Dapagliflozin attenuates fat accumulation and insulin resistance in obese mice with polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS), a common endocrine disorder affecting premenopausal women, is associated with various metabolic consequences such as insulin resistance, hyperlipidemia, obesity, and type 2 diabetes mellitus (T2DM). Insulin sensitizers, such as metformin and pioglitazone, though effective, often leads to significant gastrointestinal adverse effects or weight gain, limiting its suitability for women with PCOS. There is an urgent need for safe, effective and affordable agents. Dapagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, enhances glucose elimination through urine, thereby reducing body weight and improving glucose and lipid metabolism. Nevertheless, it is not currently recommended as a therapeutic option for PCOS in clinical guidelines. In this study, we systematically examined the impact of dapagliflozin on an obese PCOS mouse model, focusing on alterations in glucose metabolism, adipose tissue morphology, and plasma lipid profile. Obese PCOS was induced in mice by continuous dihydrotestosterone (DHEA) injections over 21 days and high-fat diet (HFD) feeding. PCOS mice were then orally gavaged with dapagliflozin (1 mg/kg), metformin (50 mg/kg), or vehicle daily for 8 weeks, respectively. Our results demonstrated that dapagliflozin significantly prevented body weight gain and reduced fat mass in obese PCOS mice. Meanwhile, dapagliflozin treatment improved glucose tolerance and increased insulin sensitivity compared to the control PCOS mice. Furthermore, dapagliflozin significantly improved adipocyte accumulation and morphology in white adipose tissue, resulting in a normalized plasma lipid profile in PCOS mice. In conclusion, our results suggest that dapagliflozin is an effective agent in managing glucose and lipid metabolism disorders in obese PCOS mice.

Metal-Organic Framework-Based Nanovaccine for Relieving Immunosuppressive Tumors via Hindering Efferocytosis of Macrophages and Promoting Pyroptosis and Cuproptosis of Cancer Cells.

Current cancer vaccines face challenges due to an immunosuppressive tumor microenvironment and their limited ability to produce an effective immune response. To address the above limitations, we develop a 3-(2-spiroadamantyl)-4-methoxy-4-(3-phosphoryloxy)-phenyl-1,2-dioxetane (alkaline phosphatase substrate) and XMD8-92 (extracellular signal-regulated kinase 5 inhibitor)-codelivered copper-tetrahydroxybenzoquinone (Cu-THBQ/AX) nanosized metal-organic framework to in situ-generate therapeutic vaccination. Once inside the early endosome, the alkaline phosphatase overexpressed in the tumor cells' membrane activates the in situ type I photodynamic effect of Cu-THBQ/AX for generating •O2-, and the Cu-THBQ/AX catalyzes O2 and H2O2 to •O2- and •OH via semiquinone radical catalysis and Fenton-like reactions. This surge of ROS in early endosomes triggers caspase-3-mediated proinflammatory pyroptosis via activating phospholipase C. Meanwhile, Cu-THBQ/AX can also induce the oligomerization of dihydrolipoamide S-acetyltransferase to trigger tumor cell cuproptosis. The production of •OH could also trigger the release of XMD8-92 for effectively inhibiting the efferocytosis of macrophages to convert immunosuppressive apoptosis of cancer cells into proinflammatory secondary necrosis. The simultaneous induction of pyroptosis, cuproptosis, and secondary necrosis effectively converts the tumor microenvironment from "cold" to "hot" conditions, making it an effective antigen pool. This transformation successfully activates the antitumor immune response, inhibiting tumor growth and metastasis.

Defect-rich sonosensitizers based on CeO2 with Schottky heterojunctions for boosting sonodynamic/chemodynamic synergistic therapy.

Sonodynamic therapy (SDT) has been recognized as a promising treatment for cancer due to its advantages of superior specificity, non-invasiveness, and deep tissue penetration. However, the antitumor effect of SDT remains restricted by the limited generation of reactive oxygen species (ROS) due to the lack of highly efficient sonosensitizers. In this work, we developed the novel sonosensitizer Pt/CeO2-xSx by constructing oxygen defects through S doping and Pt loading in situ. Large amounts of oxygen defects have been obtained by S doping, endowing Pt/CeO2-xSx with the ability to suppress electron-hole recombination, further promoting ROS production. Moreover, the introduction of Pt nanoparticles can not only produce oxygen in situ for relieving hypoxia but also form a Schottky heterojunction with CeO2-xSx for further inhibiting electron-hole recombination. In addition, Pt/CeO2-xSx could effectively deplete overexpressed glutathione (GSH) via redox reactions, amplifying oxidative stress in the tumor microenvironment (TME). Combined with the excellent POD-mimetic activity, Pt/CeO2-xSx can achieve highly efficient synergistic therapy of SDT and chemodynamic therapy (CDT). All these findings demonstrated that Pt/CeO2-xSx has great potential for cancer therapy, and this work provides a promising direction for designing and constructing efficient sonosensitizers.

GLIMS: A two-stage gradual-learning method for cancer genes prediction using multi-omics data and co-splicing network.

Identifying cancer genes is vital for cancer diagnosis and treatment. However, because of the complexity of cancer occurrence and limited cancer genes knowledge, it is hard to identify cancer genes accurately using only a few omics data, and the overall performance of existing methods is being called for further improvement. Here, we introduce a two-stage gradual-learning strategy GLIMS to predict cancer genes using integrative features from multi-omics data. Firstly, it uses a semi-supervised hierarchical graph neural network to predict the initial candidate cancer genes by integrating multi-omics data and protein-protein interaction (PPI) network. Then, it uses an unsupervised approach to further optimize the initial prediction by integrating the co-splicing network in post-transcriptional regulation, which plays an important role in cancer development. Systematic experiments on multi-omics cancer data demonstrated that GLIMS outperforms the state-of-the-art methods for the identification of cancer genes and it could be a useful tool to help advance cancer analysis.

Programmed Targeting Pyruvate Metabolism Therapy Amplified Single-Atom Nanozyme-Activated Pyroptosis for Immunotherapy.

Increasing cellular immunogenicity and reshaping the immune tumor microenvironment (TME) are crucial for antitumor immunotherapy. Herein, this work develops a novel single-atom nanozyme pyroptosis initiator: UK5099 and pyruvate oxidase (POx)-co-loaded Cu-NS single-atom nanozyme (Cu-NS@UK@POx), that not only trigger pyroptosis through cascade biocatalysis to boost the immunogenicity of tumor cells, but also remodel the immunosuppressive TME by targeting pyruvate metabolism. By replacing N with weakly electronegative S, the original spatial symmetry of the Cu-N4 electron distribution is changed and the enzyme-catalyzed process is effectively regulated. Compared to spatially symmetric Cu-N4 single-atom nanozymes (Cu-N4 SA), the S-doped spatially asymmetric single-atom nanozymes (Cu-NS SA) exhibit stronger oxidase activities, including peroxidase (POD), nicotinamide adenine dinucleotide (NADH) oxidase (NOx), L-cysteine oxidase (LCO), and glutathione oxidase (GSHOx), which can cause enough reactive oxygen species (ROS) storms to trigger pyroptosis. Moreover, the synergistic effect of Cu-NS SA, UK5099, and POx can target pyruvate metabolism, which not only improves the immune TME but also increases the degree of pyroptosis. This study provides a two-pronged treatment strategy that can significantly activate antitumor immunotherapy effects via ROS storms, NADH/glutathione/L-cysteine consumption, pyruvate oxidation, and lactic acid (LA)/ATP depletion, triggering pyroptosis and regulating metabolism. This work provides a broad vision for expanding antitumor immunotherapy.

Single-Site Nanozymes with a Highly Conjugated Coordination Structure for Antitumor Immunotherapy via Cuproptosis and Cascade-Enhanced T Lymphocyte Activity.

The extracellular matrix (ECM) in the tumor microenvironment (TME) and upregulated immune checkpoints (ICs) on antitumor immune cells impede the infiltration and killing effect of T cells, creating an immunosuppressive TME. Herein, a cholesterol oxidase (CHO) and lysyl oxidase inhibitor (LOX-IN-3) co-delivery copper-dibenzo-[g,p]chrysene-2,3,6,7,10,11,14,15-octaol single-site nanozyme (Cu-DBCO/CL) was developed. The conjugated organic ligand and well-distributed Cu-O4 sites endow Cu-DBCO with unique redox capabilities, enabling it to catalyze O2 and H2O2 to ·O2- and ·OH. This surge of reactive oxygen species (ROS) leads to impaired mitochondrial function and insufficient ATP supply, impacting the function of copper-transporting ATPase-1 and causing dihydrolipoamide S-acetyltransferase oligomerization-mediated cuproptosis. Moreover, multiple ROS storms and glutathione peroxidase 4 depletion also induce lipid peroxidation and trigger ferroptosis. Simultaneously, the ROS-triggered release of LOX-IN-3 reshapes the ECM by inhibiting lysyl oxidase activity and further enhances the infiltration of cytotoxic T lymphocytes (CD8+ T cells). CHO-triggered cholesterol depletion not only increases ·OH generation but also downregulates the expression of ICs such as PD-1 and TIM-3, restoring the antitumor activity of tumor-infiltrating CD8+ T cells. Therefore, Cu-DBCO/CL exhibits efficient properties in activating a potent antitumor immune response by cascade-enhanced CD8+ T cell viability. More importantly, ECM remodeling and cholesterol depletion could suppress the metastasis and proliferation of the tumor cells. In short, this immune nanoremodeler can greatly enhance the infiltration and antitumor activity of T cells by enhancing tumor immunogenicity, remodeling ECM, and downregulating ICs, thus achieving effective inhibition of tumor growth and metastasis.

Contrast-enhanced ultrasound to predict malignant upgrading of atypical ductal hyperplasia.

BACKGROUND: A malignancy might be found at surgery in cases of atypical ductal hyperplasia (ADH) diagnosed via US-guided core needle biopsy (CNB). The objective of this study was to investigate the diagnostic performance of contrast-enhanced ultrasound (CEUS) in predicting ADH diagnosed by US-guided CNB that was upgraded to malignancy after surgery. METHODS: In this retrospective study, 110 CNB-diagnosed ADH lesions in 109 consecutive women who underwent US, CEUS, and surgery between June 2018 and June 2023 were included. CEUS was incorporated into US BI-RADS and yielded a CEUS-adjusted BI-RADS. The diagnostic performance of US BI-RADS and CEUS-adjusted BI-RADS for ADH were analyzed and compared. RESULTS: The mean age of the 109 women was 49.7 years ± 11.6 (SD). The upgrade rate of ADH at CNB was 48.2% (53 of 110). The sensitivity, specificity, positive predictive value, and negative predictive value of CEUS for identification of malignant upgrading were 96.2%, 66.7%,72.9%, and 95.0%, respectively, based on BI-RADS category 4B threshold. The two false-negative cases were low-grade ductal carcinoma in situ. Compared with the US, CEUS-adjusted BI-RADS had better specificity for lesions smaller than 2 cm (76.7% vs. 96.7%, P = 0.031). After CEUS, 16 (10 malignant and 6 nonmalignant) of the 45 original US BI-RADS category 4A lesions were up-classified to BI-RADS 4B, and 3 (1 malignant and 2 nonmalignant) of the 41 original US BI-RADS category 4B lesions were down-classified to BI-RADS 4A. CONCLUSIONS: CEUS is helpful in predicting malignant upgrading of ADH, especially for lesions smaller than 2 cm and those classified as BI-RADS 4A and 4B on ultrasound.

Predictive potentials of glycosylation-related genes in glioma prognosis and their correlation with immune infiltration.

Glycosylation is currently considered to be an important hallmark of cancer. However, the characterization of glycosylation-related gene sets has not been comprehensively analyzed in glioma, and the relationship between glycosylation-related genes and glioma prognosis has not been elucidated. Here, we firstly found that the glycosylation-related differentially expressed genes in glioma patients were engaged in biological functions related to glioma progression revealed by enrichment analysis. Then seven glycosylation genes (BGN, C1GALT1C1L, GALNT13, SDC1, SERPINA1, SPTBN5 and TUBA1C) associated with glioma prognosis were screened out by consensus clustering, principal component analysis, Lasso regression, and univariate and multivariate Cox regression analysis using the TCGA-GTEx database. A glycosylation-related prognostic signature was developed and validated using CGGA database data with significantly accurate prediction on glioma prognosis, which showed better capacity to predict the prognosis of glioma patients than clinicopathological factors do. GSEA enrichment analysis based on the risk score further revealed that patients in the high-risk group were involved in immune-related pathways such as cytokine signaling, inflammatory responses, and immune regulation, as well as glycan synthesis and metabolic function. Immuno-correlation analysis revealed that a variety of immune cell infiltrations, such as Macrophage, activated dendritic cell, Regulatory T cell (Treg), and Natural killer cell, were increased in the high-risk group. Moreover, functional experiments were performed to evaluate the roles of risk genes in the cell viability and cell number of glioma U87 and U251 cells, which demonstrated that silencing BGN, SDC1, SERPINA1, TUBA1C, C1GALT1C1L and SPTBN5 could inhibit the growth and viability of glioma cells. These findings strengthened the prognostic potentials of our predictive signature in glioma. In conclusion, this prognostic model composed of 7 glycosylation-related genes distinguishes well the high-risk glioma patients, which might potentially serve as caner biomarkers for disease diagnosis and treatment.

Study of clinical traits and systemic immune inflammation index assessments in patients with endogenous endophthalmitis over the last ten years.

PURPOSE: The clinical aspects and prognosis of eyes with endogenous endophthalmitis were compared over the last ten years. The occurrence and progression of endophthalmitis are linked to the systemic immune inflammation index (SII) and clinical features. METHODS: The study comprised patients with endogenous endophthalmitis and 64 patients without endophthalmitis who were treated at Hebei Province Eye Hospital in the last ten years. According to the prognostic visual acuity, patients with endophthalmitis were split into two groups: Group A and Group B. Underlying disease (hypertension, diabetes, tuberculosis), infection risk (liver abscess, urinary tract infection, and recent abdominal surgery), signs and symptoms, and complete blood count were among the evaluation parameters (neutrophil count, lymphocyte count, monocyte count, platelet count, red blood cell distribution width). The NLR, PLR, MLR, and SII values were calculated. A nonparametric test was used to examine the clinical features and complete blood count results of patients in each group. To determine the parameters linked to endophthalmitis progression, researchers used principal component and ordinal logistic regression analyses. RESULTS: The study comprised a total of 25 eyes and 22 individuals with endogenous endophthalmitis. Infectious bacteria included Staphylococcus aureus, Micrococcus luteus, Staphylococcus hemolyticus, and so on. The visual acuity of the affected eye ranged from 2.7 (1.55, 2.7) LogMAR to 1.22 (0.6, 2.7) LogMAR during the 6-month to 8-year follow-up period. The neutrophil, monocyte, and PLT counts, NLR, PLR, and SII values and other markers were considerably higher in Groups A and B than in the control group. The likelihood model of the SII and sex, age, onset time, diabetes, hypertension, monocyte count, and red blood cell distribution was the best, and its increase was strongly connected with the occurrence and progression of endophthalmitis, according to ordinal regression analysis. CONCLUSION: Patients with endophthalmitis had significantly higher blood neutrophil, monocyte, and PLT counts and SII, NLR, PLR, and MLR values. The SII can be employed as a biomarker for predicting endophthalmitis severity and prognosis.

Multi-Enzyme Co-Expressed Nanomedicine for Anti-Metastasis Tumor Therapy by Up-Regulating Cellular Oxidative Stress and Depleting Cholesterol.

Tumor cells movement and migration are inseparable from the integrity of lipid rafts and the formation of lamellipodia, and lipid rafts are also a prerequisite for the formation of lamellipodia. Therefore, destroying the lipid rafts is an effective strategy to inhibit tumor metastasis. Herein, a multi-enzyme co-expressed nanomedicine: cholesterol oxidase (CHO) loaded Co─PN3 single-atom nanozyme (Co─PN3 SA/CHO) that can up-regulate cellular oxidative stress, disrupt the integrity of lipid rafts, and inhibit lamellipodia formation to induce anti-metastasis tumor therapy, is developed. In this process, Co─PN3 SA can catalyze oxygen (O2 ) and hydrogen peroxide (H2 O2 ) to generate reactive oxygen species (ROS) via oxidase-like and Fenton-like properties. The doping of P atoms optimizes the adsorption process of the intermediate at the active site and enhances the ROS generation properties of nanomedicine. Meantime, O2 produced by catalase-like catalysis can combine with excess cholesterol to generate more H2 O2 under CHO catalysis, achieving enhanced oxidative damage to tumor cells. Most importantly, cholesterol depletion in tumor cells also disrupts the integrity of lipid rafts and inhibits the formation of lamellipodia, greatly inhibiting the proliferation and metastasis of tumor cells. This strategy by up-regulating cellular oxidative stress and depleting cellular cholesterol constructs a new idea for anti-metastasis-oriented cancer therapy strategies.

Combination of Breast Ultrasound With Magnetic Resonance Imaging in the Diagnosis of Non-mass-like Breast Lesions Detected on Ultrasound: A New Integrated Strategy to Improve Diagnostic Performance.

OBJECTIVE: The aim of the work described here was to evaluate the diagnostic performance of a new integrated strategy using breast ultrasound (US) combined with magnetic resonance imaging (MRI) to differentiate benign and malignant breast non-mass-like lesions (NMLs) detected on US. METHODS: From October 2017 to January 2021, 183 NMLs detected on US that had undergone MRI examinations were included in this respective study. Pathological results were used as the reference standard. The integrated diagnostic strategy of breast US combined with MRI based on a combination of MRI Breast Imaging Reporting and Data System (BI-RADS) with discriminant sonographic indicators highly associated with malignancy was established and validated in a cohort of 61 women. The diagnostic performances of US, MRI and the combined method were calculated and compared. RESULTS: In the training set, the area under the receiver operating characteristic curve (AUC), sensitivity and specificity of US, MRI and the integrated diagnostic strategy using US combined with MRI for NMLs were 0.730, 93.7% and 52.3%; 0.849, 94.7% and 75.0%; and 0.901, 92.6% and 87.5%, respectively. Compared with US or MRI alone, the integrated diagnostic strategy significantly increased the AUC (p < 0.001, p = 0.007) and specificity (p < 0.001, p = 0.034) while maintaining high sensitivity (p = 0.774, p = 0.551). In the validation set, the integrated strategy of US combined with MRI (AUC = 0.899) also had good performance compared with US (AUC = 0.728) or MRI (AUC = 0.838). CONCLUSION: The integrated diagnostic strategy of US combined with MRI exhibited good performance for breast NMLs compared with either modality used alone, which can improve the diagnostic specificity while maintaining high sensitivity.

Benign Phyllodes Tumors: Comparison of Prognosis among Three Different Surgical Approaches.

Purpose: To evaluate the prognosis of patients with benign phyllodes tumors (PTs) treated by different surgical methods and to explore the influencing factors of local recurrence. Methods: We retrospectively analyzed 215 benign PTs from 193 patients who underwent surgery at Chinese PLA General Hospital between October 2008 and December 2020. We stratified our analysis according to surgical factors and explored the clinicopathological factors to influence local recurrence. Results: Among 193 patients, a total of 17 (8.8%, 17/193) recurred during follow-up. There were 89 patients in the US-VAE group, of whom 6 (6.7%) recurred; 8 of 57 patients (14%) in the local lumpectomy group recurred, while 3 of 47 patients (6.4%) in the extended lumpectomy group recurred (P=0.252). Multivariate logistic regression analysis showed that tumor diameter, mitosis, and history of breast myoma were independent risk factors for tumor recurrence (P=0.005, P=0.006, and P=0.004, respectively). The intraoperative blood loss, operation time, and scar length of the US-VAE group were shorter than those of the other two groups (P < 0.05). Conclusion: Negative surgical margins of benign PTs can obtain similar prognosis as negative surgical margins >10 mm. Therefore, we recommend that a follow-up observation policy be adopted for patients with unexpected benign PTs, rather than unnecessary open surgical resection. Patients' maximum tumor diameter, mitosis, and fibroadenoma history were independent predictors for recurrence of benign PTs.

A Cholesterol Metabolic Regulated Hydrogen-Bonded Organic Framework (HOF)-Based Biotuner for Antibody Non-Dependent Immunotherapy Tailored for Glioblastoma.

The metabolic reprogramming of glioblastoma (GBM) poses a tremendous obstacle to effective immunotherapy due to its impact on the immunosuppressive microenvironment. In this work, a hydrogen-bonded organic framework (HOF) specifically designed for GBM immunotherapy is developed, taking advantage of the relatively isolated cholesterol metabolism microenvironment in the central nervous system (CNS). The HOF-based biotuner regulates extra/intracellular cholesterol metabolism, effectively blocking the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway and reducing 2B4 expression. This metabolically disrupts the immunosuppressive microenvironment of GBM and rejuvenates CD8+ T cells. Moreover, cholesterol metabolism regulation offers additional benefits in treating GBM invasion. Furthermore, tumor microenvironment (TME)-initiated chemiexcited photodynamic therapy (PDT) is enhanced during the regulation of cholesterol metabolism, and the biotuner can effectively trigger immunogenic cell death (ICD) and increase the infiltration of cytotoxic T lymphocytes (CTLs) in GBM. By reversing the immunosuppressive microenvironment and bolstering chemiexcited-PDT, this approach invigorates efficient antibody non-dependent immunotherapy for GBM. This study provides a model for enhancing immunotherapy through cholesterol metabolism regulation and explores the feasibility of a "metabolic checkpoint" strategy in GBM treatment.

Scutellarin inhibits the glioma cell proliferation by downregulating BIRC5 to promote cell apoptosis.

The expression changes of baculovirus inhibitor of apoptosis repeat-containing protein5 in brain glioma after administration of Scutellarin was detected. To explore the effort of scutellarin on anti-glioma by downregulating BIRC5.The effect of scutellarin on tumour growth and animal survival was detected by administering scutellarin to nude mice subcutaneous tumour formation and SD rats in situ tumour formation models. A significantly different gene BIRC5 was found by using the combination of TCGA databases and network pharmacology. And then qPCR was performed to detect the expression of BIRC5 in glioma tissues, cells and normal brain tissues and glial cells. CCK-8 was used to detect the IC50 of scutellarin on glioma cells. The wound healing assay, flow cytometry and MTT test were used to detect the effect of scutellarin on the apoptosis and proliferation of glioma cells. The expression of BIRC5 in glioma tissues was significantly higher than that in normal brain tissues. Scutellarin can significantly reduce tumour growth and improve animal's survival. After scutellarin was administered, the expression of BIRC5 in U251 cells was significantly reduced. And after same time, apoptosis increased and cell proliferation was inhibited. This original research showed that scutellarin can promote the apoptosis of glioma cells and inhibit the proliferation by downregulating the expression of BIRC5.

[Retracted] Increased resistin suggests poor prognosis and promotes development of lung adenocarcinoma.

Following the publication of this paper, it was drawn to the Editor's attention by a concerned reader that the colony formation assay data shown in Fig. 3A on p. 3399 were strikingly similar to data that were already under consideration for publication in another article written by different authors at different research institutes. Owing to the fact that the contentious data in the above article were already under consideration for publication prior to its submission to Oncology Reports, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a satisfactory reply. The Editor apologizes to the readership for any inconvenience caused. [Oncology Reports 40: 3392­3404, 2018; DOI: 10.3892/or.2018.6736].

Genome editing HLA alleles for a pilot immunocompatible hESC line in a Chinese hESC bank for cell therapies.

Robust allogeneic immune reactions after transplantation impede the translational pace of human embryonic stem cells (hESCs)-based therapies. Selective genetic editing of human leucocyte antigen (HLA) molecules has been proposed to generate hESCs with immunocompatibility, which, however, has not been specifically designed for the Chinese population yet. Herein, we explored the possibility of customizing immunocompatible hESCs based on Chinese HLA typing characteristics. We generated an immunocompatible hESC line by disrupting HLA-B, HLA-C, and CIITA genes while retaining HLA-A*11:01 (HLA-A*11:01-retained, HLA-A11R ), which covers ~21% of the Chinese population. The immunocompatibility of HLA-A11R hESCs was verified by in vitro co-culture and confirmed in humanized mice with established human immunity. Moreover, we precisely knocked an inducible caspase-9 suicide cassette into HLA-A11R hESCs (iC9-HLA-A11R ) to promote safety. Compared with wide-type hESCs, HLA-A11R hESC-derived endothelial cells elicited much weaker immune responses to human HLA-A11+ T cells, while maintaining HLA-I molecule-mediated inhibitory signals to natural killer (NK) cells. Additionally, iC9-HLA-A11R hESCs could be induced to undergo apoptosis efficiently by AP1903. Both cell lines displayed genomic integrity and low risks of off-target effects. In conclusion, we customized a pilot immunocompatible hESC cell line based on Chinese HLA typing characteristics with safety insurance. This approach provides a basis for establishment of a universal HLA-AR bank of hESCs covering broad populations worldwide and may speed up the clinical application of hESC-based therapies.

Multi-enzyme Co-expressed Dual-Atom Nanozymes Induce Cascade Immunogenic Ferroptosis via Activating Interferon-γ and Targeting Arachidonic Acid Metabolism.

Immunotherapy is currently the most promising treatment strategy for long-term tumor regression. However, current cancer immunotherapy shows low response rates due to insufficient immunogenicity of tumor cells. Herein, we report a strategy to keep tumor cells highly immunogenic by triggering cascade immunogenic tumor ferroptosis. We developed a six-enzyme co-expressed nanoplatform: lipoxygenase (LOX) and phospholipase A2 (PLA2)-co-loaded FeCo/Fe-Co dual-metal atom nanozyme (FeCo/Fe-Co DAzyme/PL), which can not only induce initial immunogenic tumor ferroptosis through its own multi-enzyme mimetic activities but also up-regulate arachidonic acid (AA) expression to synergize with CD8+ T cell-derived IFN-γ to induce ACSL4-mediated immunogenic tumor ferroptosis. During this process, FeCo/Fe-Co DAzyme/PL can induce lipid peroxidation (LPO) by efficiently generating reactive oxygen species (ROS) and depleting GSH and GPX4 at tumor sites. Additionally, free AA released from PLA2 catalysis is converted into arachidonyl-CoA under the activation of ACSL4 stimulated by IFN-γ, which is further incorporated into phospholipids on membranes and peroxidized with the participation of LOX. Consequently, FeCo/Fe-Co DAzyme/PL can promote irreversible cascade immunogenic ferroptosis through multiple ROS storms, GSH/GPX4 depletion, LOX catalysis, and IFN-γ-mediated ACSL4 activation, constructing an effective pathway to overcome the drawbacks of current immunotherapy.

Conventional ultrasound combined with contrast-enhanced ultrasound: could it be helpful for the diagnosis of thoracic wall recurrence after mastectomy?

OBJECTIVES: To develop a predictive model using conventional ultrasound combined with CEUS to identify thoracic wall recurrence after mastectomy. METHODS: A total of 162 women with pathologically confirmed thoracic wall lesions (benign 79, malignant 83; median size 1.9 cm, ranging 0.3-8.0 cm) underwent a mastectomy and were checked by both conventional ultrasound and CEUS and were retrospectively included. Logistic regression models of B-mode ultrasound (US) and color Doppler flow imaging (CDFI) with or without CEUS were established to assess the thoracic wall recurrence after mastectomy. The established models were validated by bootstrap resampling. The models were evaluated using calibration curve. The clinical benefit of models were assessed using decision curve analysis. RESULTS: The area under the receiver characteristic was 0.823 (95% CI: 0.76, 0.88) for model using US alone, 0.898 (95% CI: 0.84, 0.94) for model using US combined with CDFI, and 0.959 (95% CI: 0.92, 0.98) for model using US combined with both CDFI and CEUS. The diagnostic performance of the US combined with CDFI was significantly higher than that of the US alone (0.823 vs 0.898, p = 0.002) but significantly lower than that of the US combined with both CDFI and CEUS (0.959 vs 0.898, p < 0.001). Moreover, the unnecessary biopsy rate of the US combined with both CDFI and CEUS was significantly lower than that of the US combined with CDFI (p = 0.037). CONCLUSIONS: Compared to B-mode ultrasound and CDFI, CEUS improves the diagnostic performance to evaluate thoracic wall recurrence after mastectomy. KEY POINTS: • CUES is an effective supplementary method for US in the diagnosis of thoracic wall recurrence after mastectomy. • CEUS combined with both US and CDFI can significantly improve the accuracy of diagnosis of thoracic wall recurrence after mastectomy. • CEUS combined with both US and CDFI can reduce the rate of unnecessary biopsy of thoracic wall lesions after mastectomy.

Determining whether the diagnostic value of B-ultrasound combined with contrast-enhanced ultrasound and shear wave elastography in breast mass-like and non-mass-like lesions differs: a diagnostic test.

Background: Mass-like (ML) and non-mass-like (NML) are two manifestations of breast lesions on ultrasound. Contrast-enhanced ultrasound (CEUS) can make up for the limitation of B-ultrasound (US) in the observation of focal blood flow, and shear wave elastography (SWE) can supplement the hardness information of the lesion. The present study aimed to analyze the characteristic manifestations of US, CEUS, and SWE in NML and ML breast and evaluate whether the diagnostic performance of these three ultrasound techniques differs in terms of differentiating between benign and malignant breast lesions. Methods: From January to August 2021, 382 patients (417 breast lesions) underwent US, CEUS, and SWE examinations. Of these, 204 women (218 breast lesions) were included in our study due to subsequent biopsy or surgery with pathological findings. The patients were divided into ML and NML groups according to the ultrasound characteristics, and the differences in multimodal ultrasound performance between benign and malignant NML and benign and malignant ML breast lesions were compared. The diagnostic performance of US, US + CEUS, US + SWE, US + CEUS + SWE for ML, NML and all breast lesions was evaluated by analyzing sensitivity, specificity and area under receiver operating characteristic (ROC) curve (AUC). Results: Pathologically, the 218 lesions included 96 malignant and 122 benign breast lesions. The sensitivity and specificity of US + CEUS + SWE in all lesion groups, ML group and NML group were 92.7% and 90.2%, 95.9% and 90.3%, 91.3% and 79.3%, respectively. In all breast group, AUCs of US + CEUS, US + SWE, US + CEUS + SWE were statistically different from AUC of US (P=0.0010, 0.0001, 0.0001). In the ML group, the AUC of US + CEUS, US + SWE, US + CEUS + SWE were statistically different from that of US (P=0.0120, 0.0008, 0.0002). In the NML group, there was a statistical difference between US + SWE and US AUC (P=0.0149). Conclusions: US, CEUS, and SWE have an important diagnostic value for benign and malignant ML and NML breast lesions. Multimodal ultrasound combined with US, CEUS, and SWE can improve the diagnostic efficacy in distinguishing between benign and malignant ML and NML lesions.

IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis.

Diffuse infiltration is the main reason for therapeutic resistance and recurrence in glioblastoma (GBM). However, potential targeted therapies for GBM stem-like cell (GSC) which is responsible for GBM invasion are limited. Herein, we report Insulin-like Growth Factor-Binding Protein 5 (IGFBP5) is a ligand for Receptor tyrosine kinase like Orphan Receptor 1 (ROR1), as a promising target for GSC invasion. Using a GSC-derived brain tumor model, GSCs were characterized into invasive or non-invasive subtypes, and RNA sequencing analysis revealed that IGFBP5 was differentially expressed between these two subtypes. GSC invasion capacity was inhibited by IGFBP5 knockdown and enhanced by IGFBP5 overexpression both in vitro and in vivo, particularly in a patient-derived xenograft model. IGFBP5 binds to ROR1 and facilitates ROR1/HER2 heterodimer formation, followed by inducing CREB-mediated ETV5 and FBXW9 expression, thereby promoting GSC invasion and tumorigenesis. Importantly, using a tumor-specific targeting and penetrating nanocapsule-mediated delivery of CRISPR/Cas9-based IGFBP5 gene editing significantly suppressed GSC invasion and downstream gene expression, and prolonged the survival of orthotopic tumor-bearing mice. Collectively, our data reveal that IGFBP5-ROR1/HER2-CREB signaling axis as a potential GBM therapeutic target.