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Tumor microenvironment plays vital roles in shaping cancer diversity, and CD73 (ecto-5′-nucleotidase; NT5E) is an emerging immune checkpoint in modulating cancer progression via conversion of immunostimulatory ATP into immunosuppressive adenosine. However, how the CD73 is regulated and how it functions in the progression of cancer are largely unknown. Here, we showed that CD73 was overexpressed and correlated with poor prognosis of gastric cancer. CD73 links adenosinergic signaling in microenvironment switching to induction of epithelial-to-mesenchymal transition phenotype in gastric cancer during metastasis. Further pathway and gene set enrichment analysis of transcriptome data revealed the modulation role of CD73 in RICS/RhoA signaling by its extracellular function in adenosinergic pathway, which subsequently inhibited phosphorylation of LIMK/cofilin and promoted β-catenin activation. Pharmacological inhibition of CD73 adenosinergic signaling was found to induce RICS dysfunction. Dissemination and hematogenous metastasis model showed that targeting CD73 in gastric cancer could suppress experimental metastasis. To conclude, it substantiates CD73 as a target for treatment of gastric cancer metastasis and verifies RICS as an intracellular functional molecule linking CD73/adenosinergic signaling switching to RhoA/LIMK/cofilin pathway.

This study aimed to analyze the early and mid-term outcomes of aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation.From January 2015 to March 2018, 36 patients (19 men; mean ± standard deviation [SD] age, 46.70 ± 16.60 years) underwent aortic valve replacement with bovine pericardium. The bovine pericardium was intraoperatively measured and shaped using an Ozaki template, according to the shape and size of the individual patient's aortic valve leaflets. Additional procedures were performed, including ventricular septal defect repair in 5 cases, mitral valve reconstruction in 6 cases, tricuspid valve reconstruction in 6 cases, and coronary artery bypass grafting in 3 cases.There were no perioperative deaths. One elderly patient with postoperative respiratory failure recovered after symptomatic treatment. One patient with frequent ventricular tachycardia after intraoperative cardiac re-jump underwent intra-aortic balloon counterpulsation (IABP), and the IABP device was successfully removed on the second postoperative day. Within the first 6 months of follow-up, there were no death events, no reoperation events, and no additional thromboembolic events. Follow-up echocardiography was performed for 6 months, with average left ventricular ejection fraction of 62.01 ± 3.21%, mean transvalvular pressure gradient of 11.17 ± 4.90 mmHg, and mean aortic valve velocity of 1.60 ± 0.58 m/s. Compared with the preoperative transthoracic echocardiography findings, the results at the six-month follow-up were statistically significant (P < 0.05). Mild aortic valve regurgitation occurred in 2 patients (5.56%), whereas other patients had no or only minimal aortic valve regurgitation (n = 34, 94.44%). Moderate aortic valve regurgitation occurred in one patient at 9 months after the initial operation. This was found to be due to infective endocarditis, and a biological valve was finally implanted.Aortic valve replacement with bovine pericardium in the treatment of aortic valve regurgitation is feasible, and good early and mid-term results are achieved. Long-term results need to be followed up in the future.

Venous thromboembolism (VTE), which includes deep vein thrombosis (DVT) and pulmonary embolism (PE), is an important cause of post-surgery morbidity and mortality. However, it is unclear whether thromboprophylaxis with the low-molecular-weight heparin (LMWH) enoxaparin after non-orthopedic surgery could balance the cost and clinical outcomes or not. The purpose of this research was to evaluate the cost-effectiveness of enoxaparin for the universal prophylaxis of VTE and associated long-term complications in patients after non-orthopedic surgery compared with no prevention in a Chinese healthcare setting. A decision model, which included both acute VTE and long-term complications, was developed to assess the economic outcomes of the two strategies for patients after non-orthopedic surgery. Quality-adjusted life years (QALYs) and direct medical costs were measured over a 5-year horizon. Incremental cost-effectiveness ratios (ICERs) were calculated. Compared with no prevention, patients under enoxaparin treatment with Caprini risk scores of 3–4, 5–6, 7–8, and ≥ 9 increased by 0.012, 0.017, 0.034, and 0.102 in QALYs, respectively. The results were either that ICERs of thromboprophylaxis with enoxaparin over no prevention were lower than the thresholds or that thromboprophylaxis with enoxaparin was dominant. For patients with a Caprini risk score ≥ 9, thromboprophylaxis with enoxaparin is dominant across the whole drug use duration range. The sensitivity analysis confirmed the results. As the first analysis evaluating the economic outcomes of enoxaparin in patients undergoing general non-orthopedic surgery, this study suggests that thromboprophylaxis with enoxaparin is highly cost-effective compared with no prevention in patients with Caprini risk score ≥ 3.

Aims: To conduct a lifetime cost-effectiveness analysis (CEA) of rasburicase compared with standard of care (SOC) for tumor lysis syndrome (TLS) in children with hematologic malignancies from the Chinese healthcare system perspective. Materials and methods: The CEA was performed using a decision tree model with a lifetime horizon. The model explores the cost-effectiveness of rasburicase vs SOC for both preventing TLS and treating established TLS among pediatric patients with acute myeloid leukemia (AML), acute lymphoid leukemia (ALL), and non-Hodgkin's lymphoma (NHL). Both the prophylaxis-use model and treatment-use model incorporate long-term health states of the diseases: survival without TLS and death. The efficacy data of rasburicase and SOC were obtained from published literature. Drug costs, healthcare resource utilization (HRU), and adverse event (AE) management costs were obtained via a published study with clinical experts. Costs in US dollar and quality-adjusted life year (QALY) are reported, and incremental cost-effectiveness ratios (ICERs) were also calculated. Uncertainties due to parameter fluctuations in the model were assessed through one-way sensitivity analysis and probabilistic sensitivity analysis (PSA). Results: During TLS prevention, compared with SOC, the ICER of rasburicase treatment in China are $17,580.04/QALY, $5,783.45/QALY, and $5,391.00/QALY for pediatric patients with AML, ALL, and NHL, respectively. For the established TLS treatment, compared with SOC, the ICERs of rasburicase treatment are $2,031.18/QALY, $1,142.93/QALY, and $990.37/QALY for pediatric patients with AML, ALL, and NHL, respectively. Limitations: The clinical data for SOC are based on the published study in China, and the rasburicase prevention or treatment failure rate was either calculated based on the risk ratio or directly from the clinical study among non-Chinese pediatric patients. Another study limitation was the lack of utility data for pediatric patients with TLS and without TLS. Thus, the utility scores of pediatric cancer survivors were used as an alternative. Conclusion: Rasburicase is estimated to be a cost-effective alternative to SOC in the prevention and treatment of TLS among Chinese pediatric patients with AML, ALL, and NHL.

Objective: The study objective was to evaluate the effect of en bloc arch reconstruction with frozen elephant trunk (FET) technique for acute type A aortic dissection.Methods: 41 patients with acute Stanford type A dissection underwent en bloc arch reconstruction combined with FET implantation between April 2018 and August 2020. The mean age of the patients was 46 ± 13 years, and 9 patients were female. One patient had Marfan syndrome. Six patients had pericardial tamponade, 9 had pleural effusion, 5 had transient cerebral ischemic attack, and 3 had chronic kidney disease.Results: The hospital mortality rate was 9.8% (4 patients). 2 (4.9%) patients had stroke, 23 (56.1%) had acute kidney injury, and 5 (12.2%) had renal failure requiring hemodialysis. During follow-up, the rate of complete false lumen thrombosis was 91.6% (33/36) around the FET, 69.4% (25/36) at the diaphragmatic level, and 27.8% (10/36) at the superior mesenteric artery level. The true lumen diameter at the same three levels of the descending aorta increased significantly while the false lumen diameter reduced at the two levels: pulmonary bifurcation and the diaphragm. The 1-, 2-and 3-year actuarial survival rates were 90.2% [95% confidence interval (CI), 81.2–99.2], 84.2% (95% CI, 70.1–98.3) and 70.2% (95% CI, 42.2–98), respectively.Conclusions: In patients with acute type A dissection, en bloc arch reconstruction with FET technique appeared to be feasible and effective with early clinical follow-up results. Future studies including a large sample size and long-term follow-up are required to evaluate the efficacy.

Aims Most therapeutic drugs of endometriosis have been contraceptives but symptoms recur in up to 75% of cases, which makes it a presses need to try to find novel and safer therapeutic drugs. Imperatorin is a furanocoumarin existing in many plants, possessing multiple activities, including anti-inflammatory. The purpose of this study was to assess the effects and mechanisms of imperatorin in endometriosis. Main methods Ectopic endometrial volume and hematoxylin-eosin staining were used to estimate the effects of imperatorin in experimental endometriosis model rats. Potential mechanisms of imperatorin in endometriosis were systematically analyzed by network pharmacology and molecular docking. Western blotting and enzyme-linked immunosorbent assay were employed to evaluate proteins expression and cytokines levels in PI3K/Akt/NF-κB pathway. Key findings Imperatorin could significantly inhibit the growth and ameliorate the histopathological features of ectopic endometrium in experimental endometriosis rats. Network pharmacology approaches showed that imperatorin might regulate inflammatory response and cellular function via primarily affecting PI3K-Akt pathway, Endocrine resistance, Th17 cell differentiation in endometriosis. Moreover, 7 core targets (PIK3CA, AKT1, SRC, MAPK8, MAPK14, ERBB2 and CCND1) resulted from the intersection of KEGG and PPI network topological analysis were used to dock with imperatorin, which indicated that imperatorin could preferably fit in the binding pocket of the above target proteins, except for CCND1. Lastly, imperatorin markedly inhibited the activation of PI3K/Akt/NF-κB pathway via suppressing the phosphorylation levels of PI3K, Akt and p65 in the ectopic endometrium tissue. Significance Our findings revealed that imperatorin is a significant multi-target natural active ingredient for treatment endometriosis.

Background Tumors display a high rate of glucose metabolism and the SLC2A (also known as GLUT) gene family may be central regulators of cellular glucose uptake. However, roles of SLC2A family in mechanism of metabolite communication with immunity in gastric cancer remains unknown. Methods Bioinformatics analysis and IHC staining were used to reveal the expression of SLC2A3 in gastric cancer and the correlation with survival prognosis. Real-time PCR, western blots, OCR, ECAR, lactate production and glucose uptake assays were applied to determine the effect of SLC2A3 on glycolysis reprogramming. We then investigated the consequences of SLC2A3 upregulation or inhibition on aerobic glycolysis, also explored the underlying mechanism. Bioinformatics analysis and in vitro and in vivo research were used to reveal the role of SLC2A3 in macrophage infiltration and transition. Results Here, we show that SLC2A3 acts as a tumor promoter and accelerates aerobic glycolysis in GC cells. Mechanistically, the SLC2A3-STAT3-SLC2A3 feedback loop could promote phosphorylation of the STAT3 signaling pathway and downstream glycolytic targeting genes. Moreover, SLC2A3 potentially contributes to M2 subtype transition of macrophage infiltration in the GC microenvironment. Conclusions SLC2A3 could be used as a prognostic biomarker to determine prognosis and immune infiltration in GC and may provide an intervention strategy for GC therapy.

The antimetabolite 5-fluorouracil (5-FU) is a widely used chemotherapy regimen for the treatment of gastric cancer (GC). However, resistance to 5-FU remains a major drawback in the clinical use. The treatments of anti-tumor chemo-agents recruit tumor associated macrophages (TAMs) which are highly implicated in the chemoresistance development, but the underlying molecular mechanism is unclear. Here, we demonstrate that YAP1 is overexpressed in resistant GC tissues compared to sensitive GC tissues. Further, IL-3 secreted by YAP1-overexpressed GC could skew macrophage polarization to M2-like phenotype and inducing GLUT3-depended glycolysis program. Meanwhile, polarized M2 macrophages enhance 5-FU resistance in tumor cells by secreting CCL8 and activating phosphorylation of JAK1/STAT3 signaling pathway.

Trastuzumab is the only target to be approved as the first-line treatment of HER2 positive metastatic gastric cancer, but ubiquitous resistance decreases its therapeutic benefit. In this study, we found HER4, phosphorylation HER4 (p-HER4) and the mesenchymal marker Vimentin increased in trastuzumab-resistant cells (MKN45TR and NCI-N87TR), while epithelial markers expressions in trastuzumab-resistant cell lines and animal models decreased. Additionally, silencing HER4 prevented the epithelial-mesenchymal transition and led to decreased proliferation and migration in vitro and in vivo. The expression of YAP1, a vital downstream interacted target of HER4, decreased when HER4 was knocked down. Interestingly, stimulation of NRG1 could compromise the inhibitory impact and rescue cell survival; whereas, transfection of siYAP1 sensitized trastuzumab-treated cells. Expression analysis of the proteins in patient-derived xenograft model (PDX) mice showed that HER4, p-HER4, YAP1, and Vimentin were clearly upregulated in the trastuzumab-resistant mice compared to mice without trastuzumab resistance. However, HER2 and E-cadherin were downregulated in response to continuous treatment with trastuzumab. These findings elucidated that the central role of the HER4-YAP1 axis in trastuzumab resistance of HER2-positive gastric cancer cells through induction of EMT. Hence, regulating the HER4-YAP1 axis might be a promising strategy for clinical interventions in patients with HER2-positive gastric cancer.

Driver genes conducing to peritoneal metastasis in advanced gastric cancer remain to be clarified. S100A4 is suggested to evolve in metastasis of gastrointestinal cancer, we aim to explore the role of S100A4 plays in metastasis of advanced gastric cancer and the potential mechanism. Transfection of siRNA or cDNA was applied to alter the expression of protein S100A4 and MYH9, investigation of the expression of epithelial and mesenchymal transition (EMT) associated markers was followed. Cell migration assay was used to screen the alteration of migration ability regulated by S100A4 and MYH9. IHC analysis for tissue sample microarray was performed to reveal their relationship with clinical pathological parameters and potential capacity of predicting survival. Consistent overexpression of S100A4 and MYH9 were found in peritoneal metastasis and primary site compared with adjacent normal tissue. Low expression of S100A4 led to increased epithelial markers as wells as decline of mesenchymal makers, while overexpression of S100A4 led to inverse impact. S100A4 expression was closely correlated with increased migration ability and EMT process induced by TGF-β stimulation. Interference of S100A4 led to downregulation of MYH9 and inactivation of Smad pathway through participating in EMT process, which could be reversed by overexpression of MYH9. Moreover, co-expression of S100A4 and MYH9 was identified in tissue microarray and confirmed by immunofluorescence assay. In conclusion, overexpression of S100A4 and downstream molecular MYH9 in advanced gastric cancer predicted poor prognosis; oncogene S100A4 facilitate EMT process induced by TGF-β stimulation, suggesting a potential target in management of peritoneal metastasis of gastric cancer.

Background To conduct an indirect treatment comparison of patients with high-volume mHSPC and a cost analysis between Abi-ADT and Doc-ADT therapies in China. Methods The Bucher technique for indirect treatment comparison was used. A cost analysis was conducted from both healthcare and patient perspectives. Results The indirect treatment comparison demonstrated no significant difference in PFS for Abi-ADT versus Doc-ADT (HR: 0.84, 95% CI 0.66–1.07). Doc-ADT therapy costs less than Abi-ADT, with potential savings of up to RMB 887,057 per patient from the healthcare perspective and RMB 226,210 per patient from the patient perspective. Conclusions No significant differences in PFS between Doc-ADT and Abi-ADT therapy for patients with high-volume mHSPC. Doc-ADT therapy is a cost-saving alternative to Abi-ADT in China.

Purpose Induction immunosuppression therapy is used to support optimal outcomes in kidney transplantation. This study was to assess the cost-effectiveness of rabbit antithymocyte globulin (r-ATG) versus ATG-Fresenius (ATG-F) in kidney transplantation in the Chinese setting from the perspective of the health care payer. Methods A 2-part survival model was developed, consisting of a short-term part and a long-term part. The short-term part analyzed the first year, using the decision tree, and consisted of the functioning transplant, acute rejection (AR), delayed graft function (DGF), dialysis, and death health states. The long-term part analyzed 2 to 5 years, using Markov model, and consisted of the functioning transplant, chronic dysfunction, recurring primary disease, dialysis, and death health states, with capture of the association between DGF and graft loss. Costs, including drug acquisition and other direct medical costs, were derived from China IQVIA database (formerly known as IMS) hospital database, chart review, and physician interviews. Clinical outcomes and utility were retrieved from published literature. The model calculated quality-adjusted life-years (QALYs) and total costs per patient. Costs and QALYs were discounted at an annual rate of 3.5%. Univariate sensitivity analysis and probability sensitivity analysis (PSA) were conducted to assess the impact of uncertainty of the variables on the results. Findings Patients who received r-ATG had more clinical effectiveness than patients who received ATG-F mainly because of less AR, DGF, and dialysis. The incremental QALY was 0.01 over a 1-year time horizon and 0.0496 over a 5-year time horizon. R-ATG and ATG-F drug costs were ¥10,783 and ¥8409, respectively. However, the total treatment costs of the r-ATG arm were lower than the ATG-F arm because of lower costs related to DGF, AR, dialysis, and adverse events. In total, r-ATG saved ¥5423 over the 1-year and ¥7042 over the 5-year time horizon. R-ATG was dominant with lower total direct medical costs and higher QALYs compared with ATG-F. Both univariate sensitivity analysis and PSA found the robustness of the model results. PSA results indicated that r-ATG was cost-effective compared with ATG-F in 86.81% of the simulations, considering Implications From the perspective of the health care payer, r-ATG should be considered as the preferred treatment agent for induction therapy for Chinese patients undergoing kidney transplantation because of its lower overall medical costs and greater QALYs gained compared with ATG-F. The study was limited by lack of long-term efficacy data among the Chinese population and lack of comprehensive real-world higher quality costs data.

In our previous study, low expression of FAM172A protein was found in colon cancer tissues. This research was planned to explore the functions of FAM172A gene and examine the mechanisms of its transcriptional regulation. Firstly, flow cytometry showed that FAM172A inhibited proliferation and promoted apoptosis and differentiation of colon cancer cells. Then through continuous truncation, we identified the minimal functional promoter region of FAM172A. Subsequently, we found that STAT1, as a transcription factor, could bind to the minimal FAM172A promoter, as evaluated using Chromatin immunoprecipitation (ChIP) and Electrophoreticmobility shift assay (EMSA). The results of Western blot analysis and qRT-PCR indicated that STAT1 was able to upregulate the expression of FAM172A. Our results showed that FAM172A could suppress proliferation of colon cancer cells, and STAT1 could bind to the minimum promoter region of FAM172A and upregulated the expression of FAM172A. These results may provide advanced insights into the functions of FAM172A and its regulatory mechanisms.

The purpose of this study was to determine the combined effect of transmyocardial laser revascularization (TMLR) and the implantation of endothelial progenitor cells (EPCs) on cardiac function of ischemic hearts in canines. The left anterior descending artery (LAD) was occluded to establish the canine model of acute myocardial infarct (AMI). Four weeks later, the animals were randomly divided into four groups: TMLR group, in which transmyocardial laser-induced channels were established at the ischemic region; EPCs+TMLR group, in which EPCs were locally transplanted into laser-induced channels at the ischemic region; EPCs group, in which the EPCs were injected into the ischemic region; control group, in which the AMI animals received neither TMLR nor EPCs. The peripheral blood (50 mL) was sampled in all groups. Mononuclear cells from the peripheral blood were separated and cultured to obtain spindle-shaped attaching (AT) cells in vitro. AT cells were labeled with 1, 1′-dioctadecyl-1 to 3,3, 3′,3′-tetramethyl-indocarbocyanine perchlorate (DiI) before injecting into the laser-induced channels or ischemic region. Four weeks after the first operation, TMLR was performed in the TMLR group and EPCs+TMLR group, and at the same time, the EPCs originating from the AT cells were mixed with calcium alginate (CA). Then the EPCs-CA composites were implanted into myocardial channels induced by laser in the EPCs+TMLR group, and into the myocardial infarct area in the EPCs group. All dogs underwent echocardiography at second month after LAD occlusion. Finally the samples of myocardium around the LAD were subjected to histochemical and immunohistologic examinations. The results showed there was no significant difference in the diameter of left atrium and ventricle before treatment among all groups (P>0.05). Eight weeks after modeling, the regional contractility in the LAD territory in the EPCs+TMLR group was increased as compared with control group and TMLR group, but there was no significant difference between control group and TMLR group. Neoangiogenesis was observed in the EPCs+TMLR group, and the fibrosis was seen in the TMLR group. There was no significant difference in neoangiogenesis around the channels induced by laser among EPCs+TMLR, EPCs and TMLR groups. It was concluded that TMLR combined with EPCs could improve the regional and global cardiac function in AMI, and augment neovascularizaiton in channels of ischemic myocardium induced by laser.