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.

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.

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.

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

Cardiomyocyte apoptosis leads to the functional incapacitation of myocardial plasmodium and plays an important role in the pathogenesis of heart failure transformed from compensable cardiac hypertrophy. Mitochondria are the main source of apoptosis-inducing molecule of various cells, and the role of caspartate-specific cysteinyl proteinase (caspase)-dependent mechanism has generally been accepted in the cardiomyocyte apoptosis. However, the significance of caspase-independent apoptosis-inducing factor (AIF) mechanism is not yet understood. The purpose of this study was to evaluate hypoxia-reperfusion-induced alterations of AIF mRNA and protein expressions in hypertrophic cardiomyocytes. Cardiomyocyte hypertrophy was produced by angiotensin II (0.1 mumol/L). The cells were cultured under the condition of hypoxia (95% N2 and 5% CO2; the O2 partial pressure was lower than 5 mmHg) for 8 h or 12 h (named as H8h and H12h groups, respectively), and then exposed to normal culture environment (named as H8h/R and H12h/R groups, respectively). Apoptosis was detected with Hoechst 33258 staining. The AIF mRNA and protein expressions were detected by RT-PCR and Western blot and quantified by gel scanning. The results were as follows: (1) The level of AIF mRNA expression was 0.29+/-0.08 (optical density, relative value) in the control group (hypertrophic cardiomyocytes cultured in normal environment). Compared with that in the control group, the levels of AIF mRNA expression were significantly higher in the groups of H8h and H12h (0.52+/-0.04 and 0.85+/-0.10), indicating that this effect was time-dependent. A further increase of AIF mRNA expression was observed in the groups of H8h/R (1.09+/-0.12) and H12h/R (1.41+/-0.23). (2) The level of AIF protein expression was 0.29+/-0.04 in the control group. Compared with that in the control group, the levels of AIF protein expression were significantly higher in the groups of H8h and H12h (2.07+/-0.15 and 3.12+/-0.19). The AIF protein expression was increased further in the groups of H8h/R (4.57+/-0.25) and H12h/R (5.71+/-0.27). The nuclear translocation of AIF protein was obvious only in the groups of H8h/R and H12h/R. (3) The expressions of AIF mRNA and protein were almost completely inhibited by AIF siRNA transfection. The siRNA transfection also reduced the apoptosis of hypertrophic cardiomyocytes in the groups of H8h/R and H12h/R but not in the groups of H8h and H12h. The apoptosis rate was significantly reduced by both AIF siRNA transfection and Ac-DEVD-cmk, an inhibitor of caspase-3. This reduction induced by two factors was more evident than that by one factor. (4) AIF nuclear translocation induced by hypoxia-reperfusion was not affected by inhibition of the activity of caspase-3. These data suggest that AIF plays a pivotal role in the apoptosis of hypertrophic cardiomyocytes induced by hypoxia-reperfusion.
Apoptosis ; Apoptosis Inducing Factor ; metabolism ; Cardiomegaly ; Cell Hypoxia ; Myocytes, Cardiac ; cytology ; Reperfusion Injury

Xuanwei district in Yunnan Province of China has pretty high incidence of lung cancer in China, even a- round the world. Studies have shown that there exists a close relationship between lung cancer and local indoor air pollution caused by Bituminous coal. Considering that the indoor air pollution in Xuanwei District is caused by "open fireplace", an indoor air pollution simulation system was designed, and an F344 rats lung damage model was estab- lished for this indoor air pollution fireplace. The model is based on indoor air pollution simulation system with signal multiplexer control and multi-channel acquisition, and mining PID algorithm was used for polynomial fitting to each test point, and a relatively constant PM2. 5 air pollution status was simulated. The results showed that the system could simulate a variety of states of air pollution, provide a new test method for evaluation of human injury caused by indoor air pollution and a new idea for the study of the incidence of lung cancer in Xuanwei district and other places.
Air Pollution, Indoor ; analysis ; Animals ; China ; Coal ; adverse effects ; Humans ; Incidence ; Lung ; drug effects ; pathology ; Lung Neoplasms ; epidemiology ; Models, Biological ; Particulate Matter ; analysis ; Rats ; Rats, Inbred F344

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.

Objective To investigate the effects of functional magnetic resonance imaging (fMRI)with acute ischemic stroke (AIS) patients,and to evaluate the relationship between brain reorganization and motor recovery.Methods Nine AIS patients and 9 healthy volunteers were assessed by fMR1 during passive finger clenching at a pace of 1 Hz.The fMRI results were analyzed using SPM2 software.Lateral indices (LIs) and activated regions were calculated,and the relationship between LI and muscle strength was examined.Results In the control group,activation was observed in the contralateral sensorimotor cortex (SMC) and the bilateral supplementary area (SMA) during the passive movement.In the AIS group,similar results were recorded dur- ing unaffected hand movement,but the ipsilateral activation areas were greater than those on the eontralateral side during movement of the affected hand.LI results confirmed that movement of the affected hand mainly elici- ted activation in the ipsilateral hemisphere.Conclusion The different fMRI manifestations of patients and nor- mal subjects reflect brain compensation,and fMRI is valuable for studying the correlation between motor function and brain reorganization.