Cancer immunotherapy has been increasingly applied in the treatment of advanced malignancies. Consequently, immune checkpoints have become a major concern. As PD-1 is an important immunomodulatory protein, the blockade of PD-1 and its ligand PD-L1 is a promising tumour immunotherapy for human carcinoma. In this review, we first discuss the role of the PD-1/PD-L1 interaction in gastrointestinal tract cancers. Targeting PD-1 and PD-L1 in immune cells and tumour cells may show remarkable efficiency in gastrointestinal tract cancers. Second, the PD-1/PD-L1-associated signalling pathway involved in cancer immunotherapy in gastrointestinal tract cancers is discussed. Most importantly, this review summarizes the PD-1/PD-L1-targeted immunotherapy combinations with relevant signalling pathways, which may result in a breakthrough for the treatment of gastrointestinal tract cancers, such as gastric cancer, colorectal cancer and liver cancer. Meanwhile, the review provides a deeper insight into the mechanism of checkpoint blockade immunotherapies.
Objective To observe the effects of tissue factor pathway inhibitor(TFPI) on thrombosis formation in rabbit carotid arteries after ballon injury. Methods Fouty rabbits with the weight 2.5-3.0 kg were respectively divided into 4 groups, Ad-TFPI, Ad-LacZ, PBS and normal control groups. The normal control group was not given any treatment and other 3 groups were given 0.2 ml Ad-TFPI, Ad-LacZ or PBS reproduced by the Dispatch catheter respectively after the PTCA balloon iniury on the right carotid arteries. Ten days after gene transfer the repeated balloon injury was performed in the 3 groups, and the first balloon injury was performed in the normal control group by the same method. The carotid blood flow was recovered immediately after the injury. Thirty minutes later all the animals were sacrificed. The injured carotid arteries and one part of contralateral normal artery were cut down, scissored along the long axis, flattened and fixed in the 2% glutaral. The platelet aggregation and thrombosis formation on the luminal surfaces was observed under electron microscope. Results The electron microscope results showed that the vascular endothelial cell structure was integrated and lined up in order in the nomal artery which had no any injury. After the balloon injury in the normal control group, the structure of the endothelial cell was disintegrated, and there was some platelet aggregation but no fibrosis formation. A large amount of platelet aggregated but no fibrosis formed in Ad-TFPI group after the repeated balloon injury. A large amount of fibrosis formed and red cells piled up in the Ad-LacZ and PBS group. The positive rate of thrombosis formation among groups had siginificant differences(χ2=14.95, P 0.05). The positive rate in Ad-LacZ group(80%) was higher than in the normal control group(10%, χ2=9.90, P 0.05). The positive rate in PBS group(70%) was higher than that in the normal control group(10%, χ2=7.50, P< 0.01). Conclusions The repeated balloon injury method can cause a large amount of fibrosis formation in the rabbit carotid. TFPI gene inhibits thrombosis formation in balloon-injured rabbit carotid arteries.
Key words:
Tissue factor pathway inhibitor; Gene therapy; Carotid artery injuries; Thrombosis formation; Microscopy; electron; scanning
Abstract MicroRNA‐143‐3p (miR‐143‐3p) is involved in the initiation of inflammatory response and the progression of cardiovascular diseases. Myocardial hypertrophy is a common symptom in numerous cardiovascular diseases. In the current study, we attempted to demonstrate the role of miR‐143‐3p in the development of myocardial hypertrophy by focusing on its association with inflammation. Myocardial hypertrophy was induced by transverse aortic constriction (TAC) method in vivo and by H 2 O 2 administration in vitro. The expression status of miR‐143‐3p and downstream effectors were detected in animal heart tissues and H9c2 cells. Furthermore, the effect of miR‐143‐3p inhibition on H 2 O 2 ‐induced changes in ERK5/PPARδ/NF‐κB axis was assessed. TAC induced oxidative stress and inflammation in rat heart tissues, which was associated with the increased expressions of miR‐143‐3p and p‐ERK5. However, the up‐regulated expression of miR‐143‐3p had no effect on the expression of ERK5, which was a direct target of miR‐143‐3p. The results of in vitro assays showed that H 2 O 2 administration increased the levels of miR‐143‐3p and p‐EKR5 and induced the activation of NF‐κB pathway. After the inhibition of miR‐143‐3p, the activation of EKR5 and NF‐κB pathway was suppressed, whereas the expression of PPARδ was up‐regulated. The current study demonstrated that miR‐143‐3p is crucial to the initiation of inflammatory response induced by myocardial hypertrophy. The activation of ERK5 following miR‐143‐3p up‐regulation appears to be a complementary response to induce the subsequent anti‐inflammatory signaling transduction, which needed further exploration.
Abstract Objective: By combining the expression profiles of metabolism-related genes (MRGS) with clinical information, the expression quantities of MRGS and the influence on development and prognosis were systematically analyzed, so as to provide a theoretical basis for the clinical study on the prognosis of Ewing's sarcoma.Methods: MRGs expression profiles of 64 patients with Ewing's sarcoma were obtained from the GEO dataset. Univariate Cox regression analysis was used to identify metabolization-related differentially expressed genes (DEGs) related with prognosis in Ewing's sarcoma patients. Then, multivariate Cox analysis was used to calculate novel prognostic markers based on metabolism-related DEGs. Finally, the new prognostic index was verified on the basis of the prognostic models.Results: Univariate Cox regression analysis identified 20 metabolization-related DEGs, 9 of which were significantly associated with Ewing's sarcoma patients' overall survival. Subsequently, we used nine metabolism-related DEGs to construct metabolism-related prognostic signature for patients with Ewing's sarcoma. Based on the 9 DEGs regression coefficient, we put forward the formula of each patient's risk score, and then divided the patients into high-risk group and low-risk group. The results indicated that the survival rate and survival time were higher in the low-risk group and lower in the high-risk group. Multivariate Cox analysis showed that risk score index was indeed an independent prognostic factor for Ewing's sarcoma. In addition, the area under the receiver operating characteristic (ROC) curve for overall survival was 0.985. And a nomogram model was established.Conclusion: The experimental results suggest that the 9 metabolism-related DEGs marker may be effective in predicting the prognosis of Ewing's sarcoma to some extent, helping to individualize treatment of patients at different risks.
Myocardial infarction (MI) is an unsolved health problem which seriously affects human health around the world. miR-34a-5p acting as a tumor-suppressor is associated with left ventricular remodeling. We aimed to explore the functional roles of miR-34a-5p in cardiomyocytes. Hypoxia-induced cell injury in H9c2, HL-1 and human cardiac myocytes was analyzed according to the decrease of cell viability and increase of apoptosis. Expression of miR-34a-5p was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR) when the concentration of O2 was decreased. Then, the effects of aberrantly expressed miR-34a-5p on proliferation and apoptosis of cardiomyocytes incubated under hypoxia were assessed. Finally, the downstream protein and signaling pathways of miR-34a-5p were explored. The hypoxic model was successfully constructed after incubation under hypoxia for 48 h. When the concentration of O2 decreased, the miR-34a-5p level was increased significantly. Then, we found miR-34a-5p aggravated hypoxia-induced alterations of proliferation and apoptosis in cardiomyocytes. Zinc finger E-box binding homeobox 1 (ZEB1) was identified as a target of miR-34a-5p, and miR-34a-5p conferred its function via targeting ZEB1. Finally, miR-34a-5p inhibition reversed hypoxia-induced decreases of phosphorylated kinases in the JAK/STAT and PI3K/AKT pathways through up-regulating ZEB1. Our study revealed that miR-34a-5p inhibition protected cardiomyocytes against hypoxia-induced cell injury through activating the JAK/STAT and PI3K/AKT pathways by targeting ZEB1.
Colorectal cancer (CRC) remains one of the most common cancers worldwide. HS1-associated protein X-1 (HAX-1) has been highlighted as an important marker in many types of cancers. However, little is known about the role of HAX-1 in CRC. The aim of this study was to analyze the correlation of HAX-1 expression with the clinicopathological features of CRC. The protein and mRNA levels of HAX-1 were examined by immunohistochemistry (IHC) and real-time quantitative reverse-transcriptase polymerase chain reaction (RT-qPCR) in CRC tissues and adjacent noncancerous tissues. Survival curves were made with follow-up data. The relations of the prognosis with clinical and pathological characteristics were analyzed. Using IHC and RT-qPCR, we showed that HAX-1 expression was significantly higher in CRC tissues than in adjacent noncancerous tissues (P < 0.05). High HAX-1 expression was significantly associated with lymph node metastasis (P = 0.034) and tumor (T) node (N) metastasis (M) stage (P = 0.028) of patients with CRC. The Kaplan-Meier survival curves indicated that overall survival was significantly worse in CRC patients with HAX-1 overexpression. Multivariate analysis showed that high HAX-1 expression was an independent predictor of overall survival. In conclusion, our data for the first time provide a basis for the concept that overexpression of HAX-1 may contribute to the malignant progression of CRC and predict poor prognosis for patients with this disease. HAX-1 might be an important marker for tumor progression and prognosis, as well as a potential therapeutic target of CRC.
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