Progress in the application of exosomes as therapeutic vectors in tumor-targeted therapy.

Cancer is the second leading cause of death in the world with a high annual incidence level. Researchers have been working on developing treatments for cancer. Targeted therapy is an emerging treatment modality that is more novel than surgery, radiotherapy and chemotherapy. In targeted therapy, exogenous nanoscale microparticles are applied as carriers for drugs or genes. However, conventional particles have certain limitations attributed to non-specific cytotoxicity, biocompatibility and low delivery efficacy in individual therapeutic vector systems. Exosomes are small vesicles secreted by various cells that consist of lipid bilayer membranes without organelles. Due to their excellent biocompatibility, exosomes have received increased attention in recent years for targeted therapy applications. This review briefly introduces the current status of targeted therapy, and exosomes are introduced by their structural characteristics, physiological effects and separation methods. This review also discusses the applications of engineered exosomes derived from different cells in the field of targeted therapies and compares the two-way regulation of mesenchymal stromal cell-derived exosomes in tumor therapy.

The upregulation of Annexin A2 by TLR4 pathway facilitates lipid accumulation and liver injury via blocking AMPK/mTOR-mediated autophagy flux during the development of non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide. In this study, we aimed to investigate the role and regulatory mechanism of Annexin A2 (ANXA2) in the pathogenesis of NAFLD. METHODS: Histological analyses and ELISA were used to illuminate the expression of ANXA2 in NAFLD and healthy subjects. The role of ANXA2 was evaluated using high-fat diet (HFD)-fed mice via vein injection of adeno-associated viruses (AAV) knocking down ANXA2 or non-targeting control (NC) shRNAs. Moreover, HepG2 and LO2 cells were employed as in vitro hepatocyte models to investigate the expression and function of ANXA2. RESULTS: ANXA2 was confirmed to be one of three hub genes in liver injury, and its expression was positively correlated with NAFLD activity score (NAS) and macrophage infiltration in NAFLD. Moreover, ANXA2 was significantly upregulated in NAFLD patients and HFD-fed mice. LPS/TLR4 pathway strongly upregulated ANXA2 expression, which is mediated by direct ANXA2 promoter binding by TLR4 downstream NF-κB p65 and c-Jun transcription factors. Increased ANXA2 expression was correlated with decreased autophagy flux and autophagy was activated by the depletion of ANXA2 in the models of NAFLD. Furthermore, ANXA2 interference led to the activation of AMPK/mTOR signaling axis, which may play a causal role in autophagy flux and the amelioration of steatosis. CONCLUSIONS: ANXA2 is a pathological predictor and promising therapeutic target for NAFLD. ANXA2 plays a crucial role in linking inflammation to hepatic metabolic disorder and injury, mainly through the blockage of AMPK/mTOR-mediated lipophagy.

Prediction models for clear cell renal cell carcinoma ISUP/WHO grade: comparison between CT radiomics and conventional contrast-enhanced CT.

OBJECTIVE: Comparing the prediction models for the ISUP/WHO grade of clear cell renal cell carcinoma (ccRCC) based on CT radiomics and conventional contrast-enhanced CT (CECT). METHODS: The corticomedullary phase images of 119 cases of low-grade (I and II) and high-grade (III and IV) ccRCC based on 2016 ISUP/WHO pathological grading criteria were analyzed retrospectively. The patients were randomly divided into training and validation set by stratified sampling according to 7:3 ratio. Prediction models of ccRCC differentiation were constructed using CT radiomics and conventional CECT findings in the training setandwere validated using validation set. The discrimination, calibration, net reclassification index (NRI) and integrated discrimination improvement index (IDI) of the two prediction models were further compared. The decision curve was used to analyze the net benefit of patients under different probability thresholds of the two models. RESULTS: In the training set, the C-statistics of radiomics prediction model was statistically higher than that of CECT (p < 0.05), with NRI of 9.52% and IDI of 21.6%, both with statistical significance (p < 0.01).In the validation set, the C-statistics of radiomics prediction model was also higher but did not show statistical significance (p = 0.07). The NRI and IDI was 14.29 and 33.7%, respectively, both statistically significant (p < 0.01). Validation set decision curve analysis showed the net benefit improvement of CT radiomics prediction model in the range of 3-81% over CECT. CONCLUSION: The prediction model using CT radiomics in corticomedullary phase is more effective for ccRCC ISUP/WHO grade than conventional CECT. ADVANCES IN KNOWLEDGE: As a non-invasive analysis method, radiomics can predict the ISUP/WHO grade of ccRCC more effectively than traditional enhanced CT.

Progress of Exosomes in the Diagnosis and Treatment of Pancreatic Cancer.

Pancreatic cancer (PC) is a digestive system tumor that is highly malignant, with an increasing incidence rate, poor prognosis, and a low 5-year survival rate. The overwhelming majority of patients with PC are in an advanced stage at the time of diagnosis and have lost the opportunity for radical surgery. The efficacy of radiotherapy and chemotherapy for PC is very poor. Therefore, it is of great significance to explore the mechanisms of PC development and new therapeutic targets. Exosomes are extracellular vesicles that mediate the exchange of substances and information between cells. In recent years, exosomes have been shown to play a key role in the development and progression of PC and might be useful for both its diagnosis and treatment. This article reviews the composition and function of exosomes and their roles in the development, diagnosis, and treatment of PC.

CCL2 expression correlates with Snail expression and affects the prognosis of patients with gastric cancer.

We aim to explore the associations of CCL2 and Snail in gastric cancer to the clinicopathologic features and prognosis of gastric cancer (GC). In our study, the expression of CCL2 and Snail in clinical specimens of 178 GC patients was detected by immunohistochemistry. High expression of CCL2 and Snail were closely related to the clinicopathologic features. The results showed there is a link between CCL2 and Snail expression at protein levels (Pearson Χ2=40.751, P<0.001). The Kaplan-Meier survival analysis showed that CCL2 or Snail expression was correlated with 5-year survival rate (P<0.001, P<0.001, respectively). Univariate analysis showed that CCL2, Snail, pTNM stage, depth of invasion, nodal involvement, metastasis and tumor diameter were significantly associated with 5-year survival rate respectively. Multivariate Cox analysis showed that the CCL2, Snail and nodal involvement were independent prognostic factor for patients with GC. In conclusion, the expression of CCL2 is significantly correlated with Snail expression and may be used as a predictive co-biomarker for patient prognosis and tumor aggressiveness in GC. The exactly mechanism between CCL2 and Snail in the process of EMT in GC need further investigation.