Objective: To evaluate the efficacy and safety of adding toripalimab to bevacizumab and platinum-based chemotherapy as first-line treatment for refractory recurrent or metastatic (R/M) cervical cancer (CC). Methods: Patients were administered toripalimab (240 mg) + bevacizumab (7.5 mg/kg) combined with platinum-based chemotherapy once every three weeks for six cycles, followed by the maintenance therapy involving toripalimab + bevacizumab once every 3 weeks for 12 months or when disease progression or intolerable toxicity occurred. The primary endpoint was the objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1. The secondary endpoints were safety profiles, disease control rate (DCR), progression-free survival (PFS), and overall survival (OS). Results: Twenty-four patients were enrolled in this study and in the final analysis. The median follow-up duration was 18.6 (range, 3.3–28.5) months. The ORR was 83.3% (95% confidence interval [CI]=62.6–95.3) and the DCR was 95.8% (95% CI=78.9–99.9); 9 (37.5%) patients achieved complete response, 11 (45.8%) achieved partial response, and 3 (12.5%) had stable disease. The median PFS was 22.6 (95% CI=10.4–34.7) months and the median OS was not reached. The most common grade 3 treatment-related adverse events (AEs) were neutropenia (41.7%) and leukopenia (16.7%). The most common immune-related AEs (irAEs) were thyroid dysfunction (37.5%) and increased adrenocorticotropic hormone (37.5%) and serum cortisol levels (33.3%). No grade ≥3 irAEs were observed. Conclusion Toripalimab combined with bevacizumab and platinum-based chemotherapy show promising clinical efficacy and favorable safety profile, providing an alternative firstline treatment option for patients with R/M CC.

Objective:To investigate the role and mechanism of N 6-methyladenosine (m 6A) methyltransferase-like 3 (METTL3) in vascular calcification (VC) of chronic kidney disease (CKD) through apoptosis-associated protein. Methods:(1) Real-time fluorescence quantitative PCR was used to test METTL3 mRNA in serum of maintenance hemodialysis (MHD) patients. (2) Western blotting was used to detect the expression of METTL3 protein in high-phosphorus stimulated vascular smooth muscle cells (VSMCs), and immunofluorescence double lable was used to observe the distribution of METTL3 and Runt-related transcription factor 2 (Runx2). The METTL3 overexpressed and knockdown plasmids were constructed and transfected into VSMCs. Alizarin red staining was used to detect calcification degree. Western blotting was used to detect the expressions of osteogenic markers [Runx2, bone morphogenetic protein-2(BMP-2), collagen Ⅰ] and apoptosis- related proteins Bax and Bcl-2. (3) SD rats were randomly divided into control group, CKD-VC group and S-adenosylhomocysteine (SAH) intervention group. The calcification of thoracic aorta was evaluated by von Kossa staining, and the protein expressions of Runx2, Bax and Bcl-2 were detected by immunohistochemistry and Western blotting.Results:(1) METTL3 mRNA expression in MHD patients with VC was significantly lower than that in non-VC patients ( P<0.05), and was negatively correlated with coronary artery calcium score ( r=-0.65, P<0.001). (2) The expression of METTL3 in VSMCs stimulated by high phosphorus was decreased and showed a time dependence. Immunofluorescence double label showed that METTL3 and Runx2 were co-expressed in the nucleus. METTL3 was overexpressed in high-phosphorus induced VSMCs, and the expressions of Runx2, collagen I and BMP-2 were significantly decreased, accompanied by the decrease of calcified nodules and Bax/Bcl-2 ratio (all P<0.05). Conversely, METTL3 knockdown aggravated VSMCs calcification by inducing apoptosis. (3) Furthermore, METTL3 inhibitor SAH was administered in vivo, and it was found that inhibition of METTL3 expression significantly increased the calcification of rat thoracic aorta, and the Bax/Bcl-2 ratio and Runx2 expression were up-regulated. Conclusions:Serum METTL3 level is reduced in MHD patients with VC. In vivo and in vitro studies demonstrate that METTL3 inhibits VC in CKD by mediating the apoptosis-related protein Bax/Bcl-2.

Isomalto-oligosaccharides (IMO) have good physiochemical properties and excellent physiological functions to make it widely used in food, medicine, feed, cosmetics and other industries. However, the procedures for industrial production of IMO are complicated. Therefore, it is necessary to develop an economical and easy-to-operate method. The genes encoding for β-amylase and α-transglucosidase were fused and co-displayed on the yeast cell surface of Yarrowia lipolytica which can convert liquefied starch to IMO in one step. The highest IMO purity of 75.3% was obtained using the displayed fusion-enzyme at 50 °C. This method showed potential application in IMO production.
Oligosaccharides ; Starch ; Yarrowia ; beta-Amylase

Objective To investigatethe significance of serum carbohydrate antigen (CA) 125,car cinoembryonic antigen (CEA),cytokeratin 19 fragment (CYFRA21-1),neuron-specific enolase (NSE),and squamous cell carcinoma antigen (SCCA) in the diagnosis of bone metastasis from lung cancer.Methods A total of 222 patients,including 91 lung cancer patients with bone metastasis (49 males,42 females,average age (60.07± 10.60) years;group A),75 lung cancerpatientswithout bone metastasis (57 males,18 females,average age (62.20± 12.63) years;group B),56 patients with benign lung diseases (34 males,22 females,average age (61.45± 10.66) years;group C) were recruited from January 2015 to January 2016.The electrochemiluminescence was applied to detect serum levels of CA125,CEA,CYFRA21-1,NSE and SCCA.Kruskal-Wallis,Wilcoxon rank sum test,x2 test and receiver operating characteristic (ROC) curve analysis were used to analyze data.Results The levels of serum CA125,CEA,CYFRA21-1,NSE in group A were higher than those in group B and C (H values:13.45-44.96,all P＜0.05);while SCCA was not significantly different among the 3 groups (H=2.56,P＞0.05).The areas under ROC curves for CA125,CEA,CYFRA21-1,NSE,SCCA were 0.667,0.702,0.602,0.664,0.440,respectively.The positive rate of serum NSE in small cell lung cancer (SCLC) patients was higher than that in non-small-cell lung cancer (NSCLC) patients (17/18 vs 32.88％ (24/73);x2=22.11,P＜0.05);CEA was highly expressed in adenocarcinoma,and SCCA was highly expressed in squamous cell carcinoma.Patients with grade Ⅲ+ Ⅳ metas tasis (n =52) had higher levels of CA 125,CEA,NSE compared to patients with Ⅰ + Ⅱ metastasis (n =39;z values:from-2.54 to-0.32,all P＜0.05).The sensitivity of combined detection of 5 tumor markers was 97.80％ (89/91),which was significantly higher than that of single tumor marker (x2 values:35.46-138.23,all P＜0.05).Conclusion Serum levels of CA125,CEA,CYFRA21-1,NSE and SCCA play a role in the diagnosis of bone metastasis from lung cancer,and the combined detection of the 5 tumor markers contribute to the early detection of bone metastases.

OBJECTIVETo explore the impact of plasma homocysteinemia(Hcy) on contrast-induced nephropathy (CIN) after percutaneous coronary intervention (PCI) in acute coronary syndrome (ACS) patients.

METHODSConsecutive 684 ACS patients undergoing first PCI in our department between January 2013 and December 2014 were prospectively enrolled.Patients were divided into 2 groups according to the pre-procedural plasma Hcy level: high-Hcy group (Hcy≥10 μmol/L, n=404) and control group (Hcy<10 μmol/L, n=280). The CIN was defined as serum creatinine ≥ 44.2 μmol/L or 25% increase compared to baseline within 48-72 h after PCI.The baseline clinical data and the ratio of CIN were compared between the 2 groups.Multivariate logistic regression analysis was used to define the independent risk factors for CIN.

RESULTSCIN occurred in 133(19.4%) out of 684 enrolled patients, and the incidence of CIN was significantly higher in high Hcy group than in the control group (22.0%(89/404)vs. 15.7%(44/280), P=0.040). After adjusting the confounding factors, including age, acute myocardial infarction, co-morbidities(hypertension, diabetes mellitus, and old myocardial infarction), laboratory examination (level of cystatin C and uric acid), glomerular filtration rate, left ventricular ejection fraction, angiographic and procedural characteristics (3 diseased vessels, multiple stent implantation), treatment at admission (spironolactone, digoxin), multivariate logistic regression analysis showed that high Hcy was independently associated with the development of CIN (OR=1.70, 95%CI 1.60-2.64, P=0.021).

CONCLUSIONElevated Hcy prior PCI is an independent risk factor of CIN in ACS patients undergoing first PCI.

Acute Coronary Syndrome ; Diabetes Mellitus ; Glomerular Filtration Rate ; Humans ; Hyperhomocysteinemia ; Incidence ; Kidney Diseases ; Myocardial Infarction ; Percutaneous Coronary Intervention ; Risk Factors ; Ventricular Function, Left

Aim To investigate the anti-angiogenesis and anti-xenograftes of UA in zebrafish larvaes. Meth-ods 24 hour post-fertilization ( hpf ) TG zebrafish was treated with different concentration of UA for 24h, and the number of intersegmental vessels( IVS) were detec-ted under fluorescent microscope respectively;then the models of AB/TG zebrafish xenografts were established by be micro-injected with SMMC-7721 or HT-29 cell at 48hpf respectively, and after cocultured with UA for 48h, optical density (OD) of the SMMC-7721 cell and subintestinal veins ( SIVs) induced by HT-29 were e-valuated under confocal microscope. Results ISV as-say showed that UA could cause IVS missing or disap-perance, inhibition ratio reaching 20. 25% and 26. 65%. UA blocked the spread of SMMC-7721 cells in zebrafish and OD value,and inhibition ratios at three concentrations were 38. 01%, 54. 69%, 61. 88%, re-spectively; in another SIVs assay induced by xeno-grafts, UA at concentration 10 and 15mg·L-1 showed that SIVs were inhibited (P<0. 01) obviously. Con-clusion UA could inhibit the angiogenesis and the growth of SMMC-7721/HT-29 xenografts,and the anti-tumor mechanism may be related with VEGFR2 expres-sion.

The rule of law is the basic approach of realizing harmonic relationship between doctors and patients.Therefore,the law on medicine and health should be consolidated,and the rights and obligations of both parties should be specified.Meanwhile,the enforcement of law should be strict and civilized,while developing the legal awareness of the people to maintain their rights legally,and creating nice medical sequences and doctor-patient relationship in legal environment.

Objective To explore the effects of Kangshuaiyizhi capsule on ChAT/AchE and NE, DA and 5-HT levels in the brain tissue of aging model rats, and explore its effect of protecting cerebral function. Methods Totally 72 rats were randomly divided into normal group and model group. The subacutely aging model rats were made by injecting D-gal (0.125 g/kg) into abdominal cavity continually, then aging rats were divided by random number table into model group, Naofukang group and Kangshuaiyizhi high-, low-dose group. After intervented with correspongding drugs for 60 days, activity of ChAT and AchE, cerebral cortex NE, DA, and 5-HT levels were detected. Results Activity of AchE was much higher (P<0.05), but level of ChAT, NE, DA and 5-HT in model group were significantly downregulated compared with normal group (P<0.05). After treated with Kangshuaiyizhi capsule, activity of AchE was downregulated, ChAT, NE, DA and 5-HT levels were significantly upregulated (P <0.01, P <0.05). Conclusion Kangshuaiyizhi capsule can regulate cholinergic and monoamine neurotransmitter levels in the brain tissue of aging model rats, and play a very important role in protecting cerebral function.

Objective To investigate the effects of medicine androgen deprivation therapy(ADT)on quality of life in patients with prostate cancer.Methods A total of 42 consecutive advanced prostate cancer patients without any other anti-androgen medications after ADT[A subcutaneous depot injection of LHRH-agonist(Zoladex) was instituted every 28 days]were enrolled.Levels of serum testosterone and prostatic specific antigen(PSA)were obtained just prior to ADT and after ADT.The general and disease-specific health-related quality of life were assessed.Results The average testosterone level was less than 50 mg/L after medical ADT in 3 weeks.And PSA level declined dramatically in one month.Although there were no significant differences on physical discomfort and limitations to daily activities.Urinary obstruction symptoms after ADT were disappeared and the size of prostate were reduced after one month.The appetite and vigor were worsened.Overall health status and sexual function were significantly reduced.Conclusion The ADT could make serum testosterone and PSA decline dramatically in short time,and worsen some general health-related quality of life.

BACKGROUND: The dynamic changes of pneumocyte apoptosis and aspartate-specific cysteine proteases-3 (caspase-3) expression in lung tissue of rats during the process of lung ischemia/reperfusion (I/R) injury and the possible action mechanisms remain unclear.OBJECTIVE: This study was to observe the dynamic changes of pneumocyte apoptosis and caspase-3 expression in the rat lung tissue during the process of lung I/R injury, and to analyze the role of pneumocyte apoptosis and the possible action mechanism.DESIGN: A randomized controlled animal experiment.SETTING: Emergency Center, First Hospital, Nanjing Medical University.MATERIALS: This study was carried out in the Animal Laboratory of the First Hospital of Nanjing Medcial University and Nanjing Center for Radioimmunity between April 2006 and September 2006. Twenty-eight male healthy SD rats of clean grade, with body weight of 250 to 350 g, aged 49 to 76 days, were provided by the Experimental Animal Center of Nanjing Medical University. The involved rats were randomized into experimental group and control group, with 14 rats in each.METHODS: ①Experimental intervention: Rats in the experimental group were created into models of lung I/R injury according to the method of Eppinger et al. They were occluded for 45 minutes at the porta of lung (no systolic and diastolic reactions in lung tissue being considered as successful occlusion), and then they were reperfused (recovery of systolic and diastolic function being considered as successful reperfusion); After that, lung tissues were harvested at 3 and 6 hours after lung I/R injury, 7 rats at each time point. Each rat in the control group was subjected to a thoracotony only, but lung tissues were isolated at the same time point by the same method. ②Experimental evaluation: Apoptotic cells in the lung tissue were detected with a flow cytometer by Annexin-V-PI staining, and apoptosis rate was calculated. Caspase-3 expression in the lung tissue was observed by immunohistochemical method and image analysis. Wet to dry weight ratio(W/D) of lung tissue of rats in the two groups was calculated; the number of injured pulmonary alveoli at I/R 3 hours/that at I/R 6 hours was calculated for quantitative evaluation of injured lung tissue; Patho-morphological changes of lung tissue were observed by haematoxylin & eosin staining under an optical microscope.MAIN OUTCOME MEASURES: ①Pneumocyte apoptosis rate and caspase-3 expression in the lung tissue. ②W/D of lung tissue and quantitative evaluation of injured lung tissue. ③Patho-morphological changes of lung tissue.RESULTS: Twenty-eight rats were involved in the final analysis, without deletion. ①Pneumocyte apoptosis rates in the experimental group at I/R 3 and 6 hours were significantly increased as compared with control group (P＜0.01). In the experimental group, pneumocyte apoptosis rate was decreased a little at I/R 6 hours than at I/R 3 hours (P＜0.05). ②Caspase-3 expression in the lung tissue of rats of experimental group reached its top at I/R 3 hours, and was decreased a little at I/R 6 hours. At each time point, caspase-3 expression in the experimental group was increased as compared with control group (P＜0.01). ③In the experimental group, the number of injured pulmonary alveoli at I/R 3 hours/that at I/R 6 hours and W/D ratios of lung tissues were significantly increased as compared with control group (P＜0.01). In the experimental group, two ratios at I/R 6 hours were higher than those at I/R 3 hours (P＜0.05).④In the experimental group, the structure of pulmonary alveoli was destructed, collapsed and disappeared; lots of inflammatory cell infiltration was found; Patho-morphological changes of injured lung tissue at I/R 6 hours were severer than those at I/R 3 hours. No obvious changes were found in the control group.CONCLUSION: At the early stage of lung I/R injury, the alteration of caspase-3 maybe activate pneumocyte apoptosis and induce the apoptosis of lung tissue, and thereby leads to lung injury.