Mevalonate improves anti-PD-1/PD-L1 efficacy by stabilizing CD274 mRNA

Mevalonate metabolism plays an important role in regulating tumor growth and progression; however, its role in immune evasion and immune checkpoint modulation remains unclear. Here, we found that non-small cell lung cancer (NSCLC) patients with higher plasma mevalonate response better to anti-PD-(L)1 therapy, as indicated by prolonged progression-free survival and overall survival. Plasma mevalonate levels were positively correlated with programmed death ligand-1 (PD-L1) expression in tumor tissues. In NSCLC cell lines and patient-derived cells, supplementation of mevalonate significantly up-regulated the expression of PD-L1, whereas deprivation of mevalonate reduced PD-L1 expression. Mevalonate increased CD274 mRNA level but did not affect CD274 transcription. Further, we confirmed that mevalonate improved CD274 mRNA stability. Mevalonate promoted the affinity of the AU-rich element-binding protein HuR to the 3'-UTR regions of CD274 mRNA and thereby stabilized CD274 mRNA. By in vivo study, we further confirmed that mevalonate addition enhanced the anti-tumor effect of anti-PD-L1, increased the infiltration of CD8+ T cells, and improved cytotoxic function of T cells. Collectively, our findings discovered plasma mevalonate levels positively correlated with the therapeutic efficacy of anti-PD-(L)1 antibody, and provided the evidence that mevalonate supplementation could be an immunosensitizer in NSCLC.

The impact of lipids on the cancer-immunity cycle and strategies for modulating lipid metabolism to improve cancer immunotherapy

Lipids have been found to modulate tumor biology, including proliferation, survival, and metastasis. With the new understanding of tumor immune escape that has developed in recent years, the influence of lipids on the cancer-immunity cycle has also been gradually discovered. First, regarding antigen presentation, cholesterol prevents tumor antigens from being identified by antigen presenting cells. Fatty acids reduce the expression of major histocompatibility complex class I and costimulatory factors in dendritic cells, impairing antigen presentation to T cells. Prostaglandin E2 (PGE2) reduce the accumulation of tumor-infiltrating dendritic cells. Regarding T-cell priming and activation, cholesterol destroys the structure of the T-cell receptor and reduces immunodetection. In contrast, cholesterol also promotes T-cell receptor clustering and relative signal transduction. PGE2 represses T-cell proliferation. Finally, regarding T-cell killing of cancer cells, PGE2 and cholesterol weaken granule-dependent cytotoxicity. Moreover, fatty acids, cholesterol, and PGE2 can improve the activity of immunosuppressive cells, increase the expression of immune checkpoints and promote the secretion of immunosuppressive cytokines. Given the regulatory role of lipids in the cancer-immunity cycle, drugs that modulate fatty acids, cholesterol and PGE2 have been envisioned as effective way in restoring antitumor immunity and synergizing with immunotherapy. These strategies have been studied in both preclinical and clinical studies.

Study on the effect of Xiaoqinglong decoction on vascular endothelin inpulmonary hypertension rat based on Jiebiaokuoluo method / 中华危重病急救医学

Objective:To discuss the effect of Xiaoqinglong decoction on vascular endothelin (ET) in rats pulmonary hypertension (PAH) model based on the Jiebiaokuoluo method.Methods:Sixty male SD rats were randomly divided into six groups: control group, PAH model group, positive drug group, and Xiaoqinglong decoction in the high-dose, medium-dose and low-dose groups, 10 rats in each group. The control group did not receive any treatment. The remaining groups were kept in low-pressure oxygen tanks, injections of lipopolysaccharide (LPS) at 200 μL on day 1 and day 14, respectively. The rats were smoked twice a day from day 2 to day 30 (except day 14) at 4 hours intervals. The rats were placed in a low-temperature environment for 1 hour per day, and were put into cold water to swim (for 2 weeks), while the rats were given a cold diet. After modeling, the control group and the PAH model group were given equal volumes of normal saline; the positive drug group was given bosentan (100 mg/kg); Xiaoqinglong decoction 15, 10 and 5 g/kg was given, respectively, in the high, medium and low dose groups; once daily for 30 days. The mean pulmonary artery pressure (mPAP) and right ventricle systolic pressure (RVSP) were then measured with right heart catheterization and the right ventricle hypertrophy index (RVHI) was assessed; ET-1 and nitric oxide (NO) levels were determined by radioimmunoassay.Results:Compared with the control group, the levels of mPAP, RVSP, RVHI and ET-1 were significantly increased in the PAH model group [mPAP (mmHg, 1 mmHg≈0.133 kPa): 33.20±1.04 vs. 13.20±1.03, RVSP (mmHg): 62.40±1.54 vs. 24.20±1.02, RVHI: 42.90±2.51 vs. 25.40±2.01, ET-1 (ng/L): 100.80±20.34 vs. 81.50±13.84, all P < 0.05], while NO levels were significantly decreased (mmol/L: 23.20±1.81 vs. 31.70±1.49, P < 0.05). Compared with the PAH model group, the levels of mPAP, RVSP, RVHI and ET-1 in the positive drug group and high, medium, low dose groups of Xiaoqinglong decoction were significantly decreased [mPAP (mmHg): 25.50±0.84, 26.90±0.74, 27.10±1.19, 29.10±0.75 vs. 33.20±1.04, RVSP (mmHg): 54.40±5.14, 50.10±1.67, 53.10±1.05, 56.60±1.07 vs. 62.40±1.54, RVHI: 41.10±1.19, 31.20±1.67, 31.30±1.89, 40.30±1.88 vs. 42.90±2.51, ET-1 (ng/L): 70.70±7.89, 69.90±2.92, 71.70±4.32, 73.90±5.19 vs. 100.80±20.34, all P < 0.05], while NO levels were significantly increased (mmol/L: 32.50±2.06, 34.70±1.16, 32.70±1.33, 30.10±1.19 vs. 23.20±1.81, all P < 0.05), and with the increased dose of Xiaoqinglong decoction, the change was more obvious, and the effect was better in the high-dose group. Conclusion:Xiaoqinglong decoction can reduce rats PAH by regulating ET-1 and NO levels in a dose-dependent manner.

Traslation and reliability and validity of Chinese version Healthcare Education Micro Learning Environment Measure / 中国实用护理杂志

Objective:To translate the Healthcare Education Micro Learning Environment Measure (HEMLEM), and test the reliability and validity of the Chinese version of HEMLEM.Methods:HEMLEM was translated into Chinese version, convenient sampling and electronic questionaire survey methods were applied, and the reliability and validity of the scale was tested by electronic questionnaire survey among 141 nursing interns in China-Japan Friendship Hospital from November to December, 2021.Results:The Cronbach α coefficient of internal consistency of the total scale was 0.971, and the Cronbach α coefficient of the two sub-scales was 0.953 and 0.951, respectively, and the retest reliability was 0.901, the correlation coefficient with the Chinese version of Clinical Learning Environment Assessment Scale was 0.799. Two common factor was extracted from exploratory factor analysis, with a cumulative contribution of 83.478%.Conclusions:The Chinese version of HEMLEM has the same structure as the original scale, and has high reliability and validity, which can be used to evaluate the teaching environment of clinical departments.

Construction of nurses level promotion training system under vertical nursing management model / 中国实用护理杂志

Objective:On the basis of the development of nurses' core competence and the hierarchical management, to construct a nursing training system that meets the development and needs of clinical nursing.Methods:The energy level system of nurses was constructed: design and develop training modules for practical nurse, competent nurse, advanced nurse and specialist nurse. Developed energy level education and training modules, and determined the access conditions and assessment standards for energy level promotion, so as to ensure that the effect of education and training was achieved and met the requirements for nurse level promotion. The satisfaction of nurses with the training system was preliminarily evaluated.Results:Nurse level training system in line with clinical nurses' career development was constructed, and established an online education platform suitable for clinical nurses' learning. Nurses had high satisfaction with level promotion training system, with an average evaluation score of 4.0-4.9 (full score is 5), and the lowest satisfaction score of A2 level (4.0).Conclusions:The training system for level promotion of clinical nurses is feasible, which can meet the training needs of clinical nurses and help to improve the comprehensive clinical nursing ability of nurses.

Strategies and thoughts on the homogenization training of specialized nurse teachers / 中国实用护理杂志

To analyze and summary the setting of admission standards, training methods and certification and assessment methods of specialized nursing teachers, in order to lay the foundation for the homogenization training of specialized nursing teachers in China, and at the same time, provide guarantee for the improvement of the homogenization level of national specialized nursing training bases.

Two cases of female-restricted X-linked syndromic mental retardation-99 caused by USP9X gene variations / 中华实用儿科临床杂志

Objective:To summarize and analyze the clinical and genotype features of female-restricted X-linked syndromic mental retardation-99(MRXS99F, OMIM: 300968)caused by USP9 X gene mutation, and to improve the clinicians′ understanding of the disease. Methods:Clinical data and genotypes of 2 children with MRXS99F treated in the Children′s Hospital of Nanjing Medical University in March 2020 (case 1) and June 2020 (case 2) were analyzed, and the relevant databases at home and abroad were reviewed to summarize the clinical characteristics and gene variation characteristics of the disease.Results:The 2 cases were 6 months old (case 1) and 5 years old (case 2), both showed psychomotor retardation.Case 1 presented a short stature, pigment abnormality, characteristic facial features, hypotonia, recurrent respiratory tract infections, laryngeal cartilage hypoplasia, atrial septal defect, feeding difficulty, hearing loss and brain hypoplasia.Case 2 had abnormal electroencephalogram.As confirmed by whole-exome sequencing, two children carried c. 6972+ 1G>A, c.6437C>T of USP9 X, respectively.Neither of the 2 variations was previously reported.Twenty-two cases of MRXS99F caused by USP9 X gene mutation were reported in 4 literatures globally, and 24 cases were combined with this study.The clinical manifestations of 20/22 children had special faces.All of them accompanied mental retardation combined with motor and language retardation, and carried neonatal variation. Conclusions:This is the first case report of MRXS99F induced by USP9 X gene variation in China.MRXS99F caused by functional deletion and variation of USP9 X gene is mainly characterized by psychomotor retardation, language disorder, special face and multiple congenital malformations.For children with unexplained growth retardation, special face and multiple congenital malformations, genetic testing like high-throughput sequencing should be carried out as early as possible to determine the etiology.

Epigenetic strategies synergize with PD-L1/PD-1 targeted cancer immunotherapies to enhance antitumor responses

Immunotherapy strategies targeting the programmed cell death ligand 1 (PD-L1)/programmed cell death 1 (PD-1) pathway in clinical treatments have achieved remarkable success in treating multiple types of cancer. However, owing to the heterogeneity of tumors and individual immune systems, PD-L1/PD-1 blockade still shows slow response rates in controlling malignancies in many patients. Accumulating evidence has shown that an effective response to anti-PD-L1/anti-PD-1 therapy requires establishing an integrated immune cycle. Damage in any step of the immune cycle is one of the most important causes of immunotherapy failure. Impairments in the immune cycle can be restored by epigenetic modification, including reprogramming the environment of tumor-associated immunity, eliciting an immune response by increasing the presentation of tumor antigens, and by regulating T cell trafficking and reactivation. Thus, a rational combination of PD-L1/PD-1 blockade and epigenetic agents may offer great potential to retrain the immune system and to improve clinical outcomes of checkpoint blockade therapy.

Network correlation of circRNA-miRNA and regulatory mechanisms of female major depressive disorder / 中华行为医学与脑科学杂志

Objective:To obtain differential expression profiles of circRNAs and miRNAs in peripheral blood of female patients with major depressive disorder based on high-throughput sequencing technology, and then construct an interaction network.Based on the outcome, it made a further exploration of the possible occurrence and development mechanisms of female major depressive disorder through functional annotation and pathway enrichment analysis.Methods:According to the ceRNA theory, circRNA-miRNA network was constructed by TargetScan software via predicting the binding sites.Subsequently, the GO functional enrichment analysis was performed, and KEGG pathway enrichment analysis were utlized to illustrate the target genes of co-expressed miRNAs.Thereby, the key genes related to major depressive disorder could be screened out.Results:A total of 724 differential circRNAs and 26 differential miRNAs were detected in female patients with major depressive disorder.And hsa_circ_0086092 and hsa-miR-146a-3p were the most co-expressed.Go functional annotations pointed out that it involved the regulation of nucleobase-containing compound metabolic process, regulation of RNA splicing, regulation of cell communication, amino acid transfer, regulation of RNA metabolic process, regulation of signaling and other biological processes.KEGG pathway analysis showed that target genes were mainly enriched in neurotrophin signaling pathway, Rap1 signaling pathway, FoxO signaling pathway, AMPK signaling pathway, cocaine addiction, mTOR signaling pathway, Jak-STAT signaling pathway, cAMP signaling pathway, etcetera.Among the predicted target genes, BDNF, FGF2, MAPK14, GRIN2A, GRIN2B, GRM2 and PDE4 have the highest correlation with major depressive disorder.Conclusion:Hsa_circ_0086092 may be involved in the occurrence and development of female major depressive disorder through interaction with hsa-miR-146a-3p.

Bioinformatics analysis of peripheral blood circRNAs in female patients with major depressive disorder / 中华行为医学与脑科学杂志

Objective:To screen the circRNAs with differential expression between female patients with major depressive disorder and healthy women, and to explore the circRNAs that might be associated with depressive disorder through bioinformatics analysis.Methods:Using high-throughput sequencing screen differentially expressed circRNAs of female major depressive disorder patients, |log 2FC|≥1 and FDR<0.05 were used to determine whether circRNA had a difference in expression.According to the miRNA sponges function of circRNA, the online databases were used to predict miRNAs which may be targeted by circRNAs, and miRNAs related target genes were also predicted by the five most different circRNA.GO and KEGG pathway enrichment analysis were used to predict biological processes for the target genes and signaling pathways.Based on the results of high-throughput sequencing, biological processes and signaling pathways related to depression, circRNAs related to depression were screened. Results:Thirteen targeted miRNAs were predicted by the five most different circRNAs(hsa_circ_0020959, hsa_circ_0005959, hsa_circ_0033064, hsa_circ_0006862, hsa_circ_0027732), and multiple biological processes and signaling pathways related to depressive disorders were predicted by the target genes, such as glucocorticoid receptor signaling pathway, interleukin-7 response, nervous system development, Wnt signaling pathway, FoxO signaling pathway, thyroid hormone signaling pathway, neurotrophin signaling pathway, and so on.Conclusion:All the 5 circRNAs enriched biological processes or signaling pathways related to depressive disorder, among which hsa_circ_0005959, hsa_circ_0033064, hsa_circ_0006862 and hsa_circ_0027732 may be more closely related to female major depressive disorder.

Practice of multidisciplinary discussion on case coding of cerebral infarction / 中华医院管理杂志

It is an important measure to establish an effective communication mechanism for filling in the front page of medical records to ensure the good operation of diagnosis-related groups. Taking cerebral infarction as an example, the authors carried out the pilot work of multidisciplinary cooperation mode based on disease types around its coding axis. The multi-disciplinary assistance model could provide a good platform for communication and learning among multiple disciplines, break the barriers between disciplines, improve the quality of the front page and medical record writing of clinicians, and improve the quality and efficiency of coders′ coding.

The research of nursing human resource optimization in emergency department / 中华急诊医学杂志

Objective To explore the way to optimize nursing human resources and analysis the effects of setting up the nurse part-time position in emergency department. Methods The nurses were recruited in the hospital of other departments, and these nurses worked in the rescue unite during the rush hour, the Practice Environment Scale of the Nursing Work Index (PES-NWI) was used to measure the effects of the alleviation nurse shortage, and the statistical methods was t test. Results The Part-time nurse is significantly to alleviate the pressure of the nurse shortage in emergency department, especially the cooperation ability between doctors and nurses were significantly improved. Conclusions Part-time nurses as a way to alleviate the shortage of nurse human resources is acceptable,which also could help promote the care quality.

Study on effect of curcumin in inhibiting proliferation of multidrug resistant liver cancer HepG2/ADM cells and its mechanism / 重庆医学

Objective To observe the inhibitory effect of curcumin on the proliferation of multidrug resistance liver cancer line HepG2/ADM cells and to explore its mechanisms.Methods HepG2/ADM cells were prepared and cultured in vitro,and treated by different concentrations (5,10,20,40 μmol/L) of curcumin for 24,48,72 h respectively.The effect of curcumin on proliferation of HepG2/ADM cells was measured by CCK-8 reagent;the concentration of intracellular rhodamine-123 (Rh-123) and adriamycin (ADM) were determined by flow cytometry;the level change of intracellular mdr-1 mRNA in each group was determined by RT-PCR,the P-gp protein level was detected by Western blot.Results Compared with the blank control and DMSO group,curucmin had more obvious inhibitory effect on HepG2/ADM cells proliferation (P＜0.05),and could more remarkably inhibit the intracellular Rh-123 excretion(P＜0.05).The RT-PCR and Western blot results showed that curcumm more significantly decrease the mdr-1 mRNA and P-gp protein levels in dose-time dependent manner (P＜0.05).Conclusion Curcumin could significantly inhibit the proliferation of multidrug-resistant HepG2/ADM cells,and its mechanism may be related with inhibiting mdr-1 gene expression and its encoded P-gp protein level,which are closely related with MDR.

Comparison of the Preventive and Therapeutic Effect of Different Dosage Forms of Vinegar Testudinis Car-apax on Mice with Hemopenia or Osteoporosis / 中国药房

OBJECTIVE:To compare the preventive and therapeutic effect of Vinegar testudinis carapax (VTC) water decoc-tion and powder on mice with hemopenia or osteoporosis. METHODS:Mice were randomly divided into normal group (1%CMC-Na),model group (1% CMC-Na),positive group (Compound e-jiao slurry 20 mL/kg or Gusongbao capsule 1.98 g/kg), VTC water decoction and powder low-dose,medium-dose,high-dose groups(1.95,3.90,7.80 g/kg),10 in each group. In hemo-penia mice model experiment,except for the normal group,mice in other groups were intraperitoneally injected cyclophosphamide 0.1 g/kg for modeling,and intragastrically given medicines from the first day(positive drug was Compound e-jiao slurry),once a day,for 8 d. After administration,peripheral blood levels of white blood cells (WBC),red blood cells (RBC),hemoglobin (HG),hematocrit(HCT),platelet(PLT)and bone marrow nucleated cells(BMNC)numbers in femur of mice were determined. In osteoporosis mice model experiment,except for the normal group,mice in other groups were intragastrically given retinoic acid 0.105 g/kg for modeling,and intragastrically given relevant medicines from the first day(positive drug was Gusongbao capsule), once a day,for 30 d. After administration,alkaline phosphatase(ALP)level,organ(thymus,liver,spleen,ovary)coefficients, dry masses and degreasing,ash quality of the femur,and contents of femur calcium and phosphorus in serum of mice were detect-ed. RESULTS:In hemopenia mice model experiment,compared with normal group,WBC,RBC,HG,HCT,PLT levels in pe-ripheral blood and BMNC numbers in femur of mice in model group were decreased (P0.05). Compared with model group,ALP level in serum and dry mass,phosphorus content of femur of mice in VTC water decoction high-dose group were significantly in-creased (P<0.05);ALP level in serum and dry mass,phosphorus content of femur of mice in VTC,powder medium-dose, high-dose group,the ash mass,ash mass/dry mass of degreasing,contents of femur calcium and phosphorus in VTC powder medi-um-dose group were significantly increased(P<0.05). CONCLUSIONS:VTC water decoction shows better preventive and thera-peutic effect on hemopenia mice;while VTC powder shows better preventive and therapeutic effect on osteoporosis mice.

Correlation studies on tuberculosis patient′s self-efficacy and coping style / 中国实用护理杂志

Objective To describe the status of the self-efficacy and coping styles of tuberculosis patients,analysis the relationship between self-efficacy and coping styles. Methods With the method of convenient sampling, used the general information questionnaire self-designed, General Self-Efficacy Scale (GSES) and Medical Coping Modes Questionnaire (MCMQ) to take questionnaire survey on 132 patients with pulmonary tuberculosis.Applicated SPSS19.0 software for the statistics, and analyzed the relationship between self-efficacy and coping styles on patients with pulmonary tuberculosis. Results The mean score of self-efficacy in 132 pulmonary tuberculosis patients was 24.90 ± 7.04,which was in the medium to low level. The proportion of mediun,lower,higher level of self-efficacy was 44.70% (59/132), 39.40%(52/132),15.90%(21/132).Scores of the coping styles on face,avoid, yield were 21.16±9.23,16.55± 2.83,9.68 ± 4.12.Patients self-efficacy level was positively correlated with face coping style (r=0.242, P<0.05), avoid coping style (r=0.150, P<0.05),and negatively correlated with the yield response (r=-0.008, P<0.05). Conclusions The general self-efficacy level of tuberculosis patients is at a lower level. Tuberculosis patients should have more choice to handle it.

Application of allergen specific immunotherapy in children with allergic diseases / 国际儿科学杂志

Allergen specific immunotherapy(AIT) is a desensitization treatment for IgE-mediated allergic diseases.Combined with pharmacological therapy,AIT is used to treat allergic asthma,allergic rhinitis and atopic dermatitis caused by allergens that cannot be avoided.AIT is the only treatment modality that can alter the natural course of allergic disease.However,because of the lack of studies,there still exists controversy about the application of immunotherapy in children with allergic diseases.The mechanism ofAIT,its clinical efficacy and safety in children with allergic diseases are reviewed.

Value of texture feature analysis of MRI dynamic contrast enhancement in diagnosis of benign and malignant breast nodules / 中国医学影像技术

Objective To assess the diagnostic value of texture analysis of MRI in differential dignosis of benign and ma lignant breast nodules.Methods The MRI data of 78 patients (80 breast nodules) identified by surgical pathology were retrospectively studied.Sixty-three texture parameters were obtained from each nodule.ROC curve of texture parameters in differential diagnosis of benign and malignant breast nodules were performed.Results In all of the 63 texture parameters,the run length nonuniformity (RLN) had the highest AUC value (0.836) and accuracy,the diagnostic sensitivity,specificity,accuracy,positive predictive value and negative predictive value in differentiation of breast nodules were 82.93％ (34/41),94.87％ (37/39),88.75％ (71/80),94.44％ (34/36) and 84.09％ (37/44).The sensitivity,specificity,accuracy,positive predictive value,and negative predictive value of breast imaging reporting and data system (BIRADS) were 95.12％ (39/41),87.18％ (34/39),91.25％ (73/80),88.63％ (39/44),and 94.44％ (34/36).The difference of diagnostic accuracy between texture parameter and BI-RADS had no statistical significance (P =0.11).BIRADS combined texture parameter improved specificity significantly (P＜0.001).Conclusion The texture analysis could be complementary to improve the accuracy of BI-RADS-MRI in breast nodules.

Optimization of Water Extraction Technology for Shenqi Yiqi Capsules with Multi-index Comprehensive Score-orthogonal Test / 中国药房

OBJECTIVE:To optimize water extraction technology of Shenqi yiqi capsules. METHODS:The water extraction technology of Shenqi yiqi capsules was optimized by L9(34)orthogonal test with amount of water added,decoction times and decoc-tion time as factors using the extraction rate of astragaloside,calyosin-7-O-β-D-glycoside,icariin and bergenin as index,and the verification test was made. RESULTS:The best extraction technology was as follows as 8-fold water,decocting for 3 times,2 h each time;comprehensive score of 3 batches of samples in validation test were 98.95,99.71 and 99.98(RSD<2%,n=3). CON-CLUSIONS:The water extraction technology optimized by multi-index comprehensive score-orthogonal test is stable,scientific and reasonable.

Comparison study on sampling methods of Oncomelania hupensis snail sur-vey in marshland schistosomiasis epidemic areas in China / 中国血吸虫病防治杂志

Objective To optimize and simplify the survey method of Oncomelania hupensis snail in marshland endemic re?gion of schistosomiasis and increase the precision,efficiency and economy of the snail survey. Methods A quadrate experimen?tal field was selected as the subject of 50 m×50 m size in Chayegang marshland near Henghu farm in the Poyang Lake region and a whole?covered method was adopted to survey the snails. The simple random sampling,systematic sampling and stratified ran?dom sampling methods were applied to calculate the minimum sample size,relative sampling error and absolute sampling error. Results The minimum sample sizes of the simple random sampling,systematic sampling and stratified random sampling meth?ods were 300,300 and 225,respectively. The relative sampling errors of three methods were all less than 15%. The absolute sampling errors were 0.221 7,0.302 4 and 0.047 8,respectively. Conclusion The spatial stratified sampling with altitude as the stratum variable is an efficient approach of lower cost and higher precision for the snail survey.