Multimodal data integration using machine learning to predict the risk of clear cell renal cancer metastasis: a retrospective multicentre study.

PURPOSE: To develop and validate a predictive combined model for metastasis in patients with clear cell renal cell carcinoma (ccRCC) by integrating multimodal data. MATERIALS AND METHODS: In this retrospective study, the clinical and imaging data (CT and ultrasound) of patients with ccRCC confirmed by pathology from three tertiary hospitals in different regions were collected from January 2013 to January 2023. We developed three models, including a clinical model, a radiomics model, and a combined model. The performance of the model was determined based on its discriminative power and clinical utility. The evaluation indicators included area under the receiver operating characteristic curve (AUC) value, accuracy, sensitivity, specificity, negative predictive value, positive predictive value and decision curve analysis (DCA) curve. RESULTS: A total of 251 patients were evaluated. Patients (n = 166) from Shandong University Qilu Hospital (Jinan) were divided into the training cohort, of which 50 patients developed metastases; patients (n = 37) from Shandong University Qilu Hospital (Qingdao) were used as internal testing, of which 15 patients developed metastases; patients (n = 48) from Changzhou Second People's Hospital were used as external testing, of which 13 patients developed metastases. In the training set, the combined model showed the highest performance (AUC, 0.924) in predicting lymph node metastasis (LNM), while the clinical and radiomics models both had AUCs of 0.845 and 0.870, respectively. In the internal testing, the combined model had the highest performance (AUC, 0.877) for predicting LNM, while the AUCs of the clinical and radiomics models were 0.726 and 0.836, respectively. In the external testing, the combined model had the highest performance (AUC, 0.849) for predicting LNM, while the AUCs of the clinical and radiomics models were 0.708 and 0.804, respectively. The DCA curve showed that the combined model had a significant prediction probability in predicting the risk of LNM in ccRCC patients compared with the clinical model or the radiomics model. CONCLUSION: The combined model was superior to the clinical and radiomics models in predicting LNM in ccRCC patients.

M2 Macrophage Hybrid Membrane-Camouflaged Targeted Biomimetic Nanosomes to Reprogram Inflammatory Microenvironment for Enhanced Enzyme-Thermo-Immunotherapy.

Excessive inflammatory reactions caused by uric acid deposition are the key factor leading to gout. However, clinical medications cannot simultaneously remove uric acid and eliminate inflammation. An M2 macrophage-erythrocyte hybrid membrane-camouflaged biomimetic nanosized liposome (USM[H]L) is engineered to deliver targeted self-cascading bienzymes and immunomodulators to reprogram the inflammatory microenvironment in gouty rats. The cell-membrane-coating endow nanosomes with good immune escape and lysosomal escape to achieve long circulation time and intracellular retention times. After being uptaken by inflammatory cells, synergistic enzyme-thermo-immunotherapies are achieved: uricase and nanozyme degraded uric acid and hydrogen peroxide, respectively; bienzymes improved the catalytic abilities of each other; nanozyme produced photothermal effects; and methotrexate has immunomodulatory and anti-inflammatory effects. The uric acid levels markedly decrease, and ankle swelling and claw curling are effectively alleviated. The levels of inflammatory cytokines and ROS decrease, while the anti-inflammatory cytokine levels increase. Proinflammatory M1 macrophages are reprogrammed to the anti-inflammatory M2 phenotype. Notably, the IgG and IgM levels in USM[H]L-treated rats decrease substantially, while uricase-treated rats show high immunogenicity. Proteomic analysis show that there are 898 downregulated and 725 upregulated differentially expressed proteins in USM[H]L-treated rats. The protein-protein interaction network indicates that the signaling pathways include the spliceosome, ribosome, purine metabolism, etc.

Inflammatory markers and the risk of idiopathic sudden sensorineural hearing loss: A Mendelian randomization study.

Background: Observational studies suggest that inflammatory markers may increase the risk of idiopathic sudden sensorineural hearing loss (ISSHL). However, the causal relationship between the two has not been established. We sought to assess the possible causal effect between several genetically predicted inflammatory markers and ISSHL by Mendelian random (MR) analysis. Methods: We extracted single nucleotide polymorphisms (SNPs) associated with C-reactive protein (CRP), Tumor necrosis factor-α (TNF-α), and fibrinogen from abstract data from the European Individual Large genome-wide association studies (GWAS). Genetic data for ISSHL were obtained from the FinnGen study (n = 196,592). Effect estimates were assessed using inverse variance weighting (IVW) as the primary method. Sensitivity analyses were performed using weighted median, MR-Egger, and MR-PRESSO to evaluate heterogeneity and pleiotropy. Results: In the random-effects IVW approach, there was a significant causal relationship between genetic susceptibility to CRP levels and ISSHL (OR = 1.23, 95% CI = 1.02-1.49, P = 0.03). In contrast, genetic TNF-α and fibrinogen were not risked factors for ISSHL (OR = 1.14, 95% CI = 0.88-1.49, P = 0.30; OR = 0.74, 95% CI = 0.07-7.96, P = 0.30; OR = 1.05, 95% CI = 0.88-1.25, P = 0.59). All the above results were consistent after validation by different Mendelian randomization methods and sensitivity analyses. Conclusion: This Mendelian randomization study provides causal evidence that CRP is a risk factor for ISSHL, while TNF-α and fibrinogen do not increase the risk for ISSHL Introduction.

Pharmacological targeting of MTHFD2 suppresses NSCLC via the regulation of ILK signaling pathway.

Lung cancer is the most common cause of cancer related deaths worldwide with the highest mortality rate. Non-small cell lung cancer (NSCLC) accounts for about 85 % of lung cancers. Mitochondrial methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a bifunctional enzyme and is the most differentially expressed metabolic enzyme in various tumors including lung cancer. However, little is known about how MTHFD2 functions in NSCLC. Integrin-linked kinase (ILK) signaling plays key a role in tumor progression including metastasis, proliferation and migration. Here, we show that MTHFD2 inhibition results in suppression of cell growth, migration, invasion and epithelial-mesenchymal transition (EMT) in NSCLC. Microarray analysis suggests that MTHFD2 is positively associated with ILK signaling based on western blotting results. In addition, the phosphorylation of AMPKα plays an essential role in MTHFD2 regulation of ILK signaling. Further, the small-molecule compound C18 inhibits MTHFD2 with great efficiency. C18 blocks MTHFD2/ILK signaling pathway and restrains cell growth, migration, invasion, and EMT of NSCLC and induces apoptosis. In brief, our study found that the positive impact of MTHFD2 is mediated via ILK signaling pathway in NSCLC. Thus, blocking MTHFD2 represents a promising therapeutic strategy against NSCLC clinically.

Clinical Features and Treatment of Congenital Pyriform Sinus Fistula: Analysis of 12 Cases.

BACKGROUND: Congenital pyriform sinus fistula (CPSF) is a rare congenital disease derived from the remnants of the third or fourth branchial cleft. OBJECTIVES: To investigate the imaging characteristics, clinical manifestations, surgical methods, complications, and personalized treatment of CPSF. MATERIAL AND METHODS: The clinical data of 12 CPSF patients admitted to the Department of Otorhinolaryngology Head and Neck Surgery of the First Affiliated Hospital of Wenzhou Medical University from March 2016 to May 2021 were retrospectively analyzed. Cryogenic plasma radiofrequency ablation, carbon dioxide laser resection, and external cervical excision were selected based on the individual condition, and postoperative complications and efficacy were evaluated. RESULTS: There were 6 men and 6 women. Neck abscess or thyroiditis was considered at the initial diagnosis. In 11 of the cases, the CPSF was on the left side, whereas in the rest one case, it was on the right. A pyriform fossa fistula was observed during hypopharyngeal iodine angiography. Eight patients were treated with endoscopic piriform fossa fistula laser resection, two with cryogenic plasma radiofrequency ablation, and the rest with external cervical fistula resection. There was no evidence of postoperative hoarseness, pharyngeal fistula, dysphagia, and other complications. CONCLUSION AND SIGNIFICANCE: CPSF is less common in adults than in children. For patients with recurrent neck abscesses, CPSF should be highly suspected, timely angiography should be performed as soon as possible, and care should be taken to avoid missed diagnoses. The primary method for piriform fossa fistula removal is surgical treatment. Finally, tailoring treatment regimens to the patient's condition can significantly improve curative efficacy.

Oral supramolecular nanovectors for dual natural medicine codelivery to prevent gastric mucosal lesion.

The oral administration of a single formulation loaded with more than one natural medicine to treat chronic diseases has advantages such as convenience, effectiveness, and economy. Here, using biomaterials approved by the drug administration, we fabricated supramolecular nanovectors containing dual natural medicines to prevent gastric mucosal lesions. Nanovectors exhibited superior intestinal absorption and bioavailability, which might be due to their high dispersion, good muco-adhesiveness, blood-lymph circulation transport, lipid sensing, and protective effects. Molecular docking results clarified the possible mechanisms in aspects of efflux pump (p-glycoprotein and multidrug resistance protein 1) inhibition effects, metabolic enzyme (cytochrome P450 3A4/1A2) blocking effects, serum albumin deposit effects, and dual drug interaction effects. Nanovectors decreased ethanol-induced gastric mucosal lesions by lowering the gastric ulcer index, preventing oxidative damage, decreasing interleukin-6, tumor necrosis factor-α and malondialdehyde, increasing glutathione, superoxide dismutase, and prostaglandin E2 levels. The interactions of inhibitor of nuclear factor-κB or κB kinase-related proteins and dual drugs or nanovector components were simulated computationally to provide an understanding of the gastro-protective action mechanism. In all, industrializable supramolecular nanovectors could effectively co-deliver dual natural medicines via the oral route by improving the pharmacokinetic behavior and exerting protective efficacy of the gastric mucosa by decreasing the oxidative stress and inflammatory level.

Biomimetic lipidic nanovectors for effective asparaginase supramolecule delivery.

Effectiveness of enzyme therapy is limited by enzyme drawbacks such as short half-life, low bioavailability and high immunogenicity. We loaded asparaginase (Aase) into hydroxypropyl- or sulfonbutylether-beta cyclodextrin to form supramolecular amphiphilic molecules by self-assembly followed by entrapment inside the cores of two biomimetic lipidic nanovectors (AS-XLNs). Supramolecular structure was simulated by molecular docking. AS-XLNs maintained superior activity through isolating Aase from external environment due to docking with cyclodextrin and coating with biomimetic membrane. Fluorescent probes and computational simulations were used to reveal possible interactions between serum albumin/trypsin and Aase/nanovector membrane components which were partly responsible for enhanced bioavailability and bioactivity of AS-XLNs compared to Aase. AS-XLNs significantly increased cytotoxicity against pulmonary tumor cells due to synergistic effects of Aase and nanovector membrane components (killing tumor cells through apoptosis induced by asparagine depletion and autophagy inhibition or via targets such as vascular endothelial growth factor A, alpha-amylase, p-selectin or androgen receptor).

Development of a composite membrane with underwater-oleophobic fibrous surface for robust anti-oil-fouling membrane distillation.

Membrane fouling caused by non-polar foulants is a challenging problem for hydrophobic membranes, which hinders the industrial implementation of membrane distillation (MD). The hydrophilic coating can create a hydration layer at solid-water interface, thereby the hydrophilic surfaces are expected to supply a barrier inhibiting adhesion of hydrophobic foulants. Hence, it should be possible to develop anti-fouling composite membranes through constructing a hydrophilic skin layer onto hydrophobic MD membranes. Herein, we fabricated a novel composite membrane for excellent anti-oil-fouling performance in MD process by electrospinning polyetherimide (PEI) nanofibers on the hydrophobic polyvinylidene fluoride (PVDF) membrane surface, followed by cross-linking with ethanediamine (EDA). The membrane morphology and structure properties, surface zeta potential and wettability, thermal stability were all systematically characterized, and force spectroscopy was used to quasi-quantitatively evaluate oil-membrane adhesion force. Compared with the PVDF membrane, the PVDF/PEI-EDA composite membrane exhibited strong resistance to crude oil with underwater oil contact angle of about 145° and low oil-membrane adhesion force, which contributed to the stable performance during MD desalinating an oily and saline solution. The fabricated composite membrane with underwater-oleophobic fibrous surface can effectively mitigate oil-fouling in MD and promote MD to treat highly saline wastewater with high concentration of hydrophobic foulants.