Targeting OXCT1-mediated ketone metabolism reprograms macrophages to promote antitumor immunity via CD8+ T cells in hepatocellular carcinoma.

BACKGROUND & AIMS: The liver is the main organ of ketogenesis, while ketones are mainly metabolized in peripheral tissues via the critical enzyme 3-oxoacid CoA-transferase 1 (OXCT1). We previously found that ketolysis is reactivated in hepatocellular carcinoma (HCC) cells through OXCT1 expression to promote tumor progression; however, whether OXCT1 regulates antitumor immunity remains unclear. METHODS: To investigate the expression pattern of OXCT1 in HCC in vivo, we conducted multiplex immunohistochemistry experiments on human HCC specimens. To explore the role of OXCT1 in mouse HCC tumor-associated macrophages (TAMs), we generated LysMcreOXCT1f/f (OXCT1 conditional knockout in macrophages) mice. RESULTS: Here, we found that inhibiting OXCT1 expression in tumor-associated macrophages reduced CD8+ T-cell exhaustion through the succinate-H3K4me3-Arg1 axis. Initially, we found that OXCT1 was highly expressed in liver macrophages under steady state and that OXCT expression was further increased in TAMs. OXCT1 deficiency in macrophages suppressed tumor growth by reprogramming TAMs toward an antitumor phenotype, reducing CD8+ T-cell exhaustion and increasing CD8+ T-cell cytotoxicity. Mechanistically, high OXCT1 expression induced the accumulation of succinate, a byproduct of ketolysis, in TAMs, which promoted Arg1 transcription by increasing the H3K4me3 level in the Arg1 promoter. In addition, pimozide, an inhibitor of OXCT1, suppressed Arg1 expression as well as TAM polarization toward the protumor phenotype, leading to decreased CD8+ T-cell exhaustion and slower tumor growth. Finally, high expression of OXCT1 in macrophages was positively associated with poor survival in patients with HCC. CONCLUSIONS: In conclusion, our results demonstrate that OXCT1 epigenetically suppresses antitumor immunity, suggesting that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer. IMPACT AND IMPLICATIONS: The intricate metabolism of liver macrophages plays a critical role in shaping hepatocellular carcinoma progression and immune modulation. Targeting macrophage metabolism to counteract immune suppression presents a promising avenue for hepatocellular carcinoma treatment. Herein, we found that the ketogenesis gene OXCT1 was highly expressed in tumor-associated macrophages (TAMs) and promoted tumor growth by reprogramming TAMs toward a protumor phenotype. Pharmacological targeting or genetic downregulation of OXCT1 in TAMs enhances antitumor immunity and slows tumor growth. Our results suggest that suppressing OXCT1 activity in TAMs could be an effective approach for treating liver cancer.

Deep learning-assisted diagnosis of parotid gland tumors by using contrast-enhanced CT imaging.

OBJECTIVES: Imaging interpretation of the benignancy or malignancy of parotid gland tumors (PGTs) is a critical consideration prior to surgery in view of therapeutic and prognostic values of such discrimination. This study investigates the application of a deep learning-based method for preoperative stratification of PGTs. MATERIALS AND METHODS: Using the 3D DenseNet-121 architecture and a dataset consisting of 117 volumetric arterial-phase contrast-enhanced CT scans, we developed a binary classifier for PGT distinction and tested it. We compared the discriminative performance of the model on the test set to that of 12 junior and 12 senior head and neck clinicians. Besides, potential clinical utility of the model was evaluated by measuring changes in unassisted and model-assisted performance of junior clinicians. RESULTS: The model finally reached the sensitivity, specificity, PPV, NPV, F1-score of 0.955 (95% CI 0.751-0.998), 0.667 (95% CI 0.241-0.940), 0.913 (95% CI 0.705-0.985), 0.800 (95% CI 0.299-0.989) and 0.933, respectively, comparable to that of practicing clinicians. Furthermore, there were statistically significant increases in junior clinicians' specificity, PPV, NPV and F1-score in differentiating benign from malignant PGTs when unassisted and model-assisted performance of junior clinicians were compared. CONCLUSION: Our results provide evidence that deep learning-based method may offer assistance for PGT's binary distinction.

[Risk factors associated with chronic obstructive pulmonary disease: a comparison between urban and rural populations in Chengdu].

OBJECTIVE: To determine risk factors associated with the prevalence of chronic obstructive pulmonary disease (COPD) in urban and rural populations in Chengdu. METHODS: A multistage random cluster sampling method was adopted to select participants from four communities in Chengdu. All residents aged 40-70 yr. were eligible to participate in this study, which involved a questionnaire survey, physical examination and portable spirometry. Those with airflow limitations were also given post-bronchodilator testing 15 min after inhalation of a dose of 200 microg salbutamol. We defined a forced expiratory volume in one second/forced vital capacity (FEV1/FVC) of less than 70% as COPD. Logistic regression models were performed to identify risk factors of COPD. RESULTS: Of a total of 1931 eligible participants, 1579 (81.77%) completed the questionnaire and spirometry. About 8.35% were identified with COPD: 7.69% in urban vs. 12.37% in rural (P<0.05). The prevalence of COPD increased with age (P<0.05) in the male and total populations. Rural COPD patients had a higher level of smoking rate and use of coal as fuel for cooking than their urban counterparts (P<0.05). But rural COPD patients had a lower level of BMI, waist circumference, literacy, and average household income per capita than their urban counterparts (P<0.05). The multivariate analysis showed that tobacco smoking index (pack-year), education, age and BMI were predictors of COPD for male patients; whereas, coal fuel usage, income and BMI were predictors of COPD for female patients. CONCLUSION: COPD prevalence is higher in rural areas than in urban Chengdu. Major risk factors of COPD include smoking, coal fuels and BMI.

[Effect of oxymatrine on the distribution of dendritic cells in lung and spleen tissues of asthmatic mice].

OBJECTIVE: To study the effect of oxymatrine (Oxy) on airway inflammation and the distribution of dendritic cells (DC) in lung and spleen tissues of asthmatic mice. METHODS: Fifty BALB/c mice were assigned into five groups (n=10): an asthma model group, a dexamethasone (Dex) treatment group and three Oxy treatment groups (Oxy dose: 20, 40 and 80 mg/kg respectively). The histological changes of lung tissues were observed by hematoxylin and eosin staining. The expression of 33D1 antigen (a marker of DC) in lung and spleen tissues were detected by immunohistochemical staining. RESULTS: The inflammatory reactions of the lung tissues in the Dex or Oxy treatment groups were less severe than those in the asthma model group. 33D1 antigen was remarkably expressed in the lung and spleen tissues of the asthma model group. After Dex treatment, the expression of 33D1 antigen in the lung and spleen tissues decreased significantly (P<0.01). 33D1 antigen expression in the lung tissues was significantly reduced in all of the three Oxy treatment groups in a dose-dependent manner compared with that in the asthma model group (P<0.01). The treatment with Oxy of 40 and 80 mg/kg decreased significantly the 33D1 antigen expression in the spleen tissues (P<0.01). CONCLUSIONS: Oxy can alleviate airway inflammation and reduce the number of DC in lung and spleen tissues of asthma mice, which may be contributed to the mechanism of Oxy for treatment of asthma.

Preliminary Studies on the Application of Grape Seed Extract in the Dyeing and Functional Modification of Cotton Fabric.

Cotton has the shortcomings of having no antibacterial, antioxidant and ultraviolet (UV) protection properties, which are of great importance for health protection purposes. In the present study, grape seed extract (GSE) mainly composed of proanthocyanins (tannins) was employed to simultaneously import pale colors and the three aforementioned functions to cotton fabric. The tests on the application conditions of GSE showed that pH and GSE concentration had great impact on the color depth of cotton fabric, and the color hue of dyed fabric could be controlled in the absence of pH regulators due to the weakly acidic nature of GSE solution. The fabric dyed with 10%owf (on the weight of fabric) GSE exhibited an excellent inhibition effect towards Escherichia coli, whereas the one dyed with 20%owf GSE had high antioxidant activity of 97%. The fabric dyed with 5%owf GSE offered excellent UV protection. This study reveals that GSE can be used as a functional finishing agent for health protection in cotton textiles in addition to coloration capability.

Adsorption, Antibacterial and Antioxidant Properties of Tannic Acid on Silk Fiber.

Natural bioactive compounds have received increasing attention in the functional modification of textiles. In this work, tannic acid was used to impart antibacterial and antioxidant functions to silk using an adsorption technique, and the adsorption properties of tannic acid on silk were studied. The adsorption quantity of tannic acid on silk increased with decreasing pH in the range of 3-7. The rates of the uptake of tannic acid by silk were well correlated to the pseudo-second-order kinetic model, and the calculated activation energy of adsorption was 93.49 kJ/mol. The equilibrium adsorption isotherms followed the Langmuir model. The adsorption rate and isotherm studies demonstrated that the chemical adsorption of tannic acid on silk occurred through the ion-ion interaction between tannic acid and silk. Tannic acid displayed good building-up properties on silk. The silk fabric treated with 0.5% tannic acid (relative to fabric weight) exhibited excellent and durable antibacterial properties. Moreover, the silk fabrics treated with 2% and 5% tannic acid had good and durable antioxidant properties. The treatment by tannic acid had less impact on the whiteness of the silk fabric. In summary, tannic acid can be used as a functional agent for preparing healthy and hygienic silk materials.

Bioactive and UV protective silk materials containing baicalin - The multifunctional plant extract from Scutellaria baicalensis Georgi.

There has been a phenomenal increase in the research and development of new health and hygiene-related textile products. This work reports a novel approach to develop antibacterial, antioxidant and UV-protective silk using an adsorption technique of baicalin (a bioactive ingredient from the root of Scutellaria baicalensis Georgi). Baicalin displayed high adsorption capability at pH2.75, contributing to the sufficient functionalities on silk. The equilibrium adsorption research showed that the Langmuir isotherm was able to describe the behavior of baicalin, indicating the electrostatic interactions between the ionized carboxyl groups in baicalin and the positively charged amino groups in silk. The treated silk with 2% owf (on the weight of fiber) baicalin exhibited excellent antioxidant activity, high antibacterial activities against Escherichia coli and Staphylococcus aureus, and very good ultraviolet protection ability comparable to that of the commercial benzotriazole ultraviolet absorber. The baicalin treatment had no obvious impact on the functional groups, crystal structure and surface morphology of silk. The functionalities of the treated silk obviously declined after first laundering cycle and slowly decreased in the following washing cycles. Encouraging results demonstrate that the baicalin-functionalized silk is a promising material for protective clothing and medical textiles.