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Compared with traditional structures, lattice structures show more excellent mechanical properties, e.g., higher rigidity and lighter weight. The additive manufacturing (AM) technology enables complex lattice structure to be realized. The path planning problem of AM for lattice structures faces new challenges that have been barely explored before now, because the lattice structures have unique characteristics of complex geometrical features and high-precision processing requirements. Despite many efforts toward path generation, the printing efficiency problem of the lattice structures is more than one single printing path can resolve. Using machine learning method based on a support vector machine (SVM) system, the goal of this paper is to automatically determine a suitable filling path for each sub-domain of the slicing layer of the lattice structures. Moreover, a route is found to traverse every scattered sub-domain by solving a traveling salesman problem (TSP). We demonstrate various testing examples and the experimental results to show the superiority and effectiveness of our method in terms of classification accuracy, filling effects, and linking path length.

Thoracic aortic aneurysm (TAA) is a localized or diffuse dilatation of the thoracic aortas, and causes many sudden deaths each year worldwide. However, there is no effective pharmacologic therapy. Here, we show that AGGF1 effectively blocks TAA-associated arterial inflammation and remodeling in three different mouse models (mice with transverse aortic constriction, Fbn1 C1041G/+ mice, and β-aminopropionitrile-treated mice). AGGF1 expression is reduced in the ascending aortas from the three models and human TAA patients. Aggf1 +/- mice and vascular smooth muscle cell (VSMC)-specific Aggf1 smcKO knockout mice show aggravated TAA phenotypes. Mechanistically, AGGF1 enhances the interaction between its receptor integrin α7 and latency-associated peptide (LAP)-TGF-β1, blocks the cleavage of LAP-TGF-β1 to form mature TGF-β1, and inhibits Smad2/3 and ERK1/2 phosphorylation in VSMCs. Pirfenidone, a treatment agent for idiopathic pulmonary fibrosis, inhibits TAA-associated vascular inflammation and remodeling in wild type mice, but not in Aggf1 +/- mice. In conclusion, we identify an innovative AGGF1 protein therapeutic strategy to block TAA-associated vascular inflammation and remodeling, and show that efficacy of TGF-β inhibition therapies require AGGF1. Thoracic aortic aneurysm (TAA) causes many sudden deaths each year, however, no effective drug treatment is available. Here, the authors show that AGGF1 protein therapy attenuates TAA in three different mouse models through integrin α7-mediated inhibition of TGF-β1 maturation and ERK1/2 signalling.

Computer-aided manufacturing (CAM) software outputs machining data by encoding a tool-path into a series of G-codes which are composed of various lengths of line segments. The discontinuities of these line segments may cause inefficiency for computer numerical control (CNC) system. To achieve high-speed continuous motions, corner smoothing algorithms based on look-ahead methods are widely used. However, it is difficult to meet smoothing trajectories in real-time requirements. Based on machine learning method, in this paper, a support vector machine (SVM) system is presented for directly outputting classification results of the various geometric continuities at the transition corners. The feature values used for generating continuity classification model are extracted from sampling paths of the previous publication work: the machining parameters, length, fairness criteria, the root mean square (RMS) contour errors, and dominant stage type of movement of each sampling path are calculated. The acceleration/deceleration (ACC/DEC) feedrate planning scheme is used to determine the feedrate at the transition corners. Simulations and experiments show that the proposed algorithm can realize accurately and efficiently continuity classification in real-time requirements under the conditions of machining accuracy.

Background Pseudomonas aeruginosa is a prevalent nosocomial pathogen causing respiratory tract infections, and its biofilm formation poses challenges to treatment and influences prognosis. However, the data on strong biofilm-forming strains in Chinese respiratory tract infection patients and their independent prognostic value remain unclear. Methods This retrospective study included 362 inpatients with Pseudomonas aeruginosa -induced respiratory tract infections (Jan 2021–Jun 2023). Strains were subjected to crystal violet staining for biofilm quantification and Vitek2 Compact system for antimicrobial susceptibility testing. Global Optimal Matching and Logistic regression were used for analysis. Results 54.7% of isolates were strong biofilm-forming strains, with a higher multidrug resistance rate (53.0% vs 35.4%, p  = 0.001). After Global Optimal Matching, patients infected with strong biofilm-forming strain had longer hospital stays (28.5 vs 19.0 days, p  < 0.001) and higher 30/60-day mortality (18.3%/20.1% vs 7.9%/8.5%, p  < 0.01). Strong biofilm formation, multidrug resistance, invasive mechanical ventilation, and diabetes were independent mortality risk factors. Conclusion Pseudomonas aeruginosa with strong biofilm formation is common in Chinese respiratory tract infection patients, associated with increased drug resistance and mortality, serves as an independent short-term prognostic factor for mortality. This study fills gaps in Chinese population data and validates the clinical utility of biofilm detection, providing critical evidence to guide clinical risk stratification and treatment. Graphical Abstract

Cantharidin (CTD), a natural terpenoid toxin secreted by blister beetles, acts as a potent inhibitor of protein phosphatase. As the principal active component of Mylabris, a traditional Chinese medicine, CTD has attracted considerable interest due to its dual properties, combining potent anti-tumor activity with significant toxicity. Contemporary pharmacological research demonstrates that CTD inhibits the growth and proliferation of diverse cancer cells lines. It exhibits antibacterial and antiparasitic properties, and demonstrates pesticidal activity in agricultural applications. Despite these benefits, CTD exhibits a prominent double-edged profile, marked by severe toxic effects, including cardiotoxicity, nephrotoxicity, gastrointestinal toxicity, and reproductive toxicity. Our prior research has identified the heart and liver as primary targets of CTD’s acute toxicity, where it induces apoptosis and necrosis of cardiomyocytes and hepatocytes. Recent efforts to mitigate its toxicity while preserving efficacy have focused on the structural modifications of CTD and the development of its derivatives. Additionally, CTD has been demonstrated to enhance anti-tumor efficacy when combined with other drugs, particularly against certain drug-resistant tumors. This review comprehensively evaluates CTD’s pharmacology and toxicology, synthesizes pertinent toxicological data, and explores strategies for toxicity reduction to guide future research.

Reliable monitoring of metabolites in biofluids is critical for diagnosis, treatment, and long‐term management of various diseases. Although widely used, existing enzymatic metabolite assays face challenges in clinical practice primarily due to the susceptibility of enzyme activity to external conditions and the low sensitivity of sensing strategies. Inspired by the micro/nanoscale confined catalytic environment in living cells, the coencapsulation of oxidoreductase and metal nanoparticles within the nanopores of macroporous silica foams to fabricate all‐in‐one bio‐nanoreactors is reported herein for use in surface‐enhanced Raman scattering (SERS)‐based metabolic assays. The enhancement of catalytical activity and stability of enzyme against high temperatures, long‐time storage or proteolytic agents are demonstrated. The nanoreactors recognize and catalyze oxidation of the metabolite, and provide ratiometric SERS response in the presence of the enzymatic by‐product H2O2, enabling sensitive metabolite quantification in a “sample in and answer out” manner. The nanoreactor makes any oxidoreductase‐responsible metabolite a candidate for quantitative SERS sensing, as shown for glucose and lactate. Glucose levels of patients with bacterial infection are accurately analyzed with only 20 µL of cerebrospinal fluids, indicating the potential application of the nanoreactor in vitro clinical testing. Inspired by the spatially confined micro‐/nano‐environment in living cells, a plasmonic bio‐nanoreactor is developed by the coencapsulation of enzyme and surface‐enhanced Raman scattering tags within macroporous silica foams. The nanoreactor shows enhanced biocatalytic activity and stability, and thus the capability of molecular recognition and detection provides an all‐in‐one optical biosensor for reliable in vitro metabolic testing.

Induction of cuproptosis in tumor cells is an emerging direction for cancer drug development. Plumbagin (PLB), a natural biological molecule, has anticancer activities, partially via copper‐dependent mechanisms. But it remains unclear if PLB can induce cuproptosis in hepatocellular carcinoma (HCC). In this study, PLB showed HCC‐suppressive activities and caused representative molecular phenotypes of cuproptosis, whereas tetrathiomolybdate, an inhibitor of cuproptosis, could alleviate these effects the most. The mRNA and protein expression levels of the primary hepatic copper exporter, ATPase copper transporting beta (ATP7B), decreased in PLB‐treated HCC cells, which might cause the accumulation of intracellular copper and trigger cuproptosis. An upstream ATP7B‐regulatory microRNA, microRNA‐302a‐3p (miR‐302a‐3p), was identified by quantification and validated by the overexpression/inhibition experiment and luciferase reporter assay. Moreover, PLB was found to reduce the protein level of DNA‐methyltransferase 1 (DNMT1), thereby enhancing the promoter hypomethylation and the expression of miR‐302a‐3p. Gene manipulation experiments further demonstrated that ATP7B, miR‐302a‐3p, and DNMT1 mediated PLB‐induced cuproptosis. Preliminary clinical analyses showed that low ATP7B expression levels were associated with better prognosis, supporting the importance of ATP7B‐lowering therapeutic strategies in HCC. Together, our results indicate that PLB triggers HCC cuproptosis via the DNMT1/miR‐302a‐3p/ATP7B axis, providing a potential therapeutic strategy for HCC. A natural biological molecule, plumbagin (PLB), suppresses hepatocellular carcinoma via cuproptosis. PLB treatment transcriptionally downregulates the primary hepatic copper exporter, ATP7B, thereby accumulating intracellular copper ions to trigger cuproptosis. ATP7B downregulation by PLB is mediated by the DNMT1/miR‐302a‐3p axis through epigenetic processes .

Hepatocellular carcinoma (HCC) is a prevalent malignant tumor worldwide. Ferroptosis is emerging as an effective target for tumor treatment as it has been shown to potentiate cell death in some malignancies. However, it remains unclear whether histone phosphorylation events, an epigenetic mechanism that regulates transcriptional expression, are involved in ferroptosis. Our study found that supplementation with anisomycin, an agonist of p38 mitogen-activated protein kinase (MAPK), induced ferroptosis in HCC cells, and the phosphorylation of histone H3 on serine 10 (p-H3S10) was participated in anisomycin-induced ferroptosis. To investigate the anticancer effects of anisomycin-activated p38 MAPK in HCC, we analyzed cell viability, colony formation, cell death, and cell migration in Hep3B and HCCLM3 cells. The results showed that anisomycin could significantly suppress HCC cell colony formation and migration and induce HCC cell death. The hallmarks of ferroptosis, such as abnormal accumulation of iron and elevated levels of lipid peroxidation and malondialdehyde, were detected to confirm the ability of anisomycin to promote ferroptosis. Furthermore, coincubation with SB203580, an inhibitor of activated p38 MAPK, partially rescued anisomycin-induced ferroptosis. And the levels of p-p38 MAPK and p-H3S10 were successively increased by anisomycin treatment. The relationship between p-H3S10 and ferroptosis was revealed by ChIP sequencing. The reverse transcription PCR and immunofluorescence results showed that NCOA4 was upregulated both in mRNA and protein levels after anisomycin treatment. And by C11-BODIPY staining, we found that anisomycin-induced lipid reactive oxygen species was reduced after NCOA4 knockdown. In conclusion, the anisomycin-activated p38 MAPK promoted ferroptosis of HCC cells through H3S10 phosphorylation.

BACKGROUND: Adenoid cystic carcinoma of the external auditory canal is a rare primary malignancy, and surgery is the primary management strategy. This study aims to optimize management strategies and improve prognosis of adenoid cystic carcinoma of the external auditory canal. METHODS: Seventeen patients with adenoid cystic carcinoma of external auditory canal who had been admitted to a single institution from January 2008 to March 2019 were recruited and retrospectively reviewed. Among patients with T1 tumors, 2 underwent local external auditory canal resection, 1 received lateral temporal bone resection + superficial parotidectomy. Among patients with T2 tumors, all 5 patients underwent lateral temporal bone resection + superficial parotidectomy. Among patients with T3 tumors, 3 underwent subtotal temporal bone resection + superficial parotidectomy, 2 underwent subtotal temporal bone resection + superficial parotidectomy + radiotherapy, and 1 underwent extended temporal bone resection + superficial parotidectomy + radiotherapy. Among patients with T4 tumors, 2 underwent subtotal temporal bone resection + superficial parotidectomy and 1 underwent extended temporal bone resection + total parotidectomy + radiotherapy. RESULTS: The common manifestations included otalgia (82.4%), hearing loss (23.5%), external auditory canal mass (23.5%), otorrhea (17.6%), and aural fullness (5.9%). In the study, 5/17 (29.4%) patients had been misdiagnosed preoperatively, 5/17 (29.4%) patients revealed local recurrence, and 3/17 patients (17.6%) were identified with distant metastasis postoperatively. The 3- and 5-year overall survival rates were 88.2% and 82.3%, respectively. There was no significant difference in overall survival (P = .746) and disease-free survival (P = .933) between patients receiving different surgical approaches. Three out of 17 patients (17.6%) died of T2, T3, and T4 diseases, respectively. CONCLUSION: Otalgia is the most common manifestation of adenoid cystic carcinoma of the external auditory canal, and misdiagnosis is frequently encountered. Surgery is the preferred therapy, and local resection is associated with relapse, lateral temporal bone resection is strongly recommended in patients with early-stage tumor. Regular follow-up should be routinely conducted postoperatively to early identify local recurrence. KEYWORDS: ACC, EAC, surgery, prognosis

Dietary intervention provides a novel approach for cancer therapy. Elaidic acid (EA), which accounts for 80-90% of total trans fatty acids in foods, has recently been found to exert anti-tumor effects. However, the biological functions and underlying mechanisms of EA remain elusive in hepatocellular carcinoma (HCC). In this study, targeted fatty acid metabolomics demonstrated that among 44 types of fatty acids, the concentration of EA decreased most significantly when comparing plasma from HCC patients with plasma from healthy people. Through assays using HCC orthotopic and xenograft mouse models, we further revealed that dietary EA attenuates HCC growth. Notably, when gut microbiota was depleted using a cocktail of antibiotics, the anti-tumor effect of EA was diminished, confirming that EA suppresses HCC tumor growth by modulating gut microbiota. Mechanistically, analysis of 16S ribosomal RNA sequencing showed that dietary EA markedly increases the abundance of intestinal . Subsequent untargeted metabolomic sequencing analysis further demonstrated that dietary EA drives the production of -derived spermidine (SPD), which attenuates HCC growth as well as . The observed impact correlated with the phosphorylation of p38 MAPK and the upregulation of biomarkers pertinent to apoptosis and proliferation, including tumor protein 53, bcl-2-associated X protein, and cysteine-requiring aspartate protease 3. Taken together, our findings highlight the important role of intestinal -derived SPD in EA-mediated HCC suppression, thereby offering a promising dietary strategy for HCC treatment.