for cancer therapy.

Modified bone marrow mesenchymal stem cells derived exosomes loaded with MiRNA ameliorates non-small cell lung cancer.

The study aimed to reveal the function of LXY30 peptide-modified bone marrow mesenchymal stem cell-derived exosomes (LXY30-Exos) in NSCLC. LXY30 peptide is a peptide ligand targeting α3ß1 integrin, and LXY30 specifically binds to Exos derived from different cells. We use transmission electron microscopy to identify LXY30-Exos and tracking analysis for particles, and the LXY30-Exos internalized by NSCLC cells in vitro and targeted NSCLC tumours in vivo were verified by multiple molecular technologies. The functions of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 were assessed using cell proliferation, migration and cell apoptosis assays. Meanwhile, the safety of the above engineered Exos was evaluated in vivo. After LXY30-Exos were isolated and identified, LXY30-Exos were confirmed to be internalized by NSCLC cells in vitro and specifically targeted NSCLC tumours in vivo. Functionally, LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 weakened the proliferation, migration and cell cycle of NSCLC cells induced cellular apoptosis in vitro and restrained the tumour progression in vivo. Meanwhile, the safety of LXY30-Exos-encapsulated miR-30c, miR-181b or miR-613 was confirmed in vivo. Overall, miR-30c, miR-181b and miR-613 encapsulated in LXY30 peptide-modified BMSC-Exos relieved NSCLC.

PILRB potentiates the PI3K/AKT signaling pathway and reprograms cholesterol metabolism to drive gastric tumorigenesis and metastasis.

Paired immunoglobin-like type 2 receptor beta (PILRB) mainly plays a crucial role in regulating innate immunity, but whether PILRB is involved in cancer is poorly understood. Here, we report that PILRB potentiates the PI3K/AKT pathway to drive gastric tumorigenesis by binding and stabilizing IRS4, which could hyperactivate the PI3K/AKT pathway. Firstly, the levels of PILRB are upregulated in human gastric cancer (GC) specimens and associated with poor prognosis in patients with GC. In addition, our data show that PILRB promotes cell proliferation, colony formation, cell migration and invasion in GC cells in vitro and in vivo. Mechanistically, PILRB recruits the deubiquitination enzymes OTUB1 to IRS4 and relieves K48-linked ubiquitination of IRS4, protecting IRS4 protein from proteasomal-mediated degradation and subsequent activation of the PI3K/AKT pathway. Importantly, the levels of PILRB are positively correlated with IRS4 in GC specimens. Meanwhile, we also found that PILRB reprogrammed cholesterol metabolism by altering ABCA1 and SCARB1 expression levels, and PILRB-expression confers GC cell resistance to statin treatment. Taken together, our findings illustrate that the oncogenic role of PILRB in gastric tumorigenesis, providing new insights into the regulation of PI3K/AKT signaling in GC and establishing PILRB as a biomarker for simvastatin therapy resistance in GC.

LINC00665 aggravates the malignant phenotypes in chondrosarcoma cells through miR-665/FGF9 pathway.

Long non-coding RNAs (lncRNAs) have been demonstrated to participate in a variety of physiological and pathological processes, including tumor initiation and development. Nevertheless, few of them have been investigated in chondrosarcoma. Here, we were intended to unveil the role of long intergenic non-protein coding RNA 665 (LINC00665) in chondrosarcoma. RT-qPCR was adopted for gene expression detection. The biological processes in chondrosarcoma cells were detected by CCK-8, EdU, TUNEL, Transwell and wound healing assays. The relationships between genes in chondrosarcoma cells were evaluated by a series of mechanism experiments including RIP, luciferase reporter assays and so on.LINC00665 expressed at a high level in chondrosarcoma cell lines. LINC00665 interference suppressed cell proliferation, migration and invasion in chondrosarcoma. Besides, LINC00665 interacted with microRNA-665 (miR-665), which was then verified to be down-regulated in chondrosarcoma cells. Additionally, LINC00665 and miR-665 were mutually inhibited by each other in chondrosarcoma cells. Importantly, LINC00665 stimulated fibroblast growth factor 9 (FGF9) expression in chondrosarcoma cells via sponging miR-665. Furthermore, FGF9 participated in the regulation of LINC00665-promoted chondrosarcoma development. CONCLUSION: LINC00665 facilitates chondrosarcoma progression via miR-665/FGF9 axis, which might indicate a new path for the treatment of chondrosarcoma.

[Relationship between macrophage pyroptosis and atherosclerosis based on theory of "spleen in correlation with endoplasmic reticulum"].

The key pathogenesis of atherosclerosis(AS) in traditional Chinese medicine(TCM) lies in the combination of phlegm and stasis due to spleen deficiency. In Western medicine, it is believed that pyroptosis can lead to atherosclerosis, and endoplasmic reticulum stress has been shown to promote pyroptosis. According to the theories of " spleen in correlation with endoplasmic reticulum",guided by spleen governing transportation and transformation, and endoplasmic reticulum processing proteins, it is believed that the syndrome of phlegm combined with stasis due to spleen deficiency has similarities with the mechanism of macrophage pyroptosis induced by endoplasmic reticulum stress in accelerating the progression of AS. This study explored the correlation between phlegm combined with stasis due to spleen deficiency and pyroptosis induced by endoplasmic reticulum stress, and then analyzed the modern medical mechanisms of phlegm combined with stasis due to spleen deficiency in mediating atherosclerosis. The discussion enriches the theory of spleen in correlation with endoplasmic reticulum, provides research ideas on the prevention and treatment of AS by invigorating spleen,eliminating phlegm, and resolving stasis, and lays a theoretical foundation for the clinical application of spleen-invigorating TCM in the treatment of AS.

GREM1 Negatively Regulates Osteo-/Dentinogenic Differentiation of Dental Pulp Stem Cells via Association with YWHAH.

OBJECTIVE: To investigate the biological regulatory function of Gremlin1 (GREM1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein eta (YWHAH) in dental pulp stem cells (DPSCs), and determine the underlying molecular mechanism involved. METHODS: Alkaline phosphatase (ALP) activity, alizarin red staining, scratch migration assays and in vitro and in vivo osteo-/dentinogenic marker detection of bone-like tissue generation in nude mice were used to assess osteo-/dentinogenic differentiation. Coimmunoprecipitation and polypeptide microarray assays were employed to detect the molecular mechanisms involved. RESULTS: The data revealed that knockdown of GREM1 promoted ALP activity, mineralisation in vitro and the expression of osteo-/dentinogenic differentiation markers and enhanced osteo-/ dentinogenesis of DPSCs in vivo. GREM1 bound to YWHAH in DPSCs, and the binding site was also identified. Knockdown of YWHAH suppressed the osteo-/dentinogenesis of DPSCs in vitro, and overexpression of YWHAH promoted the osteo-/dentinogenesis of DPSCs in vitro and in vivo. CONCLUSION: Taken together, the findings highlight the critical roles of GREM1-YWHAH in the osteo-/dentinogenesis of DPSCs.

The combined application of electromagnetic navigation and porcine fibrin sealant in microwave ablation of lung tumors.

Purpose: This retrospective study aims to assess the efficacy of the combined application of electromagnetic navigation (EMN) and porcine fibrin sealant (PFS) in the microwave ablation (MWA) treatment of lung tumors. Material and methods: In our department from January 2022 to August 2023, 73 patients underwent MWA under standard computed tomography (CT) guidance (CT group) or CT guidance with additional application of EMN and PFS (CT-EMN-PFS group), respectively. The basic data of patients were recorded and analyzed using the Student's t-test and Chi-square test between the two groups, and single factor and multi-factors binary logistic regression analyses were conducted to determine the risk factors of pneumothorax; meanwhile the incidence of complications, the number of CT scans and dose length product (DLP) were calculated and compared between the two guidance modes. Results: Forty-seven patients underwent standard CT-guided MWA, meanwhile the remaining 26 patients underwent CT-guided MWA with combined application of EMN and PFS. The patients with lesions close to the bronchi or interlobar fissures, and underlying emphysema had a higher risk of pneumothorax, the corresponding odds ratio (OR) was 23.290 (p = 0.004), 33.300 (p = 0.019), and 8.007 (p = 0.012), respectively; the combined use of EMN and PFS could reduce the incidence of pneumothorax, with an OR of 0.094 (95 % confidence interval [CI]: 0.015-0.602, p = 0.013). The incidence rates of pneumothorax, pneumorrhagia and pleural effusion were 59.57 %, 61.70 %, and 19.15 % respectively in the CT group, and 30.77 %, 50.00 % and 7.69 % respectively in the CT-EMN-PFS group. The incidence rate of pneumothorax in the CT-EMN-PFS group was significantly lower than that in the CT group (p = 0.017). The median number of CT scans was 9 in the CT group and 5 in the CT-EMN-PFS group, respectively, meanwhile the median DLP was 1060.69 mGy*cm in the CT group and 600.04 mGy*cm in the CT-EMN-PFS group, respectively, which indicated there was a statistical difference in the amount of radiation exposure between the two groups (p < 0.001). Conclusion: The combined application of EMN and PFS demonstrates for the first time that there is a lower incidence rate of pneumothorax and significantly less radiation exposure during the MWA of the lung tumors.

Diagnostic Value of Contrast-Enhanced Ultrasound in Benign and Malignant Adnexal Masses: A Meta-Analysis.

In the diagnosis of gynecological tumors, determining the benign or malignant nature of adnexal masses is a crucial and complex issue. Contrast-enhanced ultrasound (CEUS) is a relatively novel and increasingly used diagnostic method. Therefore, this study evaluated the diagnostic value of CEUS in differentiating benign and malignant adnexal masses through meta-analysis and systematic review. We systematically searched PubMed, Embase, Web of Science, and the Cochrane Library for studies published up to April 2024 regarding the use of CEUS in diagnosing benign and malignant adnexal masses. STATA 14.0 software was used for data analysis, pooling the sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio (DOR) of eligible studies. After initial screening, 305 studies were identified, 13 of which met the inclusion criteria and were analyzed in this meta-analysis. The pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, and DOR of CEUS for the diagnosis of benign and malignant adnexal masses were 0.92 (95% confidence interval [CI]: 0.88-0.95), 0.88 (95% CI: 0.82-0.93), 8.00 (95% CI: 5.00-12.90), 0.09 (95% CI: 0.06-0.14), and 91.00 (95% CI: 45.00-185.00), respectively. The area under the summary receiver operating characteristic curve (AUC) was 0.95 (95% CI: 0.93-0.97). CEUS is a noninvasive, nonradiative imaging modality with high accuracy and reliability in the diagnosis of benign and malignant adnexal masses. To provide an effective adjunct tool in the clinic, future studies can further explore the specific application value of CEUS and its performance in different populations.

Regulatory networks of coresident subgenomes during rapid fiber cell elongation in upland cotton.

Cotton, an intriguing plant species shaped by polyploidization, evolution, and domestication, holds particular interest due to the complex mechanisms governing fiber traits across its two subgenomes. However, the regulatory elements or transcriptional networks between subgenomes during fiber elongation remain to be fully clarified. Here, we analyzed 1462 cotton fiber samples to reconstruct the gene-expression regulatory networks that influence fiber cell elongation. Inter-subgenome expression quantitative trait loci (eQTLs) largely dictate gene transcription, with a notable tendency for the D subgenome to regulate A-subgenome eGenes. This regulation reveals synchronized homoeologous gene expression driven by co-localized eQTLs and divergent patterns that diminish genetic correlations, thus leading to preferential expression in the A and D subgenomes. Hotspot456 emerged as a key regulator of fiber initiation and elongation, and artificial selection of trans-eQTLs in hotspot456 that positively regulate KCS1 has facilitated cell elongation. Experiments designed to clarify the roles of trans-eQTLs in improved fiber breeding confirmed the inhibition of GhTOL9 by a specific trans-eQTL via GhWRKY28, which negatively affects fiber elongation. We propose a model in which the GhWRKY28-GhTOL9 module regulates this process through the ESCRT (endosomal sorting complex required for transport) pathway. This research significantly advances our understanding of cotton's evolutionary and domestication processes and the intricate regulatory mechanisms that underlie significant plant traits.

Tumor Microenvironment-Responsive Biodegradable Nanomedicine for Self-Enhanced Synergistic Chemo-, Photothermal, and Chemodynamic Therapy.

The nanoscale multidrug codelivery system for synergistic therapy is an effective strategy for tumor treatment. However, the low drug delivery efficiency and poor therapeutic effects limit its application. Here, based on the coordination effect of Artemisinin (Art), quercetin (Qc), and Fe3+, we had constructed a safe and efficient carrier-free hyaluronic acid (HA)-modified Art-Fe-Qc nanoparticles (AFQ@HA NPs) for enhanced chemotherapy/photothermal therapy (PTT)-chemodynamic therapy (CDT) synergistic therapy, which achieved an ultrahigh drug loading efficiency and a multifunction anticancer strategy. The results showed that high drug loading was achieved based on drug coordination self-assembly, with Art and Qc contents of 38.6 and 42.7%, respectively. At the same time, based on the Qc-Fe coordination molecular network, the system had excellent photothermal conversion performance with an efficiency of 57.3% and could effectively inhibit the expression of HSP70, achieving enhanced PTT. Further, under the stimulation of excessive H2O2 and glutathione (GSH) in the tumor microenvironment, the AFQ@HA NPs were continuously degraded, while releasing Art and Fe3+/Fe2+ to achieve iron ion-enhanced CDT. The results of in vitro and in vivo experiments showed that AFQ@HA NPs could achieve chemotherapy-PTT-CDT synergistic therapy in response to tumor microenvironment by passively targeting and actively targeting tumor cells with CD44, demonstrating its excellent targeted antitumor effects.

Sintilimab combined with anlotinib and chemotherapy as second-line or later therapy in extensive-stage small cell lung cancer: a phase II clinical trial.

Treatment options for patients with relapsed extensive-stage small cell lung cancer (ES-SCLC) remain scarce. This study aims to evaluate the efficacy and safety of combining anlotinib and sintilimab plus chemotherapy as a second line or later therapy for ES-SCLC patients. This is a phase II clinical trial (ChiCTR2100049390) conducting at Shandong Cancer Hospital. Patients with ES-SCLC and received at least one prior systemic treatment were enrolled. The trial design involved a combination therapy (sintilimab, anlotinib, and nab-paclitaxel) administered over six 21-day cycles, followed by maintenance sintilimab therapy. The primary endpoint was objective response rate (ORR). Circulating tumor DNA sequencing was employed for exploratory analysis. From July 2021 to April 2023, 25 eligible patients were enrolled. The confirmed ORR was 60% (95% CI: 38.7-78.9%) and the DCR was 76% (95% CI: 54.9-90.6%). The mPFS was 6.0 months (95% CI: 5.4-9.7), and the 6-month PFS rate was 49.2%. The mOS was 13.4 months (95% CI: 11.8-NR), with a 12-month survival rate of 62.2%. Treatment-related adverse events (TRAEs) of any grade occurred in 80% of patients, with the most common being fatigue (40%) and nausea (32%). TRAEs of Grade 3 or higher were reported in 12% of patients. ctDNA analysis indicated that low on-treatment blood tumor mutation burden was associated with longer PFS and OS and a potential role of KMT2D mutation in treatment resistance. This combination therapy shows promising efficacy and a manageable safety profile as a second-line or later treatment for ES-SCLC, with genomic insights providing potential biomarkers for treatment response.

EtROP38 suppresses apoptosis of host cells infected with Eimeria tenella by inhibition of the p38MAPK pathway.

Coccidiosis is an important parasitic disease that has serious adverse effects on the global poultry industry. The mechanism by which the pathogenic factors of Eimeria tenella damage host cells is unknown. Some kinases from the rhoptry compartment can regulate apoptosis of host cells. This study focused on revealing the role and critical nodes of E. tenella rhoptry protein (EtROP) 38 in controlling the apoptosis of host cells via the P38 mitogen-activated protein kinase (MAPK) signaling pathway. The cells were treated with EtROP38 protein, siRNA p38MAPK, or both. The rate of infection, apoptosis, and the dynamic changes in the expression and activation of key factor genes of the P38MAPK signaling pathway in host cells infected with E. tenella were measured. The results showed that the addition of EtROP38 and/or knockdown of the host cells p38 gene reduced the apoptosis rate of cecal epithelial cells (CECS), decreased the mRNA expressions of p38, p53, c-myc, c-fos, and c-jun and increased the expression of p65, decreased the protein expressions of c-myc, c-fos, and c-jun, decreased the p38 protein phosphorylation level, and increased the p65 protein phosphorylation level in CECS. When E. tenella was inoculated for 4-96 h, the addition of Et ROP38 and/or host cell p38 knockdown both increased the infection rate of host cells, and this effect was more pronounced with the addition of EtROP38 with the host cell p38 knockdown. These observations indicate that E. tenella can inhibits the activation of the p38MAPK signaling pathway in host cells via EtROP38, which suppresses apoptosis in host cells.

A pathology foundation model for cancer diagnosis and prognosis prediction.

Histopathology image evaluation is indispensable for cancer diagnoses and subtype classification. Standard artificial intelligence methods for histopathology image analyses have focused on optimizing specialized models for each diagnostic task1,2. Although such methods have achieved some success, they often have limited generalizability to images generated by different digitization protocols or samples collected from different populations3. Here, to address this challenge, we devised the Clinical Histopathology Imaging Evaluation Foundation (CHIEF) model, a general-purpose weakly supervised machine learning framework to extract pathology imaging features for systematic cancer evaluation. CHIEF leverages two complementary pretraining methods to extract diverse pathology representations: unsupervised pretraining for tile-level feature identification and weakly supervised pretraining for whole-slide pattern recognition. We developed CHIEF using 60,530 whole-slide images spanning 19 anatomical sites. Through pretraining on 44 terabytes of high-resolution pathology imaging datasets, CHIEF extracted microscopic representations useful for cancer cell detection, tumour origin identification, molecular profile characterization and prognostic prediction. We successfully validated CHIEF using 19,491 whole-slide images from 32 independent slide sets collected from 24 hospitals and cohorts internationally. Overall, CHIEF outperformed the state-of-the-art deep learning methods by up to 36.1%, showing its ability to address domain shifts observed in samples from diverse populations and processed by different slide preparation methods. CHIEF provides a generalizable foundation for efficient digital pathology evaluation for patients with cancer.

Dissecting the Distinct Tumor Microenvironments of HRD and HRP Ovarian Cancer: Implications for Targeted Therapies to Overcome PARPi Resistance in HRD Tumors and Refractoriness in HRP Tumors.

High-grade serous tubo-ovarian cancer (HGSTOC) is an aggressive gynecological malignancy including homologous recombination deficient (HRD) and homologous recombination proficient (HRP) groups. Despite the therapeutic potential of poly (ADP-ribose) polymerase inhibitors (PARPis) and anti-PDCD1 antibodies, acquired resistance in HRD and suboptimal response in HRP patients necessitate more precise treatment. Herein, single-cell RNA and single-cell T-cell receptor sequencing on 5 HRD and 3 HRP tumors are performed to decipher the heterogeneous tumor immune microenvironment (TIME), along with multiplex immunohistochemistry staining and animal experiments for validation. HRD tumors are enriched with immunogenic epithelial cells, FGFR1+PDGFRß+ myCAFs, M1 macrophages, tumor reactive CD8+/CD4+ Tregs, whereas HRP tumors are enriched with HDAC1-expressing epithelial cells, indolent CAFs, M2 macrophages, and bystander CD4+/CD8+ T cells. Significantly, customized therapies are proposed. For HRD patients, targeting FGFR1+PDGFRß+ myCAFs via tyrosine kinase inhibitors, targeting Tregs via anti-CCR8 antibodies/TNFRSF4 stimulation, and targeting CXCL13+ exhausted T cells by blocking PDCD1/CTLA-4/LAG-3/TIGIT are proposed. For HRP patients, targeting indolent CAFs, targeting M2 macrophages via CSF-1/CSF-1R inhibitors, targeting bystander T cells via tumor vaccines, and targeting epithelial cells via HDAC inhibitors. The study provides comprehensive insights into HRD and HRP TIME and tailored therapeutic approaches, addressing the challenges of PARPi-resistant HRD and refractory HRP tumors.