Imatinib,a small-molecule kinase inhibitor,has proven useful in the treatment of recurrent or metastatic gastrointestinal stromal tumors ,However,resistance to imatinib is a more and more serious problem.This review summarizes the existing knowledge of the imatinib resistance mechanism in gastrointestinal stromal tumors and describes the treatment directions in further.

Objective To summary the clinical applied value of interventional therapy in hepatic venous outflow obstruction after orthotopic liver transplantation(OLT).Methods The clinical data of 27 patients suspect with hepatic outflow obstruction out of OLT patients were analyzed retrospec- tively.Most of them presented with liver dysfunction,like ascites,jaundice,or hydropsia of lower ex- tremity as BCS.These patients accepted venography and endovascular treatment if venous outflow ob- struction was found.Results By venography,one case of thrombus in inferior vena cava,one case of hepatic vein stenosis,13 cases of inferior vena cava stenosis(3 cases were associated with hepatic vein stenoses)were identified.Stent implantation was successfully performed on 10 patients,and balloon angioplasty on 4 patients.Rapid,dramatic resolution of symptoms was achieved in those patients. Hepatic vein restenosis occurred in one case 8 months after balloon dilatation,and treated with stent implantation.Inferior vena cava restenosis occurred in one case 2 years after balloon dilation,and trea- ted with another balloon expanding.Patients remained completely asymptomatic at 4 months to 5 years of follow-up.Conclusion The venacavographic balloon angioplasty and metallic stent replacement are safe and useful for post-OLT with venous outflow obstruction.

Adult ; Aged ; Aged, 80 and over ; Biliary Tract Neoplasms ; complications ; Cholangitis ; etiology ; Cholestasis ; etiology ; therapy ; Drainage ; adverse effects ; Female ; Hepatic Encephalopathy ; etiology ; Humans ; Intraoperative Period ; Jaundice, Obstructive ; etiology ; therapy ; Liver Neoplasms ; complications ; Male ; Middle Aged ; Pancreatitis ; etiology ; Stents ; adverse effects

OBJECTIVETo investigate the effect of Shenqi Fuzheng Injection (SFI) in radiation pneumonitis and its influence on the levels of plasma transforming growth factor beta (TGF-beta), tumor necrosis factor-alpha (TNF-alpha) and interleukin-10 (IL-10) at various stages (pre-, mid- and post-radiation) of radiotherapy (RT).

METHODSFifty-eight patients enrolled in this study were randomized into two groups, all received conventional radio therapy, but the treatment group was intravenously dripped with SFI additionally, once daily, starting 3 days before radiotherapy to 1 week after the end of it. Levels of TGF-beta, TNF-alpha and IL-10 in blood samples collected and frozen at different time point of RT, before radiotherapy (Pre-RT), after received 40-50 Gy radiation (Mid-RT) and in time of terminating RT (Post-RT), were measured with enzyme linked immunosorbent assay (ELISA). And the occurrence of radiation pneumonitis was analyzed according to RTOG acute radiation pneumonitis criteria.

RESULTSLevel of TGF-beta increased in both groups after RT, either Mid- or Post-RT, but in comparing with that at Pre-RT, statistical significant (P < 0.05) only showed in the control group at Post-RT time when it raised to peak, while in inter-group comparing insignificance was shown. Level of TNF-alpha also increased in both groups, but statistical significance only showed in the control groups as compared with that of Pre-RT, accordingly, it was lower in the treatment group than that in the control group at corresponding time points (P < 0.05). Level of IL-10 decreased gradually in the process of RT, as compared with that at Pre-RT, significant difference was shown in both groups at Post-RT but not at Mid-RT, as compared between groups, no significance (P < 0.05) was shown, though the treatment group showed a high tendency. As for the ratio of IL-10/TNF-alpha, significant difference of lowering in the control group after RT was shown as compared with that at Pre-RT (P < 0.05), and also as compared with that in the treatment group at corresponding time point (P < 0.05). The occurrence of radiation pneumonia > or = grade 2 in the treatment group was significantly lower than that in the control group (chi2 = 8.7133, P < 0.01).

CONCLUSIONPlasma level of TNF-alpha and ratio of IL-10/ TNF-a could be the practicable indexes for estimating the susceptibility of acute radiation pneumonia; SFI can regulate the network of cytokine, and thus be effective in preventing and treating radiation pneumonitis.

Adult ; Aged ; Aged, 80 and over ; Carcinoma, Non-Small-Cell Lung ; radiotherapy ; Carcinoma, Squamous Cell ; radiotherapy ; Cytokines ; blood ; Drugs, Chinese Herbal ; therapeutic use ; Esophageal Neoplasms ; radiotherapy ; Female ; Humans ; Interleukin-10 ; blood ; Lung Neoplasms ; radiotherapy ; Male ; Middle Aged ; Phytotherapy ; Radiation Pneumonitis ; blood ; prevention & control ; Tumor Necrosis Factor-alpha ; blood ; Young Adult

Objective:Tacrolimus prolonged-release(PR) formulation is a new once-daily formulation of the calcineurin inhibitor tacrolimus,which is currently used in adult liver or kidney transplant patients,and is also gradually widely used in children with nephrotic syndrome.The present study was undertaken to preliminarily investigate the pharmacokinetic characteristics of tacrolimus PR in pediatric nephrotic syndrome recipients.Methods:This single-center open-label prospective study was performed in pediatric nephrotic syndrome recipients.Pharmacokinetic samples were collected from eight pediatric subjects with nephrotic syndrome from Department of Pediatric Nephrology in Peking University First Hospital between June and August 2011.They followed administration of single oral doses of tacrolimus PR formulation at 0.02 mg/kg (n =2),0.05 mg/kg (n =2) and 0.10 mg/kg (n =4).Blood samples were taken before the dose and 1,2,4,6,8,10,12 and 24 h after drug intake.No other medicines or interacting food or drinks were taken during the study period.Blood concentrations were measured using an enzyme multiplied immunoassay technique.Pharmacokinetic analysis was performed using WinNolin Phoenix software Version 6.0 (Pharsight,Cary,NC,USA).Results:The pharmacokinetic data were best described by a non-compartment model.Pharmacokinetic parameters of tacrolimus PR formulation in the 3 ascending doses groups (0.02 mg/kg,0.05 mg/kg and 0.10 mg/kg) were as follows:the maxi mum drug concentrations (Cm=/D) were (1.7 ± 1.0) μg/L,(3.1 ± 1.9) μg/L,(8.0 ± 3.5) μg/L,respectively;Areas under the drug concentration-time curve (AUCo-∞/D) were (47.2 ± 47.1) h · μg/ L,(84.0 ± 13.1) h · μg/L,(175.6 ± 107.1) h · μg/L,respectively;Oral clearance rates were (0.8±0.9) L/(h·kg),(0.4±0.1) L/(h · kg),(1.9 ±1.3) L/(h · kg),respectively;Body weight normalized distribution volumes were (7.0 ± 3.4) L/kg,(12.4 ± 8.4) L/kg and (73.6 ± 68.6) L/kg,respectively.Both mean Cmax normalized level for the administered dose (Cmax/D) and mean AUC0-∞ normalized level for the administered dose (AUC0-∞/D) were higher in the 0.05 mg/kg dosage group than in the 0.02 and 0.10 mg/kg dosage group.There were two peaks in the drug concentrations in every dose group;a primary peak appeared at the end of about 2 h followed by a small secondary peak at h 12,which was more noticeable in the 0.10 mg/kg dose group than in the two lower dosages.Conclusion:The pharmacokinetic characteristics of tacrolimus PR formulation were initially explored in pediatric patients with nephritic syndrome.The data presented form a basis for subsequent larger scale studies on pharmacokinetics of tacrolimus PR formulation in nephritic syndrome children.

The aim of this study is to develop a convenient and effective method for the identification of heparin from pigs (include Sus scrofa domestica Brisson and Sus scrofa riukiuanus). Based on sequences of D-loop region of pigs and the other animals, two pairs of highly specific primers were designed for distinguishing heparin of pigs from other animals. The primers were employed to amplify D-loop region of DNA templates extracted from pig and seven other animal species that amounted to 49 samples. AS-PCR (allele-specific PCR) and ARMS (amplification refractory mutation system) were all suitable for fast identification of heparin from pig with anneal temperature at 54-56 degrees C in AS-PCR and with wider anneal temperature in ARMS,at 52-58 degrees C. An about 170 bp DNA fragments were amplified from separately pigs and whereas no DNA fragment was amplified from other samples under the same reaction condition.
Alleles ; Animals ; Base Sequence ; DNA Mutational Analysis ; methods ; DNA Primers ; DNA, Mitochondrial ; genetics ; Drug Contamination ; prevention & control ; Heparin ; analysis ; genetics ; Horses ; genetics ; Molecular Sequence Data ; Phylogeny ; Polymerase Chain Reaction ; methods ; Quality Control ; Ruminants ; genetics ; Sequence Alignment ; Sequence Analysis, DNA ; Sus scrofa ; genetics

Adult ; Heroin Dependence ; drug therapy ; prevention & control ; Humans ; Male ; Methadone ; therapeutic use ; Patient Compliance ; Treatment Outcome

OBJECTIVETo investigate the dynamic changes of plasma levels of prostacycline (PGI2) and thromboxane A2 (TXA2) and their relationship with the severity of hepatic injury in rats with nonalcoholic fatty liver disease (NAFLD).

METHODSWe established a NAFLD model, with a fat-rich diet consisting of 10% lard oil + 2% cholesterol, which was given to Sprague-Dawley rats (n=48) for a period of 8, 12, 16 and 24 weeks. The other rats were fed standard diets and were used as normal controls (n=24). At sacrifice, liver pathology scores were evaluated and plasma levels of PGI2, its stable metabolic product 6-keto-PGF1 alpha and TXA2, and TXB2 were determined by radioimmunoassay.

RESULTSSimple fatty livers were observed in the model group at 8 weeks. From 12 weeks to 24 weeks, the livers gradually progressed from simple steatohepatitis to liver fibrosis. Plasma levels of TXB2 in the model group increased higher than in the control group after 8 weeks [(52.4+/-3.15) ng/L vs (41.1+/-1.45) ng/L] and continued to increase over time, with the highest levels at 24 weeks [(117.7+/-7.47) ng/L]. A strong positive correlation (r=0.537) was seen between plasma TXB2 levels and the severity of liver injury. Plasma 6-keto-PGF1 alpha concentrations decreased in the model group in comparison with the control group after 8 weeks [(31.1+/-1.62) ng/L vs (36.5+/-1.68) ng/L] and continued to decrease over time, with the lowest concentrations at 24 weeks [(3.4+/-2.43) ng/L t=3.77]. A negative correlation was shown between the 6-keto-PGF1 alpha level and the severity of the liver injury.

CONCLUSIONA rat model of NAFLD was established successfully by feeding a fat-rich diet for 24 weeks. In this model, the imbalance of plasma PGI2 and TXA2 levels (increased TXB2 and decreased 6-keto-PGF1 alpha levels) may play a role in the pathogenesis of experimental NAFLD.

6-Ketoprostaglandin F1 alpha ; blood ; Animals ; Epoprostenol ; blood ; Fatty Liver ; blood ; Liver ; pathology ; Male ; Rats ; Rats, Sprague-Dawley ; Thromboxane A2 ; blood ; Thromboxane B2 ; blood

OBJECTIVETo study the causes of poorer antiviral response to neutralizing anti-interferon-alpha antibodies (NA) in male chronic hepatitis B patients treated with recombinant interferon-alpha (rIFN-alpha).

METHODSTwo hundred sixty-nine patients (198 males and 71 females) with histologically proven chronic hepatitis B were treated with 5 MU recombinant interferon-alpha 1b (rIFN-alpha 1b) subcutaneously thrice weekly for 6-37 (median 10.0) months. For each patient, serum HBV DNA levels were detected with fluorescent-quantitative PCR, HBeAg with enzymoimmunoassay, and NA with an antiviral neutralizing biological assay during therapy.

RESULTSNA was found in 70 (35.4%) of the 198 males and in 15 (21.1%) of the 71 females during treatment (x2 = 4.894, P = 0.027). At the end of treatment combined-response was achieved in 21 (24.7%) of the 85 NA-positive patients and in 100 (54.3%) of the 184 NA-negative cases (x2 = 20.642). Stratification analysis by NA showed that combined-response rate was significantly lower in males than in females (18.6%, 13/70 vs. 53.3%, 8/15, x2 = 8.024) among NA-positive patients while it was similar in males and in females (50.8%, 65/128, vs. 62.5%, 35/56, x2 = 2.156) among NA-negative patients. In stratification analysis by gender, it was significantly lower in NA-positive patients than in NA-negative ones (18.6%, 13/70 vs. 53.3%, 8/15, x2 = 8.024) among males but there was no significant difference between combined-response rates among females.

CONCLUSIONThe poorer antiviral response to recombinant interferon-alpha in male chronic hepatitis B patients than in female patients is related to the neutralizing anti-interferon antibodies.

Antibodies ; blood ; Antiviral Agents ; immunology ; therapeutic use ; DNA, Viral ; blood ; Female ; Hepatitis B, Chronic ; drug therapy ; immunology ; Humans ; Interferon Type I ; immunology ; therapeutic use ; Male ; Neutralization Tests ; Recombinant Proteins ; Sex Factors ; Treatment Outcome

OBJECTIVETo evaluate the inhibitory effect of 5-fluorouracil (5-Fu) on HT-1080 human fibrosarcoma cells in vitro.

METHODSHT-1080 human fibrosarcoma cells were cultured for 3 days in the proliferation period. Then adriamycin or 5-Fu at different concentrations were used to treat these cells for 24 h, 72 h and 144 h. MTT assay was used to evaluate the cytotoxic effects through measuring optical density and calculating the inhibition rate of cell growth. Morphologic changes of the cells were observed under a phase contrast microscope. Flow cytometry (FCM) was performed to detect the changes in cell cycle and DNA ploidy in the fibrosarcoma cells treated with 5-Fu.

RESULTS10 µg/ml 5-Fu showed an inhibition rate of 45.9% (24 h), 64.7% (72 h) and 90.6% (144 h) of the HT-1080 cell growth. 100 µg/ml 5-Fu showed an inhibition rate of 53.1% (24 h), 86.4% (72 h), 93.0% (144 h) of the HT-1080 cell growth, results similar to those in the adriamycin group. Untreated fibrosarcoma cells accounted for 67.5% in G(1) phase, 21.2% in S phase and 11.3% in G(2) phase. With the increasing drug concentrations, cells in G(1) + S phase increased rapidly and no cells in G(2) phase were observed later. The cells treated with 5-Fu showed a G(1) + S cell cycle arrest.

CONCLUSIONS5-Fu has an antitumor activity in human fibrosarcoma HT-1080 cells in vitro, in a time-dependent and dose-dependent manner. The cytotoxity of 5-Fu at high concentrations and continuous use can induce tumor cell cycle arrested at G(1) + S phase, a similar result induced with adriamycin.

Antibiotics, Antineoplastic ; pharmacology ; Antimetabolites, Antineoplastic ; administration & dosage ; pharmacology ; Cell Cycle ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dose-Response Relationship, Drug ; Doxorubicin ; pharmacology ; Fibrosarcoma ; pathology ; Fluorouracil ; administration & dosage ; pharmacology ; Humans ; Time Factors