Objective To investigate the effects of poly adenosine diphosphate ribose polymerase (PARP) inhibitor AG014699 on the proliferation of triple negative breast cancer (TNBC) cell line MDA?MB?231.Methods Cell proliferation and cytotoxicity test kit ( CCK?8) was used to detect the proliferation of MDA?MB?231 cells in different concentrations of AG014699 (0.1,1.0,10.0,20.0 and 40.0 mmol／L), DTX (10－9,10－8,10－7,10－6 and 10－5 mol／L) and CBP (10－6,10－5,10－4 and 10－3 mol／L).Flow cytometry was used to detect cell apoptosis and cell cycle distribution.Results The effects of AG01469 at different concentrations (0.1,1.0,10.0,20.0 and 40.0 μmol／L) on proliferation activity of MDA?MB?231 cells were (94.83 ± 3.93)%, ( 79.42 ± 5.52)%, ( 63.75 ± 4.34)%, ( 38.97 ± 8.42)%, ( 29.70 ± 3.35 )%, with statistically significant differences (F＝75.54,P＜0.01,different concentrations pairwise comparison: all P ＜0.05). The efficacy of AG014699 in combination with DTX at different concentrations (( 69.77 ±17.94)%,(58.34± 2.59)%,( 52.81 ± 2.01)%, ( 41.23 ± 3.38)%, ( 24.82 ± 0.73)%) was compared with that of single DTX (( 81.24 ± 11.91)%, ( 85.74 ± 3.10)%, ( 72.74 ± 4.66)%, ( 55.18 ± 3.19)%, (45.95±3.82)%).The differences were statistically significant (t values were －0.923,－11.748,－6.802,－5.199,－9.410,respectively,with P＞0.05 at 10－9 concentration and P＜0.01 at all other concentrations ). The efficacy of AG014699 combined with CBP ((78.33± 2.89)%,( 60.44± 1.95)%,( 50.55± 3.07)%, (12.07± 1.63)%) and single CBP (( 90.00 ± 6.18)%, ( 87.87 ± 2.30)%,( 76.82 ± 3.37)%,( 40.71 ±1.68)%) was compared,and the cell activity was significantly reduced,indicating statistically significant differences ( t values were －1.935,－15.756,－9.981,－21.192, respectively, and P＞0.05 at 10－6 concentration,P＜0.05 at all the other concentrations ).The q value was＞1.15 when AG014699 was combined with 10－3 mmol／L CBP, which showed synergistic effect.When combined with other effective concentrations of DTX or CBP,the q value was between 0.85 and 1.15,showing additive effect.Conclusion PARP inhibitor AG014699 assisted DTX or CBP can inhibit the proliferation of TNBC cell line MDA?MB?231.By means of simple addition or systematic effect,it can inhibit the triple negative breast cancer.

OBJECTIVETo investigate the effects of ischemic postconditioning (IPTC) on the changes of matrix metalloproteinases-2 (MMP-2) and tissue inhibitor of metalloproteinase-2 (TIMP-2) protein and mRNA levels in rat heart subjected to ischemia/reperfusion, and explore the mechanism by which IPTC protects myocardial interstitium following ischemic/reperfusion (I/R).

METHODSTwenty four healthy male SD rats were randomly divided into 3 groups (n = 8): sham control (SC) group, I/R group and IPTC group. The parameters of left ventricular function including left ventricular systolic pressure (LVSP) and its derivate (±dp/dt) were measured; the amount of myocardial collagen contents was determined by hydroxyproline quantification; the plasma activity of creatine kinase (CK) and lactate dehydrogenase (LDH) was detected; the protien levels of MMP-2 and TIMP-2 was measured by Western blot and the mRNA levels of MMP-2 and TIMP-2 was detected by real-time PCR.

RESULTSThe myocardial collagen contents, left ventricular function and the protein and mRNA levels of TIMP-2 were significantly decreased in I/R group compared with those of SC group, wherease the activities of CK and LDH in the plasma and the protein and mRNA levels of MMP-2 were significantly enhanced in I/R group when compared to SC group. Compared with I/R group, the myocardial collagen contents, left ventricular function and the protein and mRNA levels of TIMP-2 were increased in IPTC group, the activities of CK and LDH in the plasma and the protein and mRNA level of MMP-2 were decreased in IPTC group.

CONCLUSIONThese findings indicate that IPTC has protective effects on myocardial interstitial after the myocardial ischemia/reperfusion injury, and IPTC may exert its cardioprotectve effect via inhibiting MMP-2 and enhancing TIMP-2 expression in cardiac muscle.

Animals ; Collagen ; metabolism ; Creatine Kinase ; metabolism ; Ischemic Postconditioning ; Male ; Matrix Metalloproteinase 2 ; metabolism ; Myocardial Reperfusion Injury ; physiopathology ; Myocardium ; metabolism ; Rats ; Rats, Sprague-Dawley ; Real-Time Polymerase Chain Reaction ; Tissue Inhibitor of Metalloproteinase-2 ; metabolism ; Ventricular Function, Left

Objective:To explore the impact of sleep duration, physical exercise, and their interactions on the risk of dyslipidemia in older adults aged ≥80 (the oldest old) in China.Methods:The study subjects were the oldest old from four rounds of Healthy Aging and Biomarkers Cohort Study (2008-2009, 2011-2012, 2014 and 2017-2018). The information about their demographic characteristics, lifestyles, physical examination results and others were collected, and fasting venous blood samples were collected from them for blood lipid testing. Competing risk model was used to analyze the causal associations of sleep duration and physical exercise with the risk for dyslipidemia. Restricted cubic spline (RCS) function was used to explore the dose-response relationship between sleep duration and the risk for dyslipidemia. Additive and multiplicative interaction model were used to explore the interaction of sleep duration and physical exercise on the risk for dyslipidemia.Results:The average age of 1 809 subjects was (93.1±7.7) years, 65.1% of them were women. The average sleep duration of the subjects was (8.0±2.5) hours/day, 28.1% of them had sleep duration for less than 7 hours/day, and 27.2% had sleep for duration more than 9 hours/day at baseline survey. During the 9-year cumulative follow-up of 6 150.6 person years (follow-up of average 3.4 years for one person), there were 304 new cases of dyslipidemia, with an incidence density of 4 942.6/100 000 person years. The results of competitive risk model analysis showed that compared with those who slept for 7-9 hours/day, the risk for dyslipidemia in oldest old with sleep duration >9 hours/day increased by 22% ( HR=1.22, 95% CI: 1.07-1.39). Compared with the oldest old having no physical exercise, the risk for dyslipidemia in the oldest old having physical exercise decreased by 33% ( HR=0.67, 95% CI: 0.57-0.78). The RCS function showed a linear positive dose-response relationship between sleep duration and the risk for hyperlipidemia. The interaction analysis showed that physical exercise and sleep duration had an antagonistic effect on the risk for hyperlipidemia. Conclusion:Physical exercise could reduce the adverse effects of prolonged sleep on blood lipids in the oldest old.

Objective To monitor the antifungal resistance of clinical isolates of Candida spp.in the East China region.Methods MALDI-TOF MS or molecular methods were used to re-identify the strains collected from January 2018 to December 2022.Antifungal susceptibility testing was performed using the broth microdilution method.The susceptibility test results were interpreted according to the breakpoints of 2022 Clinical and Laboratory Standards Institute(CLSI)documents M27 M44s-Ed3 and M57s-Ed4.Results A total of 3 026 strains of Candida were collected,65.33％of which were isolated from sterile body sites,mainly from blood(38.86％)and pleural effusion/ascites(10.21％).The predominant species of Candida were Candida albicans(44.51％),followed by Candida parapsilosis complex(19.46％),Candida tropicalis(13.98％),Candida glabrata(10.34％),and other Candida species(0.79％).Candida albicans showed overall high susceptibility rates to the 10 antifungal drugs tested(the lowest rate being 93.62％).Only 2.97％of the strains showed dose-dependent susceptibility(SDD)to fluconazole.Candida parapsilosis complex had a SDD rate of 2.61％and a resistance rate of 9.42％to fluconazole,and susceptibility rates above 90％to other drugs.Candida glabrata had a SDD rate of 92.01％and a resistance rate of 7.99％to fluconazole,resistance rates of 32.27％and 48.24％to posaconazole and voriconazole non-wild-type strains(NWT),respectively,and susceptibility rates above 90％to other drugs.Candida tropicalis had resistance rates of 29.55％and 26.24％to fluconazole and voriconazole,respectively,resistance rates of 76.60％and 21.99％to posaconazole and echinocandins non-wild-type strains(NWT),and a resistance rate of 2.36％to echinocandins.Conclusions The prevalence and species distribution of Candida spp.in the East China region are consistent with previous domestic and international reports.Candida glabrata exhibits certain degree of resistance to fluconazole,while Candida tropicalis demonstrates higher resistance to triazole drugs.Additionally,echinocandins resistance has emerged in Candida albicans,Candida glabrata,Candida tropicalis,and Candida parapsilosis.