Acute cardiac tamponade after Endostar treatment of non-small cell lung cancer: A case report.

RATIONALE: Recombinant human endostatin (Endostar) is extensively utilized in China for the clinical management of patients with driver gene-negative non-small cell lung cancer (NSCLC) at stage TNM IV. This report describes the case of a lung cancer patient treated exclusively with Endostar maintenance therapy, who experienced a rapid deterioration in respiratory function. PATIENT CONCERNS: The case involved a patient with a pathologically confirmed squamous cell carcinoma of the left lung, treated in our department. Following 1 month of albumin-bound paclitaxel chemotherapy and localized radiotherapy for the left lung lesion, the patient initiated treatment with a single agent, Endostar 30mg, on October 19, 2021. The medication was administered via intravenous infusion over a 7 days. DIAGNOSIS: On October 23, 2021, the patient exhibited symptoms of chest constriction, discomfort, coughing, and sputum production. By October 28, the patient presented with pronounced dyspnea and respiratory distress. An emergency CT scan detected pericardial tamponade and significant deviations in several blood parameters from pretreatment values. INTERVENTIONS: Percardial puncture and catheter drainage were recommended as therapeutic intervention. OUTCOMES: Considering the patient advanced age, the patient and their family opted to refuse this medical procedure, leading to the patient unfortunate demise on November 2, 2021. LESSONS: Medical professionals should remain vigilant for the potential, albeit rare, risk of Endostar inducing acute pericardial tamponade, a severe and potentially fatal complication.

Identification and affinity enhancement of T-cell receptor targeting a KRASG12V cancer neoantigen.

Neoantigens derived from somatic mutations in Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS), the most frequently mutated oncogene, represent promising targets for cancer immunotherapy. Recent research highlights the potential role of human leukocyte antigen (HLA) allele A*11:01 in presenting these altered KRAS variants to the immune system. In this study, we successfully generate and identify murine T-cell receptors (TCRs) that specifically recognize KRAS8-16G12V from three predicted high affinity peptides. By determining the structure of the tumor-specific 4TCR2 bound to KRASG12V-HLA-A*11:01, we conduct structure-based design to create and evaluate TCR variants with markedly enhanced affinity, up to 15.8-fold. This high-affinity TCR mutant, which involved only two amino acid substitutions, display minimal conformational alterations while maintaining a high degree of specificity for the KRASG12V peptide. Our research unveils the molecular mechanisms governing TCR recognition towards KRASG12V neoantigen and yields a range of affinity-enhanced TCR mutants with significant potential for immunotherapy strategies targeting tumors harboring the KRASG12V mutation.

Inflammation modifies the platelet reactivity among thrombocytopenia patients undergoing percutaneous coronary intervention.

Percutaneous coronary intervention (PCI) patients combined with thrombocytopenia (TP) are usually considered to be at low ischemic risk, receiving less proper antiplatelet therapy. However, recent studies reported a paradoxical phenomenon that PCI patients with TP were prone to experience thrombotic events, while the mechanisms and future treatment remain unclear. We aim to investigate whether inflammation modifies platelet reactivity among these patients. Consecutive 10 724 patients undergoing PCI in Fuwai Hospital were enrolled throughout 2013. High-sensitivity C-reactive protein (hsCRP) ≥2 mg/L was considered inflammatory status. TP was defined as platelet count <150×109/L. High on-treatment platelet reactivity (HTPR) was defined as adenosine diphosphate-induced platelet maximum amplitude of thromboelastogram >47mm. Among 6617 patients finally included, 879 (13.3%) presented with TP. Multivariate logistic regression demonstrated that patients with TP were associated with a lower risk of HTPR (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.53-0.76) than those without TP in the overall cohort. In further analysis, among hsCRP <2 mg/L group, patients with TP exhibited a decreased risk of HTPR (OR 0.53, 95% CI 0.41-0.68); however, in hsCRP ≥2mg/L group, TP patients had a similar risk of HTPR as those without TP (OR 0.83, 95% CI 0.63-1.08). Additionally, these results remain consistent across subgroups, including patients presenting with acute coronary syndrome and chronic coronary syndrome. Inflammation modified the platelet reactivity of PCI patients with TP, providing new insights into the mechanisms of the increased thrombotic risk. Future management for this special population should pay more attention to inflammation status and timely adjustment of antiplatelet therapy in TP patients with inflammation.

What is the context? Recent studies reported a paradoxical phenomenon that percutaneous coronary intervention (PCI) patients with thrombocytopenia (TP) were prone to experience thrombotic events. The potential mechanisms underlying the increased thrombotic risk and how to manage antiplatelet therapy in PCI patients with TP remain unclear.Growing attention has been paid to immunothrombosis. Inflammation is closely associated with high-on treatment platelet reactivity (HTPR) and thrombotic risk.HTPR is an independent risk factor of thrombosis and can provide information for guiding antiplatelet therapy.What is new? This prospective cohort study enrolled 10 724 patients undergoing PCI in Fuwai Hospital (National Center for Cardiovascular Diseases, Beijing, China), with HTPR risk being the study endpoint of interest.We first reported that inflammation significantly modified the platelet reactivity of PCI patients with TP.When hsCRP level <2 mg/L, PCI patients with TP had a decreased risk of HTPR. However, when hsCRP ≥2 mg/L, TP patients had similar HTPR risk as those without TP.HsCRP levels could modify the relationship between TP and HTPR risks both in patients with acute coronary syndrome and chronic coronary syndrome.What is the impact? These results provide insights into potential mechanisms of the increased thrombotic risk in PCI patients with TP. Specifically, inflammation might be involved in the thrombotic risk of PCI patients with TP by modifying the platelet reactivity.As for future management, personalized antiplatelet therapy should be administrated to TP patients with inflammation status.

Tight regulation of a nuclear HAPSTR1-HUWE1 pathway essential for mammalian life.

The recently discovered HAPSTR1 protein broadly oversees cellular stress responses. This function requires HUWE1, a ubiquitin ligase that paradoxically marks HAPSTR1 for degradation, but much about this pathway remains unclear. Here, leveraging multiplexed proteomics, we find that HAPSTR1 enables nuclear localization of HUWE1 with implications for nuclear protein quality control. We show that HAPSTR1 is tightly regulated and identify ubiquitin ligase TRIP12 and deubiquitinase USP7 as upstream regulators titrating HAPSTR1 stability. Finally, we generate conditional Hapstr1 knockout mice, finding that Hapstr1-null mice are perinatal lethal, adult mice depleted of Hapstr1 have reduced fitness, and primary cells explanted from Hapstr1-null animals falter in culture coincident with HUWE1 mislocalization and broadly remodeled signaling. Notably, although HAPSTR1 potently suppresses p53, we find that Hapstr1 is essential for life even in mice lacking p53. Altogether, we identify novel components and functional insights into the conserved HAPSTR1-HUWE1 pathway and demonstrate its requirement for mammalian life.

Isoalantolactone exerts anti-melanoma effects via inhibiting PI3K/AKT/mTOR and STAT3 signaling in cell and mouse models.

BACKGROUND AND AIM: Although the anti-cancer activity of isoalantolactone (IATL) has been extensively studied, the anti-melanoma effects of IATL are still unknown. Here, we have investigated the anti-melanoma effects and mechanism of action of IATL. MTT and crystal violet staining assays were performed to detect the inhibitory effect of IATL on melanoma cell viability. Apoptosis and cell cycle arrest induced by IATL were examined using flow cytometry. The molecular mechanism of IATL was explored by Western blotting, confocal microscope analysis, molecular docking, and cellular thermal shift assay (CETSA). A B16F10 allograft mouse model was constructed to determine the anti-melanoma effects of IATL in vivo. The results showed that IATL exerted anti-melanoma effects in vitro and in vivo. IATL induced cytoprotective autophagy in melanoma cells by inhibiting the PI3K/AKT/mTOR signaling. Moreover, IATL inhibited STAT3 activation both in melanoma cells and allograft tumors not only by binding to the SH2 domain of STAT3 but also by suppressing the activity of its upstream kinase Src. These findings demonstrate that IATL exerts anti-melanoma effects via inhibiting the STAT3 and PI3K/AKT/mTOR signaling pathways, and provides a pharmacological basis for developing IATL as a novel phytotherapeutic agent for treating melanoma clinically.

Serum PRO-C3 is useful for risk prediction and fibrosis assessment in MAFLD with chronic kidney disease in an Asian cohort.

BACKGROUND: Metabolic dysfunction-associated fatty liver disease (MAFLD) is an emerging risk factor for chronic kidney disease (CKD). N-terminal propeptide of collagen type 3 (PRO-C3) is a biomarker of advanced fibrosis in MAFLD and PRO-C3 may be involved in renal fibrosis. We aimed to use PRO-C3 measurements to generate a new algorithmic score to test the prediction of MAFLD with chronic kidney disease (MAFLD-CKD). METHODS: A derivation and independent validation cohort of 750 and 129 Asian patients with biopsy-confirmed MAFLD were included. Serum PRO-C3 concentration was measured and regression analyses were performed to examine associations with MAFLD-CKD. A derivative algorithm for MAFLD-CKD risk prediction was evaluated with receiver operator characteristic (ROC) curve analysis. RESULTS: The study included two Asian cohorts (n = 180 with MAFLD-CKD; mean-eGFR: 94.93 mL/min/1.73 m2; median-urinary albumin-to-creatinine ratio: 6.58 mg/mmol). PRO-C3 was associated with the severity of MAFLD-CKD and independently associated with MAFLD-CKD (adjusted odds ratio = 1.16, 95% confidence interval [CI]: 1.08-1.23, p < .001). A new non-invasive score (termed PERIOD) including PRO-C3 efficiently predicted MAFLD-CKD (AUROC = .842, 95% CI: .805-.875). Accuracy, specificity and negative predictive values were 80.2%, 85.1% and 88.4%, respectively. In the validation cohort, the PERIOD score had good diagnostic performance (AUROC = .807, 95% CI: .691-.893) with similar results in all patient subgroups. In the MAFLD-CKD subgroup, the accuracy for identifying advanced fibrosis was further improved by combining the PRO-C3-based ADAPT with the Agile 3+ scores (AUROC = .90, 95% CI: .836-.964). CONCLUSIONS: The PERIOD score is helpful for accurately predicting the risk of MAFLD-CKD. PRO-C3 can also be used to assess liver fibrosis in people with MAFLD-CKD.

Renal function alters the association of lipoprotein(a) with cardiovascular outcomes in patients undergoing percutaneous coronary intervention: a prospective cohort study.

Background and hypothesis: Lipoprotein(a) [Lp(a)] and renal dysfunction are both independent risk factors for cardiovascular disease. However, it remains unclear whether renal function mediates the association between Lp(a) and cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI). Methods: From a large prospective cohort study, 10 435 eligible patients undergoing PCI from January 2013 to December 2013 were included in our analysis. Patients were stratified into three renal function groups according to their baseline estimated glomerular filtration rate (eGFR) (<60; 60-90; ≥90 ml/min/1.73 m2). The primary endpoint was a composite of all-cause death, nonfatal MI, ischemic stroke, and unplanned revascularization [major adverse cardiac and cerebrovascular events (MACCE)]. Results: Over a median follow-up of 5.1 years, a total of 2144 MACCE events occurred. After multivariable adjustment, either eGFR <60 ml/min/1.73 m2 or elevated Lp(a) conferred a significantly higher MACCE risk. Higher Lp(a) was significantly associated with an increased risk of MACCE in patients with eGFR <60 ml/min/1.73 m2. However, this association was weakened in subjects with only mild renal impairment and diminished in those with normal renal function. A significant interaction for MACCE between renal categories and Lp(a) was observed (P = 0.026). Patients with concomitant Lp(a) ≥30 mg/dl and eGFR <60 ml/min/1.73 m2 experienced worse cardiovascular outcomes compared with those without. Conclusion: The significant association between Lp(a) and cardiovascular outcomes was mediated by renal function in patients undergoing PCI. Lp(a)-associated risk was more pronounced in patients with worse renal function, suggesting close monitoring and aggressive management are needed in this population.

A Cysteine-Maleimide-Based Design for Hemostatic, Antibacterial, and Biodegradable Wound Dressing.

The field of clinical surgery frequently encounters challenges related to atypical wound tissue healing, resulting in the development of persistent chronic wounds or aesthetically displeasing scar tissue. The use of wound dressings crafted from mussel adhesive proteins and hyaluronic acid has demonstrated the potential in mitigating these undesirable outcomes. However, the synergistic effects of these two biomaterials remain underexplored. In this study, we have engineered a versatile, degradable, and biocompatible dressing that comprises recombinant 3,4-dihydroxyphenylalanine (DOPA)-modified mussel adhesive proteins and maleimide-functionalized hyaluronic acid. We have successfully fabricated this biocompatible dressing and conducted comprehensive experimental assessments to confirm its hemostatic, antibacterial, and biocompatible characteristics. Importantly, this dressing exclusively incorporates biologically derived materials characterized by low toxicity and minimal immunogenicity, thus holding immense promise for clinical applications in the field of wound healing.

NMAAP1 regulated macrophage polarizion into M1 type through glycolysis stimulated with BCG.

Bacillus Calmette Guerin (BCG) perfusion is widely used as cancer adjuvant therapy, in which macrophages play an important role. Novel macrophage activated associated protein 1 (NMAAP1), upregulated after BCG's activation, was proved to promote macrophage polarization to the M1 type. We found that BCG could stimulate mice BMDM to the M1 type and kill tumor cells. After the deletion of NMAAP1, the tumor volume of mice became larger, and the number of M1 type macrophages in the tumor decreased significantly. When macrophages were induced into the M1 type, aerobic glycolysis, the Warburg effect manifested in the increased uptake of glucose and the conversion of pyruvate to lactic acid. NMAAP1 could bind with IP3R and regulate macrophage polarization to the M1 type. However, the specific mechanism of how NMAAP1 regulates macrophage polarization towards the M1 type and plays an antitumor role must be clarified. NMAAP1 could promote the release of lactic acid and pyruvate, enhance the glycolysis of macrophages, and affect the expression of HIF-1α. After inhibition of glycolysis by 2-DG and lactic acid generation by FX11, the effects of NMAAP1 promoting macrophage polarization to the antitumor M1 type were weakened. Furthermore, NMAAP1 upregulated the expression of HIF-1α, which is associated with glycolysis. Moreover, the Ca2+/NF-κB pathway regulated HIF-1α expression by NMAAP1 in the macrophages. NMAAP1 promotes the polarization of macrophages towards the M1 type by affecting the Warburg effect stimulated by BCG.

Study on diagnosing thyroid nodules of ACR TI-RADS 4-5 with multimodal ultrasound radiomics technology.

BACKGROUND: Explore the feasibility of using the multimodal ultrasound (US) radiomics technology to diagnose American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) 4-5 thyroid nodules. METHOD: This study prospectively collected the clinical characteristics, conventional, and US elastography images of 100 patients diagnosed with ACR TI-RADS 4-5 nodules from May 2022 to 2023. Independent risk factors for malignant thyroid nodules were extracted and screened using methods such as the least absolute shrinkage and selection operator (LASSO) logistic regression (LR) model, and a multimodal US radiomics combined diagnostic model was established. Using a multifactorial LR analysis and a Rad-score rating, the predictive performance was validated and evaluated, and the final threshold range was determined to assess the clinical net benefit of the model. RESULTS: In the training set, the US radiomics combined predictive model area under curve (AUC = 0.928) had higher diagnostic performance compared with clinical characteristics (AUC = 0.779), conventional US (AUC = 0.794), and US elastography model (AUC = 0.852). In the validation set, the multimodal US radiomics combined diagnostic model (AUC = 0.829) also had higher diagnostic performance compared with clinical characteristics (AUC = 0.799), conventional US (AUC = 0.802), and US elastography model (AUC = 0.718). CONCLUSION: Multi-modal US radiomics technology can effectively diagnose thyroid nodules of ACR TI-RADS 4-5, and the combination of radiomics signature and conventional US features can further improve the diagnostic performance.

Single-cell RNA-seq reveals a microenvironment and an exhaustion state of T/NK cells in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a heterogeneous blood cancer. Effective immunotherapies for AML are hindered by a lack of understanding of the tumor microenvironment (TME). Here, we retrieved published single-cell RNA sequencing data for 128,688 cells derived from 29 bone marrow aspirates, including 21 AML patients and eight healthy donors. We established a global tumor ecosystem including nine main cell types. Myeloid, T, and NK cells were further re-clustered and annotated. Developmental trajectory analysis indicated that exhausted CD8+ T cells might develop via tissue residual memory T cells (TRM) in the AML TME. Significantly higher expression levels of exhaustion molecules in AML TRM cells suggested that these cells were influenced by the TME and entered an exhausted state. Meanwhile, the upregulation of checkpoint molecules and downregulation of granzyme were also observed in AML NK cells, suggesting an exhaustion state. In conclusion, our comprehensive profiling of T/NK subpopulations provides deeper insights into the AML immunosuppressive ecosystem, which is critical for immunotherapies.

Pigeon MDA5 inhibits viral replication by triggering antiviral innate immunity.

Pigeons are considered less susceptible, and display few or no clinical signs to infection with avian influenza virus (AIV). Melanoma differentiation-associated gene 5 (MDA5), an important mediator in innate immunity, has been linked to the virus resistance. In this study, the pigeon MDA5 (piMDA5) was cloned. The bioinformatics analysis showed that the C-terminal domain (CTD) of MDA5 is highly conserved among species while the N-terminal caspase recruitment domain (CARD) is variable. Upon infection with Newcastle diseases virus (NDV) and AIV, piMDA5 was upregulated in both pigeons and pigeon embryonic fibroblasts (PEFs). Further study found that overexpression of piMDA5 mediated the activation of interferons (IFNs) and IFN-stimulated genes (ISGs) while inhibiting NDV replication. Conversely, the knockdown of piMDA5 promoted NDV replication. Additionally, CARD was found to be essential for the activation of IFN-ß by piMDA5. Furthermore, pigeon MDA5, chicken MDA5, and human MDA5 differ in inhibiting viral replication and inducing ISGs expression. These findings suggest that MDA5 contributes to suppressing viral replication by activating the IFN signal pathway in pigeons. This study provides valuable insight into the role of MDA5 in pigeons and a better understanding of the conserved role of MDA5 in innate immunity during evolution.

First Identification and Pathogenicity Evaluation of an EV-G17 Strain Carrying a Torovirus Papain-like Cysteine Protease (PLCP) Gene in China.

Enterovirus G (EV-G) is prevalent in pig populations worldwide, and a total of 20 genotypes (G1 to G20) have been confirmed. Recently, recombinant EV-Gs carrying the papain-like cysteine protease (PLCP) gene of porcine torovirus have been isolated or detected, while their pathogenicity is poorly understood. In this study, an EV-G17-PLCP strain, 'EV-G/YN23/2022', was isolated from the feces of pigs with diarrhea, and the virus replicated robustly in numerous cell lines. The isolate showed the highest complete genome nucleotide (87.5%) and polyprotein amino acid (96.6%) identity in relation to the G17 strain 'IShi-Ya4' (LC549655), and a possible recombination event was detected at the 708 and 3383 positions in the EV-G/YN23/2022 genome. EV-G/YN23/2022 was nonlethal to piglets, but mild diarrhea, transient fever, typical skin lesions, and weight gain deceleration were observed. The virus replicated efficiently in multiple organs, and the pathological lesions were mainly located in the small intestine. All the challenged piglets showed seroconversion for EV-G/YN23/2022 at 6 to 9 days post-inoculation (dpi), and the neutralization antibody peaked at 15 dpi. The mRNA expression levels of IL-6, IL-18, IFN-α, IFN-ß, and ISG-15 in the peripheral blood mononuclear cells (PBMCs) were significantly up-regulated during viral infection. This is the first documentation of the isolation and pathogenicity evaluation of the EV-G17-PLCP strain in China. The results may advance our understanding of the evolution characteristics and pathogenesis of EV-G-PLCP.

A novel 5-gene prognostic signature to improve risk stratification of cytogenetically normal acute myeloid leukemia.

PURPOSE: Prognostic prediction is a challenging task in cytogenetically normal acute myeloid leukemia (CN-AML) patients. In this study, we aimed at developing a novel prognostic signature to predict and stratify the survival of CN-AML patients. METHODS: Using a training dataset (GSE12417), 5-gene prognostic signature was established to predict survival of CN-AML patients. The prognostic performance of this prognostic signature was further validated in testing dataset (TCGA CN-AML cohort) and validation dataset (GSE6891 CN-AML cohort). RESULTS: In training, testing and validation datasets, the increased 5-gene risk score was significantly related with inferior overall survival (OS) of patients, and the area under the receiver operating characteristic curve (AUC) demonstrated that our prognostic signature had overall prediction accuracy. The excellent prognostic value of the 5-gene prognostic signature was also supported by the comparison with three previously proposed prognostic models. For the intermediate-risk CN-AML patients and the CN-AML patients with FLT3 or NPM1 mutation, our model could also well dichotomize them into two subgroups with distinct prognosis. Multivariate analysis demonstrated that 5-gene risk score was the only independent risk factor in TCGA CN-AML cohort. Nomogram including the 5-gene risk score performed well in predicting 1-year, 2-year and 3-year OS. CONCLUSION: In summary, our novel 5-gene prognostic signature facilitated the improvement in risk stratification of CN-AML patients.

For patients with prior coronary artery bypass grafting and recurrent myocardial ischemia, percutaneous coronary intervention on bypass graft or native coronary artery?-A 5-year follow-up cohort study.

BACKGROUND: Real-world data on target vessel of percutaneous coronary intervention (PCI) for patients with prior coronary artery bypass grafting (CABG) was still limited. HYPOTHESIS: A prospective cohort was examined to determine the frequency and outcomes of native coronary artery PCI versus bypass graft PCI in patients with prior CABG. METHODS: A large-sample observational study enrolled a total of 10 724 patients with coronary artery disease (CAD) underwent PCI in 2013. Two- and five-year clinical outcomes were compared between graft PCI group and native artery PCI group in patients with prior CABG. RESULTS: A total of 438 cases had CABG history in the total cohort. Graft PCI group and native artery PCI group accounted for 13.7% and 86.3%, respectively. The rates of 2- and 5-year all-cause death and major adverse cardiovascular and cerebral events (MACCE) showed no significant difference between the two groups (p > .05). Two-year revascularization risk was lower in graft PCI group than native artery PCI group (3.3% and 12.4%, p < .05), but 5-year myocardial infarction (MI) risk was higher (13.3% and 5.0%, p < .05). In multivariate COX regression models, graft PCI group was independently associated with lower 2-year revascularization risk (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.05-0.88; p = .033), but higher 5-year MI risk than native artery PCI group (HR: 2.61; 95% CI: 1.03-6.57; p = .042). Five-year all-cause death and MACCE risk showed no difference between the two groups in model. CONCLUSIONS: In patients with prior CABG underwent PCI, patients in graft PCI group had higher 5-year MI risk than patients received native artery PCI. But, 5-year mortality and MACCE was not significantly different between graft PCI group and native artery PCI group.

A traditional prescription comprising Astragali Radix and Schisandra chinensis Fructus induces apoptosis and protective autophagy in hepatocellular carcinoma cells.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) poses a growing challenge to global health efforts. The 5-year survival rate of HCC patients is still dismal. A traditional prescription Qi-Wei-Wan (QWW) comprising Astragali Radix and Schisandra chinensis Fructus has traditionally been used for HCC treatment according to traditional Chinese medicine theory, but the pharmacological basis is not clear. AIM OF THE STUDY: This study aims to investigate the anti-HCC effects of an ethanolic extract of QWW (hereafter, QWWE) and the mechanism of action. MATERIALS AND METHODS: An UPLC-Q-TOF-MS/MS method was developed to control the quality of QWWE. Two human HCC cell lines (HCCLM3 and HepG2) and a HCCLM3 xenograft mouse model were employed to investigate the anti-HCC effects of QWWE. The anti-proliferative effect of QWWE in vitro was determined by MTT, colony formation and EdU staining assays. Apoptosis and protein levels were examined by flow cytometry and Western blotting, respectively. Nuclear presence of signal transducer and activator of transcription 3 (STAT3) was examined by immunostaining. Transient transfection of pEGFP-LC3 and STAT3C plasmids was performed to assess autophagy and determine the involvement of STAT3 signaling in QWWE's anti-HCC effects, respectively. RESULTS: We found that QWWE inhibited the proliferation of and triggered apoptosis in HCC cells. Mechanistically, QWWE inhibited the activation of SRC and STAT3 at Tyr416 and Tyr705, respectively; inhibited the nuclear translocation of STAT3; lowered Bcl-2 protein levels, while increased Bax protein levels in HCC cells. Over-activating STAT3 attenuated the cytotoxic and apoptotic effects of QWWE in HCC cells. Moreover, QWWE induced autophagy in HCC cells by inhibiting mTOR signaling. Blocking autophagy with autophagy inhibitors (3-methyladenine and chloroquine) enhanced the cytotoxicity, apoptotic effect and the inhibitory effect on STAT3 activation of QWWE. Intragastric administration of QWWE at 10 mg/kg and 20 mg/kg potently repressed tumor growth and inhibited STAT3 and mTOR signaling in tumor tissues, but did not significantly affect mouse body weight. CONCLUSION: QWWE exhibited potent anti-HCC effects. Inhibiting the STAT3 signaling pathway is involved in QWWE-mediated apoptosis, while blocking mTOR signaling contributes to QWWE-mediated autophagy induction. Blockade of autophagy enhanced the anti-HCC effects of QWWE, indicating that the combination of an autophagy inhibitor and QWWE might be a promising therapeutic strategy for HCC management. Our findings provide pharmacological justifications for the traditional use of QWW in treating HCC.

Corrigendum: Association between diagnostic efficacy of acoustic radiation force impulse for benign and malignant thyroid nodules and the presence or absence of non-papillary thyroid cancer: A meta-analysis.

[This corrects the article DOI: 10.3389/fonc.2023.1007464.].

Association between diagnostic efficacy of acoustic radiation force impulse for benign and malignant thyroid nodules and the presence or absence of non-papillary thyroid cancer: A meta-analysis.

Purpose: The aim of this study was to investigate the diagnostic efficacy of Acoustic Radiation Force Impulse (ARFI) for benign and malignant thyroid nodules in the presence and absence of non-papillary thyroid cancer (NPTC) and to determine the cut-off values of Shear Wave Velocity (SWV) for the highest diagnostic efficacy of Virtual Touch Quantification (VTQ) and Virtual Touch Tissue Imaging and Quantification (VTIQ). Methods: The diagnostic accuracy of ARFI for benign and malignant thyroid nodules was assessed by pooling sensitivity, specificity and area under the curve (AUC) in each group in the presence and absence of both non-papillary thyroid glands, using histology and cytology as the gold standard. All included studies were divided into two groups according to VTQ and VTIQ, and each group was ranked according to the magnitude of the SWV cutoff value to determine the SWV cutoff interval with the highest diagnostic efficacy for VTQ and VTIQ. Results: A total of 57 studies were collected on the evaluation of ARFI for the diagnosis of benign and malignant thyroid nodules. The results showed that the presence of non-papillary thyroid carcinoma led to differences in the specificity of VTIQ for the identification of benign and malignant thyroid nodules, and the differences were statistically significant. In addition, the diagnostic efficacy of VTQ was best when the cutoff value of SWV was in the interval of 2.48-2.55 m/s, and the diagnostic efficacy of VTIQ was best when the cutoff value of SWV was in the interval of 3.01-3.15 m/s. Conclusion: VTQ and VTIQ have a high diagnostic value for benign and malignant thyroid nodules; however, when the malignant nodules in the study contain non-papillary thyroid carcinoma occupying the thyroid gland, the findings should be viewed in a comprehensive manner.

Secondary bile acids improve risk prediction for non-invasive identification of mild liver fibrosis in nonalcoholic fatty liver disease.

BACKGROUND: Dysregulated bile acid (BA) metabolism has been linked to steatosis, inflammation, and fibrosis in nonalcoholic fatty liver disease (NAFLD). AIM: To determine whether circulating BA levels accurately stage liver fibrosis in NAFLD. METHODS: We recruited 550 Chinese adults with biopsy-proven NAFLD and varying levels of fibrosis. Ultra-performance liquid chromatography coupled with tandem mass spectrometry was performed to quantify 38 serum BAs. RESULTS: Compared to those without fibrosis, patients with mild fibrosis (stage F1) had significantly higher levels of secondary BAs, and increased diastolic blood pressure (DBP), alanine aminotransferase (ALT), body mass index, and waist circumstance (WC). The combination of serum BAs with WC, DBP, ALT, or Homeostatic Model Assessment for Insulin Resistance performed well in identifying mild fibrosis, in men and women, and in those with/without obesity, with AUROCs 0.80, 0.88, 0.75 and 0.78 in the training set (n = 385), and 0.69, 0.80, 0.61 and 0.69 in the testing set (n = 165), respectively. In comparison, the combination of BAs and clinical/biochemical biomarkers performed less well in identifying significant fibrosis (F2-4). In women and in non-obese subjects, AUROCs were 0.75 and 0.71 in the training set, 0.65 and 0.66 in the validation set, respectively. However, these AUROCs were higher than those observed for the fibrosis-4 index, NAFLD fibrosis score, and Hepamet fibrosis score. CONCLUSIONS: Secondary BA levels were significantly increased in NAFLD, especially in those with mild fibrosis. The combination of serum BAs and clinical/biochemical biomarkers for identifying mild fibrosis merits further assessment.