OBJEVTIVETo evaluate the therapeutic effects of different therapeutic regimens for non-small-cell lung cancer (NSCLC) with or without EML4-ALK rearrangement.

METHODSTwenty-one ALK-positive and 50 ALK-negative NSCLC patients who received voluntarily EML4-ALK testing and 75 NSCLC patients without AL testing were enrolled in this study. The 3 groups of patients received different treatments, and the therapeutic effects, progression-free survival (PFS), and treatment-related adverse events were analyzed.

RESULTSCrizotinib treatment obviously prolonged the PFS in EML4-ALK-positive patients with an objective response rate (OOR) of 61.9% and a median response duration of 16 months, which were significantly better than those in with ALK-negative patients and patients without ALK testing who received different second-line therapies.

CONCLUSIONCrizotinib is superior to platinum-based chemotherapy in NSCLC patients with ALK rearrangement. ALK rearrangement id not a modifier of the effect of chemotherapy regimens in NSCLC patients.

Carcinoma, Non-Small-Cell Lung ; drug therapy ; Disease-Free Survival ; Humans ; Lung Neoplasms ; drug therapy ; Oncogene Proteins, Fusion ; Pyrazoles ; administration & dosage ; therapeutic use ; Pyridines ; administration & dosage ; therapeutic use

Adjuvants, Immunologic ; administration & dosage ; Administration, Intranasal ; Animals ; Antibodies, Viral ; blood ; Bacterial Toxins ; administration & dosage ; Capsid Proteins ; Enterotoxins ; administration & dosage ; Escherichia coli Proteins ; administration & dosage ; Female ; Hemagglutination Inhibition Tests ; Human papillomavirus 16 ; immunology ; Immunization ; Interferon-gamma ; biosynthesis ; Lymphocyte Activation ; Mice ; Mice, Inbred C57BL ; Oncogene Proteins, Viral ; genetics ; immunology ; Papillomavirus Vaccines ; Vaccines, DNA ; administration & dosage ; immunology ; Viral Vaccines ; administration & dosage ; immunology ; Virion ; immunology

More than 99% of cervical cancers have been associated with human papillomaviruses (HPVs), particularly HPV type 16. The clear association between HPV infection and cervical cancer indicates that HPV serves as an ideal target for development of preventive and therapeutic vaccines. Although the recently licensed preventive HPV vaccine, Gardasil, has been shown to be safe and capable of generating significant protection against specific HPV types, it does not have therapeutic effect against established HPV infections and HPV-associated lesions. Two HPV oncogenic proteins, E6 and E7, are consistently co-expressed in HPV-expressing cervical cancers and are important in the induction and maintenance of cellular transformation. Therefore, immunotherapy targeting E6 and/or E7 proteins may provide an opportunity to prevent and treat HPV-associated cervical malignancies. It has been established that T cell-mediated immunity is one of the most crucial components to defend against HPV infections and HPV-associated lesions. Therefore, effective therapeutic HPV vaccines should generate strong E6/E7-specific T cell-mediated immune responses. DNA vaccines have emerged as an attractive approach for antigen-specific T cell-mediated immunotherapy to combat cancers. Intradermal administration of DNA vaccines via a gene gun represents an efficient way to deliver DNA vaccines into professional antigen-presenting cells in vivo. Professional antigen-presenting cells, such as dendritic cells, are the most effective cells for priming antigen-specific T cells. Using the gene gun delivery system, we tested several DNA vaccines that employ intracellular targeting strategies for enhancing MHC class I and class II presentation of encoded model antigen HPV-16 E7. Furthermore, we have developed a strategy to prolong the life of DCs to enhance DNA vaccine potency. More recently, we have developed a strategy to generate antigen-specific CD4+ T cell immune responses to further enhance DNA vaccine potency. The impressive pre- clinical data generated from our studies have led to several HPV DNA vaccine clinical trials.
Female ; Humans ; Oncogene Proteins, Viral/genetics/immunology ; Papillomaviridae/*genetics/immunology ; Papillomavirus Infections/immunology/*prevention & control ; Papillomavirus Vaccines/*administration & dosage ; Repressor Proteins ; Uterine Cervical Neoplasms/*prevention & control ; Vaccines, DNA/*administration & dosage ; Viral Vaccines/administration & dosage

OBJECTIVETo investigate whether the protective effect of therapy with different combined neuroprotectant agents was better than that of single agent on focal cerebral ischemia.

METHODSThe right middle cerebral artery in the rats was occluded with suture occlusion technique. The rats were divided into five groups treated with FDP (50 mg/kg, n = 10), MK-801 (1 mg/kg, n = 10) and NAC (150 mg/kg, n = 10) singly, or in combination, respectively, by intraperitoneal infusion 30 minutes after vessel occlusion. The rats were weighed and assessed neurologically, based on a 5-point scale, six and 24 hours after focal cerebral ischemia. The expression of anti-apoptotic protein bcl-2 was observed with SDS-PAGE protein electrophoresis and Western blot technique.

RESULTThe optical density of bcl-2 increased more distinctly in the rats treated with combined neuroprotective agents than that with any single agent six and 24 hours after cerebral ischemia, with a statistically significant difference (P < 0.05).

CONCLUSIONSTreatment with combined neuroprotectant agents could un-regulate the anti-apoptotic protein bcl-2 more distinctly than that with any single agents. Combined use of neuroprotectants might be more effective than that of single agent in protecting rats' brain from ischemia.

Acetylcysteine ; administration & dosage ; Actins ; analysis ; Animals ; Brain Ischemia ; drug therapy ; metabolism ; Dizocilpine Maleate ; administration & dosage ; Drug Therapy, Combination ; Fructosediphosphates ; administration & dosage ; Male ; Molecular Weight ; Neuroprotective Agents ; administration & dosage ; Proto-Oncogene Proteins c-bcl-2 ; analysis ; Rats ; Rats, Wistar

OBJECTIVETo investigate the anti-apoptosis effect of intensive insulin treatment on cardiac myocytes and its underlying mechanism in severe scald rats.

METHODSTwelve SD rats were suffered from 30% TBSA full thickness scald, and they were divided into: IT group [with intravenous injection of isotonic saline including insulin (15 mU x kg(-1) x min(-1)) and 100 g/L glucose], B group [with treatment of isotonic saline (2 mL x kg(-1) x %TBSA(-1) x 8 h(-1)]. Six SD rats received sham burn as controls[sham(S)group, with treatment of fluid at physiologic dose]. + dp/ dtmax (the rate of the rise of left ventricular pressure) and -dp/ dtmax (the rate of the fall of left ventricular pressure)at 6 post burn hour (PBH)were recorded. Apoptosis were determined by TUNEL staining and DNA ladder. The phosphorylation f Akt and protein expression of Bcl-2 in cardiomyocyte were assayed by Western blotting.

RESULTSThe + dp/ dtmax in the S group, IT group and B group at6 PBH were respectively (5.5 +/- 0.5) x 10(3) mm Hg/s, (3.4 +/- 0.4) x 10(3 mm Hg/s and (2.5 +/- 0.5) x 10(3) mm Hg/s (1 mm Hg = 0.133 kPa), the - dp/ dtmax were respectively (4.55 +/- 0.34) x 10(3) mmHg/s, (2.94 +/- 0.22) x 10(3) mm Hg/s and (2.05 +/- 0.19) x 10(3) mmHg/s.The +/- dp/dtmax in IT group was significantly higher than those in B group( P < 0.01). The apoptosis index in B group was (13.1 +/- 3.4)%, which was obviously higher than that in IT group (6.7 +/- 1.8)% and S group (0.6 +/- 0.4)% (P < 0.01). DNA ladder showed that no DNA fragmentation in S group, but obvious DNA fragmentation forming ladder pattern in B group, and no obvious ladder pattern in IT group. The phosphorylation of Akt and level of Bcl-2 protein in B group were markedly higher than those in IT group ( P < 0.05 or P < 0.01).

CONCLUSIONIntensive insulin treatment can upregulate the activity of Akt and enhance the expression of Bcl-2, and they might constitute the mechanisms for anti-apoptosis in cardiomyocyte and protection of cardiac function.

Animals ; Apoptosis ; drug effects ; Burns ; drug therapy ; pathology ; Insulin ; administration & dosage ; pharmacology ; Male ; Myocytes, Cardiac ; cytology ; metabolism ; Phosphorylation ; Proto-Oncogene Proteins c-akt ; metabolism ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVESTo explore the effect of lead acetate on the apoptosis of rat brain neural cells and the relationship between the apoptosis and the bcl-2 as well as bax gene expression.

METHODSLead acetate was given to SD rats by intraperitoneal injection for 5 days at the dosage of 25, 50 and l00 mg/kg body weight respectively. The rates of apoptosis and the expression of bcl-2 (Bcl-2) and bax (Bax) in neural cells from cerebral cortex, hippocampus and carebellum were measured respectively by flow cytometry (FCM).

RESULTSThe rates of apoptosis in neural cells from cerebral cortex, hippocampus and cerebellum in every treatment group were significantly higher than that of control (P < 0.01), and there was a significant dose-response relationship (r = 0.998, 0.989 and 0.997 respectively). The expression of bcl-2 was significantly decreased, whereas bax was significantly increased, in neural cells from cerebral cortex, hippocampus and cerebellum in every lead acetate treatment group (FI) compared with the control group, and there was a significant dose-response relationship (r = -0.886, -0.787 and -0.832 respectively for bcl-2, r = 0.971, 0.988 and 0.991 respectively for bax). The value of Bcl-2/Bax in every treatment group decreased significantly compared with control, and there was a nice dose-response relationship (r = -0.863, -0.829 and -0.999, respectively). Correlation analysis showed that rates of apoptosis were inversely correlated with the expression of bcl-2 (r = -0.750, -0.509, and -0.667, respectively), whereas positively correlated with the expression of bax (r = 0.748, 0.56l, and 0.668, respectively). And there were inverse correlations between the rates of apoptosis and Bcl-2/Bax expression.

CONCLUSIONLead may induce apoptosis in rat brain neural cells through the down regulation of bcl-2 and the up regulation of bax gene expression.

Animals ; Apoptosis ; Brain ; cytology ; drug effects ; metabolism ; Female ; Male ; Organometallic Compounds ; administration & dosage ; pharmacology ; Proto-Oncogene Proteins ; biosynthesis ; Proto-Oncogene Proteins c-bcl-2 ; biosynthesis ; Rats ; Rats, Sprague-Dawley ; bcl-2-Associated X Protein

OBJECTIVE: To investigate the effect of intranasal glucocorticoids treatment on the expression of c-fos and c-myc nasal polyps. METHOD: Immunohistochemistry method was used to determine c-fos and c-myc expression in nasal polyps from patients with topical steroids treatment for 10-12 weeks and untreated patients. RESULT: The rate of c-fos expressing cases was 15% and the rate of c-myc expressing cases was 20% in nasal polyps from topical steroid treated patients, but in untreated patients, the rate of c-fos expressing cases was 80% and the rate of c-myc expressing cases was 85%. There were significant differences between two groups (P < 0.01). The c-fos and c-myc expression was remarkably downregulated in nasal polyps from topical steroid treated patients compared to untreated patients. CONCLUSION The results show that glucocorticoids may induce cell apoptosis in nasal polyps by depressing the c-fos and c-myc expression.
Adult ; Budesonide ; administration & dosage ; therapeutic use ; Case-Control Studies ; Female ; Glucocorticoids ; therapeutic use ; Humans ; Male ; Nasal Polyps ; drug therapy ; metabolism ; Proto-Oncogene Proteins c-fos ; metabolism ; Proto-Oncogene Proteins c-myc ; metabolism

Chronic myelogenous leukemia (CML) is a myeloproliferative disorder from hematopoietic stem cell disorder characterized by the consecutive expression of bcr-abl gene, and the translation product of which has enhanced tyrosine kinase activity and can activate a series of downstream signal transduction proteins and results in the occurence of CML. Although the application of imatinib (IM) makes nearly all patients with CML in chronic phase achieve a complete hematologic remission, and 90%of those treated in the early chronic phase achieve a complete cytogenetic remission, but the development of resistance to IM in the course of treatment and even in the beginning of the treatment forced people to develop new agents and to combine the new agents with IM in order to achieve better therapeutic result. This article reviews the experimental advances of targeted therapeutics in CML recent years.
Antineoplastic Agents ; administration & dosage ; Benzamides ; Drug Delivery Systems ; Humans ; Imatinib Mesylate ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive ; drug therapy ; Piperazines ; administration & dosage ; Protein Kinase Inhibitors ; administration & dosage ; Protein-Tyrosine Kinases ; antagonists & inhibitors ; Proto-Oncogene Proteins c-abl ; biosynthesis ; genetics ; Proto-Oncogene Proteins c-bcr ; biosynthesis ; genetics ; Pyrimidines ; administration & dosage

AIMTo investigate the inhibitory effects and mechanism of action of isoliensinine (IL) on the proliferation of porcine coronary arterial smooth muscle cells (CASMCs) induced by phenylephrine (Phen) and its mechanisms of action.

METHODSMTT assay, immunohistochemical method and Western blotting were adopted.

RESULTSIL (0.03 - 3 micromol x L(-1)) could inhibit the CASMCs proliferation induced by Phen (0.1 micromol x L(-1)) in a concentration-dependent manner. IL (0.1 micromol x L(-1)) antagonized Phen-induced overexpression of PDGF-beta and bFGF from 0.545 +/- 0.026 and 0.47 +/- 0.03 to 0.458 +/- 0.019 and 0.376 +/- 0.017 (P < 0.01 , P < 0.01). IL (0.1 micromol x L(-1)) also decreased c-fos, c-myc and hsp70 overexpression induced by Phen from 0.57 +/- 0.04, 0.44 +/- 0.04 and (173 +/- 36)% to 0.46 +/- 0.05, 0.372 +/- 0.021 and (115 +/- 35)% respectively (P < 0.01, P < 0.01, P < 0.01).

CONCLUSIONIL exerted antiproliferative effect on CASMCs induced by phenylephrine, and its mechanisms were related to decrease the overexpression of growth factors (PDGF-beta, bFGF), protooncogene (c-fos, c-myc) and hsp70.

Animals ; Cell Proliferation ; drug effects ; Cells, Cultured ; Coronary Vessels ; cytology ; Dose-Response Relationship, Drug ; Fibroblast Growth Factor 2 ; metabolism ; HSP70 Heat-Shock Proteins ; metabolism ; Isoquinolines ; administration & dosage ; isolation & purification ; pharmacology ; Muscle, Smooth, Vascular ; cytology ; Nelumbo ; chemistry ; Phenylephrine ; antagonists & inhibitors ; Plants, Medicinal ; chemistry ; Proto-Oncogene Proteins c-fos ; metabolism ; Proto-Oncogene Proteins c-myc ; metabolism ; Proto-Oncogene Proteins c-sis ; metabolism ; Swine

OBJECTIVETo retrospectively analyze the treatment outcomes and side effects of childhood acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) or ATRA + arsenic trioxide (As2O3).

METHODSFrom 1992 to 2006, 45 patients with newly diagnosed APL were enrolled. All of them were PML-RAR alpha positive. 24 patients were induced with ATRA (group A) and 21 with ATRA + As2O3 (group B). The remission rate and side effects were observed.

RESULTS1) 19 (79.2%) patients in group A achieved CR, while 21(100%) patients in group B achieved CR. The CR rate in group A was lower than that in group B (P=0.027). 2) The recovery time of coagulation parameters and PLT count in group B was shorter than that in group A. 3) The overall survival (OS) and event-free survival(EFS) in group A were 77.8% and 66.9% at 41 months of follow-up, and in group B were 100% and 100% respectively at 34 months of followup. Group A had a significant lower EFS (P=0.0357)than group B. 4) The time of PML-RAR alpha fusion gene converting to negative in group A was longer (P=0.026) than that in group B.

CONCLUSIONSATRA + As2O3 for patients with newly diagnosed childhood APL is a feasible treatment with higher CR rate, less side effects and longer long-term survival.

Adolescent ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Arsenicals ; administration & dosage ; Child ; Child, Preschool ; Female ; Follow-Up Studies ; Humans ; Leukemia, Promyelocytic, Acute ; drug therapy ; genetics ; Male ; Oncogene Proteins, Fusion ; genetics ; Oxides ; administration & dosage ; Prognosis ; Retrospective Studies ; Treatment Outcome ; Tretinoin ; administration & dosage