Antiviral Agents ; pharmacology ; therapeutic use ; DNA, Viral ; blood ; Hepatitis B ; blood ; drug therapy ; virology ; Hepatitis B Surface Antigens ; blood ; Hepatitis B e Antigens ; blood ; Hepatitis B virus ; drug effects ; physiology ; Humans ; Interferon-alpha ; pharmacology ; therapeutic use ; Kinetics ; Lamivudine ; pharmacology ; therapeutic use ; Models, Statistical ; Viral Load

Worldwide sales of biologic drugs exceeded 100 billion USD in 2011. About 32% is from therapeutic monoclonal antibody (mAb). With many blockbuster biopharmaceutical patents expiring over the next decade, there is a great opportunity for biosimilar to enter the worldwide especially emerging market. Both European Medicines Agency (EMA) and Food and Drug Administration (FDA) have introduced regulatory frameworks for the potential approval of biosimilar mAb therapeutics. Rather than providing a highly abbreviated path, as in the case for small molecule chemical drug, approval for biosimilar mAb will require clinical trial and the details will be very much on a case-by-case basis. Since mAb is the dominant category of biologic drugs, mAb will be the focus of this review. First, the United States (US) and European Union (EU) approved mAb and those in phase 3 trials will be reviewed, then strategies on how to win biosimilar competition will be reviewed.
Animals ; Antibodies, Bispecific ; therapeutic use ; Antibodies, Monoclonal ; therapeutic use ; Antibodies, Monoclonal, Humanized ; therapeutic use ; Biosimilar Pharmaceuticals ; standards ; Clinical Trials, Phase III as Topic ; Drug Approval ; European Union ; Humans ; United States ; United States Food and Drug Administration

The cardiovascular circulation feedback control treatment instrument (CFCTI) is an automatic feedback control treatment system, which has the function of monitoring, alarming, trouble self-diagnosis and testing on the line in the closed loop. The instrument is designed based on the successful clinical experiences and the data are inputted into the computer in real-time through a pressure sensor and A/D card. User interface window is set up for the doctor's choosing different medicine. The orders are outputted to control the dose of medicine through the transfusion system. The response to medicine is updated continually. CFCTI can avoid the man-made errors and the long interval of sampling. Its reliability and accuracy in rescuing the critical patients are much higher than the traditional methods.
Automation ; instrumentation ; Cardiovascular System ; Feedback ; Medication Systems

OBJECTIVETo investigate if WAVE1 is involved in mult drug-resistance (MDR) of human leukemia cell line K562/A02.

METHODSThe level of WAVE1 in K562 and K562/A02 cells was assayed by Western blot and RT-PCR; K562 cells and K562/A02 cells were transient transfected with pEFBOS-WAVE1 reconstructed plasmid or specifically siRNA to WAVE1. 50% inhibition concentration (IC50) of doxorubicin on K562/A02 was determined by WST-8 assay. Hoechst33258 staining was used to examine cell morphological changes and to calculate percentage of apoptotic nuclei. The mRNA level of mdrl was assayed by RT-PCR. The Bcl-2 protein was assayed by Western blot.

RESULTS1. The WAVE1 expression at mRNA and protein level in K562/A02 cells was increased by about 70% and 63% respectively as compared with that in K562 cells. 2. Overexpression of WAVE1 in K562 cells by transient transfection significantly increased the resistance to doxorubicin, and increased IC50 from (0.05 +/- 0.00) microg/ml to (2.99 +/- 0.12) microg/ml, and at 1 microg/ml or 5 microg/ml of doxorubicin treatment, cell apoptotic nuclei rate was decreased by 30% or 35% respectively. 3. Suppression of WAVE1 in K562/A02 cells by siRNA resulted in a reversal of MDR to doxorubicin, and decreased IC50 from (4.29 +/- 0.15) microg/ml to (1.85 +/- 0.07) microg/ml, and at 1 microg/ml or 5 microg/ml of doxorubicin treatment, cell apoptotic nuclei rate was increased by 24% or 21% respectively. 4. Overexpression of WAVE1 in K562 cells significantly increased the mdrl mRNA and the Bcl-2 protein, and suppression of WAVE1 in K562/A02 cells by siRNA decreased the mRNA and the protein.

CONCLUSIONWAVE1 involves in the MDR mechanisms in K562/A02 leukemia cells through regulation the level of mdrl and Bcl-2.

Apoptosis ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Genetic Vectors ; Humans ; K562 Cells ; Plasmids ; genetics ; RNA Interference ; RNA, Messenger ; genetics ; Transfection ; Wiskott-Aldrich Syndrome Protein Family ; genetics ; metabolism

OBJECTIVETo investigate whether WASP/Verprolin homologous protein 1 (WAVE1) plays a role in the pathogenesis of childhood acute lymphoblastic leukemia (ALL).

METHODSWAVE1 mRNA and protein expression in bone marrow mononuclear cells (BMMCs) was measured by RT-PCR and Western blotting respectively in 4 children with ALL relapse, 15 children with ALL in complete remission (CR) and 40 children with newly diagnosed ALL. Ten normal bone marrow samples were used as controls. Jurkat cells were treated with different concentrations of adriamycin (ADM). The cell proliferation was detected with MTT. The apoptosis rate was measured by flow cytometry. WAVE1 mRNA and protein expression of Jurkat cells treated with ADM was detected by RT-PCR and Western blotting respectively.

RESULTSWAVE1 was not expressed or weakly expressed in BMMCs from normal controls and patients with ALL in CR. Higher WAVE1 mRNA and protein expression was found in BMMCs from patients with newly diagnosed ALL and patients with relapse ALL when compared with the controls and the patients in CR (P<0.01). ADM significantly inhibited the proliferation of the Jurkat cells and the inhibitory effect was dose-and time-dependent (P<0.05). After ADM treatment for 24 hrs, the percentage of apoptosis cells increased significantly and WAVE1 mRNA and protein expression of Jurkat cells decreased significantly when compared with the untreated controls (P<0.05).

CONCLUSIONSThe WAVE1 expression increased in children with ALL. WAVE1 may be related to the development of ALL and may be severed as a marker for the evaluation of the severity of ALL in children.

Adolescent ; Antibiotics, Antineoplastic ; pharmacology ; Apoptosis ; drug effects ; Blotting, Western ; Cell Proliferation ; drug effects ; Child ; Child, Preschool ; Doxorubicin ; pharmacology ; Female ; Humans ; Infant ; Jurkat Cells ; Male ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; etiology ; metabolism ; RNA, Messenger ; analysis ; Wiskott-Aldrich Syndrome Protein Family ; analysis ; genetics ; physiology

The aim of this study was to determine the dynamic expression profile of hepatitis B surface antigen (HBsAg) according to hepatic parenchyma cells' volume at different stages of liver fibrosis during the immune clearance phase. Eighty-nine patients with HBeAg-positive chronic hepatitis B (CHB) in the immune clearance stage were recruited for study. Each patient's serum HBsAg levels were detected by electrochemiluminescence. The serum HBsAg levels were apportioned according to hepatic parenchyma cells' volume at liver fibrosis stages 1, 2, 3, and 4 and compared by ANOVA. The unapportioned serum HBsAg levels (IU/mL) at liver fibrosis stages 1 (227.2+/-237.7), 2 (211.0+/-131.4), 3(300.1+/-144.6), and 4 (278.7+/-148.8) were not significantly different (all comparisons, P range: 0.061 to 0.759). However, when the serum HBsAg levels were apportioned by the same hepatic parenchyma cells' volume at liver fibrosis stages 1 (343.9+/-359.8), 2 (336.4+/-209.5), 3 (508.7+/-245.1), and 4 (525.2+/-274.8), the levels were significantly different (all comparisons, F = 3.045 and P = 0.033; stage 1 vs. 3, P = 0.041; stage 1 vs. 4, P = 0.046; stage 2 vs. 3, P = 0.028; stage 2 vs. 4, P = 0.034). During the immune clearance phase of chronic hepatitis B, increased HBsAg expression is associated with increased hepatic parenchyma cells' volume and progressive liver fibrosis stage.
Adolescent ; Adult ; Cell Size ; Child ; Female ; Hepatitis B Surface Antigens ; blood ; Hepatitis B, Chronic ; metabolism ; pathology ; Humans ; Liver ; cytology ; metabolism ; Liver Cirrhosis ; metabolism ; pathology ; Male ; Middle Aged ; Young Adult

Abstract: Our previous work revealed berberine can significantly enhance the susceptibility of fluconazole against fluconazole-resistant Candida albicans, which suggested that berberine has synergistic antifungal activity with fluconazole. Preliminary SAR of berberine needs to be studied for the possibility of investigating its target and SAR, improving its drug-likeness, and exploring new scaffold. In this work, 13-substitutited benzyl berberine derivatives and N-benzyl isoquinoline analogues were synthesized and characterized by 1H NMR and MS. Their synergetic activity with fluconazole against fluconazole-resistant Candida albicans was evaluated in vitro. The 13-substitutited benzyl berberine derivatives 1a-1e exhibited comparable activity to berberine, which suggested that the introduction of functional groups to C-13 can maintain its activity. The N-benzyl isoquinolines, which were designed as analogues of berberine with its D ring opened, exhibited lower activity than berberine. However, compound 2b, 2c, and 4b showed moderate activity, which indicated that berberine may be deconstructed to new scaffold with synergistic antifungal activity with fluconazole. The results of our research may be helpful to the SAR studies on its other biological activities.
Antifungal Agents ; pharmacology ; Berberine ; pharmacology ; Candida albicans ; drug effects ; Drug Resistance, Fungal ; Drug Synergism ; Fluconazole ; pharmacology ; Isoquinolines ; pharmacology ; Microbial Sensitivity Tests

The development of CT and the clinical application of CT pulmonary angiography (CTPA) in diagnosing pulmonary embolism were introduced,and the methods for decreasing CTPA radiation dose and the importance of iterative reconstruction for low-dose scanning were analyzed.The development and application of contrast agent were described,and the ways to reduce contrast agent dose was expounded.Double-low CTPA combined with iterative reconstruction was pointed out to decrease greatly the radiation dose and contrast agent iodine dose while ensured image quality,and thus the damages to the patient by radiation and contrast agent could be lowered at the most.

ABSTRACT:OBJECTIVE To explore the preventive effect of evodiamine on inflammation associated colorectal carcinoma through the establishment of model in mice.METHODS The mice were administrated with AOM/DSS and divided into con-trol group,model group,low dose of evodiamine group(10EV)and high dose of evodiamine group(20EV).Body weights and death rates of mice were recorded once a week.The length of colorectum,tumor number and sizes were compared among all groups.Morphology of colorectal tissues in each group were stained by HE.Immunohistochemical analysis was used to detect the expression of COX-2 and PCNA.RESULTS AOM/DSS caused the loss of body weight and increased mortality of mice, while evodiamine improved the condition,and also reduced the development of colorectal cancer,alleviated the inflammatory response and inhibited abnormal proliferation of cancer cells.CONCLUSION Evodiamine can display promising preventive effects on inflammation-associated colorectal cancer,which is relative to the reduction of inflammation and abnormal cell prolif-eration.

OBJECTIVETo examine the association of activation of calcium-sensing receptors (CaSR) with apoptosis in cardiomyocytes under simulated ischemia/reperfusion.

METHODSVentricular cardiomyocytes of neonatal rats were incubated in ischemia-mimetic solution for 2 h, then re-incubated in normal culture medium for 24 h to establish a model of simulated ischemia/reperfusion (I/R). Cell apoptosis was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL assay). The expression of CaSR mRNA was detected by reverse transcriptase polymerase chain reaction (RT-PCR). The expression of Caspase -3 and Bcl-2 was detected by Western blotting.

RESULTThe simulated I/R enhanced the expression of CaSR and cardiomyocyte apoptosis. GdCl(3), a specific activator of CaSR, further increased the expression of CaSR and cardiomyocyte apoptosis, along with upregulation of Caspase-3 and downregulation of Bcl-2.

CONCLUSIONCaSR is associated with I/R injury and apoptosis in neonatal rat ventricular cardiomyocytes via suppressing Bcl-2 and promoting Caspase -3 expression.

Animals ; Apoptosis ; physiology ; Caspase 3 ; metabolism ; Cells, Cultured ; Myocardial Reperfusion Injury ; metabolism ; pathology ; Myocytes, Cardiac ; metabolism ; pathology ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Receptors, Calcium-Sensing ; metabolism ; Signal Transduction