Genomic instability is one of the most pervasive characteristics of cancer cells,and DNA damage response (DDR) pathway plays a crucial role in genomic stability.The DDR pathway is a complex signaling network,which involves cell DNA repair,apoptosis and cell cycle regulation.Deficiencies in these repair pathways can result in several different genetic disorders,including cancer.Targeted therapy based on inhibiting the DDR pathway in cancers offers a novel therapy strategy for patients with tumors lacking specific DDR functions.Many small-mole-cule compounds targeting DDR pathway are typically developed for solid cancer therapy.The poly (ADP-ribose) polymerase (PARP) inhibitor is a kind of DDR inhibitors which exploits the principle of synthetic lethality to selectively kill cancer cells.This review highlights the molecular mechanisms of PARP inhibitor action,the progress of PARP inhibitors in cancer therapy,drug resistance and the challenge of PARP inhibitor in the future.

Objective To evaluate the changes of peak segmental and transmural radial displacement (RD) of left ventricle(LV) during acute myocardial ischemia with different LV pacing patterns. Methods Left anterior descending coronary artery (LAD) was ligated to induce acute myocardial ischemia in open-chest Beagle canine models ( n=10). Two-dimensional gray-scale images with overlaid tissue Doppler velocity imaging in three standard LV short-axis views were acquired with different pacing patterns in a randomized sequence in three complete cardiac cycles. Parameters including peak RD, peak RD time(RD-Tc) ,the standard deviation of TC(RD-TSD) of 12 segments and their myocardial layers(subend,mid,subepi) were measured and analyzed using TDI-Q workstation. Results ① There were no significant differences of peak RD between three myocardial layers of LV wall in each different pacing pattern group;There were no significant difference of peak RD from segments and transmural layers among the different LV pacing patterns. ②With acute myocardial ischemia the RD correlation of LV lateral pacing( LVL-P) and LV border pacing(LVB-P) patterns were higher than that of LV apical pacing(LVA-P) pattern between global segment and its subend, mid, subepi. ③ RD-Tc of 12 LV segments and their subend, mid, subepi appeared after T wave and there were no significant differences of RD-Tc among different LV pacing patterns. ④RD-TSD of the corresponding segments during LVL-P,LVA-P and LVB-P patterns were significant lower than those during acute yocardial ischemia(P<0. 05). Conclusions The existed RD correlation of LVA-P between subend.mid, subepi and the segment were lowest among the different ischemic LV pacing patterns; the synchronization of transmural RD could be recovered partly with LVL-P, LVA-P and LVB-P patterns. The echocardiographic study of LV transmural RD might be useful to reveal the segmental and the transmural myocardial mechanical state with different LV pacing patterns during acute ischemia in detail.

Cholelithiasis is one of the clinically common and frequently encountered diseases. In this paper, the Chinese Meteria Medica and prescriptions utilized to treat cholelithasis were discussed in four aspects. In addition, we discussed the clinical effect and mechanism of actions of these drugs in order to provide some reference for future drug development in this area.
Animals ; Cholelithiasis ; drug therapy ; prevention & control ; Drug Combinations ; Drugs, Chinese Herbal ; isolation & purification ; therapeutic use ; Humans ; Phytotherapy ; Plants, Medicinal ; chemistry

The full-length cDNA of hTIMP-1 was obtained from a surgical patient with HCC by the method of RT-PCR. Then it was cloned into the adenoviral shuttle plasmid pAdTrack-CMV, and subsequently cotransformed into competent BJ5183 cells with the adenoviral backbone plasmid pAdEasy-1. Thereupon, a recombinant adenoviral plasmid containing full-length cDNA of hTIMP-1 was generated by homologous recombination in E. coli. The adenoviruses (AdhTIMP-1) were packaged and amplified in adenoviral packaging cells HEK 293. Then the viral titer was checked by green fluorescent protein (GFP), and the expression of hTIMP-1 was detected by the techniques of Western blot and RT-PCR. The recombinant adenovirus vector carrying human TIMP-1 was successfully constructed and expressed in vitro and may pave the way for further application in liver gene therapy.
Adenoviridae ; genetics ; metabolism ; Carcinoma, Hepatocellular ; metabolism ; Cell Line ; Cloning, Molecular ; DNA, Complementary ; genetics ; Extracellular Matrix ; metabolism ; Genetic Vectors ; Humans ; Recombinant Fusion Proteins ; biosynthesis ; genetics ; Tissue Inhibitor of Metalloproteinase-1 ; biosynthesis ; genetics

OBJECTIVETo understand the effects of moderate lead poisoning on the hippocampus tissue of rabbits in juvenile stage.

METHODSSixteen 45-day-old male New Zealand rabbits were randomly divided into blank group and lead-exposed group,8 for each group. Rabbits in the lead-exposed group were treated with 5 mg x kg(-1) x d(-1) lead acetate in their forage for 6 weeks to establish a moderate lead poisoning animal model. The blood lead levels and the lead contents in the hippocampus were determined by atomic absorption spectrometer and inductively coupled plasma-mass spectrometry respectively. Histopathology and ultra-microstructure in the hippocampus tissue were observed by light microscope and electron microscope. The NR1, NR2A and NR2B protein expressions in the CA1 hippocampal region were analyzed through immunohistochemical method.

RESULTSCompared with those of blank group, the blood lead levels of lead-exposed group were significant increased, (428.63 +/- 9.46) vs (66.38+/-3.93) microg/L (t = 100.08, P<0.01); and lead contents of hippocampus was significantly increased, (44.57+/-2.03) vs (21.20+/-1.53) ng/g, (t = 26.05, P<0.01); the hippocampus wet weight were significant decreased, (0.735 +/-0.012) vs (0.808+/-0.010), (t =12.97, P<0.01); the coefficient of hippocampus wet weight, was (0.458 +/-0.004) vs (0.476+/-0.005), (t =7.87, P<0.01). The significant declines in both the positive rate of NR1 and NR2A in the CA1 hippocampal region for NR1: (37.44 +/- 2.05)% vs (41.81+/-2.50)% (t = 3.82, P<0.01) and for NR2A: 21.97+/-1.08 vs 25.48+/-1.30 (t =5.89, P<0.01) were also observed. With light microscope and electron microscope, the histopathology and ultra-microstructure of neuron and glial cell in the hippocampus tissue were changed.

CONCLUSIONThe impairment of hippocampus of rabbits in juvenile stage with chronic moderate lead poisoning were observed, and the histopathology and N-methyl-D-aspartate receptor protein expressions in the hippocampus tissue were changed.

Animals ; Chronic Disease ; Disease Models, Animal ; Hippocampus ; drug effects ; metabolism ; pathology ; Lead Poisoning ; metabolism ; Male ; Rabbits ; Receptors, N-Methyl-D-Aspartate ; metabolism

OBJECTIVEVasoactive intestinal peptide (VIP) is a neuro-peptide that can modulate immunity. Previous studies indicated that VIP can attenuate the deleterious consequences of severe sepsis and septic shock by regulating production of inflammatory cytokines in immune activated cells. The signaling induced by bacterial components occurs primarily through Toll like receptors (TLRs). TLRs have been recognized to play a key role in pathogen recognition and innate immunity. It was convincingly demonstrated that lung is one of early suffered disaster organ and may trigger multiple organ dysfunction syndrome in sepsis. The present study was conducted to investigate the effects of VIP on TLR2/4 mRNA expressions on acute lung injury of endotoxic shock induced by lipopolysaccharide (LPS) in rat.

METHODForty Sprague-Dawley rats were randomly divided into 3 groups, i.e., LPS shock group (n = 16), LPS + VIP group (n = 16), and control group (n = 8). LPS shock model was established by LPS (E. coli O(55)B(5) 10 mg/kg) with tail intravenous injection. The rats in LPS + VIP group were given a bolus of 5 nmol VIP intravenous injection follow by LPS. The rats in control group were given normal saline. The rats were sacrificed at 6 h, 24 h after being injected. The lung tissues were collected. The TLR2 mRNA and TLR4 mRNA expressions were detected by RT-PCR from the lung tissues. Pathological changes of the lungs were observed by light microscope and electron microscope 24 h after LPS injection.

RESULT(1) Lung histopathology: the alveolar space was full with leukocyte, necrotic cells, segmental hemorrhage and protein effusion. Partial alveolar space was enlarged, lung interstitial edema were observed in LPS shock group. However, pathological changes of LPS + VIP group were milder than those in LPS shock group. (2) The expressions of TLR2 mRNA and TLR4 mRNA were significantly higher in LPS shock group compared with those of the control group (F = 16.638, P = 0.000; t = 5.876, P = 0.000), TLR2 mRNA and TLR4 mRNA expression on 24 h was down-regulated in LPS + VIP shock subgroup than those in LPS shock subgroup (F = 16.676, P = 0.000; t = 3.946, P < 0.001).

CONCLUSIONExpressions of TLR2 mRNA and TLR4 mRNA were up-regulated on LPS induced lung injury in rats. VIP mitigated lung injury induced by LPS, which may be related to TLR2 mRNA and TLR4 mRNA down-regulation of expression. The effect of VIP may suggest a protective mechanism in sepsis. VIP may play a potential protective role in severe infection.

Acute Lung Injury ; chemically induced ; metabolism ; pathology ; Animals ; Down-Regulation ; Lipopolysaccharides ; Lung ; metabolism ; pathology ; Male ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley ; Toll-Like Receptor 2 ; genetics ; metabolism ; Toll-Like Receptor 4 ; genetics ; metabolism ; Up-Regulation ; Vasoactive Intestinal Peptide ; pharmacology

OBJECTIVETo observe the biomechanical effects of the lateral wall of the femur in treating femoral intertrochanteric fractures with intramedullary or extramedullary fixation to guide the choice of clinical fixed methods.

METHODSTwelve adults femur specimens of intertrochanteric fractures were belong to the type A1 of the AO fracture classification and randomly divided into the lateral wall complete PFNA group, the lateral wall complete PF-LCP group, the lateral wall breakage PFNA group, lateral wall breakage PF-LCP group, every group had 3 specimens. The four groups of specimens were subjected to compressive loading experiment with Universal Material Testing Machine. The maximum loading force was observed. The distance between fracture ends, the distance of fracture dislocation and the sliding distance of the fracture fragments along the intertrochanteric were measured with Calipers.

RESULTSThe maximum loading force of lateral wall complete PFNA group were larger than that of lateral wall complete PF-LCP group, and the maximum loading force of lateral wall breakage PFNA group were larger than that of lateral wall breakage PF-LCP group, there were significant differences (<0.05). The distance between fracture ends of the four groups before compression were not significant differences(>0.05). The distance between fracture ends, the distance of fracture dislocation and the sliding distance of the fracture fragments were not significant differences between lateral wall complete PFNA group and lateral wall complete PF-LCP group after compression (>0.05). But the distance between fracture ends, the distance of fracture dislocation and the sliding distance of the fracture fragments of lateral wall breakage PFNA group were less than that of lateral wall breakage PF-LCP group(<0.05).

CONCLUSIONSIntramedullary fixation of intertrochanteric fractures have stronger loading force. Both intramedullary and extramedullary fixation of intertrochanteric fractures have strong stability when the lateral wall of the femur is complete, but intramedullary fixation of intertrochanteric fractures is stronger stability than extramedullary fixation when the lateral wall of the femur is broken. So the intramedullary fixation is the first choice for the treatment of intertrochanteric fracture.

OBJECTIVETo explore the effect of chelation therapy with succimer (DMSA) in male rabbits of moderate lead poisoning during juvenile stage.

METHODSTwenty-four 45-day-old male New Zealand rabbits were randomly divided into three groups (therapy group, TG; positive control group, PG and negative control group, NG, n=8). The TG and PG were orally exposed to lead acetate (5 mg x kg(-1) x d(-1)) for 6 weeks. Rabbits in TG were orally supplied DMSA 1050 mg/m2 in the first week and 700 mg/m2 in the next two weeks, while the other two groups wren't blood and urinary samples of all rabbits were collected per week. The tissues and organs of all rabbits were collected after 12 weeks. The blood lead levels (BLLs) were determined by atomic absorption spectrometer. The urine lead levels and the lead contents of tissue and organ were determined by inductively coupled plasma-mass spectrometry. Histopathology of tissue and organ was observed by light microscope.

RESULTSCompared with PG, the lead level in the morning urine of TG with DMSA chelating was increased significantly. The level was peaked at (1246.96 +/- 157.91) microg/L on the first day after chelating. While the base line was (40.97 +/- 1.77) microg/L before chelating. Meanwhile, the BLLs were sharply declined from (429.63 +/- 10.82) microg/L to (238.50 +/- 11.82) microg/L. The urine lead levels of TG decreased through the 3-week chelating and 3-week discontinuation. The urine lead levels of these two groups were significantly different (F=2934.35, P<0.01). Compared to each two groups in these three groups, there were significant difference (P<0.01). The authors found the reversion of BLLs in first week after stop chelating. The BLLs of PG presented the slow course of declining in the same time, were (135.50 +/- 7.09) microg/L, very close to the level of TG for (149.88 +/- 11.39) microg/L. Compared with treatment discontinuation for 3 weeks, the urine lead levels and the body weight gain of the therapy group increased more than that of PG, and the BLLs and the lead concentrations in tissues and organs decreased more than that of PG, and histopathology in the liver tissues and testicle tissues were improved.

CONCLUSIONDMSA chelating for the rodent models of moderate lead poisoning might reduce the BLLs and soft tissue lead contents quickly and effectively, decrease toxic effects of lead in a short period of time, thus alleviate the impairment of lead poisoning on tissues and organs by decreasing lead burden, and bring out improvement on the growth retardation caused by lead poisoning.

Animals ; Chelation Therapy ; Lead ; blood ; urine ; Lead Poisoning ; drug therapy ; Male ; Rabbits ; Succimer ; therapeutic use

OBJECTIVETo investigate the effect of dietary calcium on plasma lipoprotein profile in castrated and ovariectomized hamsters.

METHODSMale, castrated, female and ovariectomized hamsters (n=36 each group) were randomly divided into three sub-groups (n=12) and fed one of the three diets containing 0, 2, and 8 g calcium per kg diet for a period of six weeks. Changes in plasma lipoprotein profile were monitored at the end of week 0, 3 and 6.

RESULTSPlasma total cholesterol (TC), non-high density lipoprotein cholesterol (non-HDL-C), triacylglycerols (TG) and TC/HDL-C were decreased only in intact female and ovariectomized hamsters. In contrast, three levels of dietary calcium had no effect on lipoprotein profiles in both intact male and castrated hamsters.

CONCLUSIONBeneficial modification of lipoprotein profile by dietary calcium was gender-dependent at least in hamsters.

Animals ; Calcium, Dietary ; therapeutic use ; Cholesterol ; blood ; Cholesterol, Dietary ; adverse effects ; Cholesterol, HDL ; blood ; Cricetinae ; Female ; Male ; Triglycerides ; blood

OBJECTIVE: To investigate the predictive value of cervical length（CL）changes in spontaneous preterm birth（SPTB）in twin pregnancies in the second and third trimesters of pregnancy.METHODS: A retrospective analysis was made of 166 cases of twin pregnant women who underwent transvaginal ultrasound to measure CL during the second trimester of pregnancy（20~25 weeks）and the third trimester of pregnancy（28~32 weeks）from January 2014 to December 2017 in the Third Hospital of Peking University and Tongzhou Maternal and Child Health Hospital of Beijing.Evaluate the predictive value of CL changes in SPTB before 32 and 34 weeks.The area under the receiver-operating characteristics（ROC）curve was compared by bootstrap method.Assessment of the value of CL in the third trimester of pregnancy and CL in the second trimester of pregnancy alone in predicting SPTB before 32 and 34 weeks.RESULTS: Of the 166 cases,90 were full-term delivery and 76 were premature delivery.The median CL of mid and late pregnancy was 34 mm and 29 mm respectively,and it was 35.5 mm and 31 mm,and in full-term delivery.32.5 mm and21 mm in premature delivery,respectively.There were significant differences among the three groups（All P<0.001）.According to whether the shortening of CL was more than 20%,they are divided into shortening group（CL shortening more than 20%,78 cases）and stabilizing group（no shortening of CL or shortening less than 20%,88 cases）.The preterm birth rate of shortening group was 2.22 times and 1.85 times higher than that of stabilizing group before 32 weeks and 34 weeks,but there was no significant difference.Of 40 cases with CL≤ 25 mm,there were 34 cases in shortening group,6 cases in stabilizing group.Excluding these twin pregnant women,the preterm birth rate in the shortening group increased by 7.58 times and 2.09 times than that in the stabilizing group before 32 weeks and 34 weeks.There was a significant difference in the preterm birth rate between the shortening group and the stabilizing group before 32 weeks（P=0.049）.The area under ROC curve of preterm birth predicted by CL in late pregnancy was increased compared with that in mid-pregnancy before 32 weeks and 34 weeks,but the difference was not statistically significant.CONCLUSION: In twin pregnancies,the CL shortening ≥ 20% at 28~32 weeks of gestation increases the risk of preterm birth before 32 weeks;with CL>25 mm and CL shortening≥ 20%,it can better predict preterm birth before 32 weeks.