Genome-wide analysis identify novel germline genetic variations in ADCY1 influencing platinum-based chemotherapy response in non-small cell lung cancer

To explore the pharmacogenomic markers that affect the platinum-based chemotherapy response in non-small-cell lung carcinoma (NSCLC), we performed a two-cohort of genome-wide association studies (GWAS), including 34 for WES-based and 433 for microarray-based analyses, as well as two independent validation cohorts. After integrating the results of two studies, the genetic variations related to the platinum-based chemotherapy response were further determined by fine-mapping in 838 samples, and their potential functional impact were investigated by eQTL analysis and in vitro cell experiments. We found that a total of 68 variations were significant at P < 1 × 10-3 in cohort 1 discovery stage, of which 3 SNPs were verified in 262 independent samples. A total of 541 SNPs were significant at P < 1 × 10-4 in cohort 2 discovery stage, of which 8 SNPs were verified in 347 independent samples. Comparing the validated SNPs in two GWAS, ADCY1 gene was verified in both independent studies. The results of fine-mapping showed that the G allele carriers of ADCY1 rs2280496 and C allele carriers of rs189178649 were more likely to be resistant to platinum-based chemotherapy. In conclusion, our study found that rs2280496 and rs189178649 in ADCY1 gene were associated the sensitivity of platinum-based chemotherapy in NSCLC patients.

A novel PI3K inhibitor XH30 suppresses orthotopic glioblastoma and brain metastasis in mice models

Glioblastoma is carcinogenesis of glial cells in central nervous system and has the highest incidence among primary brain tumors. Brain metastasis, such as breast cancer and lung cancer, also leads to high mortality. The available medicines are limited due to blood-brain barrier. Abnormal activation of phosphatidylinositol 3-kinases (PI3K) signaling pathway is prevalent in glioblastoma and metastatic tumors. Here, we characterized a 2-amino-4-methylquinazoline derivative XH30 as a potent PI3K inhibitor with excellent anti-tumor activity against human glioblastoma. XH30 significantly repressed the proliferation of various brain cancer cells and decreased the phosphorylation of key proteins of PI3K signaling pathway, induced cell cycle arrest in G1 phase as well. Additionally, XH30 inhibited the migration of glioma cells and blocked the activation of PI3K pathway by interleukin-17A (IL-17A), which increased the migration of U87MG. Oral administration of XH30 significantly suppressed the tumor growth in both subcutaneous and orthotopic tumor models. XH30 also repressed tumor growth in brain metastasis models of lung cancers. Moreover, XH30 reduced IL-17A and its receptor IL-17RA in vivo. These results indicate that XH30 might be a potential therapeutic drug candidate for glioblastoma migration and brain metastasis.

Research Progress of Proteolysis Targeting Chimeria in NSCLC Therapy / 中国肺癌杂志

Proteolysis targeting chimeria (PROTAC) degrades target proteins by utilizing the ubiquitin-proteasome pathway, subverting the concept of traditional small molecule inhibitors. Among the common mutation targets of non-small cell lung cancer (NSCLC), PROTAC technology has successfully achieved the effective degradation of kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK ) and other proteins in preclinical studies. PROTAC drugs with their unique event-driven advantages, are expected to overcome acquired drug resistance caused by small molecule inhibitors and show good therapeutic potential for undruggable targets, thereby providing a new strategy for the treatment of NSCLC.
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Multi-omics approaches identify

Autophagy is a critical cellular homeostatic mechanism, and its dysfunction is linked to invasive breast carcinoma (BRCA). Recently, several omics methods have been applied to explore autophagic regulators in BRCA; however, more reliable and robust approaches for identifying crucial regulators and druggable targets remain to be discovered. Thus, we report here the results of multi-omics approaches to identify potential autophagic regulators in BRCA, including gene expression (EXP), DNA methylation (MET) and copy number alterations (CNAs) from The Cancer Genome Atlas (TCGA). Newly identified candidate genes, such as

Impact of pre-pregnancy body mass index, weight gain and blood lipid level during pregnancy on pregnancy outcome in patients with gestational diabetes mellitus / 浙江大学学报·医学版

To explore the effects of pre-pregnancy body mass index (BMI), weight gain and blood lipid level during pregnancy on pregnancy outcome in patients with and without gestational diabetes mellitus(GDM). A total of 12 650 singleton pregnant women without history of hypertension and diabetes who were admitted at Women's Hospital, Zhejiang University School of Medicine for delivery from January 2018 to April 2019 were enrolled in the study. There were 2381 cases complicated with gestational diabetes (GDM group) and 10 269 cases without GDM (non-GDM group). The pre-pregnancy BMI and weight gain during pregnancy were documented in two groups. The factors related to perinatal outcome were analyzed. In both GDM and non-GDM pregnant women, pre-pregnancy overweight and excessive weight gain during pregnancy were independent factors of large for gestational age infant (LGA), small for gestational age infant (SGA) and first cesarean section (<0.01 or <0.05). Excessive weight gain during pregnancy was also an independent risk factor of preeclampsia (<0.05). Triglyceride levels in the second trimester were independently associated with multiple adverse pregnancy outcomes, such as LGA, preeclampsia, initial cesarean delivery, premature delivery. Controlling excessive or insufficient weight gain during pregnancy can significantly reduce the incidence of LGA and SGA. And controlling BMI before pregnancy can effectively reduce the incidence of LGA, preeclampsia and the first cesarean section. For non-GDM pregnant women, abnormal blood lipid levels in the second trimester may be closely related to multiple adverse pregnancy outcomes, and active dietary guidance or treatment is also required.

Evaluation value of changes in β-human chorionic gonadotropin for the curative effect of methotrexate on ectopic pregnancy / 中国基层医药

Objective:To analyze the evaluation value of changes in β-human chorionic gonadotrophin (β-HCG) for the curative effect of methotrexate (MTX) on ectopic pregnancy (EP).Methods:A retrospective analysis was performed in 80 EP patients who admitted to Jinhua People's Hospital from January 2013 to August 2019.Results:Of the 80 EP patients, success and failure rates of treatment were 77.50% (62/80) and 22.5% (18/80), respectively.According to different treatment results, they were divided into success group (62 cases) and failure group (18 cases). Before treatment, hemodynamic index of fallopian tube artery[resistance index (RI)] in success group was higher than that in failure group ( t=4.150, P<0.05). Before treatment, after 1d, 4d and 7d of treatment, the serum levels of β-HCG in success group were lower than those in failure group ( t=69.496, 76.618, 217.488, 310.203, all P<0.05). The results of Pearson correlation analysis showed that RI was negatively correlated with serum level of β-HCG before treatment, after 1d, 4d and 7d of treatment ( r=-0.374, -0.396, -0.471, -0.482, all P<0.05). The receiver operating characteristic (ROC) curves analysis showed that after 4d and 7d of treatment, areas under the curve (AUC) of β-HCG for evaluating the curative effect of MTX on EP were 0.821 and 0.829, respectively, which were higher than before treatment and after 1d of treatment (0.685, 0.701) ( P<0.05). Conclusion:The changes of β-HCG are of high clinical value in evaluating the curative effect of MTX on EP, which can be applied as an important monitoring index.

A new butterfly femoral artery compression device vs manual compression for hemostasis of femoral artery puncture point after peripheral endovascular interventions / 介入放射学杂志

Objective To compare the hemostatic safety and efficacy of a new butterfly femoral artery compression device (FACD) with those of manual compression (MC) in patients undergoing percutaneous peripheral endovascular interventions via femoral artery. Methods A total of 283 patients, who received percutaneous endovascular interventions via femoral artery during the period from September 2016 to December 2017, were enrolled in this study. After endovascular intervention, 167 patients received FACD to make hemostasis (FACD group), and 116 patients received MC hemostasis (MC group) . The patient's comfortableness, time used for hemostasis (min), limb immobilization time (h), and the incidence of vascular complications in both groups were analyzed. Results All 283 patients were included in analysis, the results indicated that the hemostatic success rates in FACD group and MC group were 96.4％ (161/167) and 94.0％ (109/116) respectively, the difference between the two groups was not statistically significant (P>0.05) . The postoperative Kolcaba Comfort Scale score of FACD group was (85.0 ±11.2) points, which was remarkably higher than (58.4±11.7) points of MC group (P<0.05), the time used for hemostasis in FACD group was (9.2 ±2.2) min, which was strikingly shorter than (18.5 ±2.9) min in MC group (P <0.05) . The limb immobilization time in FACD group was (10.4±2.4) hours, which was obviously shorter than (23.1±4.1) hours in MC group (P <0.05) . The incidence of vascular complications in FACD group was 3.6％, which was dramatically lower than 9.5％ in MC group (χ2=4.206, P=0.04) . Conclusion The use of the new butterfly FACD can promptly, safely and effectively stop bleeding of femoral artery puncture site. The new butterfly FACD is superior to MC in shortening hemostatic time and limb immobilization time, in reducing incidence of vascular complications, as well as in improving patient's comfortableness degree.

WM130 preferentially inhibits hepatic cancer stem-like cells by suppressing AKT/GSK3β/β-catenin signaling pathway / 中国药理学与毒理学杂志

OBJECTIVE The eradication of cancer stem cells(CSCs)is signifcant for cancer therapy and prevention.METHODS In this study,we evaluated WM130,a novel derivative of matrine,for its effect on CSCs using human hepatocellular carcinoma(HCC)cell lines,their sphere cells,and sorted EpCAM+cells. RESULTS We revealed that WM130 could not only inhibit proliferation and colony formation of HCC cells, but also suppress the expression of some stemness-related genes and up-regulate some mature hepatocyte marker genes, indicating a promotion of differentiation from CSCs to hepatocytes. WM130 also suppressed the proliferation of doxorubicin-resistant hepatoma cells, and markedly reduced the cells with CSC biomarker EpCAM.Moreover,WM130 suppressed HCC spheres,not only primary spheres but also subsequent spheres,indicating an inhibitory effect on self-renewal capability of CSCs.Interestingly,WM130 exhibiteda remarkable inhibitory preference on HCC spheres and EpCAM+cells rather than their parental HCC cells and EpCAM- cells respectively. In vivo, WM130 inhibited HCC xenograft growth, decreased the number of sphere-forming cells, and remarkably decreased the levels of EpCAM mRNA and protein in tumor xenografts. Better inhibitory effect was achieved by WM130 in combination with doxorubicin.Further mechanism study revealed that WM130 inhibited AKT/GSK3β/β-catenin signaling pathway. CONCLUSION Collectively, our results suggest that WM130 remark-ably inhibits hepatic CSCs, and this effect may via the down-regulation of the AKT/GSK3β/β-catenin pathway.These findings provide a strong rationale for the use of WM130 as a novel drug candidate in HCC therapy.

An Analysis of the Status of General Population with HCV Infection in Kunming Region from 2013 to 2015 / 昆明医科大学学报

Objective The aim of this study was to analyze the HCV seroprevalence in the general population visiting the Second Affiliated Hospital of Kunming Medical University. Methods Between January 2013 and December 2015, a total of 160, 239 subjects were screened for the presence of anti-HCV antibodies in blood serum. Anti-HCV antibodies in serum samples were detected by enzyme-linked immunosorbent assay (ELISA) . The results of anti-HCV were analyzed in the features of year, sex and age. Results The HCV seroprevalence in the general population from 2013 to 2015 was 1.11% , 1.04% and 0.91% , respectively, which was significantly higher in men than in women (1.30% vs. 0.91%,P＜0.05) . The highest HCV seroprevalence occurred in aged 31-65 years. Conclusions The analysis of the data suggests that the features of HCV-positive including year, sex and age could be beneficial for formulating scientific strategy and intervention measures of HCV infection and liver cirrhosis, liver failure and hepatocellular carcinoma caused by HCV in Kunming.

The reevaluation and surgical strategy of the superficial circumflex iliac artery perforator (SCIP) flap / 中华显微外科杂志

Objective To introduce the classification of the perforators of the superficial circumflex iliac artery(SCIA),and the superficial circumflex iliac artery perforator (SCIP) flaps based on different perforators have different characters and harvesting methods.To explore a set of coping strategy for the drawbacks of the SCIP flap.Methods Review 90 cases of SCIP flaps in August,2011 to June,2017.The pre-operative radiology navigation was conducted in all cases.Different surgical approaches were applied in flaps based on different perforators.The pedicle elongation method was adopted when necessary.The thickness of the flap,the length of the pedicle,the survival rate of the flap and the closure of the donor site were analyzed.Regular follow-up was performed after the operation.Results All flaps were followed-up for 6-15 months (average 8 months).Fifty-seven flaps were raised on the basis of the proximal perforators of the superficial branch of the SCIA,whereas 29 cases were based on the distal perforators from the deep branch,and in 4 cases,the pedicle was switched to the superficial inferior epigastric artery.In 8 cases,the arterial pedicle lengthen technique was applied with a maximum length of 10 cm.All donor sites were closed directly.Conclusion These surgical strategies simplified the intraoperative decision-making and conquered the shortcomings of the SCIP flap.It is believed that the SCIP flap can possibly become the new workhorse flap in the field of reconstructive surgery.

Mechanism of Platycarya strobilacea Sieb. et Zucc extract-induced methuosis in human nasopharyngeal carcinoma CNE1 and CNE2 cells / 南方医科大学学报

<p><b>OBJECTIVE</b>To study the effect of Platycarya strobilacea Sieb. et Zucc (PSZ) extract on methuosis of human nasopharyngeal carcinoma CNE1 and CNE2 cells and explore the underlying mechanism.</p><p><b>METHODS</b>CNE1 and CNE2 cells were treated with 1 mg/mL PSZ extract and the expressions of Rac1 mRNA and Rac1 protein were detected using RT-qPCR and Western blotting, respectively. Results CNE1 and CNE2 cells showed obvious morphological changes typical of methuosis following treatment with PSZ extract characterized by cell merging, accumulation of large cytoplasmic vacuoles, and membrane rupture without obvious changes in the nuclei. PSZ treatment resulted in up-regulated Rac1 mRNA and Rac1 protein expressions in the cells. Application of EHT 1864 obviously blocked the effect of PSZ extract in inducing methuosis in CNE1 and CNE2 cells.</p><p><b>CONCLUSION</b>PSZ extract can induce methuosis in CNE1 and CNE2 cells by inducing the overexpression of Rac1.</p>

Roles of microglia in cerebral ischemia / 国际脑血管病杂志

Microglia play a crucial role in inflammation after cerebral ischemia.A large number of studies have shown that microglia are highly plastic cells that can assume different phenotypes and functions in response to specific microenvironmental signals.Microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype,and play different roles in ischemic injury.Irnhibiting M1 while stimulating M2 may be a new approach for the treatment of ischemic stroke.

Retrograde recanalization technique for TASC Ⅱ C/D femoropopliteal arteriosclerosis obliterans / 中国介入影像与治疗学

Objective To explore the value of retrograde recanalization technique in treatment of TASCⅡ C/D femoropopliteal arteriosclerosis obliterans.Methods Totally 36 patients with TASCⅡ C/D femoropopliteal arteriosclerosis obliterans were retrospectively analyzed.Preoperative and postoperative ankle brachial index (ABI) and intermittent claudication were compared,as well as postoperative vascular patency rate and complications were analyzed.Results The retrograde recanalization technique were successfully performed in all 36 patients.The walking distance and ABI of 7 days,and 3,6,12 months postoperation were increased significantly compared with preoperation (all P＜0.05).The postoperative vascular patency rate of 3,6 and 12 months was 97.22％,91.67％ and 72.22％,respectively.There was no death nor amputation during the follow-up period,and the incidence of perioperative complications was 11.11 ％ (4/36).Conclusion Retrograde recanalization technique can be used to treat TASC Ⅱ C/D femoropopliteal arteriosclerosis obliterans when anterograde access failed.

Discussion on the strategies for maintenance management of medical devices of hospital based on the risk analysis / 中国医学装备

Objective:To discuss the management and maintenance of medical equipment in hospital, the department of biomedical and engineering should develop a reasonable management plan to meet the needs of using safety management of medical equipment based on the risk analysis.Methods: Make up a strategy based on the analysis of application risk according to the clinical function, physical risk, fault avoidable probability and the adverse events recorded, and conduct the preventative maintenance and safety performance inspection. Results: The focus of clinical engineering professionals change from passive acceptance to repair equipment to preventive equipment maintenance, and carry out safety performance inspection to reduce the risk caused by the failure of equipment which is harmful to the patients.Conclusion: The clinical engineering professionals need to pay attention to the application risk and improve the management strategy while they improve the technical level.

Roles of CD200 and CD200R in cerebral ischemia / 国际脑血管病杂志

Inflammation plays an important role in the pathophysiological mechanism of acute ischemic stroke.CD200 expressed in neurons interacts with CD200 receptor (CD200R) on microglia cells.It can inhibit microglia activation and alleviate the inflammation after cerebral ischemic injury.This article reviews the roles of CD200 and CD200R in the activation of microglia after cerebral ischemia.

Clinical characteristics and gene mutation analysis of one pedigree with infantile glycogen storage disease type II / 中国当代儿科杂志

The clinical data of 2 infants with infantile glycogen storage disease type II (GSD II) from one pedigree were collected. The method of dried blood spots (DBS) was applied to collect peripheral blood samples, and the activity of acid alpha-D-glucosidase (GAA) in leukocytes was measured. The coding region of GAA gene in this pedigree was amplified by polymerase chain reaction and then direct sequencing was used to analyze mutations in GAA gene. The two infants were twins, who were admitted to the hospital due to feeding difficulties, generalized muscle weakness and hypotonia, cardiomegaly, and cardiac insufficiency when they were 10 months old. The GAA activity in leukocytes in the two infants was significantly lower than in normal controls. Gene sequencing revealed 2 compound heterozygous mutations in the two infants, i.e., G1942A and G2214A, respectively. G1942A had been proved pathogenic, and the latter one, G2214A, was a nonsense mutation, resulting in the change of tryptophan, the 738th amino acid of GAA, into a stop codon. The two infants were diagnosed with GSD II by gene detection and no enzyme replacement therapy could be provided to them. Follow-up visits showed that the two infants died at home at the age of 15 months and 17 months, respectively. GSD II is caused by deficiency of GAA activity resulting from mutation of GAA gene. The detection of GAA activity in peripheral blood by DBS and GAA gene detection are effective and feasible methods for diagnosis of GSD II.

Toxicity of lidocaine solid lipid nanoparticles in human neurons / 中华麻醉学杂志

Objective To investigate the toxicity of lidocaine solid lipid nanoparticles (SLNs) in human neurons.Methods Lidocaine-loaded SLNs were prepared using high pressure homogenization.SHSY5Y cells were cultured in vitro and inoculated on 96-well plates (100 μl/well) at a density of 5× 105 cells/ml.SH-SY5Y cells were randomized into 10 groups (n =30 each) using a random number table:control group (group C), different concentrations of lidocaine groups (L1-4 groups), different concentrations of lidocaine SLN groups (L-SLN1-4 groups), and blank SLN group (group SLN).The cells were cultured routinely in group C.The cells were incubated with the culture medium containing lidocaine with the final concentrations of 1.000％, 0.500％, 0.250％ and 0.125％ in L1-4 groups, respectively.In LSLN1-4 groups, the cells were incubated with the culture medium containing lidocaine SLNs with the final concentrations of 1.000％, 0.500％, 0.250％ and 0.125％ in L1-4 groups, respectively.Before incubation (at the corresponding time points in group C), and at 1, 12 and 24 h of culture or incubation (T0-3) , 6 wells in each group were selected for measurement of the cell survival rate (using methyl thiazolyl tetrazolium assay).The cell morphology was examined with optical microscope at T3.Results Compared with that at T0, the cell survival rate was significantly decreased at each time point in L1-4 and L-SLN1,2 groups, at T2,3 in L-SLN3 group, and at T3 in L-SLN4 group (P＜0.05) , and no significant change was found in SLN and C groups (P＞0.05).The cell survival rate was significantly lower at T2,3 in L1-4 and L-SLN1-3 groups, and at T3 in group L-SLN4 than that at T1, and at T3 in L1-4 and L-SLN1-4 groups than that at T2 (P＜0.05).Compared with group C, the cell survival rate was significantly decreased at each time point in L1-4 and L-SLN1,2 groups, at T2,3 in group L-SLN3, and at T3 in group L-SLN4 (P＜0.05) , and no significant change was found in group SLN (P＞0.05).Compared with group L-SLN at the corresponding concentration, the cell survival rate was significantly decreased at each time point in group L1-4 (P＜0.05).Conclusion Lidocaine SLNs have toxic effect on human neurons, but the effect is weaker than that caused by Iidocaine solution.

Analysis on key factors of safety in use and quality control for high frequency surgical unit / 中国医学装备

Objective: To analysis the key factors of quality control for high frequency surgical unit to provide reference to ensure accurate and standard. Methods:To analysis the details of quality control on protective earth impendence, resistor-capacitor network, test error on definition, structure, magnitude and other aspects. Results:To master the key factors of quality control is important for the promotion of operability of the quality control work and decrease the using risk, and then to improve the quality of medical services ensure the safety of patients and medical staff. Conclusion: To analysis the each key factor is important significance to the quality control for high frequency surgical unit.

Orthogonal design based optimization of a mouse model of acute liver failure induced by D-galactosamine and lipopolysaccharide / 中华肝脏病杂志

<p><b>OBJECTIVE</b>To apply an orthogonal design optimization strategy to a mouse model of acute liver failure induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) exposure.</p><p><b>METHODS</b>A four-level orthogonal array design (L16(45)) was constructed to test factors with potential impact on successful establishment of the model (D-GalN and LPS dosages, and dilution rate of the D-GalN/LPS mixture). The mortality rate of mice within 24 hours of D-GalN/LPS administration was determined by the Kaplan-Meier method. The model outcome was verified by changes in serum alanine transferase level, liver histology, and hepatocyte apoptosis.</p><p><b>RESULTS</b>The orthogonal array identified the optimal model technique as intraperitoneal injection of a combination of D-GalN and LPS at dosages of 350 mg/kg and 30 mug/kg, respectively, and using a dilution rate of 3. The dosages tested had no effect on survival. The typical signs of liver failure appeared at 6 hrs after administration of the D-GalN/LPS combination.</p><p><b>CONCLUSION</b>The orthogonal design optimization strategy provided a procedure for establishing a mouse model of acute liver failure induced by D-GalN and LPS that showed appropriate disease outcome and survival, and which will serve to improve future experimental research of acute liver failure.</p>

Discussion on electromagnetic compatibility of RFID technology used in medical devices management / 中国医学装备

Objective:To master the methods of reducing electromagnetic interference by RFID system, and presents the feasible technical advices for hospital’s implementation to ensure the safety of applications of electronic medical devices. Methods:According to analysis the causes of electromagnetic interference by RFID system, the methods of suppressing the electromagnetic interference are put forward for practical application. Results:The clinical engineers could refer to the methods of suppressing the electromagnetic interference and then conduct and use the RFID system, taking account of the management efficiency and the safety of applications of the medical devices. Conclusion:To determine the proper strategy for RFID system application in medical management of hospital may reduce the electromagnetic interference to the electrical devices of hospital and ensure its safety of application.