Analysis and prediction of the efficacy and influencing factors of camrelizumab combined with TACE and sorafenib in the treatment of advanced hepatocellular carcinoma.

BACKGROUND: TACE combined with targeted therapy is a method for the treatment of hepatocellular carcinoma. After adding camrelizumab, some patients had gained benefits, but some patients have produced serious adverse reactions. Therefore, more studies are needed to prove the efficacy and adverse reactions, and prediction models are needed to help with decision-making. METHODS: With ethics committee approval, a bi-center retrospective study was finished. A total of 235 patients were enrolled and divided into the treatment group of camrelizumab combined with TACE and sorafenib and the treatment group of TACE and sorafenib. The survival rate, short-term efficacy and adverse reactions were compared, and the efficacy prediction model was established. RESULTS: The 2-year survival time and objective response rate of the treatment group of camrelizumab combined with TACE plus sorafenib were higher than those of TACE plus sorafenib. Camrelizumab increased the proportion of reactive capillary proliferation, but had no effect on other adverse reactions. The established nomogram can accurately predict the response to the treatment. CONCLUSIONS: Camrelizumab combined with TACE and sorafenib can improve the survival rate of patients with hepatocellular carcinoma, and it is an effective treatment. The nomogram model can predict the efficacy, which is beneficial for patients.

Human umbilical cord mesenchymal stem cell-derived exosomes promote microcirculation in aged diabetic mice by TGF-ß1 signaling pathway.

BACKGROUND: Microvascular dysfunction is one of the most common pathological characteristics in Type 2 diabetes. Human mesenchymal stem cell-derived exosomes (hUCMSCs-Exo) have diverse functions in improving microcirculation; however, the molecular mechanism of hUCMSCs-Exo in regulating burn-induced inflammation is not well understood. METHODS: hUCMSCs-Exo were extracted by hypervelocity centrifugation method, and exosome morphology was observed by transmission electron microscopy, exosome diameter distribution was detected by particle size analysis, and exosome specific proteins were identified by Western blot.2. DB/DB mice were randomly divided into exosomes group and PBS group. Exosomes and PBS were injected into the tail vein, respectively, and the calf muscle tissue was taken 28 days later. 0.5% Evans blue fluorescence assessment microvascular permeability. The expression of CD31 was detected by immunofluorescence.The morphology and function of microvessels in muscle tissue of lower limbs was evaluated by transmission electron microscopy.3. TMT proteomics was used to detect the changes of differential protein expression in lower limb muscle tissues of the PBS group and the exosome group, and data analysis was performed to screen key signal molecules and their involved biological pathways. Key signal molecules CD105 were verified by Western blot. The expression of TGF-ß1 in exosomes were evaluated by Western blot. RESULTS: Electron microscopy showed that hUCMSCs-Exo presented a uniform vesicle structure, and NTA showed that its diameter was about 160 nm. Western blot showed positive expression of specific proteins CD9, CD81 and TSG101 on exosomes.2. There is no significant change in blood glucose and body weight before and after the exosome treatment. The exosome group can significantly reduce the exudation of Evans blue. Compared with the PBS group. Meanwhile, CD31 immunofluorescence showed that the red fluorescence of exosome treatment was significantly increased, which was higher than that of PBS group. Transmission electron microscopy showed smooth capillary lumen and smooth and complete surface of endothelial cells in the exosome group, while narrow capillary lumen and fingerlike protrusion of endothelial cells in the PBS group.3.Quantitative analysis of TMT proteomics showed that there were 82 differential proteins, including 49 down-regulated proteins and 33 up-regulated proteins. Go enrichment analysis showed that the differential proteins were involved in molecular function, biological process, cell components,among which CD105 was one of the up-regulated proteins. Through literature search, CD105 was found to be related to endothelial cell proliferation. Therefore, this study verified the changes of CD105 in the exosome group, and it was used as the mechanism study of this study. 4. Western blot analysis showed that the expression of CD105 protein in lower limb muscle tissue of exosome group was significantly increased compared with that of PBS group. Based on the fact that CD105 is a component of the TGF-ß1 receptor complex and exosomes are rich in growth factors and cytokines, this study further examined the expression of TGF-ß1 in exosomes, and the results showed that exosomes had high expression of TGF-ß1. CONCLUSION: By improving the integrity of microvascular endothelial cells, hUCMSCs-Exo can improve the permeability of microvessels in diabetic lower muscle tissue, further promote the proliferation of lower limb muscle cells and inhibit the apoptosis of tissue cells. The mechanism may be associated with exosomes rich in TGF-ß1, which is likely to promote endothelial cell proliferation and improve permeability through binding to the endothelial CD105/TßR-II receptor complex, while promoting angiogenesis and protecting skeletal muscle cells from apoptosis.

Human Placenta-Derived Mesenchymal Stem Cells Ameliorate Diabetic Neuropathy via Wnt Signaling Pathway.

Objectives: To investigate the effect of placenta-derived mesenchymal stem cells (PMSCs) on diabetic peripheral neuropathy and explore the role of Wnt signaling pathway. Method: Twenty-seven male db/db mice were randomly categorized into the control group, PMSC group, and PMSC treatment with Wnt inhibitor treatment group. Intervention was initiated in week 22. Thermal stimulation response was determined with a plantar analgesia tester. The mice were sacrificed on 7, 14, and 28 days. The morphology of sciatic nerves was observed by electron microscopy, and the expression of protein gene product (PGP) 9.5, S100ß, and Ku80 was detected by immunofluorescence. Bax, ß-catenin, and dishevelled1 (DVL1) were detected by western blot. Results: Thermal stimulation response was improved in the PMSC group on 14 and 28 days. Compared with the control group, PGP9.5 was increased in the PMSC group, accompanied by a significant increase in the expression of S100ß. On the contrary, LGK974 inhibited the effect of PMSCs on thermal stimulation response and the expression of PGP9.5 and S100ß. Both PGP9.5 and S100ß were correlated with Ku80 in fluorescence colocalization. The myelin sheath of sciatic nerves in the PMSC group was uniform and dense compared with that in the control group. The effects of PMSCs promoting myelin repair were significantly inhibited in the PMSC+LGK974 group. Bax in the PMSC group expressed less than the control group. In contrast, the expressions of ß-catenin and DVL1 were higher compared with that in the control group on the 14th and 28th days. The expression of DVL1 and ß-catenin was lower in the PMSC+LGK974 group than in the PMSC group. Conclusions: PMSCs improved the symptoms of diabetic peripheral neuropathy, along with the improvement of nerve myelin lesions, promotion of nerve regeneration, and activation of Schwann cells, which might be related to the regulation of Wnt signaling pathway and inhibition of apoptosis.

LncRNA OIP5-AS1 promotes cell proliferation and migration and induces angiogenesis via regulating miR-3163/VEGFA in hepatocellular carcinoma.

Long noncoding RNAs (lncRNAs) have been reported to play a significant role in the occurrence and progression of tumors. In different tumors, they can either act as an oncogene or tumor suppressor via modulating various target mRNAs. OIP5-AS1 belongs to lncRNA family. It has been reported to be involved in the tumorigenesis of some cancers, such as bladder cancer, gastric cancer, and multiple myeloma. However, the role it plays in hepatocellular carcinoma (HCC) remains unclear. This study aims to explore the inherent mechanism of lncRNA OIP5-AS1 in HCC. In the first place, qRT-PCR found that OIP5-AS1 and VEGFA expressions were significantly increased while miR-3163 was obviously reduced in HCC cells and tissues. Next, a series of functional experiments found that knockdown of OIP5-AS1 suppressed HCC cell proliferation, migration and angiogenesis abilities while promoting cell apoptosis simultaneously. Last but not least, miR-3163 inhibition or VEGFA overexpression can reverse the anti-tumor effect of OIP5-AS1. In summary, OIP5-AS1 affects HCC proliferation, metastasis, and angiogenesis in HCC by regulating VEGFA expression through sponging miR-3163.