V-doped MoS2 nanozymes providing reactive oxygen species and depleting glutathione for photothermally-enhanced nanocatalytic therapy.

Introduction: The tumor microenvironment and multidrug resistance of tumor cells seriously impair the activity of the nanozymes. Methods: Herein, a polyethylene glycol (PEG)-modified vanadium-doped molybdenum disulfide (V-MoS2@PEG) nanozymes were constructed to enhance anti-tumor activity through multi-enzymatic catalysis and photothermal effect with simultaneous reactive oxygen species replenishment and glutathione depletion. Results and discussion: V-MoS2@PEG nanosheets exerted peroxidase activity by causing molybdenum ion (Mo4+) to react with hydrogen peroxide to form toxic hydroxyl radicals (·OH). Meanwhile, the V-doping can deplete glutathione avoiding ·OH consumption. In addition, the high heat generated by V-MoS2@PEG nanozymes under near-infrared laser irradiation brought about a desirable local temperature gradient, which produced an enhanced catalytic effect by promoting band bending. Furthermore, the photothermally inspired polarized charge increased the permeability of the tumor cell membrane and promoted further aggregation of the nanozymes, which realized the combination of photothermal therapy with multi-enzymatic catalysis, solved the problem of multi-enzyme catalysis, and improved the anti-tumor efficiency.

Superparamagnetic Iron Oxide-Erastin-Polyethylene Glycol Nanotherapeutic Platform: A Ferroptosis-Based Approach for the Integrated Diagnosis and Treatment of Nasopharyngeal Cancer.

Erastin can induce ferroptosis in tumor cells as an effective small molecule inhibitor. However, its application is hampered by a lack of water solubility. This study investigated the effects of superparamagnetic iron oxide (SPIO)-erastin-polyethylene glycol (PEG) nanoparticles prepared by loading SPIO-PEG nanoparticles with erastin on ferroptosis. SPIO-erastin-PEG nanoparticles exhibited square and spherical shapes with good dispersibility. The zeta potential and hydrodynamic size of SPIO-erastin-PEG were measured as (-37.68 ± 2.706) mV and (45.75 ± 18.88) nm, respectively. On T2-weighted imaging, the nanosystem showed significant contrast enhancement compared to no-enhancement magnetic resonance imaging (MRI). SPIO-erastin-PEG induced ferroptosis by increasing reactive oxygen species and iron content and promoting the accumulation of lipid peroxides and the degradation of glutathione peroxidase 4. Pharmacokinetic experiments revealed a half-life of 1.25 ± 0.05 h for the SPIO-erastin-PEG solution in circulation. Moreover, significant antitumorigenic effects of SPIO-erastin-PEG have been demonstrated in 5-8F cells and mouse-bearing tumors. These results indicated that the synthesized SPIO-erastin-PEG nanoplatform could induce ferroptosis effects in vitro and in vivo while exhibiting favorable physical characteristics. This approach may provide a new strategy for theranostic nanoplatform for nasopharyngeal cancer.

Precision USPIO-PEG-SLex Nanotheranostic Agent Targeted Photothermal Therapy for Enhanced Anti-PD-L1 Immunotherapy to Treat Immunotherapy Resistance.

Background: The anti-Programmed Death-Ligand 1 (termed aPD-L1) immune checkpoint blockade therapy has emerged as a promising treatment approach for various advanced solid tumors. However, the effect of aPD-L1 inhibitors limited by the tumor microenvironment makes most patients exhibit immunotherapy resistance. Methods: We conjugated the Sialyl Lewis X with a polyethylene glycol-coated ultrasmall superparamagnetic iron oxide (USPIO-PEG) to form UPS nanoparticles (USPIO-PEG-SLex, termed UPS). The physicochemical properties of UPS were tested and characterized. Transmission electron microscopy and ICP-OES were used to observe the cellular uptake and targeting ability of UPS. Flow cytometry, mitochondrial membrane potential staining, live-dead staining and scratch assay were used to verify the in vitro photothermal effect of UPS, and the stimulation of UPS on immune-related pathways at the gene level was analyzed by sequencing. Biological safety analysis and pharmacokinetic analysis of UPS were performed. Finally, the amplification effect of UPS-mediated photothermal therapy on aPD-L1-mediated immunotherapy and the corresponding mechanism were studied. Results: In vitro experiments showed that UPS had strong photothermal therapy ability and was able to stimulate 5 immune-related pathways. In vivo, when the PTT assisted aPD-L1 treatment, it exhibited a significant increase in CD4+ T cell infiltration by 14.46-fold and CD8+ T cell infiltration by 14.79-fold, along with elevated secretion of tumor necrosis factor-alpha and interferon-gamma, comparing with alone aPD-L1. This PTT assisted aPD-L1 therapy achieved a significant inhibition of both primary tumors and distant tumors compared to the alone aPD-L1, demonstrating a significant difference. Conclusion: The nanotheranostic agent UPS has been introduced into immunotherapy, which has effectively broadened its application in biomedicine. This photothermal therapeutic approach of the UPS nanotheranostic agent enhancing the efficacy of aPD-L1 immune checkpoint blockade therapy, can be instructive to address the challenges associated with immunotherapy resistance, thereby offering potential for clinical translation.

Targeted Delivery of Active Sites by Oxygen Vacancy-Engineered Bimetal Silicate Nanozymes for Intratumoral Aggregation-Potentiated Catalytic Therapy.

Biodegradable silicate nanoconstructs have aroused tremendous interest in cancer therapeutics due to their variable framework composition and versatile functions. Nevertheless, low intratumoral retention still limits their practical application. In this study, oxygen vacancy (OV)-enriched bimetallic silicate nanozymes with Fe-Ca dual active sites via modification of oxidized sodium alginate and gallic acid (GA) loading (OFeCaSA-V@GA) were developed for targeted aggregation-potentiated therapy. The band gap of silica markedly decreased from 2.76 to 1.81 eV by codoping of Fe3+ and Ca2+, enabling its excitation by a 650 nm laser to generate reactive oxygen species. The OV that occurred in the hydrothermal synthetic stage of OFeCaSA-V@GA can anchor the metal ions to form an atomic phase, offering a massive fabrication method of single-atom nanozymes. Density functional theory results reveal that the Ca sites can promote the adsorption of H2O2, and Fe sites can accelerate the dissociation of H2O2, thereby realizing a synergetic catalytic effect. More importantly, the targeted delivery of metal ions can induce a morphological transformation at tumor sites, leading to high retention (the highest retention rate is 36.3%) of theranostic components in tumor cells. Thus, this finding may offer an ingenious protocol for designing and engineering highly efficient and long-retention nanodrugs.

Chinese expert consensus on imaging diagnosis of drug-resistant pulmonary tuberculosis.

Tuberculosis (TB) remains one of the major infectious diseases in the world with a high incidence rate. Drug-resistant tuberculosis (DR-TB) is a key and difficult challenge in the prevention and treatment of TB. Early, rapid, and accurate diagnosis of DR-TB is essential for selecting appropriate and personalized treatment and is an important means of reducing disease transmission and mortality. In recent years, imaging diagnosis of DR-TB has developed rapidly, but there is a lack of consistent understanding. To this end, the Infectious Disease Imaging Group, Infectious Disease Branch, Chinese Research Hospital Association; Infectious Diseases Group of Chinese Medical Association of Radiology; Digital Health Committee of China Association for the Promotion of Science and Technology Industrialization, and other organizations, formed a group of TB experts across China. The conglomerate then considered the Chinese and international diagnosis and treatment status of DR-TB, China's clinical practice, and evidence-based medicine on the methodological requirements of guidelines and standards. After repeated discussion, the expert consensus of imaging diagnosis of DR-PB was proposed. This consensus includes clinical diagnosis and classification of DR-TB, selection of etiology and imaging examination [mainly X-ray and computed tomography (CT)], imaging manifestations, diagnosis, and differential diagnosis. This expert consensus is expected to improve the understanding of the imaging changes of DR-TB, as a starting point for timely detection of suspected DR-TB patients, and can effectively improve the efficiency of clinical diagnosis and achieve the purpose of early diagnosis and treatment of DR-TB.

Regional lymph node density-based nomogram predicts prognosis in nasopharyngeal carcinoma patients without distant metastases.

BACKGROUND: Nasopharyngeal carcinoma (NPC) is a relatively common type of cancer in Southern China, with local recurrence or distant metastases even after radical treatment; consequently, it is critical to identify the patients at higher risk for these events beforehand. This study aimed to assess the prognostic value of regional lymph node density (RLND) associated nomograms in NPC and to evaluate the utility of nomograms in risk stratification. METHODS: A total of 610 NPC patients without distant metastases (425 in the training and 185 in the validation cohort) were enrolled. The MRI-identified nodal features and clinical characteristics were documented, and the RLND was calculated. Cox analyses were conducted to identify prognostic-associated factors. Nomograms were generated based on the multivariate analysis results. The predictive accuracy and discriminative ability of the nomogram models were determined using the concordance index (C-index), receiver operating characteristic (ROC) curve, and calibration curve; the results were compared with those of the tumor-node-metastasis (TNM) classification. Decision curve analysis (DCA) and C-index were used to assess the prognostic effect and added discriminative ability of RLND. We also estimated the optimal RLND-based nomogram score cut-off values for survival prediction. RESULTS: RLND was an independent predictor of overall survival (OS) and disease-free survival (DFS), with hazard ratios of 1.36 and 1.30, respectively. RLND was utilized in the construction of nomograms, alongside other independent prognostic factors. The RLND-based nomogram models presented a more effective discriminative ability than the TNM classification for predicting OS (C-index, 0.711 vs. 0.680) and DFS (C-index, 0.681 vs. 0.669), with favorable calibration and consistency. The comparison of C-index values between the nomogram models with and without RLND provided substantiation of the crucial role RLND plays in these models. DCA confirmed the satisfactory clinical practicability of RLND. Moreover, the nomograms were used to categorize the patients into three groups (high-, middle-, and low-risk), and the Kaplan-Meier curves showed significant differences in prognosis between them (p < 0.05). These results were verified in the validation cohort. CONCLUSION: RLND stands as a robust prognostic factor in NPC. The RLND-based nomograms excel in predicting survival, surpassing the TNM classification.

A three-gene signature reveals changes in the tumor immune microenvironment in the progression from NAFLD to HCC.

Hepatocellular carcinoma (HCC) is one of the most dangerous malignant tumors. The incidence rates of obesity related NAFLD and NASH are increasing year by year, and they are the main risk factors for HCC at present. Finding the mechanism of malignant transformation of NAFLD and NASH is helpful for early prevention and diagnosis. In this study, we performed differential analysis using NAFLD data, NASH data, and HCC data to identify crossover differential genes. Then, using the clinical data of TCGA, a prognostic risk prediction model of three genes (TEAD4, SOCS2, CIT) was constructed, and survival analysis and receiver operating characteristic curves were drawn. The prognostic model was validated using ICGC, GSE116174 and GSE54236 datasets. In addition, we assessed immune status and function in high- and low-risk populations using a prognostic model. Moreover, we assessed the expression of CIT in clinical samples and HCC cell lines and validated its role in HCC development. Our study elucidates the important role of the tumor immune microenvironment in the development of NAFLD/NASH to HCC, deepens the understanding of the pathogenesis of NAFLD/NASH development to HCC, and is helpful for clinical management and decision-making.

Diagnostic value of a CT-based radiomics nomogram for discrimination of benign and early stage malignant ovarian tumors.

BACKGROUND: This study aimed to identify the diagnostic value of models constructed using computed tomography-based radiomics features for discrimination of benign and early stage malignant ovarian tumors. METHODS: The imaging and clinicopathological data of 197 cases of benign and early stage malignant ovarian tumors (FIGO stage I/II), were retrospectively analyzed. The patients were randomly assigned into training data set and validation data set. Radiomics features were extracted from images of plain computed tomography scan and contrast-enhanced computed tomography scan, were then screened in the training data set, and a radiomics model was constructed. Multivariate logistic regression analysis was used to construct a radiomic nomogram, containing the traditional diagnostic model and the radiomics model. Moreover, the decision curve analysis was used to assess the clinical application value of the radiomics nomogram. RESULTS: Six textural features with the greatest diagnostic efficiency were finally screened. The value of the area under the receiver operating characteristic curve showed that the radiomics nomogram was superior to the traditional diagnostic model and the radiomics model (P < 0.05) in the training data set. In the validation data set, the radiomics nomogram was superior to the traditional diagnostic model (P < 0.05), but there was no statistically significant difference compared to the radiomics model (P > 0.05). The calibration curve and the Hosmer-Lemeshow test revealed that the three models all had a great degree of fit (All P > 0.05). The results of decision curve analysis indicated that utilization of the radiomics nomogram to distinguish benign and early stage malignant ovarian tumors had a greater clinical application value when the risk threshold was 0.4-1.0. CONCLUSIONS: The computed tomography-based radiomics nomogram could be a non-invasive and reliable imaging method to discriminate benign and early stage malignant ovarian tumors.

A Clinical-Radiomics Nomogram Based on Magnetic Resonance Imaging for Predicting Progression-Free Survival After Induction Chemotherapy in Nasopharyngeal Carcinoma.

Purpose: This paper aimed to establish and verify a radiomics model based on magnetic resonance imaging (MRI) for predicting the progression-free survival of nasopharyngeal carcinoma (NPC) after induction chemotherapy (IC). Materials and Methods: This cohort consists of 288 patients with clinical pathologically confirmed NPC, which was collected from January 2015 to December 2018. All NPC patients were randomly divided into two cohorts: training (n=202) and validation (n=86). Radiomics features from the MRI images of NPC patients were extracted and selected before IC. The patients were classified into high- and low-risk groups according to the median of Radscores. The significant imaging features and clinical variables in the univariate analysis were constructed for progression-free survival (PFS) using the multivariate Cox regression model. A survival analysis was performed using Kaplan-Meier with log-rank test and then each model's stratification ability was evaluated. Results: Epstein-Barr virus (EBV) DNA before treatment was an independent predictor for PFS (p < 0.05). Based on the pyradiomic platform, we extracted 1,316 texture parameters in total. Finally, 16 texture features were used to build the model. The clinical radiomics-based model had good prediction capability for PFS, with a C-index of 0.827. The survival curve revealed that the PFS of the high-risk group was poorer than that of the low-risk group. Conclusion: This research presents a nomogram that merges the radiomics signature and the clinical feature of the plasma EBV DNA load, which may improve the ability of preoperative prediction of progression-free survival and facilitate individualization of treatment in NPC patients before IC.