Sequential delivery of PD-1/PD-L1 blockade peptide and IDO inhibitor for immunosuppressive microenvironment remodeling via an MMP-2 responsive dual-targeting liposome

Intelligent responsive drug delivery system opens up new avenues for realizing safer and more effective combination immunotherapy. Herein, a kind of tumor cascade-targeted responsive liposome (NLG919@Lip-pep1) is developed by conjugating polypeptide inhibitor of PD-1 signal pathway (AUNP-12), which is also a targeted peptide that conjugated with liposome carrier through matrix metalloproteinase-2 (MMP-2) cleavable peptide (GPLGVRGD). This targeted liposome is prepared through a mature preparation process, and indoleamine-2,3-dioxygenase (IDO) inhibitor NLG919 was encapsulated into it. Moreover, mediated by the enhanced permeability and retention effect (EPR effect) and AUNP-12, NLG919@Lip-pep1 first targets the cells that highly express PD-L1 in tumor tissues. At the same time, the over-expressed MMP-2 in the tumor site triggers the dissociation of AUNP-12, thus realizing the precise block of PD-1 signal pathway, and restoring the activity of T cells. The exposure of secondary targeting module II VRGDC-NLG919@Lip mediated tumor cells targeting, and further relieved the immunosuppressive microenvironment. Overall, this study offers a potentially appealing paradigm of a high efficiency, low toxicity, and simple intelligent responsive drug delivery system for targeted drug delivery in breast cancer, which can effectively rescue and activate the body's anti-tumor immune response and furthermore achieve effective treatment of metastatic breast cancer.

Exosomes' roles in the pathogenesis of Alzheimer's disease and the diagnostic and therapeutic values / 中华老年医学杂志

Exosomes are nanoscal-scale vesicles containing a variety of proteins(HSP70, actin, Alix, etc.), lipids, mRNAs and miRNAs.They are commonly found in various tissues and cells of the organism.They are involved in processes such as intercellular communication, immune regulation and cell signaling pathway regulation, and then play an important role.Recent studies have shown that exosome-mediated intercellular signaling plays an important role in the progression of Alzheimer's disease(AD). This paper reviewed the general characteristics of exosomes, clarifies the possible role of exosomes in the pathogenesis of AD, and also discussed the application prospect and the related challenges of exosomes as a new potential option in the future treatment of AD.

Study on Preparation ，Characterization and Magnetism of Magnetic Graphene Oxide Modified by Folic Acid / 中国药房

OBJECTIVE： To prepare Magnetic graphene oxide modified by folic acid （FA-GO-Fe3O4）， and to characterize it and study its magnetism. METHODS： Using graphene oxide （GO）， ferric chloride hexahydrate and ferrous chloride tetrahydrate as raw material， magnetic graphene oxide （GO-Fe3O4） was synthesized by hydrothermal coprecipitation method. FA-GO-Fe3O4 was obtained by linking amido bond to folic acid. GO， GO-Fe3O4 and FA-GO-Fe3O4 were characterized by scanning electron microscopy， infrared spectroscopy， X-ray diffraction （XRD） and particle size and Zeta potential analyzer respectively. Zeta potential was measured. The magnetism of FA-GO-Fe3O4 were investigated by the action of external magnetic field and hysteresis loop. RESULTS： Compared with GO and GO-Fe3O4， scanning electron microscopy and XRD showed that the structure of GO destroyed in the synthesis of FA-GO-Fe3O4， and there were particles attached on the surface， and amorphous phase peaks between 15 ° and 30 °. Infrared spectroscopy showed that FA-GO-Fe3O4 had absorption peaks at 574 cm－1 and 1 640 cm－1， which belonged to the characteristic absorption of Fe-O and —CONH— respectively. Zeta potentials of GO， GO-Fe3O4 and FA-GO-Fe3O4 were －24， 5.62 and －22.7 mV， respectively. FA-GO-Fe3O4 had obvious magnetism under external magnetic field， and its saturation magnetization was about 20-25 emu/g under room temperature and applied positive and negative magnetic fields. CONCLUSIONS： FA-GO-Fe3O4 prepared in this study has superparamagnetism and is more stable than GO-Fe3O4.

Application and effect of standardized graded transport scheme in intrahospital transport of emergency critical patients / 中国实用护理杂志

Objective@#To explore the effect of standardized grading transport scheme in intrahospital transport of emergency critical patients.@*Methods@#Selected a total of 1 425 critically ill patients from the emergency department in July 2017 - August 2018 as the research object, whom were transported by hospital for completing CT examination, transferring into Angiography Room or specialist ward, December 7, 586 cases of 2017 as control group, in August 1, 839 of 2018 as the observation group. Patients in the control group were transported by conventional transport, while patients in the observation group were transported by standardized graded transport scheme. The hospital transport time and adverse event incidence rates of patients in the two groups were compared.@*Results@#In the observation group, the time taken to complete CT examination, complete CT examination and transfer into angiography room, transfer into specialized wards, transfer into angiography room was respectively (25.70±2.94, 31.05±3.27, 20.04±2.54, 16.29±1.82) points, which was significantly different from (33.65±4.31, 37.12±4.16, 25.46±2.24, 20.20±2.17) points in the control group (t=16.665-26.709, P<0.01). Observation group of patients with nosocomial transhipment adverse events (a decrease in blood pressure, blood oxygen desaturation, accidental extubation, unobstructed intravenous drip, insufficient supply of oxygen, power insufficiency, the insufficient number of drugs and drug kinds) rates were 6.9% (58/839), 8.6% (72/839), 0.2% (2/839), 15.0% (126/839), 4.5% (38/839), 0.9% (8/839), 0.7% (6/839), 0, Significantly lower than the control group of 19.5% (114/586), 22.7% (133/586), 1.5% (9/586), 34.9% (205/586), 26.6% (156/586), 11.9% (70/586), 5.9% (35/586), 3.9% (23/586), the difference was statistically significant (χ2=31.950-106.173, P<0.01).@*Conclusion@#The standardized and graded transport scheme can fully warn patients of various risks in the course of intrahospital transportation, take effective preventive and control measures to ensure the safety of intrahospital transportation of emergency critical patients, and should be popularized.

Application and effect of standardized graded transport scheme in intrahospital transport of emergency critical patients / 中国实用护理杂志

Objective To explore the effect of standardized grading transport scheme in intrahospital transport of emergency critical patients. Methods Selected a total of 1 425 critically ill patients from the emergency department in July 2017- August 2018 as the research object, whom were transported by hospital for completing CT examination, transferring into Angiography Room or specialist ward, December 7, 586 cases of 2017 as control group, in August 1, 839 of 2018 as the observation group. Patients in the control group were transported by conventional transport, while patients in the observation group were transported by standardized graded transport scheme. The hospital transport time and adverse event incidence rates of patients in the two groups were compared. Results In the observation group, the time taken to complete CT examination, complete CT examination and transfer into angiography room, transfer into specialized wards, transfer into angiography room was respectively (25.70±2.94, 31.05±3.27, 20.04±2.54, 16.29±1.82) points, which was significantly different from (33.65±4.31, 37.12±4.16, 25.46± 2.24, 20.20±2.17) points in the control group (t=16.665-26.709,P＜0.01). Observation group of patients with nosocomial transhipment adverse events (a decrease in blood pressure, blood oxygen desaturation, accidental extubation, unobstructed intravenous drip, insufficient supply of oxygen, power insufficiency, the insufficient number of drugs and drug kinds) rates were 6.9% (58/839), 8.6% (72/839), 0.2% (2/839), 15.0% (126/839), 4.5% (38/839), 0.9% (8/839), 0.7% (6/839), 0, Significantly lower than the control group of 19.5% (114/586), 22.7% (133/586), 1.5% (9/586), 34.9% (205/586), 26.6% (156/586), 11.9% (70/586), 5.9% (35/586), 3.9% (23/586), the difference was statistically significant (χ2=31.950-106.173, P＜0.01). Conclusion The standardized and graded transport scheme can fully warn patients of various risks in the course of intrahospital transportation, take effective preventive and control measures to ensure the safety of intrahospital transportation of emergency critical patients, and should be popularized.

Application of CICARE mode on new entry guidance personnel communication skills training / 中国实用护理杂志

Objective To investigate the effect of CICARE mode on communication skills training of new entry guidance personnel. Methods A total of 16 new attendants were set as the control group, and routine training was used (between May 2015 and June 2015). Another 18 new attendants named as the observation group were trained in CICARE mode on the basis of routine training (between May 2016 and June 2016). The communication skills and satisfaction degree were compared between two groups. Results The scores of establishing a harmonious relationship, keen to listen, to confirm the patient problem, participation, efficient information transfer, verifying the feeling after the new recruits training for guidance staff were 3.72±0.08, 3.77±0.17, 3.60±0.08, 2.96±0.32, 3.50±0.14, 3.06±0.50 in the observation group, 3.13 ± 0.11, 3.25 ± 0.24, 2.66 ± 0.12, 2.67 ± 0.37, 2.90 ± 0.08, 2.59 ± 0.19 in the control group, the differences were statistically significant (t =2.451-27.155, P<0.05). The scores of guiding service appearance, body language, active service, health consultation, medical order, answer questions and provide help, medical environment and overall satisfaction respectively was 99.67 ± 2.58, 98.00 ± 6.05, 98.00 ± 6.05, 96.00 ± 8.07, 99.33 ± 3.62, 98.00 ± 6.05, 96.00 ± 8.07, 94.00 ± 12.91, 97.50 ± 5.48 in the observation group, and 91.33 ± 10.56, 87.67 ± 14.19, 84.67 ± 14.31, 79.67 ± 15.27, 84.33 ± 14.17, 83.67 ± 14.37, 85.67 ± 12.70, 87.00 ± 10.85, 84.67 ± 9.91 in the control group, the differences were statistically significant (t=3.215-8.775, P<0.05). Conclusions CICARE mode can not only provide normative and orderly guidance for the guiding staff, but also improve the communication ability of the guiding staff in a short time, and let the patients participate in the guiding service. It is worthy of being popularize and applied in the guided diagnosis service to increase the patient′s participation, acceptance and satisfaction.

Determination and Pharmacokinetics of PA-824 in the Plasma of Beagle Dogs by HPLC-MS/MS / 中国药师

Objective: To establish a high performance liquid chromatography-tandem mass spectrometric method ( HPLC-MS/MS) method for the determination of PA-824 in the plasma of Beagle dogs, and study the pharmacokinetics of PA-824 in Beagle dogs. Methods:Carbamazepine was used as the internal standard, and the plasma samples were pretreated with ethyl acetate for the liquid-liquid extraction of PA-824. An Eclipse Plus C18 column (100 mm × 2. 1 mm, 3. 5 μm) was used with the mobile phase consisting of methanol-water (90 :10). The flow rate was 0. 6 ml·min-1 and the column temperature was 30 ℃. The injection volume was 5 μl and the sample analysis time was 5 min. The determination was performed with an electrospray ionization ( ESI) source in the positive multiple reaction monitoring (MRM) mode. The ion pairs were m/z 360. 1→m/z 175. 0 (collision energy of 35, solution cluster volt-age of 65) for PA-824 and m/z 237. 2→m/z 194. 0 (collision energy of 28, solution cluster voltage of 83) for carbamazepine. After the oral administration, PA-824 in plasma was measured at different time points, and then the pharmacokinetic parameters were calcu-lated by DAS 2. 0 software. Results: PA-824 showed a good linear relationship within the range of 50-10000 ng · ml-1 ( r =0. 9991). The recovery was 97. 7%-105. 1%, and the RSDs of intra-day and inter-day were less than 5. 0%. At three different dosa-ges (100, 200 and 500 mg) of PA-824, AUC0-twere (5735. 18 ± 1918. 76),(11548. 47 ± 1838. 04) and (21987. 88 ± 4587. 58) ng·min·ml-1,t1/2 were(14.17 ±5.97),(11.11 ±4.39) and (13.13 ±5.46)h,and Cmaxwere(626.66 ±188.48),(2399.13 ± 516.51) and (4861.33 ±2253.61)ng·ml-1, respectively. Conclusion:The method is simple, accurate, rapid and reproducible, and suitable for the pharmacokinetic study of PA-824 in the plasma of Beagle dogs.

3D-QSAR of Thiazide 11β-Hydroxyl Steroid Dehydrogenase Inhibitors / 中国药师

Objective:To establish a three-dimensional quantitative structure-activity relationship (3D-QSAR) model for thiazide 11β-hydroxy steroid dehydrogenase ( HSD) inhibitors in order to perform structure modification and find thiazide 11β-HSD inhibitors with more activity. Methods: The 3D-QSAR model of thiazine derivatives was constructed by the method of comparative molecular force field analysis, and the model was validated by using a molecular docking method. Results:An accurate 3D-QSAR model of 11β-HSD inhibitors was obtained (CoMFA:q2 =0. 346, r2 =0. 850, where q2 was the cross-validation coefficient and r2 was the non-cross validation coefficient) . Conclusion:The results provide important theoretical basis for the rational design of novel thiazide 11β-HSD inhibitors.

Research Progress in Theacrine / 中国药师

Theacrine is one kind of natural purine alkaloids, which mainly exists in an unusual Chinese tea known as Kucha. It shows various biological activities, such as anti-depression, sedative and hypnotic effects and anti-inflammatory and analgesic activi-ties. The study on theacrine dates back to a few decades ago. According to the references published in recent years, the resource, preparation, characterization and pharmacological effects of theacrine were reviewed, and its application prospect was also explored.

Determination of PA-824 in Rat Plasma by HPLC-MS/MS and Application in Pharmaco-kinetic Study / 医药导报

Objective To develop an HPLC-MS/ MS method for quantitative determination of PA-824 in rat plasma and to study the pharmacokinetics of PA-824 in rat after oral administration. Methods An HPLC-MS/ MS method was developed and validated for determination of PA-824 in rat plasma using metronidazole as internal standard.The proteins in plasma samples were precipitated with methanol,and PA-824 was enriched for analysis by HPLC-MS/ MS.An Inertsil? ODS3 C18 column (150 mm×4.6 mm,5 μm) was applied with mobile phase composed of methanol- 0.03% triethylamine (TEA) in water (90:10) ,at a flow rate of 0. 5 mL ? min-1 and column temperature of 30 ℃ . Quantitation was performed on a triple quadrupole mass spectrometer applying electrospray ionization technique and operating in multiple reaction monitoring (MRM) and positive ion mode with transitions at 360.1/ 175.0 for PA-824 and 172.0/ 128.0 for metronidazole.The concentration of PA-824 in plasma was tested after oral administration at various time points and the data were processed with software DAS.2.0. Results The standard calibration curve for spiked rat plasma containing PA-824 was linear over the range of 0. 1 - 10. 0 μg?mL-1 . The recoveries obtained for PA-824 were greater than 92.13%.Intra-day and inter-day coefficient of variation were less than 6.6%.After oral administration,the main pharmacokinetic parameters were AUC(0-t) : ( 3 297. 503 ± 320. 958) mg ? L-1 ? min-1 , AUC(0-∞ ) :(3 558.315±338.860)mg?L-1?min-1 ,tmax:(360.000±64.143)min,Cmax:(3.5±0.3)μg?mL-1 . Conclusion The method is rapid,accurate,simple,and successfully applied in a pharmacokinetic study of fixed dose oral administration of PA-824 in rats.

Bioinformatics prediction on glutathione S-transferase antigen epitopes of Echinoccocus granulosus / 国际检验医学杂志

Objective To analyse the secondary structure of glutathions S-transferase of Echinoccocus granulosus(EgGST)and predict the B cell and T cell epitopes with informatics tools,in order to provide basic data and references for the following design of epitope vaccine.Methods The B cell and T cell epitopes of EgGST were predicted by DNAstar,Biosun software and Propred MHC class-Ⅱ Binding Peptide Prediction Server software.Results Many distinct antigenic epitopes of EgGST were identified by comput-er,there existed 8 B cell epitopes and 7 T cell epitopes.Conclusion Analysis of predicted epitopes of EgGST antigenic might be sig-nificant for future research of epitope vaccine.

The synergism and mechanism of action of rClone30-hDR5 in combination with TRAIL on HCC / 药学学报

To investigate the cell-killing effect and its possible mechanism of rClone30-hDR5 in combination with TRAIL on human hepatic carcinoma (HCC) cell line, first of all, recombinant plasmid pee12.4-hDR5 was introduced into HepG2 cells by liposome transfection. After five rounds of screening by flow cytometry, HepG2 cells expressing high levels of DR5 on cell surface were isolated. The cytotoxicity of TRAIL to selected cells was higher than that of TRAIL to HepG2 cells by MTT method (P < 0.01). The result suggested that the cloned hDR5 gene had biological activity. MTT assay showed that, rClone30- hDR5 in combination with TRAIL more efficiently inhibited the tumor growth of HepG2 cells compared to rClone30-hDR5 or TRAIL in vitro. The results of Annexin V-FITC/PI staining and Quantitative Real-time PCR indicated that rClone30-hDR5 in combination with TRAIL significantly increased the mRNA levels of caspase 3 and caspase 8, and induced the apoptosis of tumor cells. HepG2 cells were infected with rClone30-hDR5 or rClone30 at MOI of 1. The expression of hDR5 on tumor surface increased significantly by rClone30-hDR5 compared to that by rClone30, which contributed to the sensitivity to TRAIL. In conclusion, rClone30-hDR5 in combination with TRAIL has potential application value in cancer treatment.

Effect of Weichangkang Capsule on Function of Gastrointestinal Tract / 中国药房

OBJECTIVE:To verify the effect of Weichangkang capsule(WCK) on the function of gastrointestinal tract.MET-HODS:The effects on movement of charcoal powder in mice and secretion of digestive enzyme and absorption of D-xylopyranose into serum in rats were studied.RESULTS:WCK capsule markedly increased the movement of charcoal powder in mice,secretion of digestive enzyme and absorption of D-xylopyranose into serum in rats.CONCLUSION:WCK capsule could obviously improve the dysfunction of gastrointestinal tract.

Bibliometrical Analysis of Chinese Literature on Drug-Induced Renal Failure——A 227 Case Reprot / 药物流行病学杂志

To better understand the drugs, frequency and other factors involved in the drug-induced renal failure, 227 cases of renal failure reported in the Chinese medical and pharmaceutical journals were statistically analyzed. Our results showed that the drugs that tend to cause renal failure are antibiotics, involving 80 cases, followed by antituberculosis agents(38 eases)and dehydration agents. Gentamycin (47 cases) and rifrimactane(36 cases) were among the drugs with highest incidence. There were 58 cases of death due to drug-related renal failure.

Investigation and Analysis of Violation of Doctors' Right in fiv city and Asan Tieling of LiaoXi Province / 中国医学伦理学

As a special profession in our society,doctor has its special rights.An investigation of Jinzhou,Chaoyang,Huludao,Panjin,Fuxin and Tieling,Anshan in the Liaoning province review that violation of doctors' right occurs from time to time.There are several reasons for the violation,mainly coming from doctors,patients and their relatives,guidance of social media and social causes in depth.

Causes and Countermeasures of Violent Trespass against Medical Right / 中国医学伦理学

Violent trespass against medical right dangerously harms medical staffs' health,both physically and mentally.It disarranges normal infirmary system on medical diagnosis and treatment.The research carried out in 80 hospitals covering 10 provinces indicates that presently violent trespass against medical right occurs from time to time;moreover this shows an up-growing trend.Such phenomena take place in various medical colonies and medical organizations diverse themselves obviously.This passage analyzes the causes of violence from the aspects of society,hospital and physician-patient relationship.

Research Progress of Factors Associated with Intestinal Parasitic Infection / 环境与健康杂志

Intestinal parasitic infection is a serious public health problem in the world especially in the developing countries,and it is also the important part that impacts human health,especially in children in the rural areas of China.Factors such as water,environmental sanitation,health behavior and so on are related with intestinal parasitic infection.The research progress of the prevalence of intestinal parasitic infection in the world and the factors that affect the health of people,especially in children in the rural areas were reviewed in the present paper.

Effect of Ethyl acetate extract of Herba Eclipta on immune function in immunosuppressive mice / 中成药

Objective:The regulatory effects of ethyl acetate extract of Herba Eclipta EAEE on immune function were studied.Methods: The experimental immunosuppressive models were induced by injection of Cyclophosphamide or hydrocortisonc.Results: The index of thymus gland spleen in immunosuppressive mice was increased significantly. when large and small dose of EAEEP were given. EAEE remarkably enhanced the delayed type hypersensitivity in immunosuppressive mice. Conclusions: EAEE possesses notable immunomodulatory action on immune system in mice.