Myeloid-derived suppressor cells alleviate adverse ventricular remodeling after acute myocardial infarction.

The fundamental pathophysiological mechanism in the progression of chronic heart failure following acute myocardial infarction (AMI) is ventricular remodeling, in which innate and adaptive immunity both play critical roles. Myeloid-derived suppressor cells (MDSCs) have been demonstrated to function in a range of pathological conditions, such as infections, inflammation, autoimmune diseases, and tumors. However, it is unclear how MDSCs contribute to cardiac remodeling following AMI. This study aimed to identify the function and underlying mechanism of MDSCs in controlling cardiac remodeling following AMI. Following AMI in mice, MDSCs frequencies changed dynamically, considerably increased on day 7 in blood, spleens, lymph nodes and hearts, and decreased afterwards. Consistently, mice with AMI displayed enhanced cardiac function on day 14 post-AMI, reduced infract size and higher survival rates on day 28 post-AMI following the adoptive transfer of MDSCs. Furthermore, MDSCs inhibited the inflammatory response by decreasing pro-inflammatory cytokine (TNF-α, IL-17, Cxcl-1, and Cxcl-2) expression, up-regulating anti-inflammatory cytokine (TGF-ß1, IL-10, IL-4, and IL-13) expression, reducing CD3+ T cell infiltration in the infarcted heart and enhancing M2 macrophage polarization. Mechanistically, MDSCs improved the release of anti-inflammatory factors (TGF-ß1 and IL-10) and decreased the injury of LPS-induced cardiomyocytes in vitro in a manner dependent on cell-cell contact. Importantly, blockade of IL-10 partially abolished the cardioprotective role of MDSCs. This study found that MDSCs contributed to the restoration of cardiac function and alleviation of adverse cardiac remodeling after AMI possibly by inhibiting inflammation.

TMEM100 acts as a TAK1 receptor that prevents pathological cardiac hypertrophy progression.

Pathological cardiac hypertrophy is the primary cause of heart failure, yet its underlying mechanisms remain incompletely understood. Transmembrane protein 100 (TMEM100) plays a role in various disorders, such as nervous system disease, pain and tumorigenesis, but its function in pathological cardiac hypertrophy is still unknown. In this study, we observed that TMEM100 is upregulated in cardiac hypertrophy. Functional investigations have shown that adeno-associated virus 9 (AAV9) mediated-TMEM100 overexpression mice attenuates transverse aortic constriction (TAC)-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis, and impaired heart structure and function. We subsequently demonstrated that adenoviral TMEM100 (AdTMEM100) mitigates phenylephrine (PE)-induced cardiomyocyte hypertrophy and downregulates the expression of cardiac hypertrophic markers in vitro, whereas TMEM100 knockdown exacerbates cardiomyocyte hypertrophy. The RNA sequences of the AdTMEM100 group and control group revealed that TMEM100 was involved in oxidative stress and the MAPK signaling pathway after PE stimulation. Mechanistically, we revealed that the transmembrane domain of TMEM100 (amino acids 53-75 and 85-107) directly interacts with the C-terminal region of TAK1 (amino acids 1-300) and inhibits the phosphorylation of TAK1 and its downstream molecules JNK and p38. TAK1-binding-defective TMEM100 failed to inhibit the activation of the TAK1-JNK/p38 pathway. Finally, the application of a TAK1 inhibitor (iTAK1) revealed that TAK1 is necessary for TMEM100-mediated cardiac hypertrophy. In summary, TMEM100 protects against pathological cardiac hypertrophy through the TAK1-JNK/p38 pathway and may serve as a promising target for the treatment of cardiac hypertrophy.

Syndecan-4 inhibition attenuates cartilage degeneration in temporomandibular joint osteoarthritis.

BACKGROUND: Syndecan 4 (SDC4), a type I transmembrane proteoglycan, serves as a critical link between chondrocytes and the extracellular matrix. OBJECTIVE: This study aimed to explore the role of SDC4 in cartilage degeneration of temporomandibular joint osteoathritis (TMJOA). METHODS: Condylar chondrocytes were stimulated with varying concentrations of recombinant rat interleukin-1ß (rrIL-1ß) and SDC4 small interfering RNA (si-SDC4). Anti-SDC4 ectodomain-specific antibodies or IgG were intra-articularly administrated in a TMJOA model rats. SDC4 conditional knockout (SDC4-cKO) and Sdc4flox/flox mice were induced TMJOA. Cartilage degeneration was assessed using haematoxylin & eosin (H&E) and safranin O (SO) staining. Protein levels of SDC4, matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase with a thrombospondin motifs 5 (ADAMTS5), tumour necrosis factor α (TNFα), type II collagen (Col-II), aggrecan (ACAN), cleaved caspase 3 (CASP3), Ki67 and related pathways in condylar cartilage were evaluated by immunohistochemical (IHC) staining or western blot assays. RESULTS: SDC4 expression was evidently increased in MIA-model animals compared to control groups. rrIL-1ß stimulation increased the expression of SDC4, MMP3 and ADAMTS5 expression in chondrocytes, while decreasing the expression of Col-II. These effects were reversed by si-SDC4 in vitro. In vivo, SDC4 blockade reduced the death of chondrocytes and the loss of cartilage matrix, which was evidenced by increased expression of Col-II and ACAN, and a decrease in SDC4, MMP13 and cleaved-CASP3-positive cells. Furthermore, the protein levels of ACAN and Ki67 were elevated, and the ERK1/2 and P38 signalling pathways were activated following SDC4 inhibition. CONCLUSIONS: SDC4 inhibition significantly ameliorates condylar cartilage degeneration, which was mediated, at least partly, through P38 and ERK1/2 signalling. Inhibition of SDC4 may be of great value for the treatment of TMJOA.

Organic solvents-free and ambient-pressure drying melamine formaldehyde resin aerogels with homogeneous structures, outstanding mechanical strength and flame retardancy.

Atmospheric drying method for fabricating aerogels is considered the most promising way for casting aerogels on a large scale. However, the organic solvent exchange, remaining environmental pollution risk, is a crucial step in mitigating the impact of surface tension during the atmospheric drying process, especially for wet gel formed through the alkoxy-derived sol-gel process, such as melamine-formaldehyde resin (MF) aerogel. Herein, a tough polymer-assisted in situ polymerization was proposed to fabricate MF resin aerogel with a combination of mechanical toughness and strength, enabling it to withstand the capillary force during water evaporation. The monolithic MF resin aerogel through the sol-gel method can be directly prepared without additional network strengthening or organic solvent exchange. The resulting MF resin aerogel exhibits a homogeneous as well as hierarchical structure with macropores and mesopores (~6 µm and ~5 nm), high compressive modulus of 31.8 MPa, self-extinguishing property, and high-temperature thermal insulation with 97 % heat decrease for butane flame combustion. This work presents a straightforward and environmentally friendly method for fabricating MF resin aerogels with nanostructures and excellent performance in open conditions, exhibiting various applications.

Combined PET/CT and Autoantibody Detection in Lung Nodules Diagnosis.

Objective: To assess the usefulness of combining positron emission tomography/computed tomography (PET/CT) with lung cancer autoantibody detection in identifying and managing lung nodules. Methods: The researchers identified 160 patients with pulmonary nodules admitted to their hospital between January 2018 and January 2021. These patients were designated as the experimental group. Additionally, 60 healthy individuals without pulmonary nodules were admitted to the hospital during the same period. The individuals constituted the control group. All study participants underwent digital PET/CT detection and had their lung cancer autoantibody levels determined through enzyme-linked immunosorbent assay. Further testing, such as puncture or surgical pathology, was performed for patients with lung nodules. The aim was to evaluate the significance of combining PET/CT with autoantibody detection in diagnosing and treating lung nodules. Results: The study found that testing multiple autoantibodies together increased sensitivity and accuracy compared to testing individual autoantibodies. Combining PET/CT screening with autoantibody detection improved the diagnostic rate for identifying lung nodules, including benign and suspected malignant ones. Several autoantibodies were significantly higher in the experimental group compared to the control group. Testing for multiple autoantibodies showed higher sensitivity and accuracy than testing for one. Pathological examination confirmed 129 benign nodules and 31 malignant nodules. The median SUVmax values were measured at 0.7 for benign nodules and 4.8 for malignant nodules. The diagnostic efficacy of PET/CT combined with autoantibodies was determined through comparison with pathology testing and was as follows: PET/CT combined with autoantibody detection > PET/CT > autoantibody detection. Conclusion: Combining PET/CT with the detection of autoantibodies enhances the positive diagnostic rate and accuracy of lung nodules in the case of lung cancer. The SUVmax also shows excellent potential as a supplement in diagnosing both benign and malignant lung nodules, providing valuable guidance in determining the pathological types.

Tumor-associated antigen-specific cell imaging based on upconversion luminescence and nucleic acid rolling circle amplification.

Tumor-associated antigen (TAA)-based diagnosis has gained prominence for early tumor screening, treatment monitoring, prognostic assessment, and minimal residual disease detection. However, limitations such as low sensitivity and difficulty in extracting non-specific binding membrane proteins still exist in traditional detection methods. Upconversion luminescence (UCL) exhibits unique physical and chemical properties under wavelength near-infrared light excitation. Rolling circle amplification (RCA) is an efficient DNA amplification technique with amplification factors as high as 105. Therefore, the above two excellent techniques can be employed for highly accurate imaging analysis of tumor cells. Herein, we developed a novel nanoplatform for TAA-specific cell imaging based on UCL and RCA technology. An aptamer-primer complex selectively binds to Mucin 1 (MUC1), one of TAA on cell surface, to trigger RCA reaction, generating a large number of repetitive sequences. These sequences provide lots of binding sites for complementary signal probes, producing UCL from lanthanide-doped upconversion nanoparticles (UCNPs) after releasing quencher group. The experimental results demonstrate the specific attachment of upconversion nanomaterials to cancer cells which express a high level of MUC1, indicating the potential of UCNPs and RCA in tumor imaging.

A ROS storm generating nanocomposite for enhanced chemodynamic therapy through H2O2 self-supply, GSH depletion and calcium overload.

Catalytic generation of toxic hydroxyl radicals (˙OH) from hydrogen peroxide (H2O2) is an effective strategy for tumor treatment in chemodynamic therapy (CDT). However, the intrinsic features of the microenvironment in solid tumors, characterized by limited H2O2 and overexpressed glutathione (GSH), severely impede the accumulation of intracellular ˙OH, posing significant challenges. To circumvent these critical issues, in this work, a CaO2-based multifunctional nanocomposite with a surface coating of Cu2+ and L-buthionine sulfoximine (BSO) (named CaO2@Cu-BSO) is designed for enhanced CDT. Taking advantage of the weakly acidic environment of the tumor, the nanocomposite gradually disintegrates, and the exposed CaO2 nanoparticles subsequently decompose to produce H2O2, alleviating the insufficient supply of endogenous H2O2 in the tumor microenvironment (TME). Furthermore, Cu2+ detached from the surface of CaO2 is reduced by H2O2 and GSH to Cu+ and ROS. Then, Cu+ catalyzes H2O2 to generate highly cytotoxic ˙OH and Cu2+, forming a cyclic catalysis effect for effective CDT. Meanwhile, GSH is depleted by Cu2+ ions to eliminate possible ˙OH scavenging. In addition, the decomposition of CaO2 by TME releases a large amount of free Ca2+, resulting in the accumulation and overload of Ca2+ and mitochondrial damage in tumor cells, further improving CDT efficacy and accelerating tumor apoptosis. Besides, BSO, a molecular inhibitor, decreases GSH production by blocking γ-glutamyl cysteine synthetase. Together, this strategy allows for enhanced CDT efficiency via a ROS storm generation strategy in tumor therapy. The experimental results confirm and demonstrate the satisfactory tumor inhibition effect both in vitro and in vivo.

The efficacy and safety of ciprofol and propofol in patients undergoing colonoscopy: A double-blind, randomized, controlled trial.

STUDY OBJECTIVE: Propofol is a commonly utilized anesthetic for painless colonoscopy, but its usage is occasionally limited due to its potential side effects, including cardiopulmonary suppression and injection pain. To address this limitation, the novel compound ciprofol has been proposed as a possible alternative for propofol. This study sought to determine whether there are any differences in the safety and efficacy of propofol and ciprofol for painless colonoscopy. DESIGN: Randomized clinical trial. SETTING: Single-centre, class A tertiary hospital, November 2021 to November 2022. PATIENTS: Adult, American Society of Anesthesiologists Physical Status I to II and body mass index of 18 to 30 kg m-2 patients scheduled to undergo colonoscopy. INTERVENTIONS: Consecutive patients were randomly allocated in a 1:1 ratio to receive sedation for colonoscopy with ciprofol (group C) or propofol (group P). MEASUREMENTS: The primary outcome was the success rate of colonoscopy. The secondary outcomes were onset time of sedation, operation time, recovery time and discharge time, patients and endoscopists satisfaction, side effects (e.g. injection pain, myoclonus, drowsiness, dizziness, procedure recall, nausea and vomiting) and incidence rate of cardiopulmonary adverse events. MAIN RESULTS: No significant difference was found in the success rate of colonoscopy between the two groups (ciprofol 96.3% vs. propofol 97.6%; mean difference - 1.2%, 95% CI: -6.5% to 4.0%, P = 0.650). However, group C showed prolonged sedation (63.4 vs. 54.8 s, P < 0.001) and fully alert times (9 vs 8 min, P = 0.013), as well as reduced incidences of injection pain (0 vs. 40.2%, P < 0.001), respiratory depression (2.4% vs. 13.4%, P = 0.021) and hypotension (65.9% vs. 80.5%, P = 0.034). Patients satisfaction was also higher in Group C (10 vs 9, P < 0.001). CONCLUSIONS: Ciprofol can be used independently for colonoscopy. When comparing the sedation efficacy of ciprofol and propofol, a 0.4 mg kg-1 dose of ciprofol proved to be equal to a 2.0 mg kg-1 dose of propofol, with fewer side effects and greater patient satisfaction during the procedure.

Long non-coding RNAFOXD1-AS1 modulated CTCs epithelial-mesenchymal transition and immune escape in hepatocellular carcinoma in vitro by sponging miR-615-3p.

BACKGROUND: Hepatocellular carcinoma (HCC) is widely recognized as a globally prevalent malignancy. Immunotherapy is a promising therapy for HCC patients. Increasing evidence suggests that lncRNAs are involved in HCC progression and immunotherapy. AIM: The study reveals the mechanistic role of long non-coding RNA (lncRNA) FOXD1-AS1 in regulating migration, invasion, circulating tumor cells (CTCs), epithelial-mesenchymal transition (EMT), and immune escape in HCC in vitro. METHODS: This study employed real-time PCR (RT-qPCR) to measure FOXD1-AS1, miR-615-3p, and programmed death-ligand 1 (PD-L1). The interactions of FOXD1-AS1, miR-615-3p, and PD-L1 were validated via dual-luciferase reporter gene and ribonucleoprotein immunoprecipitation (RIP) assay. In vivo experimentation involves BALB/c mice and BALB/c nude mice to investigate the impact of HCC metastasis. RESULTS: The upregulation of lncRNA FOXD1-AS1 in malignant tissues significantly correlates with poor prognosis. The investigation was implemented on the impact of lncRNA FOXD1-AS1 on the migratory, invasive, and EMT of HCC cells. It has been observed that the lncRNA FOXD1-AS1 significantly influences the generation and metastasis of MCTC in vivo analysis. In mechanistic analysis, lncRNA FOXD1-AS1 enhanced immune escape in HCC via upregulation of PD-L1, which acted as a ceRNA by sequestering miR-615-3p. Additionally, lncRNA FOXD1-AS1 was found to modulate the EMT of CTCs through the activation of the PI3K/AKT pathway. CONCLUSION: This study presents compelling evidence supporting the role of lncRNA FOXD1-AS1 as a miRNA sponge that sequesters miR-655-3p and protects PD-L1 from suppression.

Exploring the metastasis-related biomarker and carcinogenic mechanism in liver cancer based on single cell technology.

Background: Hepatocellular carcinoma (HCC) is a fatal primary malignancy characterized by high invasion and migration. We aimed to explore the underlying metastasis-related mechanism supporting the development of HCC. Methods: The dataset of single cell RNA-seq (GSE149614) were collected for cell clustering by using the Seurat R package, the FindAllMarkers function was used to find the highly expression and defined the cell cluster. The WebGestaltR package was used for the GO and KEGG function analysis of shared genes, the Gene Set Enrichment Analysis (GSVA) was performed by clusterProfiler R package, the hTFtarget database was used to identify the crucial transcription factors (TFs), the Genomics of Drug Sensitivity in Cancer (GDSC) database was used for the drug sensitivity analysis. Finally, the overexpression and trans-well assay was used for gene function analysis. Results: We obtained 9 cell clusters from the scRNA-seq data, including the nature killer (NK)/T cells, Myeloid cells, Hepatocytes, Epithelial cells, Endothelial cells, Plasma B cells, Smooth muscle cells, B cells, Liver bud hepatic cells. Further cell ecological analysis indicated that the Hepatocytes and Endothelial cell cluster were closely related to the cancer metastasis. Subsequently, the NDUFA4L2-Hepatocyte, GTSE1-Hepatocyte, ENTPD1-Endothelial and NDUFA4L2-Endothelial were defined as metastasis-supporting cell clusters, in which the NDUFA4L2-Hepatocyte cells was closely related to angiogenesis, while the NDUFA4L2-Endothelial was related with the inflammatory response and complement response. The overexpression and trans-well assay displayed that NDUFA4L2 exhibited clearly metastasis-promoting role in HCC progression. Conclusion: We identified and defined 4 metastasis-supporting cell clusters by using the single cell technology, the specify shared gene was observed and played crucial role in promoting cancer progression, our findings were expected to provide new insight in control cancer metastasis.

Anti-HER2 therapy response assessment for guiding treatment (de-)escalation in early HER2-positive breast cancer using a novel deep learning radiomics model.

OBJECTIVES: Anti-HER2 targeted therapy significantly reduces risk of relapse in HER2 + breast cancer. New measures are needed for a precise risk stratification to guide (de-)escalation of anti-HER2 strategy. METHODS: A total of 726 HER2 + cases who received no/single/dual anti-HER2 targeted therapies were split into three respective cohorts. A deep learning model (DeepTEPP) based on preoperative breast magnetic resonance (MR) was developed. Patients were scored and categorized into low-, moderate-, and high-risk groups. Recurrence-free survival (RFS) was compared in patients with different risk groups according to the anti-HER2 treatment they received, to validate the value of DeepTEPP in predicting treatment efficacy and guiding anti-HER2 strategy. RESULTS: DeepTEPP was capable of risk stratification and guiding anti-HER2 treatment strategy: DeepTEPP-Low patients (60.5%) did not derive significant RFS benefit from trastuzumab (p = 0.144), proposing an anti-HER2 de-escalation. DeepTEPP-Moderate patients (19.8%) significantly benefited from trastuzumab (p = 0.048), but did not obtain additional improvements from pertuzumab (p = 0.125). DeepTEPP-High patients (19.7%) significantly benefited from dual HER2 blockade (p = 0.045), suggesting an anti-HER2 escalation. CONCLUSIONS: DeepTEPP represents a pioneering MR-based deep learning model that enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thereby providing valuable guidance for anti-HER2 (de-)escalation strategies. DeepTEPP provides an important reference for choosing the appropriate individualized treatment in HER2 + breast cancer patients, warranting prospective validation. CLINICAL RELEVANCE STATEMENT: We built an MR-based deep learning model DeepTEPP, which enables the non-invasive prediction of adjuvant anti-HER2 effectiveness, thus guiding anti-HER2 (de-)escalation strategies in early HER2-positive breast cancer patients. KEY POINTS: • DeepTEPP is able to predict anti-HER2 effectiveness and to guide treatment (de-)escalation. • DeepTEPP demonstrated an impressive prognostic efficacy for recurrence-free survival and overall survival. • To our knowledge, this is one of the very few, also the largest study to test the efficacy of a deep learning model extracted from breast MR images on HER2-positive breast cancer survival and anti-HER2 therapy effectiveness prediction.

Correlation between right-to-left shunt and sudden sensorineural hearing loss: protocol for a case-control study.

BACKGROUND AND PURPOSE: Sudden sensorineural hearing loss (SSNHL) is a neurological and otolaryngological emergency during which rapid diagnosis and early treatment are of great importance. Clinical experience indicates that a considerable number of patients with SSNHL have concurrent right-to-left shunt (RLS). With limited reports, the association between SSNHL and RLS is yet unclear and there is a need for large observational studies to explore their latent relationship. METHODS AND ANALYSIS: This proposed study is a prospective, observational case-control study. A total of 194 eligible participants matched in age and sex will be divided equally into two groups: 97 patients with SSNHL included in the case group and 97 individuals without SSNHL in the control group. Medical evaluations, including clinical characteristics, laboratory examination, audiological examination and ultrasonography examination, will be performed in all subjects. The primary outcome of the study is the difference in RLS rates between the groups. Differences in patent foramen ovale rates and other measured variables will be further assessed. A conditional logistic regression as a correlation analysis will be used to evaluate the relationship between RLS and SSNHL. DISCUSSION: This study may provide evidence on the correlation between RLS and SSNHL in order to enrich the aetiology of SSNHL. ETHICS AND DISSEMINATION: The study protocol has been approved by the Ethics Committee of Peking University Shenzhen Hospital. A written informed consent form will be signed and dated by the participants and the researchers before the study begins. The results will be disseminated in peer-reviewed publications. TRIAL REGISTRATION NUMBER: ChiCTR2200064067.

N6-methyladenosine of TRIM27 enhances the stem cell-type phenotype of cisplatin-resistant colorectal cancer cells.

Colorectal cancer (CRC), classified as a lethal form of cancer, substantially threatens human well-being. Cancer stem cells (CSCs) reflect subsets for cancerous cells having basic stem-cell type properties, being significantly involved in the development of chemoresistance and tumor relapsing. The aberrant TRIM27 expression in various types of cancer indicates its potential involvement in cancer growth and progression. The current understanding of the TRIM27 involvement in CRC remains limited. In current study indicated that TRIM27 can potentially promote CSC-type phenotype of Cisplatin (DDP)-resistant CRC cells. YTHDF1 recruitment onto m6A-amended TRIM27 was crucial for facilitating the TRIM27 translating process in DDP-resistant CRC cells. The present research proposes that TRIM27 exhibits an oncogenic role by enhancing the CSC-type properties in DDP-resistant CRC via the m6A-modified pathway. The potential therapy for combating the relapse of CRC may include TRIM27 and YTHDF1, as they have been found to have significant roles in promoting CSC-type phenotypic characteristics.

RNF13 protects against pathological cardiac hypertrophy through p62-NRF2 pathway.

Heart failure (HF) severely impairs human health because of its high incidence and mortality. Cardiac hypertrophy is the main cause of HF, while its underlying mechanism is not fully clear. As an E3 ubiquitin ligase, Ring finger protein 13 (RNF13) plays a crucial role in many disorders, such as liver immune, neurological disease and tumorigenesis, whereas the function of RNF13 in cardiac hypertrophy remains largely unknown. In the present study, we found that the protein expression of RNF13 is up-regulated in the transverse aortic constriction (TAC)-induced murine hypertrophic hearts and phenylephrine (PE)-induced cardiomyocyte hypertrophy. Functional investigations indicated that RNF13 global knockout mice accelerates the degree of TAC-induced cardiac hypertrophy, including cardiomyocyte enlargement, cardiac fibrosis and heart dysfunction. On the contrary, adeno-associated virus 9 (AAV9) mediated-RNF13 overexpression mice alleviated cardiac hypertrophy. Furthermore, we demonstrated that adenoviral RNF13 attenuates the PE-induced cardiomyocyte hypertrophy and down-regulates the expression of cardiac hypertrophic markers, while the opposite results were observed in the RNF13 knockdown group. The RNA-sequence of RNF13 knockout and wild type mice showed that RNF13 deficiency activates oxidative stress after TAC surgery. In terms of the mechanism, we found that RNF13 directly interacted with p62 and promoted the activation of downstream NRF2/HO-1 signaling. Finally, we proved that p62 knockdown can reverse the effect of RNF13 in cardiac hypertrophy. In conclusion, RNF13 protects against the cardiac hypertrophy via p62-NRF2 axis.

Focused ultrasound combined with miR-1208-equipped exosomes inhibits malignant progression of glioma.

BACKGROUND: Exosomes (Exos) can safely and effectively deliver therapeutic substances to glioma cells; however, their blood-brain barrier (BBB) crossing capacity remains limited. Focused ultrasound (FUS) can transiently, reversibly, and locally open the BBB, while the effects of FUS combined with Exos-miRNA on the treatment of glioma have not been explored to date. METHODS: Exos were extracted by differential centrifugation and the efficacy of miR-1208-loaded Exos combined with FUS in the treatment of glioma was detected by CCK-8, colony formation, flow cytometry, transwell and tumour xenografts assays. The METTL3-mediated regulation of IGF2BP2 on mRNA stability of NUP214 was determined by MeRIP-qPCR, half-life and RIP assays. RESULTS: We used Exos secreted by mesenchymal stem cells as carriers for the tumour suppressor gene miR-1208, and following FUS irradiation, more Exos carrying miR-1208 were allowed to pass through the BBB, and the uptake of miR-1208 in Exos by glioma cells was promoted, thereby achieving high-efficiency tumour-suppressive effects. Furthermore, the molecular mechanism underlying this effect was elucidated that miR-1208 downregulated the m6A methylation level of NUP214 mRNA by negatively regulating the expression of METTL3, thereby NUP214 expression and TGF-ß pathway activity were suppressed. CONCLUSIONS: MiR-1208-loaded Exos combined with FUS is expected to become an effective glioma treatment and deserves further clinical evaluation.

Exosome-derived ANXA9 functions as an oncogene in breast cancer.

Breast cancer (BCA) is one of the most prevalent cancers among women. Emerging evidence has revealed that Annexin A-9 (ANXA9) plays a crucial function in the development of some cancers. Notably, ANXA9 has been reported to be a new prognostic biomarker for gastric and colorectal cancers. However, its expression and biological function in BCA have not yet been investigated. Using online bioinformatics tools such as TIMER, GEPIA, HPA, and UALCAN, we predicted ANXA9 expression and its correlation with the clinicopathological characteristics of BCA patients. RT-qPCR and western blot were utilized to measure ANXA9 mRNA and ANXA9 protein expression in BCA patient tissues and cells. BCA-derived exosomes were identified by transmission electron microscopy. Functional assays were employed to evaluate the biological role of ANXA9 in BCA cell proliferation, migration, invasion, and apoptosis. A tumor xenograft in vivo model was utilized to assess the role of ANXA9 in tumor growth in mice. Bioinformatics and functional screening analysis revealed that ANXA9 was highly expressed in BCA patient tissues, with median ANXA9 expression 1.5- to 2-fold higher than in normal tissues (p < 0.05). RT-qPCR confirmed that ANXA9 expression in BCA tissues was around 1.5-fold higher than the adjacent normal tissues (p < 0.001). ANXA9 expression in different subtypes of BCA also showed a difference, and ANXA9 was found to be mostly significantly upregulated in luminal BCA relative to normal tissues or other histological subtypes (p < 0.001). Moreover, ANXA9 expression was elevated in different races, ages, clinical stages, node metastasis status, and menopause status groups relative to the normal group (p < 0.001). Furthermore, ANXA9 was found to be secreted by BCA tissue-derived exosomes and its expression was upregulated 1- to 7-fold in BCA cells treated with exosomes (p < 0.001), while its expression in MCF10A cells was not significantly altered by treatment with exosomes (p > 0.05). ANXA9 silencing induced a significant decrease of around 30% in the colony number of BCA cells (p < 0.01). The number of migrated and invaded BCA cells also decreased by around 65 and 68%, respectively, after silencing ANXA9 (p < 0.01). Tumor size was significantly reduced (nearly half) in the LV-sh-ANXA9 group relative to the LV-NC group in the xenograft model (p < 0.01), suggesting that ANXA9 silencing repressed tumor progression in BCA progression in vitro and in vivo. In conclusion, exosome-derived ANXA9 functions as an oncogene that facilitates the proliferation, migration, and invasiveness of BCA cells and enhances tumor growth in BCA development, which may provide a new prognostic and therapeutic biomarker for BCA patients.

[Punicalagin inhibits hepatic lipid deposition in obese mice via AMPK/ACC pathway].

Hepatic lipid deposition is one of the basic manifestations of obesity, and nowadays pharmacological treatment is the most important tool. Punicalagin(PU), a polyphenol derived from pomegranate peel, is a potential anti-obesity substance. In this study, 60 C57BL/6J mice were randomly divided into a normal group and a model group. After establishing a model of simple obesity with a high-fat diet for 12 weeks, the successfully established rat models of obesity were then regrouped into a model group, an orlistat group, a PU low-dose group, a PU medium-dose group, and a PU high-dose group. The normal group was kept on routine diet and other groups continued to feed the high-fat diet. The body weight and food intake were measured and recorded weekly. After 8 weeks, the levels of the four lipids in the serum of each group of mice were determined by an automatic biochemical instrument. Oral glucose tole-rance and intraperitoneal insulin sensitivity were tested. Hemoxylin-eosin(HE) staining was applied to observe the hepatic and adipose tissues. The mRNA expression levels of peroxisome proliferators-activated receptor γ(PPARγ) and C/EBPα were determined by real-time quantitative polymerase chain reaction(Q-PCR), and the mRNA and protein expression levels of adenosine 5'-monophosphate-activated protein kinase(AMPK), anterior cingulate cortex(ACC), and carnitine palmitoyltransferase 1A(CPT1A) were determined by Western blot. Finally, the body mass, Lee's index, serum total glyceride(TG), serum total cholesterol(TC), and low-density lipoprotein cholesterol(LDL-C) levels were significantly higher and high-density lipoprotein cholesterol(HDL-C) levels were significantly lower in the model group as compared with the normal group. The fat deposition in the liver was significantly increased. The mRNA expression levels of hepatic PPARγ and C/EBPα and the protein expression level of ACC were increased, while the mRNA and protein expression levels of CPT-1α(CPT1A) and AMPK were decreased. After PU treatment, the above indexes of obese mice were reversed. In conclusion, PU can decrease the body weight of obese mice and control their food intake. It also plays a role in the regulation of lipid metabolism and glycometabolism metabolism, which can significantly improve hepatic fat deposition. Mechanistically, PU may regulate liver lipid deposition in obese mice by down-regulating lipid synthesis and up-regulating lipolysis through activation of the AMPK/ACC pathway.

Simultaneous Detection of Multiple Tumor-targeted Gold Nanoparticles in HER2-Positive Breast Tumors Using Optoacoustic Imaging.

Purpose To develop optoacoustic, spectrally distinct, actively targeted gold nanoparticle-based near-infrared probes (trastuzumab [TRA], TRA-Aurelia-1, and TRA-Aurelia-2) that can be individually identifiable at multispectral optoacoustic tomography (MSOT) of human epidermal growth factor receptor 2 (HER2)-positive breast tumors. Materials and Methods Gold nanoparticle-based near-infrared probes (Aurelia-1 and 2) that are optoacoustically active and spectrally distinct for simultaneous MSOT imaging were synthesized and conjugated to TRA to produce TRA-Aurelia-1 and 2. Freshly resected human HER2-positive (n = 6) and HER2-negative (n = 6) triple-negative breast cancer tumors were treated with TRA-Aurelia-1 and TRA-Aurelia-2 for 2 hours and imaged with MSOT. HER2-expressing DY36T2Q cells and HER2-negative MDA-MB-231 cells were implanted orthotopically into mice (n = 5). MSOT imaging was performed 6 hours following the injection, and the Friedman test was used for analysis. Results TRA-Aurelia-1 (absorption peak, 780 nm) and TRA-Aurelia-2 (absorption peak, 720 nm) were spectrally distinct. HER2-positive human breast tumors exhibited a significant increase in optoacoustic signal following TRA-Aurelia-1 (28.8-fold) or 2 (29.5-fold) (P = .002) treatment relative to HER2-negative tumors. Treatment with TRA-Aurelia-1 and 2 increased optoacoustic signals in DY36T2Q tumors relative to those in MDA-MB-231 controls (14.8-fold, P < .001; 20.8-fold, P < .001, respectively). Conclusion The study demonstrates that TRA-Aurelia 1 and 2 nanoparticles operate as a spectrally distinct HER2 breast tumor-targeted in vivo optoacoustic agent. Keywords: Molecular Imaging, Nanoparticles, Photoacoustic Imaging, Breast Cancer Supplemental material is available for this article. © RSNA, 2023.

The value of different involvement patterns of the knee "synovio-entheseal complex" in the differential diagnosis of spondyloarthritis, rheumatoid arthritis, and osteoarthritis: an MRI-based study.

OBJECTIVES: To explore the different involvement patterns of the knee "synovio-entheseal complex (SEC)" on MRI in patients with spondyloarthritis (SPA), rheumatoid arthritis (RA), and osteoarthritis (OA). METHODS: This study retrospectively included 120 patients (male:female, 55:65) with a mean age of 39.20 years diagnosed with SPA (n = 40), RA (n = 40), and OA (n = 40) at the First Central Hospital of Tianjin between January 2020 and May 2022. Six knee entheses were assessed by two musculoskeletal radiologists according to the SEC definition. Bone marrow lesions associated with entheses include bone marrow edema (BME) and bone erosion (BE), which were classified as entheseal or peri-entheseal based on their relationship to the entheses. Three groups (OA, RA, and SPA) were established to characterize the location of enthesitis and the different SEC involvement patterns. Inter-group and intra-group differences were analyzed using the ANOVA or chi-square tests, and the inter-class correlation coefficient (ICC) test was used to determine inter-reader agreement. RESULTS: The study contained a total of 720 entheses. The SEC-based analysis revealed different involvement patterns in three groups. The OA group had the most abnormal signals in tendons/ligaments (p = 0.002). The RA group had considerably greater synovitis (p = 0.002). The majority of peri-entheseal BE was identified in the OA and RA groups (p = 0.003). Furthermore, entheseal BME in the SPA group was significantly different from those in the other two groups (p < 0.001). CONCLUSIONS: SEC involvement patterns differed in SPA, RA, and OA, which is important for differential diagnosis. SEC should be used as a whole evaluation method in clinical practice. KEY POINTS: • The "synovio-entheseal complex (SEC)" explained differences and characteristic alterations in the knee joint in patients with spondyloarthritis (SPA), rheumatoid arthritis (RA), and osteoarthritis (OA). • The various SEC involvement patterns are crucial for differentiating SPA, RA, and OA. • When "knee pain" is the only symptom, a detailed identification of characteristic alterations in the knee joint of SPA patients may help timely treatment and delay the structural damage.

Cell-Permeable PROTAC Degraders against KEAP1 Efficiently Suppress Hepatic Stellate Cell Activation through the Antioxidant and Anti-Inflammatory Pathway.

Accumulating evidence indicates that oxidative stress and inflammation are involved in the physiopathology of liver fibrogenesis. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor, which regulates the expression of redox regulators to establish cellular redox homeostasis. The Nrf2 modulator can serve as a primary cellular defense against the cytotoxic effects of oxidative stress. We designed a chimeric Keap1-Keap1 peptide (KKP1) based on the proteolysis-targeting chimera technology. The KKP1 peptide not only can efficiently penetrate into the rat hepatic stellate cell line (HSC-T6) cells but also can induce Keap1 protein degradation by the ubiquitination-proteasome degradation pathway, which releases Nrf2 and promotes the transcriptional activity of the Nrf2/antioxidant response element pathway. It then activates the protein expression of the downstream antioxidant factors, the glutamate-cysteine ligase catalytic subunit and heme oxygenase-1 (HO-1). Finally, Keap1 protein degradation inhibits the nuclear factor-kappaB inflammatory signal pathway, the downstream inflammatory factor tumor necrosis factor alpha, and the interleukin-1beta protein expression and further inhibits the expression of the fibrosis biomarker gene. The current research suggests that our designed KKP1 may provide a new avenue for the future treatment of liver fibrosis.