This study was purposed to characterize the genomic distribution of the binding sites for AML1-ETO fusion protein on chromosome 2, 9 and 19, and to further gain insights into the characteristics of transcriptional regulation by AML1-ETO in acute myeloid leukemia so as to provide theoretical basis for the development of targeted therapy and optimization for treatment. Chromatin immunoprecipitation (ChIP) coupled with high density tiling arrays (chip), also known as ChIP-chip, was utilized in this study. ChIP-DNA enriched by an anti-ETO antibody and total genomic DNA of Kasumi cells were hybridized to tiling arrays, tiled through chromosome 2, 9 and 19. The ChIP enriched regions were identified using a model based analytical tool (MAT). Genomic distribution of the ChIP regions was analyzed using publicly available CEAS web server. The Gene Ontology (GO) enrichment analysis was performed to excavated the biological significance. The results indicated that a total of 588 enriched regions were identified on chromosome 2, 9 and 19 by the anti-ETO antibody. A number of the identified regions were located within enhancers (48.86%) or introns (37.35%), much smaller fractions were within proximal promoters (5.96%) or exons (5.49%). Functional enrichment analysis showed that cell proliferation and signal transduction biological pathways were enriched in potential genes of AML-ETO. It is concluded that half of the AML1-ETO binding sites are located within known transcriptional regulatory regions (promoter, 5' UTR and enhancer), while almost another half were within the sequences which were not previously reported as regulatory regions. The potential target molecular network of AML1-ETO is involved in several essential biological processes.
Base Sequence ; Binding Sites ; Cell Line, Tumor ; Chromosomes, Human, Pair 21 ; Chromosomes, Human, Pair 8 ; Core Binding Factor Alpha 2 Subunit ; genetics ; metabolism ; DNA-Binding Proteins ; metabolism ; Genome, Human ; Humans ; Leukemia, Myeloid, Acute ; genetics ; Oncogene Proteins, Fusion ; genetics ; metabolism ; Promoter Regions, Genetic ; RUNX1 Translocation Partner 1 Protein ; Translocation, Genetic

OBJECTIVETo observe the effect of the immunonanoparticles loaded with adriamycin in reversing multidrug resistance (MDR) in liver cancer in a nude mouse model and explore the possible mechanisms.

METHODSThe cytotoxicity of adriamycin, adriamycin-loaded nanoparticles, and adriamycin-loaded immunonanoparticles was assessed in a nude mouse model bearing implant tumors of adriamycin-resistant hepatoma cell line SMMC-7721/ADM. The concentration of adriamycin in the tumor tissue was determined.

RESULTSAdriamycin-loaded immunonanoparticles showed significantly stronger cytotoxicity against the implant tumors of SMMC-7721/ADM than adriamycin-loaded nanoparticles and adriamycin. Administration of adriamycin-loaded immunonanoparticles resulted in significantly higher drug concentrations in the tumor tissue than adriamycin-loaded nanoparticles and adriamycin.

CONCLUSIONAdriamycin-loaded immunonanoparticles may reverse the MDR of liver cancers in vivo probably resulting from the close binding of the particles with the tumor cells to produce a high local concentration of adriamycin in the tumors.

Animals ; Cell Line, Tumor ; Doxorubicin ; chemistry ; metabolism ; pharmacology ; therapeutic use ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Female ; Humans ; Immunoconjugates ; chemistry ; Liver Neoplasms ; drug therapy ; metabolism ; pathology ; Mice ; Mice, Nude ; Nanoparticles ; chemistry

OBJECTIVETo study the therapeutic effects of Nexavar on liver cancer and its relation to the expressions of Ki-67 and CD34.

METHODSTwenty-eight patients with liver cancer were treated with Nexavar. The therapeutic efficacy of Nexavar on liver cancer was observed. Liver cancer tissues were examined for the expressions of Ki-67 and CD34 by immunohistochemistry. Microvessel density (MVD) was calculated according to the expression of CD34.

RESULTSOf 28 patients, none achieved a complete response (CR), 12 had a partial response (PR), 7 had stable disease (SD), and 9 progressive disease (PD). The efficacy of Nexavar was associated significantly with Ki-67 expression. The mean MVD count was 346.03-/+146.98 in PR patients, and 89.14-/+45.66 in PD patients. There was a significant difference in MVD between PR and PD patients.

CONCLUSIONThere is a better efficacy of Nexavar in treatment of liver cancer in the patients who had Ki-67-positive expression and high MVD count.

Adult ; Aged ; Antigens, CD34 ; metabolism ; Antineoplastic Agents ; therapeutic use ; Female ; Humans ; Ki-67 Antigen ; metabolism ; Liver Neoplasms ; drug therapy ; metabolism ; Male ; Middle Aged ; Niacinamide ; analogs & derivatives ; therapeutic use ; Phenylurea Compounds ; therapeutic use

OBJECTIVETo investigate the apoptosis of hepatocytes and the expression of apoptosis-regulating genes during the donor liver ischemia and reperfusion injury in rat orthotopic liver transplantation (OLT).

METHODSSeventy-two male SD rats were randomly divided into sham operation group and transplantation group. Using Ringer's lactate solution as the perfusing and preserving solution, the grafts were preserved for 4 h before orthotopic transplantation. At 1, 6 and 24 h after the reperfusion, the recipients were sacrificed, and the serum ALT and AST levels were measured; the changes of hepatocyte apoptosis was detected by TUNEL assay, and the protein expressions of the apoptosis-regulating genes were measured by flow cytometry.

RESULTSSerum ALT and AST levels were significantly higher in transplantation group than in the control group after reperfusion. In comparison with the control group, the rats in the transplantation group showed significantly increased apoptosis index in the livers, lowered Bcl-2 levels and increased FasL levels after the transplantation, especially at 6 h after liver reperfusion (P<0.01).

CONCLUSIONThe donor liver ischemia and reperfusion injury can promote hepatocyte apoptosis, which may be related with the high expression of Bcl-2 gene and low expression of FasL after reperfusion injury in rats with orthotopic liver transplantation.

Animals ; Apoptosis ; Fas Ligand Protein ; metabolism ; Gene Expression Regulation ; Hepatocytes ; cytology ; metabolism ; Liver ; metabolism ; Liver Transplantation ; adverse effects ; Male ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Rats, Sprague-Dawley ; Reperfusion Injury ; metabolism ; pathology

This study was to investigate the relationship between the CD34(+)CD38(-) cell population and its proportion in G(0) phase of de novo AML non-M(3) at diagnosis and the clinical and experimental characteristics. The flow cytometry was used to detect the expression of the cell surface antigen CD34 and CD38 in the bone marrow mononuclear cells (MNC) of the AML non-M(3) at diagnosis and investigate the cell cycle of the subpopulations, and then the relationships between the proportion of CD34(+)CD38(-)cell population and its G(0) state and the complete remission (CR) rate after the first induction chemotherapy was analyzed. The results showed that the proportion of the CD34(+)CD38(-) cell population and its G(0) phase had no relationship with the karyotypes and WBC count at new diagnosis and the Flt3/ITD status, but correlate with the blasts in the bone marrow after the first course induction chemotherapy. The proportion of the CD34(+)CD38(-) cells in patients who have visible blasts in the bone marrow at day 7 after completion of the first course induction chemotherapy was (12.47 ± 26.26)%, but the counterparts was (2.62 ± 7.20)% in the group of patients whose bone marrow had no visible blasts (p = 0.031). The proportion of the CD34(+) cell population in patients who had visible blasts in the bone marrow at day 1 after completion of the first course induction chemotherapy was (17.40 ± 21.20)%, yet the proportion of the CD34(+) cell populations was (5.64 ± 6.96)% in the patients who had no visible blasts in the bone marrow (p = 0.001). The proportion of the CD34(+)CD38(-) cell populations in the patients who achieved CR after the first course induction chemotherapy was (2.51 ± 9.72)%, which was lower than the proportion (24.92 ± 27.04%) of the non-CR patients (p = 0.001). Furthermore, the proportion (1.60 ± 4.82%) of the CD34(+)CD38(-) cell population in the AML non-M(2b) CR patients was more obviously lower than that in the non-CR patients (p < 0.001). In univariate analysis, whether or not achieved CR after the first course induction chemotherapy correlated with age (p = 0.022), the proportion of the CD34(+)CD38(-) cell population (p = 0.008) and the proportion of the visible blasts in the bone marrow at day 7 after induction therapy (p = 0.011). Multivariate analysis showed that only the proportion of the CD34(+)CD38(-) cells had correlation tendency with CR rate. It is concluded that the proportion of the CD34(+)CD38(-) cells in bone marrow of de novo AML non-M(3) is a prognostic factor to anticipate the CR rate of the first course for induction therapy.
ADP-ribosyl Cyclase 1 ; Adolescent ; Adult ; Antigens, CD34 ; Bone Marrow Cells ; cytology ; Cell Cycle ; Female ; Flow Cytometry ; Humans ; Leukemia, Myeloid, Acute ; diagnosis ; therapy ; Male ; Middle Aged ; Prognosis ; Remission Induction ; Young Adult

OBJECTIVETo prepare nanospheres coupled with the anti-human liver cancer monoclonal antibody HAb18 and evaluate its immunoreactivity and antitumor effects.

METHODSThe nanosphere coupled with the antibody was prepared by intermolecular cross-linking the anti-human liver cancer monoclonal antibody, HAb18, with human serum albumin nanospheres containing ADM [termed HAS(ADM)-NS] via a new hetero-bifunctional cross-linker SPDP. Condensation test and immunofluorescence assay were used to evaluate the immunoreactivity of the nanospheres, and specific binding of HAb18-HAS(ADM)-NS with liver cancer cell line SMMC-7721 was observed with optical and electron microscopes. The specific cytotoxic effects on the target cells were evaluated in vitro by MTT assay. HAb18-HAS(ADM)-NS, HAS(ADM)-NS and ADM were injected separately into nude mice bearing human liver carcinoma to evaluate the inhibitory activity of HAb18-HAS(ADM)-NS in vivo.

RESULTSThe immunoreactivity of HAb18-HAS(ADM)-NS was well preserved. HAb18-HAS(ADM)-NS could bind specifically with the SMMC-7721 cells. The IC(50) of HAb18-HAS(ADM)-NS against SMMC-7721 cells was 44.6 microg/ml, lower than that of HAS(ADM)-NS (345.5 microg/ml) and ADM (365.5 microg/ml). The inhibition rate of HAb18-HAS(ADM)-NS on the growth of liver cancer xenografts was significantly higher than that of HAS(ADM)-NS and ADM (P<0.001).

CONCLUSIONHAb18-HAS(ADM)-NS has immunoreactivity and can actively and specifically target the liver cancer cells. The antitumor activity of HAb18-HAS(ADM)-NS is significantly higher than that of HAS(ADM)-NS and ADM.

Animals ; Antibodies, Monoclonal ; administration & dosage ; immunology ; Antibodies, Neoplasm ; immunology ; Antineoplastic Combined Chemotherapy Protocols ; immunology ; therapeutic use ; Cell Line, Tumor ; Doxorubicin ; administration & dosage ; immunology ; Female ; Humans ; Immunotoxins ; administration & dosage ; immunology ; Liver Neoplasms ; drug therapy ; immunology ; pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; Nanospheres ; administration & dosage ; Treatment Outcome ; Xenograft Model Antitumor Assays ; methods

OBJECTIVETo investigate the feasibility and safety of adult-to-adult living-related donor liver transplantation using a right lobe graft.

METHODSThe clinical data of 2 cases of living-related donor liver transplantation performed between July, 2010 and November, 2010 were analyzed.

RESULTSLiver transplantation was performed using a right lobe graft including the middle hepatic vein in one case and a right lobe graft without the middle hepatic vein in the other. The ratio of graft volume to standard liver volume was 46.2% and 47.3% in the two cases, with GR/WR of 0.83 and 0.80, and donor residue liver of 42.1% and 39.5%, respectively. The donor operation lasted for 6.5 h and 5 h in the two cases with blood loss of about 200-250 ml without blood transfusion. The donors recovered uneventfully without any surgical complications, whose liver function was normal 7 days after the operation, and were discharged 14 days and 16 days after the surgery, respectively. The recipient operation lasted for 8 h and 7 h with blood loss of about 800-1000 ml. The right hepatic vein, hepatic artery, portal vein and bile duct reconstruction were performed by end-to-end anastomoses in the 2 recipients. Bile duct anastomosis stricture occurred in the first recipient 2 months after transplantation and was treated with percutaneous transhepatic cholangiography and drainage. The second recipient recovered smoothly without any complications. The recipients have so far survived 9 months and 5 months, respectively.

CONCLUSIONAdult-to-adult living-related donor liver transplantation is a safe and effective option for treatment of end-stage liver diseases in the context of cadaveric liver graft shortage.

Adult ; Female ; Hepatectomy ; Humans ; Liver Cirrhosis ; surgery ; Liver Neoplasms ; surgery ; Liver Transplantation ; methods ; Living Donors ; Male ; Middle Aged ; Retrospective Studies