Colorectal tumors often create an immunosuppressive microenvironment that prevents them from responding to immunotherapy.Cannabidiol(CBD)is a non-psychoactive natural active ingredient from the cannabis plant that has various pharmacological effects,including neuroprotective,antiemetic,anti-inflammatory,and antineoplastic activities.This study aimed to elucidate the specific anticancer mechanism of CBD by single-cell RNA sequencing(scRNA-seq)and single-cell ATAC sequencing(scATAC-seq)technologies.Here,we report that CBD inhibits colorectal cancer progression by modulating the suppressive tumor microenvironment(TME).Our single-cell transcriptome and ATAC sequencing results showed that CBD suppressed M2-like macrophages and promoted M1-like macrophages in tumors both in strength and quantity.Furthermore,CBD significantly enhanced the interaction between M1-like macrophages and tumor cells and restored the intrinsic anti-tumor properties of macrophages,thereby preventing tumor progression.Mechanistically,CBD altered the metabolic pattern of macro-phages and related anti-tumor signaling pathways.We found that CBD inhibited the alternative acti-vation of macrophages and shifted the metabolic process from oxidative phosphorylation and fatty acid oxidation to glycolysis by inhibiting the phosphatidylinositol 3-kinase-protein kinase B signaling pathway and related downstream target genes.Furthermore,CBD-mediated macrophage plasticity enhanced the response to anti-programmed cell death protein-1(PD-1)immunotherapy in xenografted mice.Taken together,we provide new insights into the anti-tumor effects of CBD.

Purpose/Significance To explore the characteristics and clinical significance of differentially expressed genes closely re-lated to HPV E6/E7 by using bioinformatics.Method/Process The cervical tissue and clinical information of cervical cancer in TCGA and GTEx of UCSC are used as the training set.The expression profile chip GSE63514 related to cervical cancer in GEO is used as the validation set.Firstly,the limma package of R software is used to screen DEGs of tumor and normal samples,and Venn map of genes re-lated to E6/E7 protein in MigDB is made.Survival analysis is performed by survival kit and verified by ROC and protein expression lev-els.Secondly,key genes are obtained by copy number variation and methylation correlation.Finally,the specific co-expression network is constructed and enrichment analysis and immune infiltration analysis are performed.Result/Conclusion There are 101 differentially expressed genes related to HPV E6/E7 protein,and three genes are found to have significance after screening,namely E2F1,MCM4 and PCNA.At the same time,it is found that the genes in the specific coexpression network are significantly enriched in the DNA replication and chromosome organization pathways.Immune correlation analysis shows that key genes are significantly associated with CD4 T cells,B cells and neutrophils.DNA replication,chromosome organization,etc.,are the molecular mechanisms and key genes significantly related to the development of cervical squamous cell carcinoma and HPV E6/E7 encoded proteins.

Objective:To evaluate the dose-response relationship of remimazolam for loss of consciousness during anesthesia induction in the patients undergoing coronary artery bypass grafting (CABG).Methods:American Society of Anesthesiologists Physical Status classification Ⅲ or Ⅳpatients, aged 55-64 yr, with body mass index of 21-26 kg/m 2, scheduled for elective CABG under general anesthesia, were included in this study.The trial was conducted using the modified Dixon′s up-and-down method. The initial dose of remimazolam was 0.225 mg/kg, each time the concentration increased/decreased by 0.025 mg/kg in the next patient depending on whether or not the patients lost consciousness. Criteria for loss of consciousness was considered as the modified vigilance sedation score≤1 within 3 min after remimazolam administration. The 50% effective dose (ED 50), 95% effective dose (ED 95) and their 95% confidence interval ( CI) was analyzed by probit probability analysis method. Results:The ED 50 of remimazolam for loss of consciousness during anesthesia induction was 0.175 mg/kg, 95% CI was 0.163-0.185 mg/kg, ED 95 was 0.211 mg/kg, and 95% CI was 0.197-0.255 mg/kg. Conclusions:The ED 50 and ED 95 of remimazolam were 0.175 and 0.211 mg/kg respectively when used for loss of consciousness during anesthesia induction in the patients undergoing CABG.

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68⁺ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

Objective:To elucidate the changes of cytokine expression profiles in hand, foot and mouth disease (HFMD) patients infected with non-EV-A71 enteroviruses in Jinan city, and explore the characteristics of cytokines expression.Methods:The serum samples of acute and convalescent phases were collected from non-EV-A71 enterovirus-infected HFMD patients in Jinan from 2014 to 2017. The serum samples of healthy subjects were collected as control group. The Bio-plex liquid chip platform was used for high-throughput detection of 27 cytokines. GraphPad Prism and SPSS 22.0 were used for description and statistical analysis.Results:Twenty-two serum cytokines significantly changed in non-EV-A71 infected patients, including 11 kinds of interleukin (IL), 5 kinds of chemokines, 2 kinds of growth factors, granulocyte colony stimulating factor (G-CSF), interferon-γ, tumor necrosis factor-α (TNF-α) and granulocyte-macrophage colony stimulating factor (GM-CSF). There were 21 kinds (mean ranks 17.06-19.00 pg/ml vs 5.50-8.80 pg/ml, P < 0.05) and 20 kinds (mean ranks 16.41-19.00 pg/ml vs 5.50-9.90 pg/ml, P < 0.05) of cytokines expression in acute stage and convalescent stage respectively were higher than those in healthy control group for coxsackievirus A16 (CV-A16) infected patients, and GM-CSF expression (mean ranks 9.65 pg/ml vs 21.40 pg/ml, 9.59 pg/ml vs 21.50 pg/ml, P < 0.05) were both lower than those in healthy control group. For HFMD patients infected CV-A6, there were 19 kinds (mean ranks 11.92-13.50 pg/ml vs 5.50-6.45 pg/ml, P < 0.05) and 21 kinds (mean ranks 12.00-13.50 pg/ml vs 5.50-6.40pg/ml, P < 0.05) of cytokines expression with acute and convalescent stage respectively were higher than those in healthy control group. GM-CSF expression decreased only in acute phase (mean ranks 5.00 pg/ml vs 10.60 pg/ml, P < 0.05) compared with healthy control group. Double serum analysis showed that interleukin 6 (22.79pg/ml vs 35.88 pg/ml) and interferon-induced protein 10 (IFNγ -induced protein 10) (793.56 pg/ml vs 2 157.32 pg/ml) expression in patients with CV-A16 infection during convalescent stage were lower than that in acute stage; IL-7 (3.13 pg/ml vs 1.165 pg/ml), IL-15 (27.84 pg/ml vs 16.005 pg/ml) and regulated upon activation normal T cell expressed and secreted (RANTES) (22 605.96 pg/ml vs 7 040.90 pg/ml) expression in patients with CV-A6 infection during convalescent stage increased compared with the acute stage. Conclusions:There are extensive changes in cytokine expression profile in HFMD patients with non-EV-A71 enterovirus infection. Different pathogens infection and different clinical course of HFMD have different characteristics of cytokine expression. These findings could provide scientific data for finding indicators that are meaningful for disease progression, clinical diagnosis and immunotherapy.

Objective:To identify the risk factors for postoperative central nervous system complications (CNSC) developed in pediatric patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) through determining regional cerebral oxygen saturation (rSO 2C) by near-infrared spectroscopy. Methods:A total of 60 pediatric patients with congenital heart disease undergoing elective orthodontic correction surgery under CPB, of American Society of Anesthesiologists physical status Ⅱ or Ⅲ, of both sexes, aged 6-36 months, weighing 5-19 kg, in our hospital from July 2019 to January 2020 were collected.Intraoperative bilateral rSO 2C was monitored continuously by near-infrared spectroscopy.Blood samples were taken from the central vein at 10 min after induction of anesthesia, immediately after CPB, at the end of CPB, on admission to ICU, at 4 and 8 h after entering ICU and at 1, 2 and 3 days after surgery (T 0-8) for determination of the concentrations of serum S100β protein and neuron specific enolase (NSE). At 12 months after surgery, the Pediatric Cerebral Performance Category (PCPC) score was used to evaluate the prognosis of neurological function.The patients were divided into 2 groups according to whether CNSC occurred: CNSC group and non-CNSC group.Multivariate logistic regression analysis was used to identify the risk factors for development of postoperative CNSC in pediatric patients undergoing cardiac surgery under CPB. Results:Two patients were excluded from the study.Eighteen cases developed postoperative CNSC, and the incidence was 31.0%.Compared with group non-CNSC, the minimal rSO 2 was significantly decreased, the maximal difference between pulse oxygen saturation and rSO 2C (da-rSO 2C) was increased, duration of reduction in rSO 2>25% during CPB, duration of rSO 2C<40% during CPB and duration of da-rSO 2C>50% during CPB were prolonged, and concentrations of serum S100β protein and NSE were increased at T 2-T 8 in group CNSC ( P<0.05). The results of logistic regression analysis showed that prolonged duration of reduction in rSO 2C>25% during CPB, prolonged duration of rSO 2C<40% during CPB and prolonged duration of da-rSO 2C>50% during CPB were risk factors for development of postoperative CNSC. Conclusion:Prolonged duration of reduction in rSO 2C>25% during CPB, prolonged duration of rSO 2C<40% during CPB and prolonged duration of da-rSO 2C>50% during CPB are the risk factors for postoperative CNCS developed.

Objective:To summarize the efficacy of general anesthesia for percutaneous pulmonary valve implantation (PPVI).Methods:The clinical data of 6 patients underwent PPVI under general anesthesia in Children′s Heart Center of Henan Provincial People′s Hospital from December 2017 to January 2020 were retrospectively analyzed.Systolic blood pressure, diastolic blood pressure, heart rate, central venous pressure, SpO 2 and regional cerebral oxygen saturation were recorded before anesthesia induction (T 1), after anesthesia induction (T 2), before beginning of surgery (T 3), before pulmonary valve implantation (T 4), during pulmonary valve implantation (T 5), immediately after pulmonary valve implantation (T 6) and when the patients left the operating room (T 7). Right ventricular systolic pressure, diastolic pressure, pulmonary artery systolic pressure and diastolic pressure were recorded at T 4 and T 6.The development of related complications during operation and the cardiac, liver and kidney functions before and after operation were recorded.The postoperative extubation time, intensive care unit stay time and hospital stay time were recorded. Results:Six patients (3 males, 3 females), aged (16±4) yr, weighing (41±12) kg, were analyzed.Compared with the value at T 1-4 and T 6, 7, systolic blood pressure, diastolic blood pressure, heart rate, regional cerebral oxygen saturation and SpO 2 were significantly decreased at T 5 ( P<0.05). Compared with the value at T 1-5, central venous pressure was significantly decreased at T 6, 7 ( P<0.05). Compared with the value at T 4, right ventricular diastolic pressure was significantly decreased, and pulmonary artery diastolic pressure was increased at T 6 ( P<0.05). No anesthesia- and surgery-related serious complications occurred among the patients.One patient was transferred to the ward after extubation in the operating room, and 5 patients were transferred to the intensive care unit after operation.All 6 patients were discharged successfully and entered the follow-up stage. Conclusion:General anesthesia provides better efficacy when used for PPVI, and hemodynamic monitoring of pulmonary circulation and systemic circulation should be strengthened during pulmonary valve implantation to maintain circulation stable.

Objective:To evaluate the effects of thoracic paravertebral block (TPVB) on graft patency in off-pump coronary artery bypass grafting.Methods:Fifty American Society of Anesthesiologists physical status Ⅱ or Ⅲ patients, aged 60-75 yr, weighing 50-80 kg, undergoing elective off-pump coronary artery bypass grafting under combined intravenous-inhalational anesthesia, were divided into 2 groups using a random number table method: control group (group C, n=30) and TPVB group (group T, n=20). In group T, TPVB was performed at T 4, 5 interspace under the guidance of ultrasound, a test dose of 1% lidocaine 5 ml was injected on both sides, and 2 min later 0.375% ropivacaine 15 ml was injected.According to the anatomy of coronary artery, the graft was divided into 4 parts: left internal thoracic artery-anterior descending branch (arterial graft), the middle branch or the first diagonal branch, blunt marginal branche, and right posterior descending branch or left ventricular posterior branch.The blood flow was measured and pulsatility index was calculated after graft transplantation.Central venous pressure, mean pulmonary artery pressure, cardiac output, systemic resistance index and pulmonary resistance index were recorded immediately after placement of floating catheter (T 1), immediately after sawing sternum (T 2), immediately after anastomosis of all grafts (T 3) and 5 min before leaving the room (T 4). The intraoperative cardiovascular adverse events and consumption of sufentanil were recorded. Results:Compared with group G, central venous pressure, systemic resistance index and pulmonary resistance index were significantly decreased, cardiac output were increased, the incidence of intraoperative tachycardia was decreased, the incidence of hypotension was increased, the consumption of sufentanil was reduced, the flow of left internal thoracic artery-anterior descending branch was increased, and the pulsatility index was decreased at T 3 and T 4 in group T ( P<0.05). Conclusion:TPVB can improve the patency of left internal thoracic artery-anterior descending branch in off-pump coronary artery bypass grafting.

Objective: To identify the risk factors for postoperative hyperlactatemia in the patients with type A aortic dissection. Methods: Medical records of patients with type A aortic dissection who underwent cardiovascular surgery from January 2012 to October 2017 were retrospectively collected.The patients were divided into hyperlactatemia group and non-hyperlactatemia group according to the occurrence of hyperlactatemia (blood lactic acid ≥6 mmol/L) at 8 h after surgery.The variables of which P values were less than 0.05 in univariate analysis would enter the logistic regression analysis to stratify the risk factors for postoperative hyperlactatemia in this type of patients. Results: A total of 295 patients were included, of which 80 cases developed postoperative hyperlactatemia, and the incidence was 27.1%.Logistic regression analysis showed that preoperative acute pericardial tamponade, intraoperative deep hypothermic circulatory arrest time>35 min) and massive transfusion of blood (>1 000 ml) within 8 h after operation were independent risk factors for postoperative hyperlactatemia in the patients with type A aortic dissection. Conclusion Preoperative acute pericardial tamponade, intraoperative deep hypothermic circulatory arrest time>35 min and massive transfusion of blood (>1 000 ml) within 8 h after operation are independent risk factors for postoperative hyperlactatemia in the patients with type A aortic dissection.

Objective To investigate the management of Graves' disease in Jiangsu province. Methods According to the 2011 management of GD survey from American Thyroid Association and the 2013 survey from European Thyroid Association, a questionnaire was designed for this survey to acquire the diagnosis, treatment, and follow-up of Graves' disease among endocrinologists from 35 tertiary hospitals in Jiangsu province. Results A total of 476 valid questionnaires were collected. For patients with symptoms of hyperthyroidism, a large majority of respondents monitored serum FT3 , FT4 , TSH, thyroid peroxidase antibody, thyroglobulin antibody, TSH receptor antibody, and finding of thyroid ultrasound, accounted for 95. 6％, 95. 0％, 95. 4％, 95. 8％, 90. 3％, 90. 5％, and 93. 9％physicians, respectively. 91.2％ of physicians preferred anti-thyroid drugs as the first-line treatment, and 92. 6％ of them gave priority to the use of methimazole. For the duration of anti-thyroid drugs therapy, 41.2％of endocrinologists chose 24 months, while 20％ chose 18 months. When patients have moderate and active ophthalmopathy, most respondents with medium or senior professional titles preferred anti-thyroid drugs, while most resident physicians chose radioactive iodine plus corticosteroids. When pregnancy was confirmed in the patients of Graves' disease, 88％ of respondents preferred propylthiouracil during the first trimester of pregnancy, and 58. 4％ of them would continue propylthiouracil into the second trimester. Conclusions The mastering of basic perception of Graves' disease knowledge is satisfactory among the endocrinologists. But by comparing to the American and European survey results and related guidelines, there are still some differences in diagnosis and treatment. Therefore, physicians should notice those differences and make improvement on standardized treatment for patients to raise the response ratio while reducing the recurrent events.