Polyethylene glycol (PEG) is extensively used to increasing the in vivo and in vitro stability of liposomes. However, PEGylated liposomes also produce some negative effects with further research, such as low cellular uptake, poor "endosomal escape" of pH sensitive liposome (PSL) and accelerated blood clearance (ABC) phenomenon, and this situation is referred as the "PEG dilemma". "PEG dilemma" posed severe challenges for the targeted delivery of PEGylated liposomes-loaded anticancer drugs, effective intracellular release of PEGylated PSL-encapsulated gene and protein drugs, and repeated administration of PEGylated liposomes. Therefore, it is urgent to solve the "PEG dilemma". This review focused on the definition, classification of "PEG dilemma", and discussed several possible approaches to overcome "PEG dilemma".
Antineoplastic Agents ; chemistry ; Drug Carriers ; chemistry ; Liposomes ; chemistry ; Polyethylene Glycols ; chemistry

Objective To explore the culturing strategies,curiculum provision,courses conferring methods,teaching effects as well as the associated managerial evaluations on the basis of Sino-French cooperation on medical education with the hope of summarizing helpful suggestions to Sino-Foreign cooperation on medical education. Methods The achievements of our Sino-French cooperation on medical education were analyzed and compared in the teaching models,culturing strategies along with courses conferring processes among seven-year medical students from both English-teaching and French-teaching classes. Results Our Sino-French cooperation on medical education was featured in its distinct culturing purposes and effective teaching model.Its scientifically formulated culturing strategy found its full expression in French-teaching atmosphere.The Sino-French cooperation on medical education was consistently welcomed and favorably recommended by both faculties and students. Conclusion The Sino-French cooperation on medical education has not only gained precious experience in culturing the cutting-edge medical talents with the international visions but also conduced to fulfill the goal to establish a modernized and internationalized medical school.

The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 μmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function.

Objective To study the activation of Janus protein tyrosine kinase (JAK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway and its inhibitor-signal transducer and activator of transcription-1(SOCS-1) in patients with systemic lupus erythematosus. Methods A total of 45 patients with active systemic lupus erythematosus (SLE) and 30 healthy controls were randomly selected. Western blot was performed to measure the expression of Stat1 protein and phospho-Stat1 protein (an activated form of Stat1 protein) in the monocytes after stimulation with recombinant high mobility group box1 (rHMGB1) at various time points. Expression of Stat1 protein in the skin or lesional skin was also detected. Phasic expressions of SOCS-1 mRNA in the monocytes after rHMGB1 stimulation were detected by real-time reverse transcription-polymerase chain reaction. SOCS-1 gene expression in the skin or lesional skin was also detected. Results The expression level of Stat1 proteins in the monocytes from patients with SLE was higher than that from healthy controls (t=9.16,P＜0.01) and positively correlated with SLE disease activity index (SLEDAI) (r=0.59,P＜0.01). Expression of phospho-Stat1 in the monocytes from SLE patients was time-dependently upregulated after stimulation with rHMGB1 at various time points, while expression of SOCS-1 mRNA remained unchanged(all P＞0.05). Expressions of phospho-Stat1 protein and SOCS-1 mRNA in the monocytes from healthy controls were increased transiently after stimulation with rHMGB1(all P＜0.05). Both expressions of phospho-Stat1 protein and SOCS-1 gene in the lesional skin from patients with SLE were upregulated compared with those in normal skin from healthy controls (all P＜0.01). Conclusion There are hyperactivation of JAK-STAT1 signaling pathway and negative feedback down-regulation of SOCS-1 in patients with systemic lupus erythematosus. HMGB-1 may be partly involved in the pathogenesis of SLE by the abnormal mediating function of JAK-STAT1 signal transduction pathway.

Objective To evaluate the efficacy of fascia iliaca compartment block with dexmedetomidine combined with ropivacaine for analgesia in the patients suffering from proximal femoral fractures.Methods Eighty emergency patients with proximal femoral fractures,aged 25-70yr,weighing 55-82 kg,of ASA physical status Ⅰ-[Ⅲ,were equally and randomly divided into 2 groups using a random number table:ropivacaine group (group R) and dexmedetomidine mixed with ropivacaine group (group DR).All the patients underwent fascia iliaca compartment block described by Dalens.0.4％ ropivacaine 30 ml was injected in group R,and 1 μg/kg dexmedetomidine 30 ml containing 0.4 ％ ropivacaine was injected in group DR.The severity of pain was assessed by VAS scores,and the level of sedation was assessed by Ramsay scores.At 30,60,90 and 120 min after injection (T1-4),VAS scores at rest and during activity were recorded,the effective analgesia (VAS scores at rest and during activity≤6) and satisfactory sedation (Ramsay scores 2-4) in group DR were also recorded,and the development of hemorrhage or hematoma at the puncture site,local anesthetic poisoning,adverse cardiovascular events and over-sedation was also recorded.Results Compared with group R,the rate of effective analgesia during activity was significantly increased at T2-4,and no significant change was found in the rate of effective analgesia at rest in group DR.In group DR,the rate of satisfactory sedation was 73 ％,88％,95％ and 95％ at T1-4,respectively,and no over-sedation occurred.No patients developed hemorrhage or hematoma at the puncture site,or local anesthetic poisoning in the two groups.Conclusion Fascia iliaca compartment block with 1 μg/kg dexmedetomidine combined with 4％ ropivacaine 30 ml can alleviate the early pain caused by passive activity without inducing obvious adverse reactions in the patients suffering from proximal femoral fractures.

ObjectiveTo find out if the immune system derived thyroid stimulating hormone(TSH) β splice variant(TSHβ-Ⅴ) would be regulated by circulating thyroid hormone levels to get a further understanding of the function and mechanism of this TSHβ-Ⅴ in thyroid homeostasis.MethodsA total of 20 weaning Balb/c mice (half male and half female) were selected and randomly divided into two groups according to their body mass and gender(n =10).Mice of control group were fed with common diet and deionized water.Mice of the low-iodine(LI) group were fed with low-iodine diet(containing iodine 20 - 40 μg/kg,iodine-intake about 0.25 μg/d) and deionized water.The experimental period was 3 months.At the end of the experiment,mice were executed and the blood was collected to observe the levels of TSH and thyroid hormone by chemiluminescence immunoassay (CIA) ; bone marrow (BM),peripheral blood(PBL),thyroid gland and pituitary were collected to assay the TSHβ-Ⅴ mRNA expression by real-time quantitative reverse transcriptase polymerase chain reaction (RT-PCR).ResultsThe serum free thyroxine(FT4) and total thyroxine(TT4) levels in LI group of mice[(0.47 ± 0.70)nmol/L,(2.41 ± 0.28)pmol/L] were significantly lower than that of the control group of mice [(55.2 ± 3.68) nmol/L, (32.72 ± 1.02) pmol/L,t =43.81,86.04 、all P ＜ 0.01 ] and the serum total triiodothyronine(TT3) and free triiodothyronine(FT3) reduction in LI group of mice[ (0.76 ± 0.08)nmol/L,(4.01 ± 0.40)pmol/L] were significantly lower than that of the control group of mice [ (1.10 ± 0.06)nmol/L,(5.40 ± 0.38)pmol/L,t =9.81,7.5 1,P ＜ 0.01 ].Iodine insufficiency strongly elevated the serum TSH in LI group of mice[ (35.67 ± 17.39)mU/L] than that in control group of mice[ (0.24 ± 0.10)mU/L,t =- 6.11,P ＜ 0.01 ].The mRNA levels of TSH β-Ⅴ in BM (9.62 ± 0.60) and in PBL( 9.25 ± 0.83 ) of LI group of mice were lower than those in control group of mice (7.69 ± 0.36,7.11 ± 0.41,t =6.77,5.64,P ＜ 0.01),while the mRNA level of TSH β-Ⅴ in pituitary of LI group of mice (1.99 ± 0.61) was increased compared with that in control group of mice (5.75 ± 0.98,t =- 8.02,P＜ 0.01).Compared with control group of mice(9.12 ± 0.62),the level of thyroid TSH β-Ⅴ mRNA in LI group of mice (9.32 ± 0.91 ) was not significantly changed (t =0.45,P ＞ 0.05).There was no detectable native TSHβ in BM,PBL and thyroid.The mRNA level of native TSHβ in pituitary in LI group of mice( - 7.17 ± 1.78) was dramatically elevated compared to that in control group of mice( - 1.43 ± 0.51,t =- 7.60,P ＜ 0.01 ).ConclusionsThe mRNA levels of TSHβ-Ⅴ are suppressed in BM and PBL in low iodinediet induced hypothyroidism mice,which suggest that immune system derived TSHβ-Ⅴ may be more important thannative TSHβ in immune-thyroid regulation.

Objective To study the mechanism of mast cell increase in cellular leiomyoma of uterus.Methods Tissue sections from 30 cases of cellular leiomyoma of uterus,15 cases of leiomyosarcoma and 30 cases of ordinary leiomyoma were studied using immunohistochemical double labeling techniques.The expression of mast cell tryptase ahd Ki-67 as well as mast cell tryptase and chemotactic factors RANTES,Eotaxin,monocyte chemoattractant protein-1(MCP-1),transforming growth factor-? (TGF-?)were double immunostained.Results Ki-67 in mast cells was rarely expressed in each group. Expressions of regulate upon activation normal T cell expressed and secreted(RANTES),Eotaxin and TGF-? in cellular leiomyoma were 78%,89%,91%,respectively.They were all higher than those in ordinary leiomyoma and leiomyosarcoma(P

The tumor multidrug resistance reversal effect of NPB304, a novel taxane, was studied. MTT assay was used to determine the IC50 of chemotherapy drugs. Western blotting assay was applied to analyze the expression of P-glycoprotein (P-gp). The effect of compounds on the P-gp function and P-gp ATPase activity was determined by rhodamine 123 (Rh123) accumulation assay and analysis kit, respectively. Molecular docking was employed to predict the binding force between compounds and P-gp. Transmembrane transport of NPB304 was analyzed using MDCK II and MDR1-MDCK II cell model. NPB304 displayed multidrug resistance reversal effect on KBV cells and MCF-7/paclitaxel cells, NPB304 collaborative with P-glycoprotein (P-gp) inhibitors verapamil enhanced the reversal activity, specifically, 10 μmol x L(-1) verapamil in combination with paclitaxel reversed resistance by 56.5-fold, while combined with NPB304 increased the reversal fold; NPB304 synergistically increased Rh123 accumulation in the resistant cells when combined with verapamil, and NPB304 at 0-1 μmol x L(-1) enhanced the ATPase activity activated by verapamil was observed. NPB304 existed the hydrophobic interactions with the TM regions of P-gp, and the binding force between NPB304 and the A chain of the TM region was stronger. P-gp ATPase activity assay demonstrated NPB304 at lower concentrations (0-1.5 μmol x L(-1)) could activate the P-gp ATPase, playing a role on inhibition of P-gp function. However, NPB304 did not have an obvious feature of P-gp substrate. NPB304 exerted itself and synergy with verapamil activity on reversing tumor resistance via inhibiting the P-gp function.
ATP-Binding Cassette, Sub-Family B, Member 1 ; metabolism ; Antineoplastic Agents ; pharmacology ; Biological Transport ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Drug Synergism ; Humans ; MCF-7 Cells ; Rhodamine 123 ; Taxoids ; pharmacology ; Verapamil ; pharmacology

Objective:To improve the genetic stability of HBV gene in transgenic mice.Methods:HBV transgenic mice were bred by backcross and double cross.The HBV gene expression and replication were studied with real-time PCR,ELISA and chemiluminescence.Results:The HBV transgenic mice have stably bred to 23rd generation.The serum HBsAg level is 4122.31?2044.74IU/ml;The rate of HBV transgenic mice whose serum HBV DNA reach 104~106copies/ml was 93.93%.The HBV replication and expression were improved markedly.There is no difference between male and female mice about serum HBsAg level.Conclusion:After breeding the HBV gene was expressed stably with high-level in transgenic mice.

Objective:To investigated the clinical, biochemical, and immunohistological characteristics of patients with aldosterone producing adenoma(APA)and different gene mutations.Methods:The clinical and biochemical data of 206 patients with APA who received unilateral adrenalectomy were collected. Sanger sequencing was used to identify the mutation in the hot-point of KCNJ5 and other genes. The tumor samples were stained by 11β-hydroxylase(CYP11B1)and aldosterone synthase(CYP11B2), which was quantified by McCarty′s H-score system.Results:The gene mutations were identified in 166 out of 206(80.6%)patients with APA, of which 158 cases were KCNJ5 mutation, 2 ATP1A1 mutation, 5 ATP2B3 mutation, and 1 CTNNB1 mutation. Age, duration of hypertension, and serum potassium in APA patients with genetic mutant were significantly lower than those without genetic mutation( P<0.05) while the proportion of female, systolic blood pressure, diastolic blood pressure, aldosterone/renin ratio(ARR), and plasma aldosterone concentration(PAC)post saline infusion test(SIT)were significantly higher( P<0.05). Subgroup analysis showed that age, duration of hypertension, systolic blood pressure, and proportion of left ventricular hypertrophy in APA patients with ATP1A1 and ATP2B3 mutations were significantly higher than those with KCNJ5 mutation( P<0.05)while the PAC post SIT and tumor diameter were significantly lower( P<0.05). The positive rates of CYP11B2 in APA with different mutations were not significantly different. The H-score of CYP11B1 was significantly higher [160.0(127.5, 193.5) vs 80.0(27.5, 152.3), P=0.020] and the H-score of CYP11B2 was significantly lower [155.0(123.0, 190.0) vs 240.0(140.0, 270.0), P<0.01] in APA with KCNJ5 mutation compared with those with ATPase mutation. Conclusion:The types of genetic mutation are closely correlated with the clinical, biochemical, and immunohistological phenotypes in patients with APA.