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OBJECTIVE To analyze the dose-adjusted concentrations of Posaconazole oral suspension in patients undergoing hematopoietic stem cell transplantation （HSCT） and their influential factors. METHODS Data were collected from hospitalized HSCT patients admitted to the First Affiliated Hospital of Shandong First Medical University （Shandong Provincial Qianfoshan Hospital） from January 2021 to April whtwhm@yeah.net 2023 who took Posaconazole oral suspension for the prevention of invasive fungal disease （IFD） and received blood concentration of posaconazole. The rate of concentration attainment and clinical failure rate of posaconazole for the prevention of IFD were evaluated， and one-way and multiple linear regression analyses were performed for the influential factors of dose-adjusted concentrations （C0/D） of posaconazole. RESULTS A total of 44 patients were enrolled； the mean C0 of posaconazole in patients was （0.99±0.94） µg/mL， and 20 patients had a C0≥0.7 μg/mL， with a concentration attainment rate of 45.45% for the prevention of IFD； 13 cases were clinical failures， with a clinical failure rate of 29.55%. Of 24 patients who did not achieve C0/D of posaconazole for IFD prophylaxis， one patient was a clinical failure despite timely dose adjustment of posaconazole in seven patients； seven of the thirteen patients who did not undergo dose adjustment were clinical failures； and the remaining four patients were switched to other antifungal agents. The results of univariate analysis showed that gender， body mass index （BMI）， renal function， combined use of sodium phenytoin， omeprazole and metoclopramide had a significant effect on the C0/D of posaconazole （P＜0.05）； the results of multivariate linear regression analysis showed that gender， BMI and combined use of sodium phenytoin were the independent factors affecting the C0/D of posaconazole （P＜0.05）. CONCLUSIONS Significant individual differences are reflected in the blood concentration of Posaconazole oral suspension； gender， BMI and combined use of sodium phenytoin are independent factors affecting the C0/D of posaconazole.
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Near-infrared spectroscopy (NIRS) with its fast and nondestructive advantages can be qualified for the real-time quantitative analysis. This paper demonstrates that NIRS combined with partial least squares (PLS) regression can be used as a rapid analytical method to simultaneously quantify L-glutamic acid (L-Glu) andγ-aminobutyric acid (GABA) in a biotransformation process and to guide the optimization of production conditions when the merits of NIRS are combined with response surface methodology. The high performance liquid chromatography (HPLC) reference analysis was performed by the o-phthaldialdehyde pre-column derivatization. NIRS measurements of two batches of 141 samples were firstly analyzed by PLS with several spectral pre-processing methods. Compared with those of the HPLC reference analysis, the resulting determination coefficients (R2), root mean square error of prediction (RMSEP) and residual predictive deviation (RPD) of the external validation for the L-Glu concentration were 99.5%, 1.62 g/L, and 11.3, respectively. For the GABA concentration, R2, RMSEP, and RPD were 99.8%, 4.00 g/L, and 16.4, re-spectively. This NIRS model was then used to optimize the biotransformation process through a Box-Behnken experimental design. Under the optimal conditions without pH adjustment, 200 g/L L-Glu could be catalyzed by 7148 U/L glutamate decarboxylase (GAD) to GABA, reaching 99%conversion at the fifth hour. NIRS analysis provided timely information on the conversion from L-Glu to GABA. The results suggest that the NIRS model can not only be used for the routine profiling of enzymatic conversion, providing a simple and effective method of monitoring the biotransformation process of GABA, but also be considered to be an optimal tool to guide the optimization of production conditions.
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Objective To explore the effect of CD40 small interfering RNA(siRNA)on the expressions of pe-ripheral blood interleukin(IL)-21 and IL -35 in rats with experimental autoimmune myocarditis (EAM)and its sig-nificance.Methods Twenty 6 -8 week male Lewis rats were divided into normal group,EAMgroup,CD40 siRNA group and siRNA group by using random number table,with 5 rats in each group.The normal rats were induced with phos-phate buffer saline in double foot pads on day 0 and day 7,while the rest 3 groups were induced with cardiac myosin protein to establish EAMmodels.The rats in CD40 siRNA group and siRNA group were respectively injected with CD40 siRNA and siRNA slow virus expression vector through the tail vein of rats on day 7.The rats were executed on 21 day after echocardiogram examination was made.The histopathologic changes were observed by using light microscope and the myocardial histopathology scores were calculated.Enzyme -linked immunosorbent assay was used to determine the levels of IL -21 and IL -35 in peripheral blood.Results (1)Except the normal group,the total incidence rate of rats of each group was 100%,and there was no rat death.(2)Compared with EAM group,the heart mass/body ratio and myocardial histopathology scores were lower in CD40 siRNA group,and the differences were significant (3.13 ±0.21 vs 3.80 ±0.29,2.22 ±0.43 vs 3.32 ±0.51,F =0.332,0.456,all P <0.05).(3)The echocardiogram showed that there was only 1 rat in EAM group with massive pericardial effusion,and there was no pericardial effusion in CD40 siRNA group.EAMgroup,CD40 siRNA group and siRNA group displayed hypertrophy of the ventricular septum and left ventricular wall,narrow heart cavity and weakening of ventricular wall motion.The left ventricular shortening rate in CD40 siRNA group was significantly higher than that in the EAMgroup[(63.34 ±11.06)% vs (38.56 ±6.98)%,F =16.080,P <0.05].(4)The peripheral blood level of IL -21 in CD40 siRNA group was lower than that in EAM group [(141.19 ±17.46)ng/L vs (157.81 ±17.58)ng/L,F =57.008,P <0.05],while its level of IL -35 was signifi-cantly higher than that in the EAMgroup [(195.96 ±18.26)ng/L vs (174.78 ±13.91 )ng/L,F =31.727,P <0.05].(5)The level of IL -21 in peripheral blood was positively correlated with myocardial histopathology scores in EAM group (r = 0.69,P < 0.05 ),but IL -35 was negatively correlated with myocardial histopathology scores (r =-0.64,P <0.05).Conclusions CD40 siRNA might relieve the myocardial inflammation and reduce the myocar-dial injury of EAMrats.The levels of IL -21 and IL -35 can partly reflect the degree of myocardial injury.The mecha-nism may be related to down -regulating the expression IL -21 and up -regulating the expression of IL -35.
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Objective To investigate how gene silence of CD40 by small interfering RNA(siRNA)influences the balance between Th1 / Th2 and Th17 / Treg in rats with experimental autoimmune myocarditis(EAM). Methods Lewis rats were divided into a normal - control group,EAM group,CD40 siRNA - therapy group and siRNA - control group by using random number table. EAM,CD40 siRNA - therapy and siRNA - control groups were immunized on day 0 and day 7 with purified porcine cardiac myosin to establish EAM,and CD40 siRNA was administered intravenously on day 7. The basic data of each group were observed,and the rats were executed on day 21 to study the pathology of myo-cardial tissues and the myocardial histopathology scores were calculated,and than the changes in electrocardiograms (ECG)and echocardiogram were recorded. Enzyme - linked immunosorbent assay(ELISA)was used to determine the levels of interferon(IFN) - γ,interleukin(IL) - 10,IL - 17 and transforming growth factor(TGF)- β in peripheral blood. Results (1)The overall incidence of EAM,CD40 siRNA - therapy and siRNA - control group was 100% ,and no rats died from day 0 to day 21.(2)There were only 2 premature rats in EAM and siRNA - control groups,and the ECGs of normal - control group and CD40 siRNA - therapy group were normal.(3)The echocardiogram of EAM,CD40 siRNA - therapy and siRNA - control group,displayed the left ventricular dilatation,hypertrophy of the left ventricle, the weakening of the left ventricular wall motion,and heart failure,and pericardial effusion was discovered. The left ven-tricular fractional shortening(LVFS)and the left ventricular ejection fraction(LVEF)of rats treated by CD40 siRNA were higher than those of rats in the EAM group[(46. 70 ± 8. 25)% vs(34. 28 ± 11. 81)% ,(80. 92 ± 11. 76)% vs (64. 03 ± 12. 60)% ,F = 0. 652,0. 234,all P ﹤ 0. 05].(4)Pathologic examination of the EAM group,CD40 siRNA therapy group and siRNA control groups,showed myocardial fiber fracture,myocardial tissue necrosis and inflammatory cell infiltration. But myocardial tissue pathological scores of the cardiac tissue of CD40 siRNA therapy group was lower than those of the EAM group(2. 10 ± 1. 07 vs 3. 40 ± 0. 72,F = 1. 290,P ﹤ 0. 05).(5)ELISA method examination re-vealed that the levels of IFN - γ,IL - 4,IL - 17 and TGF - β in EAM group were increased compared with those of nor-mal control group[(1 245. 55 ± 244. 56)ng/ L vs(501. 53 ± 18. 93)ng/ L,(78. 03 ± 10. 47)ng/ L vs(30. 77 ± 1. 74)ng/ L,(80. 82 ± 13. 33)ng/ L vs(27. 98 ± 3. 01)ng/ L,(156. 27 ± 12. 11)ng/ L vs(4. 33 ± 0. 79)ng/ L,t =7. 408,10. 764,9. 250,30. 608,all P ﹤ 0. 05]. However,the levels of IFN - γ and IL - 17 in CD40 siRNA therapy group were lower than those in the EAM group[(940. 62 ± 128. 40)ng/ L vs(1 245. 55 ± 244. 56)ng/ L,(60. 42 ± 12. 40) ng/ L vs(80. 82 ± 13. 33)ng/ L,t = 2. 704,2. 745,all P ﹤ 0. 05],while the levels of IL - 4 and TGF - β were higher [(97. 91 ± 13. 62)ng/ L vs(78. 03 ± 10. 47)ng/ L,(178. 84 ± 12. 10)ng/ L vs(156. 27 ± 12. 11)ng/ L,t = 2. 835, 3. 229,all P ﹤ 0. 05]. Conclusions The administration of CD40 siRNA markedly reduces myocardial inflammation of EAM rats and improves their cardiac function,which can be explained by Th1 - type and Th17 - type cytokines inhibi-ted,Th2 - type and Treg - type cytokines increased,and so then the imbalance of Th1 / Th2 and Th17 / Treg corrected.
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In the treatment of human epidermal growth factor receptor 2 (Her-2) overexpressing breast cancer,some patients have drug resistance to trastuzumab.Potential mechanisms of resistance to trastuzumab include impaired access of trastuzumab to Her-2 ; alternative signaling from insulin-like growth factor-1 receptor (IGF-1R),hepatocyte growth factor receptor (HGFR) and so on; aberrant downstream signaling caused by loss of phosphatase and tensin homologs deleted from chromosome 10 (PTEN);phosphatidylinositol 3-kinase catalytic alpha polypeptide gene (PIK3CA) mutation; over-expression of heat shock protein 90 (HSP90) and CD44. Additionally,potential strategies for overcoming resistance to trastuzumab include using new targeted medicines,such as pertuzumab,lapatinib and trastuzumab-DM1.