BACKGROUND: The molecular mechanisms driving tumorigenesis have continually been the focus of researchers. Cuproplasia is defined as copper-dependent cell growth and proliferation, including its primary and secondary roles in tumor formation and proliferation through signaling pathways. In this study, we analyzed the differences in the expression of cuproplasia-associated genes (CAGs) in pan-cancerous tissues and investigated their role in immune-regulation and tumor prognostication. METHODS: Raw data from 11,057 cancer samples were acquired from multiple databases. Pan-cancer analysis was conducted to analyze the CAG expression, single-nucleotide variants, copy number variants, methylation signatures, and genomic signatures of micro RNA (miRNA)-messenger RNA (mRNA) interactions. The Genomics of Drug Sensitivity in Cancer and the Cancer Therapeutics Response Portal databases were used to evaluate drug sensitivity and resistance against CAGs. Using single-sample Gene Set Enrichment Analysis (ssGSEA) and Immune Cell Abundance Identifier database, immune cell infiltration was analyzed with the ssGSEA score as the standard. RESULTS: Aberrantly expressed CAGs were found in multiple cancers. The frequency of single-nucleotide variations in CAGs ranged from 1% to 54% among different cancers. Furthermore, the correlation between CAG expression in the tumor microenvironment and immune cell infiltration varied among different cancers. ATP7A and ATP7B were negatively correlated with macrophages in 16 tumors including breast invasive carcinoma and esophageal carcinoma, while the converse was true for MT1A and MT2A . In addition, we established cuproplasia scores and demonstrated their strong correlation with patient prognosis, immunotherapy responsiveness, and disease progression ( P  <0.05). Finally, we identified potential candidate drugs by matching gene targets with existing drugs. CONCLUSIONS This study reports the genomic characterization and clinical features of CAGs in pan-cancers. It helps clarify the relationship between CAGs and tumorigenesis, and may be helpful in the development of biomarkers and new therapeutic agents.
Humans ; Female ; Genomics ; Carcinogenesis ; Carcinoma ; Breast Neoplasms ; Cell Transformation, Neoplastic ; Nucleotides ; Tumor Microenvironment

Objective To investigate the potential of ginkgolide B(GB)in mitigating vascular endothelial injury by antagonizing endoplasmic reticulum stress(ERS)and elucidate its underlying molecular mechanism.Methods An injury model of human bone marrow-derived endothelial progenitor cells(EPCs)induced by tunica-mycin(TM)was established.Cell proliferation was assessed using MTS assay,while cell viability was determined through Calcein-AM/EthD-I double staining.Transwell assay was employed to evaluate cell migration ability.DCFH-DA staining was utilized to measure intracellular ROS levels,and NADPH activity was quantified via ELISA.JC-1 and DiOC6 staining were performed for qualitative and quantitative assessment of mitochondrial membrane potential respectively.Qrt-pcr analysis was conducted to determine mRNA expression levels,whereas western blot analysis enabled detection of protein expression levels in the cells.Results GB dose-dependently attenuated tunicamycin-induced ERS-mediated endothelial injury in hEPCs,as evidenced by decreased cell viability,impaired cell migration,and angiogenesis inhibition(P<0.01).Furthermore,GB treatment significantly reduced ROS production and NADPH levels within the cells(P<0.01),while also inhibiting ERS-mediated decline in mitochondrial membrane potential concentration-dependently(P<0.01).Additionally,GB inhibited the expression of ERS-related proteins such as GRP78,ATF4,CHOP etc.,regulated apoptosis-related protein Bcl-xl,Bax cleaved caspase-4 cytochrome c;thereby effectively counteracting endoplasmic reticulum stress-induced cellular damage.Conclusions GB exerts a protective effect on vascular endothelium by antagonizing endoplasmic reticulum stress;this mechanism may be attributed to its ability to reduce intracellular reactive oxygen species levels.It also suppresses the expression of ERS-related proteins(CHOP78 and ATF4),and modulates apoptosis-associated proteins(Bcl-xl,Bax,cleaved caspase-4,and cytochrome c).

Background: Some of the active perianal fistulizing Crohn's disease (CD) patients achieving remission with infliximab (IFX) therapy would develop relapse of perianal fistula within weeks to years after discontinuation of IFX therapy. Aims: To assess the outcomes of patients with perianal fistulizing CD after discontinuation of IFX therapy and the risk factors for relapse of perianal fistula. Methods: The clinical data of patients with perianal fistulizing CD who received IFX therapy at Shanghai Renji Hospital between June 2013 and May 2019 and stopped IFX therapy after achieving complete or partial radiological remission were collected retrospectively and analyzed. Demographic data, clinical and imaging characteristics, as well as data of IFX treatment and relapse of perianal fistula were extracted. Kaplan-Meier analysis was performed to calculate the cumulative probabilities of perianal and luminal relapse, while Cox proportional hazards model was applied to identify the risk factors for relapse. Results: A total of 56 perianal fistulizing CD patients who had been treated with IFX and stopped IFX therapy were included. Of them 26 achieved complete radiological remission and 30 achieved partial radiological remission. The median follow-up time was 20.5 months. Twenty-one patients (37.5%) had relapse of perianal fistula. The cumulative probabilities of perianal relapse were 29.0%, 33.7% and 42.8% at 12, 24 and 60 months after IFX discontinuation, respectively; and the cumulative probabilities of luminal relapse were 21.7%, 31.2% and 56.4% at 12, 24 and 60 months after IFX discontinuation, respectively. Multivariate analysis showed that non-stricturing and non-penetrating type (HR=9.711, 95% CI: 1.210-77.939, P=0.032) and involvement of rectum (HR=3.034, 95% CI: 1.119-8.231, P=0.029) were independent risk factors for relapse of perianal fistula, while the frequency of using of IFX therapy was a protective factor (HR=0.885, 95% CI: 0.792-0.990, P=0.032). Conclusions: There is a high risk of relapse of perianal fistulizing CD after discontinuation of IFX therapy. Non-stricturing and non-penetrating type and rectal involvement are risk factors for relapse of perianal fistula, and increasing the frequencies of using IFX therapy is crucial for the maintenance of remission.

In recent years, with the application and exploration of fluorescence imaging technology in pancreatic surgery, it has brought new changes and new hope for the intraoperative treatment of pancreatic diseases. Intraoperative fluorescence imaging with indocyanine green (ICG) as probe is increasingly applied in identify neoplasms, real-time margin assessment, tissue perfusion, lymph node detection, anastomotic leakage and so on, which provides a new means for intraoperative decision-making. This article reviewed the progress in the application of ICG fluorescence imaging in pancreatic surgery.

Objective:To evaluate the clinical effect of embolization of congenital parotid arteriovenous fistula(AVF) using coils and absolute ethanol.Methods:From January 2015 to December 2019, 8 patients with congenital AVF in parotid region were admitted to the Department of Interventional Radiology Shanghai Ninth People’s Hospital. AVF was confirmed by angiography of common carotid artery and vertebral artery through femoral artery puncture with Seldinger technique. Using coaxial microcatheter to reach the fistula via artery or using direct percutaneous puncture to reach the dilated vein and introduced microcatheter to the fistula via puncture needle. Combined detachable coils with fiber coils, and used absolute ethanol to occlude the fistula. Then the outcome was evaluated.Results:There were 7 males and 1 female involved in this study. The average age was 28.5 years (3-58 years). All of the 8 patients were confirmed AVF in parotid region by angiography, five on the right and three on the left. The feeder artery was external carotid artery, and the outflow vein was external jugular vein. Among them, 6 patients used coaxial microcatheter to reach the fistula via artery, 2 patients used direct percutaneous puncture after failure via transarteral approach. All the 8 patients were treated with absolute ethanol, the total amount of which was 17.4 ml on average. After embolization, the external carotid angiography demonstrated that the fistula was completely occluded, the branches of the external carotid artery at the distal end of the fistula were normal, and there was no obvious reflux vein. After the operation, all the patients had no pulsation and tremor. The external jugular vein dilation disappeared in 4 patients. One patient had temporary facial paralysis on the same side of the operation area. The symptoms disappeared three days after treatment. This patient had undergone coils exposed three months after operation. After local debridement, the exposed coils were removed and the wound healed. The 8 patients were followed up for 6-12 months without recurrence.Conclusions:Embolization with coils combined with absolute ethanol is safe and affective treatment for congenital parotid AVF.

Objective:To evaluate the clinical effect of embolization of congenital parotid arteriovenous fistula(AVF) using coils and absolute ethanol.Methods:From January 2015 to December 2019, 8 patients with congenital AVF in parotid region were admitted to the Department of Interventional Radiology Shanghai Ninth People’s Hospital. AVF was confirmed by angiography of common carotid artery and vertebral artery through femoral artery puncture with Seldinger technique. Using coaxial microcatheter to reach the fistula via artery or using direct percutaneous puncture to reach the dilated vein and introduced microcatheter to the fistula via puncture needle. Combined detachable coils with fiber coils, and used absolute ethanol to occlude the fistula. Then the outcome was evaluated.Results:There were 7 males and 1 female involved in this study. The average age was 28.5 years (3-58 years). All of the 8 patients were confirmed AVF in parotid region by angiography, five on the right and three on the left. The feeder artery was external carotid artery, and the outflow vein was external jugular vein. Among them, 6 patients used coaxial microcatheter to reach the fistula via artery, 2 patients used direct percutaneous puncture after failure via transarteral approach. All the 8 patients were treated with absolute ethanol, the total amount of which was 17.4 ml on average. After embolization, the external carotid angiography demonstrated that the fistula was completely occluded, the branches of the external carotid artery at the distal end of the fistula were normal, and there was no obvious reflux vein. After the operation, all the patients had no pulsation and tremor. The external jugular vein dilation disappeared in 4 patients. One patient had temporary facial paralysis on the same side of the operation area. The symptoms disappeared three days after treatment. This patient had undergone coils exposed three months after operation. After local debridement, the exposed coils were removed and the wound healed. The 8 patients were followed up for 6-12 months without recurrence.Conclusions:Embolization with coils combined with absolute ethanol is safe and affective treatment for congenital parotid AVF.

OBJECTIVE：To analyze th e general characteristics and application of the models used in the pharmacoeconomic evaluation of type 2 diabetes mellitus （T2DM）therapy during the past 5 years，and to provide reference for the selection and improvement of T 2DM pharmacoeconomic model. METHODS ：Retrieved from PubMed ，Embase，CNKI，Wanfang database and VIP during Jan. 1st，2015 to Dec. 31st，2019，pharmacoeconomic evaluation literatures about T 2DM therapy were collected ；the included model was analyzed in respects of general structure ，therapy plan establishment ， short-term therapeutic efficacy ， complication simulation ，model effectiveness validation ，application frequency. RESULTS ：A total of 81 literatures were included ， involving 14 models，such as CORE model ，Cardiff model ，ECHO model ，etc. Mostly ，Markov or micro Markov simulation method were adopted to measure the patient ’s lifetime health outcome and cost mostly from the point of view of third-party payer. Seven models could simulate 2-4 therapy plans ；short-term efficacy mainly included risk factors of diabetic complications （such as glycosylated hemoglobin level and body mass ）and adverse drug reactions. Most models used intermediate indexes to simulate the occurrence of complications ，and the number of complications ranged from 3 to 15；the validity of model effectiveness included surface validity ，internal validity and external validity ，etc. Among 14 models，the most frequently used models in the past 5 years were long-term models that had been validated ，among which CORE model had the most application times （38/81，46.91％）， followed by Cardiff model （12/81，14.81％）. CONCLUSIONS ：The 14 models have similar structure. The differences of the models are mainly reflected in 3 aspects as therapy plan setting， considered short-term efficacy ， the number of model are ideally choose based on available evidences.

Objective:To investigate the best neutralization ratio of protamine and heparin during off-pump coronary artery bypass grafting(OPCABG) by analyzing the advantages and disadvantages of heparin residue after OPCABG.Methods:From July 2018 to January 2019, 112 patients undergoing elective OPCABG were included in this study. The patients’ whole blood was drawn at 2 time points, including before entering operating room and entering intensive care unit, to receive thrombelastography(TEG) and heparinase-modified thromboelastography(hmTEG) . Conventional coagulation indexes such as activated coagulation time(ACT) were also detected. All the patients were divided into 3 groups, the non-heparin residue group(30 cases), heparin residue group 1(42 cases) and heparin residue group 2(40 cases) according to the laboratory results of TEG, hmTEG and ACT. We observed the dosage of each group of protamine and heparin, as well as the ratio of heparin and protamine. The changes of R time in TEG and ACT between 3 groups were analyzed and compared. Postoperative chest tube drainage at postoperative 12 h and 48 h, cTnI peak value, incidence of perioperative myocardial infarction(MI), incidence of reoperation and poor wound healing, amount of blood loss and transfusion, and acute renal injury were compared between the 3 groups.Results:No significant trio-group differences existed in basic clinical characteristics(all P>0.05). Postoperative R(CKH)time was similar in the 3 groups( P>0.05). Comparing with heparin residue group 1 and heparin residue group 2, the ACT after protamine neutralizing heparin and postoperative R time were decreased, the dosage of protamine, ratio of heparin and protamine, cTnI peak value were increased in the non-heparin residue group( P<0.05). Comparing with heparin residue group 2, the dosage of heparin, postoperative chest tube drainage at postoperative 12h and 48h, amount of blood transfusion and transfusion probability were significantly decreased in non-heparin residue group( P<0.05), but compared with group 1 of heparin residue, there was no significant difference in the above indexes( P>0.05). The perioperative myocardial infarction, incidence of reoperation and poor wound healing, postoperative acute renal injury and time of in ICU stay showed no significant differences between the 3 groups( P>0.05). Conclusion:Moderate heparin residue after OPCAB suggests that it has myocardial protective effect, and does not significantly increase the risk of bleeding. A large number of heparin residues can affect the coagulation function and lead to bleeding tendency, increase the amount of blood loss and transfusion. It is reasonable to make ACT after protamine neutralize heparin higher than the level of ACT before operation, and not higher than 20% of the level before operation.

OBJECTIVE：To comp are cytotoxicity and anti-inflammatory effects of raw Aconitium kusnezoffii and A. kusnezoffii processed with Terminalia chebula . METHODS ：Using H 9c2 cardiomyocytes isolated from rat as subjects ，CCK-8 assay was used to detect the effects of 0.5，1，2，4，6，8，10 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula on cell inhibition rate after cultured for 4，8，12，24 h. Hoechst 33258 staining was used to observe the effects on cell morphology characteristics after treated with 2，4，6 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula . Using macrophages RAW264.7 cells as subjects ，CCK-8 assay was used to detect the effects of 0.05，0.1，0.25，0.5，0.75，1，1.5，2 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula on cell survival rate after cultured for 24 h. ELISA assay was used to detect the effects of 0.05，0.1，0.25，0.5 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula on the release of NO ， TNF-α and IL-6 in RAW 264.7 inflammation cells induced by LPS. RESULTS ：When the mass concentration was 0.5，1 mg/mL， neither raw A. kusnezoffii and A. kusnezoffii processed with T. chebula had no inhibitory effect on H 9c2 cells. When the mass concentration was 2 mg/mL，the inhibitory effects of A. kusnezoffii processed with T. chebula on H 9c2 cells was higher than that of raw A. kusnezoffii （P＜0.05 or P＜0.01）；fluorescence intensity of cells treated for 24 h was stronger than that of raw A. kusnezoffii，but its nucleus was intact. When the mass concentration was 4-10 mg/mL，the inhibitory rate of A. kusnezoffii processed with T. chebula on H 9c2 cells at different time points （except for 24 h culture of 8，10 mg/mL）was significantly lower than raw A. kusnezoffii （P＜0.05 or P＜0.01）. The characteristics of cell morphology also showed that the fluorescence intensity of raw A. kusnezoffii group at 4，6 mg/mL was stronger than that of A. kusnezoffii processed with T. chebula group，and the cell nucleus fragmentation was more serious in the raw A. kusnezoffii group. 0.05-0.5 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula had no toxicity to RAW264.7 cells. 0.25，0.5 mg/mL raw A. kusnezoffii and 0.1，0.25，0.5 mg/mL A. kusnezoffii processed with T. chebula showed significant inhibitory effect on the release of NO ，0.05，0.1，0.25，0.5 mg/mL raw A. kusnezoffii and A. kusnezoffii processed with T. chebula showed significant inhibitory effect on the release of TNF-α and IL-6 in RAW 264.7 cell（P＜0.05 or P＜ 0.01）. The inhibitory effects of A. kusnezoffii processed with T. chebula at the same concentration on the release of NO was better than that of raw A. kusnezoffii ，but poorer than raw A. kusnezoffii in the inhibitory effects on the release of TNF-α and IL-6. CONCLUSIONS：The toxicity of A. kusnezoffii can be reduced after processed with T. chebula ，especially the toxicity of it in medium or high concentration and short-term use is lower than that of raw A. kusnezoffii . At the same time ，the anti-inflammatory effect of A. kusnezoffii processed with T. chebula is comparable to that of raw A. kusnezoffii at the same concentration.

Objective Animal experiment is indispensible for the progress of medicine and medical research.Experimental animals deserve basic respect and care.This paper reviewed the history and status of the experimental animal welfare nationally and internationally to identify the ethical problems existed in animal experiments,and finally discuss the establishing of ethical review system of experimental animals.Methods According to literature review,as well as summarizing the operating practice in the affiliated hospital of Chengdu university of TCM,this study analyzed the problems in the field of experimental animal welfare protection.Results Many countries,such as Britain,Germany and the United States,have legislation on the welfare of experimental animals.There are no such laws in China while departmental regulations has formulated.At present,the weak cognition of bioethics among medical personnel,lack of corresponding certification system,lack of the ethical review system of laboratory animal are still unsolved problems.This paper summarizes the principles of ethical review,the documents of review and the elements of review.Conclusions The protection of experimental animals is a systematic project,and ethical review as the first link of animal experiments can play a good role in promoting animal experiment.