Cancer, also known as malignant tumor, is the second largest disease after heart disease, which is characterized by genomic instability and mutagenicity. Ataxia telangiectasia and RAD3-related kinase (ATR) are members of phosphatidylinositol 3-kinase (PIKK) family, belonging to serine/threonine kinase, one of the key kinases in DNA damage response (DDR) and DNA repair pathway. This paper reviews the latest progress in the ATR inhibitor field including mechanism of action (MOA), therapeutic applications, and the combination therapy from the perspective of medicinal chemistry. It also discusses the possible challenges and future directions of developing ATR inhibitor antitumor drugs, which could provide the scientists in this field the convenience for access the information and application guidance for clinical studies.

Objective To investigate the effect of blood pressure (BP) control level on perinatal outcomes in women with mild-moderate gestational hypertension (GHp). Methods Totally,344 women diagnosed initially as mild-moderate GHp who delivered in Peking University Third Hospital from January 2012 to December 2016 were recruited. They were divided into four groups according to the stabilized level of BP during pregnancy. (1) Group A:BP<130/80 mmHg(1 mmHg=0.133 kPa);(2) Group B:BP(130-139)/(80-89) mmHg; (3) Group C: BP (140-149)/(90-99) mmHg; (4) Group D: BP (150-159)/(100-109)mmHg. The clinical profile and incidence of severe GHp, pre-eclampsia with proteinuria (PE+Upro), severe pre-eclampsia (sPE), small-for-gestational age (SGA) were compared among the four groups. Student t-test was preformed to normal distributive data and Kruskal-Wallis test was used to non-normally distributed variables. Chi-square test was used in count data. Logistic regression analysis was adopted for multiple-factor analysis. Results (1) The incidence of severe GHp in group A was lower than group B (P<0.05). The incidences of severe GHp and sPE in the group B was lower than those in group C (P<0.05). While there was no difference in the incidence of PE+Upro and SGA among the four groups (P>0.05). And the incidence of severe GHp in group D had no difference with group A, B, C (P>0.05). (2) In the 48 patients who used medications to control BP, the occurence of severe GHp in those whose initial BP was(140-149)/(90-99)mmHg was lower than those of≥160/110 mmHg (P<0.05). But the incidence of severe GHp had no significant difference between patients whose initial BP was(140-149)/(90-99)mmHg and patients whose initial BP was(150-159)/(100-109)mmHg (P>0.05). The initial BP level had no impact on the incidence of PE+Upro, sPE and SGA (P>0.05). (3) Multivariate logistic regression analysis showed that the BP level before using medications (OR=3.566, 95%CI:1.080-11.771, P=0.037) and the BP level maintained (OR=4.787, 95%CI:1.115-20.551,P=0.035) were independent factor that affected the incidence of severe GHp. Edema (OR=2.651, 95%CI:1.628-4.316 P=0.000), fetal growth restriction(FGR;OR=1.103, 95%CI:1.427-5.914,P=0.002)and the onset gestational age of GHp (OR=0.755, 95%CI:0.578-0.985,P=0.038) were independent factors that affected the incidence of PE+Upro. The tendency of FGR (OR=17.787, 95%CI:1.833-40.396 P=0.000), history of PE (OR=5.294, 95%CI:1.086-25.800,P=0.039) and the BP level during pregnancy (OR=2.109, 95%CI:1.274-3.491,P=0.004) were independent factors affecting the incidence of sPE. FGR tendency was independent factor affecting the incidence of SGA (OR=25.622, 95%CI:2.596-252.864,P=0.005). Conclusion A satisfied control of BP is helpful to reduce severe GHp and sPE, but the incidence of SGA does not affected.

As one of the major sources of infection, viruses could infect all organisms including bacteria, plants, animals, and humans. Infectious diseases caused by viruses pose a great threat and damage to human health and economic activities all over the world. Adaptor-associated protein kinase 1 (AAK1) is a member of the Ark1/Prk1 family of serine/threonine kinases and a specific key kinase regulating the phosphorylation of AP-2 protein μ2 subunit T156. In the past, AAK1 has been regarded as a feasible biological target for the treatment of nerve pain. Recently, scientists have found that inhibiting AAK1 can regulate endocytosis and inhibit virus invasion into cells. Therefore, AAK1 could be the potential target of anti-virus therapy. This paper reviews the research progress of small molecule AAK1 inhibitors in the field of antiviral, analyzes the future research directions and challenges, and provides new ideas for the development of antiviral drugs targeting AAK1.

Objective To investigate the clinical effect of therapeutic cervical cerclage on short cervix syndrome for anti-premature birth in the second trimester. Methods Totally 44 singleton pregnant patients were diagnosed as short cervix syndrome, which was cervical length ≤2.5 cm without cervical dilatation,and received treatment from January 2008 and July 2015 in Peking University Third Hospital were collected. Among them, 30 patients who received therapeutic cervical cerclage were defined as cerclage group and another 14 cases who received conservative treatment were defined as un-cerclage group. The days of conservative treatment, delivery rate of different gestational weeks, birth weight of newborns, neonatal survival rate within 7 days of birth were analyzed between the two groups. Results There were no significant differences between the two groups in days of pregnancy conservative treatment [103(84-141)vs 105(85-114)days], delivery weeks [38.0(35.5-39.4)vs 38.5(37.3-39.5)weeks], birth weight of newborns [3120(2750-3400)vs 3130(2760-3545)g], and survival rate of newborns [100％(30/30)vs 13/14]. The fetuses of both groups were all delivered after 28 weeks. There was no significant difference in accumulated delivery rate between the two groups after 32 weeks, 34 weeks, and 37 weeks, respectively(all P>0.05). Conclusions The treatment of cervical cerclage is not superior to conservative means in single pregnancy of cervical length ≤2.5 cm without cervical dilatation. For such patients with short cervix syndrome, the treatment of cervical cerclage may not be necessary, but dynamic monitoring and search for the causing factors and prompt treatment are more important.

The physiological effects of Panax notoginseng seedlings under simulated drought stress by PEG 6000 on antioxidant enzymes, osmotic substances and root activities were studied. The results showed that the activity of POD and APX in roots and leaves kept rising with increasing processing concentration and time. However, on the one hand, at the same processing time, SOD in roots and leaves firstly increased and then decreased with the increase of processing concentration. On the other hand, at the same processing concentration, SOD kept rising with the extension of processing time. In addition, the activity of CAT in roots and leaves tended to increase with the increasing concentration at the same processing time, while it increased at first and then decreased with the extension of time at the same concentration. The activity of SOD and APX in stem did not change obviously, whereas CAT activity in stem increased with the increasing processing time and concentration. With the increase of processing concentration and the extension of processing time, the MDA, soluble protein, proline content and root activity in leaves and roots apparently rose. Moreover, fluorescence signal of H2O2 and NO in root tip enhanced as the processing concentration increased after treated for 1 d. In summary, P. notoginseng seedlings could deal with drought stress by means of adjusting the system of antioxidant enzyme, permeating stress substances and impeded stress signal substances. Thus, when the concentration of PEG 6000 was more than 5%, it would have harm on P. notoginseng seedlings.
Dose-Response Relationship, Drug ; Droughts ; Panax notoginseng ; drug effects ; physiology ; Polyethylene Glycols ; pharmacology ; Seedlings ; drug effects ; physiology ; Stress, Physiological ; physiology ; Superoxide Dismutase ; metabolism

The physiological response and bioaccumulation of 2-year-old Panax notoginseng to cadmium stress was investigated under a hydroponic experiment with different cadmium concentrations (0, 2.5, 5, 10 μmol · L(-1)). Result showed that low concentration (2.5 μmol · L(-1)) of cadmium could stimulate the activities of SOD, POD, APX in P. notoginseng, while high concentration (10 μmol · L(-1)) treatment made activities of antioxidant enzyme descended obviously. But, no matter how high the concentration of cadmium was, the activities of CAT were inhibited. The Pn, Tr, Gs in P. notoginseng decreased gradually with the increase of cadmium concentration, however Ci showed a trend from rise to decline. The enrichment coefficients of different parts in P. notoginseng ranked in the order of hair root > root > rhizome > leaf > stem, and all enrichment coefficients decreased with the increase of concentration of cadmium treatments; while the cadmium content in different parts of P. notoginseng and the transport coefficients rose. To sum up, cadmium could affect antioxidant enzyme system and photosynthetic system of P. notoginseng; P. notoginseng had the ability of cadmium enrichment, so we should plant it in suitable place reduce for reducing the absorption of cadmium; and choose medicinal parts properly to lessen cadmium intake.
Cadmium ; pharmacokinetics ; toxicity ; Hydroponics ; Panax notoginseng ; drug effects ; growth & development ; metabolism ; Photosynthesis ; drug effects ; Superoxide Dismutase ; metabolism

Objective To understand the molecular epidemiological characteristics of staphylococcus aureus(S.aureus),which was isolated from food poisoning in Xian between 2013 and 2017. Methods A total of 26 S.aureusisolates from 8 outbreaks were analyzed by using pulsed field gel electrophoresis(PFGE), multilocus sequence typing(MLST) and spa typing. polymerase chain reaction(PCR) analysis was used to analyze the staphylococcal enterotoxin genes sea to sei. Results 26 strains of S.aureus were divided into 7 types of A-G by PFGE; They were divided into 3 types by MSLT, ST6 accounted for 65.38% which was the main type; They were Divided into 4 types by spa typing, t701 accounted for 65.38 % which is the dominant type. The sea accounted for 76.92% (20/26) in the enterotoxin gene testing; sed-seg accounted for 23.08% (6/26); other enterotoxin genes were not detected. Conclusion The predominant type of S.aureus isolated from food poisoning in Xi'an was ST6-t701-seaprofile from 2013 to 2017. The first detection of the new enterotoxin gene seg, PFGE, MLST and spa typing were combined to fully understand the molecular epidemic characteristics of strains.

AIM To prepare capsaicin phospholipid complex gel and to investigate its pharmacokinetic behaviors.METHODS Phospholipid complex was prepared by solvent evaporation method,whose PBS solution was then poured into Carbopol 940 solution to prepare gel.With feed ratio (phospholipid-capsaicin),capsaicin concentration and reaction time as influencing factors,phospholipid complex's recombination rate as an evaluation index,the preparation was optimized by central composite design-response surface method on the basis of single factor experiment.Rabbits were percutaneously administered with phospholipid complex gel and ordinary gel,respectively,after which LC-MS/MS was adopted in the content determination of capsaicin in plasma.Then the drug concentration-time curves for two gels were drawn,followed by the calculation of their pharmacokinetic parameters.RESULTS The optimal conditions were determined to be 2.3:1 for feed ratio,16 mg/mL for capsaicin concentration,2 h for reaction time,and 55 ℃ for reaction temperature,the recombination rate was 97.84％.The phospholipid complex gel demonstrated its superiority to the ordinary gel with higher Cmax,AUC0→∞,and lower tmax.CONCLUSION Capsaicin prepared into phospholipid complex gel has obviously increased bioavailability and improved percutaneous absorption.

Chemokines and their receptors play an important role in the occurance and development of hepatocellular carcinoma(HCC).The effects of chemokines and their receptors in HCC are different,chemokines and their receptors associated with HCC are mostly expressed in promoting tumor cell proliferation,angiogenesis and invasion,but some chemokines and their receptors play an anti-tumor role.This reviews focus on the role of chemokines and their receptors in HCC.

Human glutamate decarboxylase 65(hGAD65) is an enzyme that catalyzes the transformation of L-glutamic acid into ?-aminobutyric acid.It has been found that Type 1 diabetes mellitus(T1DM)is an autoimmune disease,in which pancreatic islet ?-cells are destroyed due to immune response mediated by autoantigen.hGAD65 is considered as a key autoantigen of the autoimmune response,so anti-hGAD65 antibody(hGAD65-Ab) is the most effective and specific immune marker for T1DM diagnosis,and hGAD65 can be used to detect hGAD65-Ab in serum of T1DM patients.The hGAD65 gene was cloned into pET32a(+),then the recombinant plasmid with hGAD65 was transformed into E.coli BL21(DE3) and expressed by IPTG induction.The fusion protein containing thioredox,hexahistidine and hGAD65(Trx-hGAD65) was mostly insoluble,but the band of soluble Trx-hGAD65 could also be detected by SDS-PAGE,and it was a great improvement compared with the results reported.Trx-hGAD65 was isolated from lysate and purified by immobilized metal ion affinity chromatography(IMAC).After enterokinase digestion and IMAC purification,hGAD65 with high purity was obtained.Detection of thin-layer chromatography(TLC) showed that both Trx-hGAD65 and hGAD65 had enzymatic activity,whereas Trx-hGAD65 had better stability.Furthermore,it was confirmed that Trx-hGAD65 was able to conjugate with hGAD65-Ab in the serum of T1DM patients by ELISA assay.In conclusion,Trx-hGAD65 instead of hGAD65 can be used for T1DM diagnosis,and its application in prophylaxis and therapy of T1DM is expectable.