Nanomaterials in modulating tumor-associated macrophages and enhancing immunotherapy.

Tumor-associated macrophages (TAMs) are predominantly present in the tumor microenvironment (TME) and play a crucial role in shaping the efficacy of tumor immunotherapy. These TAMs primarily exhibit a tumor-promoting M2-like phenotype, which is associated with the suppression of immune responses and facilitation of tumor progression. Interestingly, recent research has highlighted the potential of repolarizing TAMs from an M2 to a pro-inflammatory M1 status-a shift that has shown promise in impeding tumor growth and enhancing immune responsiveness. This concept is particularly intriguing as it offers a new dimension to cancer therapy by targeting the tumor microenvironment, which is a significant departure from traditional approaches that focus solely on tumor cells. However, the clinical application of TAM-modulating agents is often challenged by issues such as insufficient tumor accumulation and off-target effects, limiting their effectiveness and safety. In this regard, nanomaterials have emerged as a novel solution. They serve a dual role: as delivery vehicles that can enhance the accumulation of therapeutic agents in the tumor site and as TAM-modulators. This dual functionality of nanomaterials is a significant advancement as it addresses the key limitations of current TAM-modulating strategies and opens up new avenues for more efficient and targeted therapies. This review provides a comprehensive overview of the latest mechanisms and strategies involving nanomaterials in modulating macrophage polarization within the TME. It delves into the intricate interactions between nanomaterials and macrophages, elucidating how these interactions can be exploited to drive macrophage polarization towards a phenotype that is more conducive to anti-tumor immunity. Additionally, the review explores the burgeoning field of TAM-associated nanomedicines in combination with tumor immunotherapy. This combination approach is particularly promising as it leverages the strengths of both nanomedicine and immunotherapy, potentially leading to synergistic effects in combating cancer.

Integrated multi-omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex.

BACKGROUND: Autosomal-recessive mutations in SPEG (striated muscle preferentially expressed protein kinase) have been linked to centronuclear myopathy with or without dilated cardiomyopathy (CNM5). Loss of SPEG is associated with defective triad formation, abnormal excitation-contraction coupling, calcium mishandling and disruption of the focal adhesion complex in skeletal muscles. To elucidate the underlying molecular pathways, we have utilized multi-omics tools and analysis to obtain a comprehensive view of the complex biological processes and molecular functions. METHODS: Skeletal muscles from 2-month-old SPEG-deficient (Speg-CKO) and wild-type (WT) mice were used for RNA sequencing (n = 4 per genotype) to profile transcriptomics and mass spectrometry (n = 4 for WT; n = 3 for Speg-CKO mice) to profile proteomics and phosphoproteomics. In addition, interactomics was performed using the SPEG antibody on pooled muscle lysates (quadriceps, gastrocnemius and triceps) from WT and Speg-CKO mice. Based on the multi-omics results, we performed quantitative real-time PCR, co-immunoprecipitation and immunoblot to verify the findings. RESULTS: We identified that SPEG interacts with myospryn complex proteins CMYA5, FSD2 and RyR1, which are critical for triad formation, and that SPEG deficiency results in myospryn complex abnormalities (protein levels decreased to 22 ± 3% for CMYA5 [P < 0.05] and 18 ± 3% for FSD2 [P < 0.01]). Furthermore, SPEG phosphorylates RyR1 at S2902 (phosphorylation level decreased to 55 ± 15% at S2902 in Speg-CKO mice; P < 0.05), and its loss affects JPH2 phosphorylation at multiple sites (increased phosphorylation at T161 [1.90 ± 0.24-fold], S162 [1.61 ± 0.37-fold] and S165 [1.66 ± 0.13-fold]; decreased phosphorylation at S228 and S231 [39 ± 6%], S234 [50 ± 12%], S593 [48 ± 3%] and S613 [66 ± 10%]; P < 0.05 for S162 and P < 0.01 for other sites). On analysing the transcriptome, the most dysregulated pathways affected by SPEG deficiency included extracellular matrix-receptor interaction (P < 1e-15) and peroxisome proliferator-activated receptor signalling (P < 9e-14). CONCLUSIONS: We have elucidated the critical role of SPEG in the triad as it works closely with myospryn complex proteins (CMYA5, FSD2 and RyR1), it regulates phosphorylation levels of various residues in JPH2 and S2902 in RyR1, and its deficiency is associated with dysregulation of several pathways. The study identifies unique SPEG-interacting proteins and their phosphorylation functions and emphasizes the importance of using a multi-omics approach to comprehensively evaluate the molecular function of proteins involved in various genetic disorders.

Treatment of chronic-phase chronic myeloid leukemia in patients randomized to dasatinib or imatinib after suboptimal responses to three months of imatinib therapy: final 5-year results from DASCERN.

Early molecular response (EMR) at 3 months is predictive of improved overall survival (OS) and progression-free survival (PFS) in patients with chronic myeloid leukemia in the chronic phase (CML-CP). Although about one-third of patients treated with first-line imatinib do not achieve EMR, long-term OS and PFS are still observed in most patients. DASCERN (NCT01593254) is a prospective, phase IIb, randomized trial evaluating a switch to dasatinib in patients who have not achieved EMR after 3 months of treatment with first-line imatinib. Early analysis demonstrated an improved major molecular response (MMR) rate at 12 months with dasatinib versus imatinib (29% vs. 13%, P=0.005). Here, we report results from the final 5-year follow-up. In total, 174 patients were randomized to dasatinib and 86 to remain on imatinib. Forty-six (53%) patients who remained on imatinib but subsequently experienced failure were allowed to cross over to dasatinib per protocol. At a minimum follow-up of 60 months, the cumulative MMR rate was significantly higher in patients randomized to dasatinib versus imatinib (77% vs. 44%, P.

Outer membrane vesicle-wrapped manganese nanoreactor for augmenting cancer metalloimmunotherapy through hypoxia attenuation and immune stimulation.

Tumor hypoxia, high oxidative stress, and low immunogenic create a deep-rooted immunosuppressive microenvironment, posing a major challenge to the therapeutic efficiency of cancer immunotherapy for solid tumor. Herein, an intelligent nanoplatform responsive to the tumor microenvironment (TME) capable of hypoxia relief and immune stimulation has been engineered for efficient solid tumor immunotherapy. The MnO2@OxA@OMV nanoreactor, enclosing bacterial-derived outer membrane vesicles (OMVs)-wrapped MnO2 nanoenzyme and the immunogenic cell death inducer oxaliplatin (OxA), demonstrated intrinsic catalase-like activity within the TME, which effectively catalyzed the endogenous H2O2 into O2 to enable a prolonged oxygen supply, thereby alleviating the tumor's oxidative stress and hypoxic TME, and expediting OxA release. The combinational action of OxA-caused ICD effect and Mn2+ from nanoreactor enabled the motivation of the cGAS-STING pathway to significantly improve the activation of STING and dendritic cells (DCs) maturation, resulting in metalloimmunotherapy. Furthermore, the immunostimulant OMVs played a crucial role in promoting the infiltration of activated CD8+T cells into the solid tumor. Overall, the nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy. STATEMENT OF SIGNIFICANCE: A tailor-made nanoreactor was fabricated by enclosing bacterial-derived outer membrane vesicles (OMVs) onto MnO2 nanoenzyme and loading with immunogenic cell death inducer oxaliplatin (OxA) for tumor metalloimmunotherapy. The nanoreactor possesses intrinsic catalase-like activity within the tumor microenvironment, which effectively enabled a prolonged oxygen supply by catalyzing the conversion of endogenous H2O2 into O2, thereby alleviating tumor hypoxia and expediting OxA release. Furthermore, the TME-responsive release of nutritional Mn2+ sensitized the cGAS-STING pathway and collaborated with OxA-induced immunogenic cell death (ICD). Combing with immunostimulatory OMVs enhances the uptake of nanoreactors by DCs and promotes the infiltration of activated CD8+T cells. This nanoreactor offers a robust platform for solid tumor treatment, highlighting the significant potential of combining relief from tumor hypoxia and immune stimulation for metalloimmunotherapy.

Linking preoperative and early intensive care unit data for prolonged intubation prediction.

Objectives: Prolonged intubation (PI) is a frequently encountered severe complication among patients following cardiac surgery (CS). Solely concentrating on preoperative data, devoid of sufficient consideration for the ongoing impact of surgical, anesthetic, and cardiopulmonary bypass procedures on subsequent respiratory system function, could potentially compromise the predictive accuracy of disease prognosis. In response to this challenge, we formulated and externally validated an intelligible prediction model tailored for CS patients, leveraging both preoperative information and early intensive care unit (ICU) data to facilitate early prophylaxis for PI. Methods: We conducted a retrospective cohort study, analyzing adult patients who underwent CS and utilizing data from two publicly available ICU databases, namely, the Medical Information Mart for Intensive Care and the eICU Collaborative Research Database. PI was defined as necessitating intubation for over 24 h. The predictive model was constructed using multivariable logistic regression. External validation of the model's predictive performance was conducted, and the findings were elucidated through visualization techniques. Results: The incidence rates of PI in the training, testing, and external validation cohorts were 11.8%, 12.1%, and 17.5%, respectively. We identified 11 predictive factors associated with PI following CS: plateau pressure [odds ratio (OR), 1.133; 95% confidence interval (CI), 1.111-1.157], lactate level (OR, 1.131; 95% CI, 1.067-1.2), Charlson Comorbidity Index (OR, 1.166; 95% CI, 1.115-1.219), Sequential Organ Failure Assessment score (OR, 1.096; 95% CI, 1.061-1.132), central venous pressure (OR, 1.052; 95% CI, 1.033-1.073), anion gap (OR, 1.075; 95% CI, 1.043-1.107), positive end-expiratory pressure (OR, 1.087; 95% CI, 1.047-1.129), vasopressor usage (OR, 1.521; 95% CI, 1.23-1.879), Visual Analog Scale score (OR, 0.928; 95% CI, 0.893-0.964), pH value (OR, 0.757; 95% CI, 0.629-0.913), and blood urea nitrogen level (OR, 1.011; 95% CI, 1.003-1.02). The model exhibited an area under the receiver operating characteristic curve (AUROC) of 0.853 (95% CI, 0.840-0.865) in the training cohort, 0.867 (95% CI, 0.853-0.882) in the testing cohort, and 0.704 (95% CI, 0.679-0.727) in the external validation cohort. Conclusions: Through multicenter internal and external validation, our model, which integrates early ICU data and preoperative information, exhibited outstanding discriminative capability. This integration allows for the accurate assessment of PI risk in the initial phases following CS, facilitating timely interventions to mitigate adverse outcomes.

STAT5 phosphorylation plus minimal residual disease defines a novel risk classification in adult B-cell acute lymphoblastic leukaemia.

The dysregulation of the Janus family tyrosine kinase-signal transducer and activator of transcription (JAK-STAT) is closely related to acute lymphoblastic leukaemia (ALL), whereas the clinical value of phosphorylated STAT5 (pSTAT5) remains elusive. Herein we performed a prospective study on clinical significance of flow cytometry-based pSTAT5 in adult B-ALL patients. A total of 184 patients were enrolled in the Precision-Classification-Directed-Target-Total-Therapy (PDT)-ALL-2016 cohort between January 2018 and December 2021, and STAT5 phosphorylation was detected by flow cytometry at diagnosis. Based on flow-pSTAT5, the population was classified into pSTAT5low (113/184, 61.1%) and pSTAT5high (71/184, 38.9%). Overall survival (OS) and event-free survival (EFS) were inferior in pSTAT5high patients than in those with pSTAT5low (OS, 44.8% vs. 65.2%, p = 0.004; EFS, 23.5% vs. 52.1%, p < 0.001), which was further confirmed in an external validation cohort. Furthermore, pSTAT5 plus flow-based minimal residual disease (MRD) postinduction defines a novel risk classification as being high risk (HR, pSTAT5high + MRD+), standard risk (SR, pSTAT5low + MRD-) and others as moderate-risk group. Three identified patient subgroups are distinguishable with disparate survival curves (3-year OS rates, 36.5%, 56.7% and 76.3%, p < 0.001), which was confirmed on multivariate analysis (hazard ratio 3.53, p = 0.003). Collectively, our study proposed a novel, simple and flow-based risk classification by integrating pSTAT5 and MRD in favour of risk-guided treatment for B-ALL.

TIE1 promotes cervical cancer progression via Basigin-matrix metalloproteinase axis.

Background: Tyrosine kinase with immunoglobulin and EGF-like domains 1 (TIE1) is known as an orphan receptor prominently expressed in endothelial cells and participates in angiogenesis by regulating TIE2 activity. Our previous study demonstrated elevated TIE1 expression in cervical cancer cells. However, the role of TIE1 in cervical cancer progression, metastasis and treatment remains elusive. Methods: Immunohistochemistry staining for TIE1 and Basigin was performed in 135 human cervical cancer tissues. Overexpressing vectors and siRNAs were used to manipulate gene expression in tumor cells. Colony formation, wound healing, and transwell assays were used to assess cervical cancer cell proliferation and migration in vitro. Subcutaneous xenograft tumor and lung metastasis mouse models were established to examine tumor growth and metastasis. Co-Immunoprecipitation and Mass Spectrometry were applied to explore the proteins binding to TIE1. Immunoprecipitation and immunofluorescence staining were used to verify the interaction between TIE1 and Basigin. Cycloheximide chase assay and MG132 treatment were conducted to analyze protein stability. Results: High TIE1 expression was associated with poor survival in cervical cancer patients. TIE1 overexpression promoted the proliferation, migration and invasion of cervical cancer cells in vitro, as well as tumor growth and metastasis in vivo. In addition, Basigin, a transmembrane glycoprotein, was identified as a TIE1 binding protein, suggesting a pivotal role in matrix metalloproteinase regulation, angiogenesis, cell adhesion, and immune responses. Knockdown of Basigin or treatment with the Basigin inhibitor AC-73 reversed the tumor-promoting effect of TIE1 in vitro and in vivo. Furthermore, we found that TIE1 was able to interact with and stabilize the Basigin protein and stimulate the Basigin-matrix metalloproteinase axis. Conclusion: TIE1 expression in cervical cells exerts a tumor-promoting effect, which is at least in part dependent on its interaction with Basigin. These findings have revealed a TIE2-independent mechanism of TIE1, which may provide a new biomarker for cervical cancer progression, and a potential therapeutic target for the treatment of cervical cancer patients.

Twenty-Four week Taichi training improves pulmonary diffusion capacity and glycemic control in patients with Type 2 diabetes mellitus.

This study evaluated the effect of 24-week Taichi training and Taichi plus resistance band training on pulmonary diffusion capacity and glycemic control in patients with Type 2 diabetes mellitus (T2DM). Forty-eight patients with T2DM were randomly divided into three groups: Group A-Taichi training: practiced Taichi 60 min/day, 6 days/week for 24 weeks; Group B-Taichi plus resistance band training: practiced 60-min Taichi 4 days/week plus 60-min resistance band training 2 days/week for 24 weeks; and Group C-controls: maintaining their daily lifestyles. Stepwise multiple regression analysis was applied to predict diffusion capacity of the lungs for carbon monoxide (DLCO) by fasting blood glucose, insulin, glycosylated hemoglobin (HbA1c), tumour necrosis factor alpha (TNF-α), von Willebrand Factor (vWF), interleukin-6 (IL-6), intercellular adhesion molecule 1 (ICAM-1), endothelial nitric oxide synthase (eNOS), nitric oxide (NO), endothelin-1 (ET-1), vascular endothelial growth factor, and prostaglandin I-2. Taichi with or without resistance band training significantly improved DLCO, increased insulin sensitivity, eNOS and NO, and reduced fasting blood glucose, insulin, HbA1c, TNF-α, vWF, IL-6, ICAM-1, and ET-1. There was no change in any of these variables in the control group. DLCO was significantly predicted (R2 = 0.82) by insulin sensitivity (standard-ß = 0.415, P<0.001), eNOS (standard-ß = 0.128, P = 0.017), TNF-α (standard-ß = -0.259, P = 0.001), vWF (standard-ß = -0.201, P = 0.007), and IL-6 (standard-ß = -0.175, P = 0.032) in patients with T2DM. The impact of insulin sensitivity was the most important predictor for the variation of DLCO based on the multiple regression modeling. This study demonstrates that 24-week Taichi training and Taichi plus resistance band training effectively improve pulmonary diffusion capacity and blood glycemic control in patients with T2DM. Variation of DLCO is explained by improved insulin sensitivity and endothelial function, and reduced inflammatory markers, including TNF-α, vWF, and IL-6.

Ultrasound-guided microwave ablation for the treatment of idiopathic granulomatous mastitis: comparison with surgical excision.

BACKGROUND: Idiopathic granulomatous mastitis (IGM) results in notable clinical symptoms and breast deformity. This study aimed to evaluate the clinical feasibility of microwave ablation (MWA) for the treatment of IGM through comparison with surgical excision. METHODS: From June 2016 to December 2020, a total of 234 consecutive patients admitted to the hospital were retrospectively included in this study. IGM was pathologically confirmed via breast biopsy in all included patients. These patients were divided into the MWA group (n = 91) and surgical group (n = 143) based on the type of treatment. Patients in both groups received oral prednisone prior to intervention. The clinical remission rate, recurrence rate, operative pain, complications, and BREAST Q score were compared between the two groups. RESULTS: There were 340 lesions in the MWA group, and 201 lesions in the surgical group were ultimately included. Significant differences in the complete remission rate (96.7% vs. 86.7%, p = 0.020), recurrence rate (3.3% vs. 13.3%, p = 0.020), operation time (48.7±14.6 min vs. 68.1±36.4 min, p < 0.001), postoperative pain (p < 0.001) and postoperative BREAST Q score (p < 0.001) were observed between the MWA and surgical groups. CONCLUSIONS: Microwave ablation is feasible for the treatment of IGM, due to its high curative rate and low recurrence rate. Because of the minimal invasiveness of MWA and sufficient preservation of the gland and contour of the breast, patients are more satisfied with the appearance of the breast. Therefore, for patients with complex conditions requiring surgery, MWA is a good alternative treatment.

RGD targeted magnetic ferrite nanoparticles enhance antitumor immunotherapeutic efficacy by activating STING signaling pathway.

Manganese has been used in tumor imaging for their ability to provide T1-weighted MRI signal. Recent research find Mn2+ can induce activation of the stimulator of interferon gene (STING) pathway to create an active and favorable tumor immune microenvironment. However, the direct injection of Mn2+ often results in toxicity. In this study, we developed an RGD targeted magnetic ferrite nanoparticle (RGD-MnFe2O4) to facilitate tumor targeted imaging and improve tumor immunotherapy. Magnetic resonance imaging and fluorescence molecular imaging were performed to monitor its in vivo biodistribution. We found that RGD-MnFe2O4 showed active tumor targeting and longer accumulation at tumor sites. Moreover, RGD-MnFe2O4 can activate STING pathway with low toxicity to enhance the PD-L1 expression. Furthermore, combining RGD-MnFe2O4 and anti-PD-L1 antibody (aPD-L1) can treat several types of immunogenic tumors through promoting the accumulation of tumor-infiltrating cytotoxic T cells. In general, our study provides a promising new strategy for the targeted and multifunctional theranostic nanoparticle for the improvement of tumor immunotherapy.

Prognostic value of CD8+T cells related genes and exhaustion regulation of Notch signaling pathway in hepatocellular carcinoma.

Immunotherapy has emerged as the primary treatment modality for patients with advanced Hepatocellular carcinoma (HCC). However, its clinical efficacy remains limited, benefiting only a subset of patients, while most exhibit immune tolerance and face a grim prognosis. The infiltration of immune cells plays a pivotal role in tumor initiation and progression. In this study, we conducted an analysis of immune cell infiltration patterns in HCC patients and observed a substantial proportion of CD8+T cells. Leveraging the weighted gene co-expression network analysis (WGCNA), we identified 235 genes associated with CD8+T cell and constructed a risk prediction model. In this model, HCC patients were stratified into a high-risk and low-risk group. Patients in the high-risk group exhibited a lower survival rate, predominantly presented with intermediate to advanced stages of cancer, displayed compromised immune function, showed limited responsiveness to immunotherapy, and demonstrated elevated expression levels of the Notch signaling pathway. Further examination of clinical samples demonstrated an upregulation of the Notch1+CD8+T cell exhaustion phenotype accompanied by impaired cytotoxicity and cytokine secretion functions that worsened with increasing Notch activation levels. Our study not only presents a prognostic model but also highlights the crucial involvement of the Notch pathway in CD8+T cell exhaustion-a potential target for future immunotherapeutic interventions.

ALYREF m5C RNA methylation reader predicts bladder cancer prognosis by regulating the tumor immune microenvironment.

BACKGROUND: 5-Methylcytidine (m5C) methylation is a recently emerging epigenetic modification that is closely related to tumor proliferation, occurrence, and metastasis. This study aimed to investigate the clinicopathological characteristics and prognostic value of m5C regulators in bladder cancer (BLCA), and their correlation with the tumor immune microenvironment. METHODS: Thirteen m5C RNA methylation regulators were analyzed using RNA-sequencing and corresponding clinical information obtained from the TCGA database. The Cluster Profiler package was used to analyze the gene ontology function of potential targets and enriched the Kyoto Encyclopedia of Genes and Genomes pathway. Kaplan-Meier survival analysis was used to compare survival differences using the log-rank test and univariate Cox proportional hazards regression. The correlation between signature prognostic m5C regulators and various immune cells was analyzed. Univariate and multivariate Cox regression analyses identified independence of the ALYREF gene signature. RESULTS: Nine out of the 13 m5C RNA methylation regulators were differentially expressed in BLCA and normal samples and were co-expressed. These 9 regulators were associated with clinicopathological tumor characteristics, particularly high or low tumor risk, pT or pTNM stage, and migration. Consensus clustering analysis divides the BLCA samples into 4 clusters. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment annotation and gene ontology function analysis identified 273 upregulated and 594 downregulated genes in BLCA. Notably, only ALYREF was significantly correlated with OS (P < .05). ALYREF exhibited significant infiltration levels in macrophage cells. Therefore, we constructed a nomogram for ALYREF as an independent prognostic factor. Additionally, we observed that both the mRNA and protein levels of ALYREF were upregulated, and immunofluorescence showed that ALYREF was mainly distributed in nuclear speckles. ALYREF overexpression was significantly associated with poor OS. CONCLUSION: Our findings demonstrated the potential of ALYREF to predict clinical prognostic risks in BLCA patients and regulate the tumor immune microenvironment. As such, ALYREF may serve as a novel prognostic indicator in BLCA patients.

Short-term reproductive outcomes analysis and prediction of the modified uterine stent treatment for mild to moderate intrauterine adhesions: experience at a single institution.

BACKGROUND: To evaluate the efficacy of modified uterine stent in the treatment of mild-to-moderate intrauterine adhesions and explore the relative indicators affecting prognosis prediction. METHODS: A total of 115 patients with mild-to-moderate intrauterine adhesions received a modified uterine stent placement after hysteroscopy adhesiolysis. The second-look hysteroscopy operated after 3 months surgery, and the third-look hysteroscopy operated after 6 months surgery if necessary. The stent was removed when the cavity shape was repaired, then the reproductive outcomes were followed up one year. RESULTS: Menstrual blood volume, endometrial thickness and volume had increased significantly after 3 months surgery. The rates of cavity repaired were 86.96% (100/115) after 3 months surgery and 100% (115/115) after 6 months surgery cumulatively. Endometrial thickness after 3-months surgery was positively associated with uterine cavity shape repaired (P<0.01). The receive operating characteristic (ROC) curve showed the rate of uterine cavity shape repaired predicted by the model was 0.92, based on the endometrial thickness after 3-months surgery. The rate of pregnancy was 86.09% (99/115) in one year, while the rate of miscarriage accounted for 26.26% (26/99). The median time interval between stent removal and subsequent conception was 3 months. It showed adhesion recurrence was the risk factor for subsequent pregnancy (P<0.01). CONCLUSIONS: A modified uterine stent placement under hysteroscopy was an effective approach for mild-to-moderate intrauterine adhesions, which is easy to operate and worthy for clinical promotion. Endometrial thickness measured by ultrasonography probably has predictive value in adhesion recurrence and subsequent pregnancy. TRIAL REGISTRATION: ChiCTR2100051524. Date of registration (retrospectively registered): 26/09/2021.

Development and Validation of a Machine Learning-Based Model Used for Predicting Hepatocellular Carcinoma Risk in Patients with Hepatitis B-Related Cirrhosis: A Retrospective Study.

Object: Our objective was to estimate the 5-year cumulative risk of HCC in patients with HBC by utilizing an artificial neural network (ANN). Methods: We conducted this study with 1589 patients hospitalized at Beijing Ditan Hospital of Capital Medical University and People's Liberation Army Fifth Medical Center. The training cohort consisted of 913 subjects from Beijing Ditan Hospital of Capital Medical University, while the validation cohort comprised 676 subjects from People's Liberation Army Fifth Medical Center. Through univariate analysis, we identified factors that independently influenced the occurrence of HCC, which were then used to develop the ANN model. To evaluate the ANN model, we assessed its predictive accuracy, discriminative ability, and clinical net benefit using metrics such as the area under the receiver operating characteristic curve (AUC), concordance index (C-index), calibration curves. Results: In total, we included nine independent risk factors in the development of the ANN model. Remarkably, the AUC of the ANN model was 0.880, significantly outperforming the AUC values of other existing models including mPAGE-B (0.719) (95% CI 0.670-0.768), PAGE-B (0. 710) (95% CI 0.660-0.759), FIB-4 (0.693) (95% CI 0.640-0.745), and Toronto hepatoma risk index (THRI) (0.705) (95% CI 0.654-0.756) (p<0.001 for all). The ANN model effectively stratified patients into low, medium, and high-risk groups based on their 5-year In the training cohort, the positive predictive value (PPV) for low-risk patients was 26.2% (95% CI 25.0-27.4), and the negative predictive value (NPV) was 98.7% (95% CI 95.2-99.7). For high-risk patients, the PPV was 54.7% (95% CI 48.6-60.7), and the NPV was 91.6% (95% CI 89.4-93.4). These findings were validated in the independent validation cohort. Conclusion: The ANNs model has good individualized prediction performance and may be helpful to evaluate the probability of the 5-year risk of HCC in patients with HBC.

Tripartite motif family - its role in tumor progression and therapy resistance: a review.

PURPOSE OF REVIEW: In this review, we summarized published articles on the role of tripartite motif (TRIM) family members in the initiation and development of human malignancies. RECENT FINDINGS: The ubiquitin-proteasome system (UP-S) plays a critical role in cellular activities, and UP-S dysregulation contributes to tumorigenesis. One of the key regulators of the UP-S is the tripartite motif TRIM protein family, most of which are active E3 ubiquitin ligases. TRIM proteins are critical for the biological functions of cancer cells, including migration, invasion, metastasis, and therapy resistance. Therefore, it is important to understand how TRIM proteins function at the molecular level in cancer cells. SUMMARY: We provide a comprehensive and up-to-date overview about the role TRIMs play in cancer progression and therapy resistance. We propose TRIM family members as potential new markers and targets to overcome therapy failure.

Network pharmacology prediction, molecular docking and in vitro experiment explored the potential mechanism of Gaoyuan'an capsule in improving hypoxia tolerance.

BACKGROUND: Tibetan medicine Gaoyuan'an capsule (GYAC) is widely used to prevent pulmonary edema at high altitude, but the specific mechanism has not been explored. In this study, we analyzed the mechanism of GYAC in hypoxia tolerance, and provided a new idea for the prevention and treatment of altitude disease. METHODS: The effective components and corresponding targets of GYAC were screened out by the Chinese herbal medicine network database, and the key targets of hypoxia tolerance were retrieved by Genecards, OMIM and PubMed database. Cytoscape 3.7.2 was used to construct GYAC ingredient-target-hypoxia tolerance-related target network. GO function annotation and KEGG enrichment analysis were performed to predict the pathways in which target genes may be involved, and molecular docking was used to verify the binding ability of the compound to target genes. In vitro, the above results were further verified by molecular experiment. RESULTS: We found that GYAC can improve hypoxia tolerance by regulating various target genes, including IL6, IFNG, etc. The main regulatory pathways were HIF-1 signaling pathway. Molecular docking showed that the affinity between luteolin and target genes (IL6, IFNG) were better. In vitro, we observed that hypoxia can inhibit cell viability and promote apoptosis of H9C2 cell. And hypoxia can promote the expression of LDH. After the addition of luteolin, the decrease of cell viability, the increase of cell apoptosis, LDH release and the decrease of mitochondrial membrane potential were inhibited. Besides, inflammatory related factors (IL-6, IL-10, IL-2, IFNG and VEGFA) expression were also inhibited hypoxic cell models. CONCLUSIONS: The results of network pharmacology and molecular docking showed that luteolin, a monomeric component of GYAC, played a role in hypoxia tolerance through a variety of target genes, such as IL6, IFNG. What's more, we have discovered that luteolin can reduce the inflammatory response in cardiac myocytes, thereby alleviating mitochondrial damage, and ultimately enhancing the hypoxia tolerance of H9C2 cardiomyocytes.

Effectiveness of adjuvant traditional Chinese medicine on macrovascular invasion in patients with hepatocellular carcinoma: a real-world propensity score-matched study.

The study aimed to investigate the potential of traditional Chinese medicine (TCM) in reducing the risk of macrovascular invasion (MVI) in Chinese patients with hepatocellular carcinoma (HCC). This retrospective analysis involved 2,267 HCC patients treated at our hospital. Propensity score (PS) matching was used to compare TCM users (n = 485) with non-users (n = 485) in terms of age, Barcelona Clinic Liver Cancer (BCLC) staging, type of treatment, and AFP. The impact of TCM on the hazard ratio (HR) of MVI was evaluated using a Cox multivariate regression model. The efficacy of TCM therapy on MVI was further examined using the log-rank test. The analysis revealed that TCM medication was a significant protective factor for MVI in HCC patients, as evidenced by the Cox analysis (adjusted HR = 0.496, 95% CI: 0.387-0.635, p < 0.001). After PS matching, the Kaplan-Meier curve demonstrated a lower occurrence rate of MVI in TCM users compared to non-users. The study findings suggest that TCM treatment has the potential to decrease the incidence of MVI in HCC patients, irrespective of etiology, BCLC staging, liver function, or treatment type. Notably, as the use of TCM increased, the percentage of MVI in patients showed a gradual decrease, indicating the potential of TCM therapy as a successful strategy for preventing MVI.

Comparison of the Efficacy Among Nilotinib, Dasatinib, Flumatinib and Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia Patients: A Real-World Multi-Center Retrospective Study.

BACKGROUND: There are limited data comprehensively comparing therapy responses and outcomes among nilotinib, dasatinib, flumatinib and imatinib for newly diagnosed chronic-phase chronic myeloid leukemia in a real-world setting. PATIENTS AND METHODS: Data from patients with chronic-phase CML receiving initial a second-generation tyrosine-kinase inhibitor (2G-TKI, nilotinib, dasatinib or flumatinib) or imatinib therapy from 77 Chinese centers were retrospectively interrogated. Propensity-score matching (PSM) analyses were performed to to compare therapy responses and outcomes among these 4 TKIs. RESULTS: 2,496 patients receiving initial nilotinib (n = 512), dasatinib (n = 134), flumatinib (n = 411) or imatinib (n = 1,439) therapy were retrospectively interrogated in this study. PSM analyses indicated that patients receiving initial nilotinib, dasatinib or flumatinib therapy had comparable cytogenetic and molecular responses (p = .28-.91) and survival outcomes including failure-free survival (FFS, p = .28-.43), progression-free survival (PFS, p = .19-.93) and overall survival (OS) (p values = .76-.78) but had significantly higher cumulative incidences of cytogenetic and molecular responses (all p values < .001) and higher probabilities of FFS (p < .001-.01) than those receiving imatinib therapy, despite comparable PFS (p = .18-.89) and OS (p = .23-.30). CONCLUSION: Nilotinib, dasatinib and flumatinib had comparable efficacy, and significantly higher therapy responses and higher FFS rates than imatinib in newly diagnosed CML patients. However, there were no significant differences in PFS and OS among these 4 TKIs. These real-world data may provide additional evidence for routine clinical assessments to identify more appropriate therapies.

Comparison of 5-ALA-PDT and LEEP of cervical squamous intraepithelial neoplasia (CIN2) with high-risk human papillomavirus infection in childbearing age women: A non-randomized controlled polit study.

BACKGROUND: 5-Aminolevulinic acid-mediated photodynamic therapy (5-ALA-PDT) is a possible minimally-invasive treatment for high-grade cervical intraepithelial neoplasia (HSIL). The present study was carried out to assess the effect of 5-ALA-PDT and loop electrosurgical excision procedure (LEEP) in cervical squamous intraepithelial neoplasia (CIN2) combined with high-risk human papillomavirus (HR-HPV) infection. METHODS: In this study, 190 patients with CIN2 and HR-HPV infection were finally included. They were divided into the LEEP Group (n = 116) and PDT Group (n = 74) according to gynecologist's recommendation and patient's willingness. All patients were followed up at 4-6 months and 12 months after treatment, including HPV testing, cytology, and colposcopy examination. RESULTS: (1) 4-6 months after treatment, the pathological regression rate was 97.30 % (72/74) in the PDT group and 98.28 % (114/116) in the LEEP group (P = 0.952). The HPV clearance rate was 81.08 % (60/74) in the PDT group and 80.17 % (93/116)in the LEEP group (P = 0.877). (2) 12 months after treatment, the pathological regression rate was 93.24 % (69/74) in the PDT group and 96.55 % (112/116) in the LEEP group (P = 0.486). The recurrence rate of CIN2 was 4.05 % (3/74) in the PDT group and 1.72 % (2/116) in the LEEP group (P = 0.608). The HPV clearance rate was 90.54 % (67/74) in the PDT group and 89.66 % (104/116)in the LEEP group (P = 0.843). The reinfection rate of HR-HPV was 5.41 % (4/74) in the PDT group and 1.72 % (2/116) in the LEEP group (P = 0.322). (3) The adverse reactions in the PDT Group were slightly lower than that in the LEEP Group (P = 0.4956), but the incidence of vaginal bleeding in the PDT group was lower than that in the LEEP group during follow-up. CONCLUSIONS: The effectiveness of 5-ALA-PDT is similar to LEEP for CIN2 with less side effects. Therefore, 5-ALA-PDT, a non-invasive treatment, may be an effective method for CIN2 patients of childbearing age.

Preparation, Structure and Properties of Epoxy/Carbonyl Iron Powder Wave-Absorbing Foam for Electromagnetic Shielding.

The application of absorbing materials for electromagnetic shielding is becoming extensive, and the use of absorbents is one of the most important points of preparing absorbing foam materials. In this work, epoxy resin was used as the matrix and carbonyl iron powder (CIP) was used as the absorbent, and the structural absorbing foam materials were prepared by the ball mill dispersion method. Scanning electron microscopy showed that the CIP was evenly dispersed in the resin matrix. The foam structures formed at pre-polymerization times of 10 min, 30 min and 50 min were analyzed, and it was found that the cell diameter decreased from 0.47 mm to 0.31 mm with the increase in the pre-polymerization time. The reflectivity of the frontal and reverse sides of the foam gradually tends to be unified at frequencies of 2-18 GHz. When the CIP content increased from 30 wt% to 70 wt%, the cell diameter increased from 0.32 mm to 0.4 mm, and the uniformity of CIP distribution deteriorated. However, with the increase in the CIP content, the absorption properties of the composite materials were enhanced, and the absorption frequency band broadened. When the CIP content reached 70 wt%, the compression strength and modulus of the foam increased to 1.32 MPa and 139.0 MPa, respectively, indicating a strong ability to resist deformation.