Epigenetic therapy with chidamide alone or combined with 5­azacitidine exerts antitumour effects on acute myeloid leukaemia cells in vitro.

Chidamide, a selective histone deacetylase inhibitor, has antitumour effects. 5­azacitidine (5­AZA), a hypomethylating agent, is effective in treating acute myeloid leukaemia (AML) and myelodysplastic syndrome. However, to the best of our knowledge, the effect of chidamide and 5­AZA on AML cell lines has not been fully investigated. In the present study, the antileukaemia activity of chidamide, alone and in combination with 5­AZA, was assessed on different subtypes of AML cell lines (M1­M5) and primary samples from several patients with AML in vitro. The results indicated that the proliferation of leukaemia cells was significantly and dose­dependently inhibited by chidamide and 5­AZA alone or in combination. The combination also had marked synergistic effects to induce apoptosis of AML cells. The apoptosis of leukaemia cells was induced via downregulation of BCL­2 and myeloid­cell leukemia 1 (MCL­1) levels. Of note, chidamide also degraded the MCL­1 protein in venetoclax­resistant U937 cells, in which the MCL­1 protein is upregulated. In addition, chidamide was able to induce myeloid differentiation (with CD11b upregulation) of AML cell lines or monocytic/dendritic differentiation (with CD86 upregulation) of primary cultured cells from several patients with AML. Chidamide was also able to promote the differentiation of the venetoclax­resistant U937 cell line by upregulating CD11b expression. In conclusion, chidamide alone or combined with 5­AZA may be an effective therapy for AML.

[The protective effect of angiopoietin-1 on early acute lung injury induced by oleic acid in mice].

OBJECTIVE: To observe the protective effects of angiopoietin-1 on acute lung injury (ALI) induced by oleic acid at early stage in mice and to investigate the expression changes of vascular endothelial growth factor (VEGF). METHODS: Ninety-six female BALB/c mice were randomly divided into 4 groups (n = 24). The control group was given normal saline (0.9 ml/kg) intravenously. The ALI group was treated with oleic acid (0.9 ml/kg) intravenously to induce ALI. In the control + angiopoietin-1 group, the mice were injected intraperitoneally with angiopoietin-1 (312.5 microg/kg) 4 h after normal saline administration. In the ALI + angiopoietin-1 group, the mice were injected intraperitoneally with angiopoietin-1 (312.5 microg/kg) 4 h after oleic acid treatment. Then 8 h later 12 mice were randomly taken from each group for bronchoalveolar lavage fluid (BALF) analysis including the protein level, cell count and differentials, and the level of IL-6 and VEGF. The wet/dry weight (W/D) of the right lung, the level of IL-6 and VEGF in serum, pathological changes of the left lung and VEGF expressions in lung tissues were examined for the rest of mice in each group. The level of IL-6 and VEGF in both serum and BALF were measured by enzyme-linked-immunosorbent assay (ELISA). Pathological changes of the lung tissue were examined and scored with light microscrope. The expression of VEGF was immunohistochemically detected in lung tissues as integrated optic density (A) measured with Image Pro Plus 5.1 software. RESULTS: The W/D, the protein level, the tota1 cel1 number and differential of polymorphonuclear leukocytes in BALF, the IL-6 level in both serum and BALF, the VEGF level in serum were significantly decreased in the ALI + angiopoietin-1 group [4.09 +/- 0.14, (176 +/- 13) microg/ml, (34.4 +/- 4.1) x 10(4)/L, (19.85 +/- 3.93) x 10(3)/L, (1318 +/- 62) pg/ml, (652 +/- 17) pg/ml, (48 +/- 5) pg/ml] as compared to the ALI group [5.32 +/- 0.51, (227 +/- 12) microg/ml, (42.2 +/- 5.2) x 10(4)/L, (26.22 +/- 2.22) x 10(3)/L, (1510 +/- 117) pg/ml, (744 +/- 13) pg/ml, (74 +/- 5) pg/ml, t = 8.16, 9.92, 4.02, 4.88, 5.03, 19.18, 14.81 respectively, all P < 0.01]. Pathological scores in the ALI + angiopoietin-1 group (1.84 +/- 0.12) improved as compared to those in the ALI group (3.44 +/- 0.21, t = 24.16, P < 0.01), and the VEGF level in BALF of the ALI + angiopoietin-1 group (179 +/- 15) pg/ml was higher than that of the ALI group (140 +/- 20) pg/ml (t = 5.31, P < 0.01). The expressions of VEGF in the lung tissues indicated by A (549 +/- 72) in the ALI + angiopoietin-1 group were higher than those in the ALI group (342 +/- 85, t = 5.22, P < 0.01), but lower than those in the control group (768 +/- 111) (t = 5.35, P < 0.01). The above measurements of the control + angiopoietin-1 group showed no difference compared to the control group (t = 0.12, 0.53, 1.27, 2.28, 1.18, 0.34, 0.13, 0.25, 0.58, 0.69 respectively, all P > 0.05). Statistical analysis was done using SPSS 10.0 software. Data are expressed as mean +/- s, with statistical significance declaved for probility valaes < 0.05. LSD-t test was used for group comparison. One-factor ANOVA was used for mdlti-group comparison. CONCLUSIONS: Angiopoietin-1 is effective in relieving the severity of acute lung injury induced by oleic acid in mice at early stage and up-regulating VEGF expression in BALF and lung tissues but down-regulating VEGF expression in serum. The results suggest that angiopoietin-1 may exert beneficial effects on ALI.

Decitabine in the Treatment of Acute Myeloid Leukemia and Myelodysplastic Syndromes, Which Combined with Complex Karyotype Respectively.

BACKGROUND: We conducted a study exploring the clinical safety and efficacy of decitabine in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS), combined with a complex karyotype. MATERIALS AND METHODS: From April 2009 to September 2013, a total of 35 patients with AML/MDS combined with a complex karyotype diagnosed in the First Affiliated Hospital of Soochow University were included for retrospective analysis. All patients were treated with decitabine alone (20 mg/m2 daily for 5 days) or combination AAG chemotherapy (Acla 20 mg qod*4d, Ara-C 10 mg/m2 q12h*7d, G-CSF 300 µg qd, the dose of G-CSF adjusted to the amount in blood routinely). RESULTS: In 35 patients, 15 exhibited a complete response (CR), and 6 a partial response (PR), the overall response rate (CR+PR) being 60% (21 of 35). Median disease-free survival was 18 months and overall survival was 14 months. In the 15 MDS patients with a complex karyotype, the CR rate was 53.3% (8 of 15); in 20 AML patients with complex karyotype, the overall response rate was 65% (13 of 20). The response rate of decitabine alone (22 cases) was 56.5% (13 of 22), while in the combination chemotherapy group (13 cases), the effective rate was 61.5% (8 of 13)(P>0.05). There are 15 patients with chromosome 7 aberration, after treatment with decitabine, 7 CR, 3 PR, overall response rate was 66.7% (10 of 15). Of 18 patients with 3 to 5 kinds of chromosomal abnormalities, 66.7% demonstrated a response; of 17 with more than 5 chromosomal abnormalities, 52.9% had a response. In the total of 35 patients, with one course (23 patients) and ≥two courses (12 patients), the overall response rate was 40.9% and 92.3% (P<0.05). Grade III to IV hematological toxicity was observed in 27 cases (75%). Grade III to IV infections were clinically documented in 7 (20%). Grades I to II non-hematological toxicity were infections (18 patients), haematuria (2 patients), and bleeding (3 patients). With follow-up until September 2013, 7 patients were surviving, 18 had died and 10 were lost to follow-up. In the 6 cases who underwent allogeneic hematopoietic stem cell transplantation (HSCT) all were still relapse-free survivors. CONCLUSIONS: Decitabine alone or combination with AAG can improve outcome of AML/MDS with a complex karyotype, there being no significant difference decitabine in inducing remission rates in patients with different karyotype. Increasing the number of courses can improve efficiency. This approach with fewer treatment side effects in patients with a better tolerance should be employed in order to create an improved subsequent chance for HSCT.

Comparison of clinical efficacy of three different neoadjuvant approaches (chemotherapy combined vaginal intracavitary irradiation, neoadjuvant chemotherapy alone or radiotherapy) combined with surgery for patients with stage Ib2 and IIa2 cervical cancer.

A total of 285 patients with stage Ib2 and IIa2 cervical cancer were categorized into three groups, and received preoperative neoadjuvant chemotherapy combined with vaginal intracavitary irradiation, neoadjuvant chemotherapy alone or radiotherapy, respectively. The effective rate of 70.6 % in group 1 was much higher than 41.4% in group 2 (P=0.000) and 46.9 % in group 3 (P=0.000); The percentage of patients receiving postoperative adjuvant therapy was 44.1% in group 1, much lower than 67.8% in group 2 (P=0.001) and 64.6% in group 3 (P=0.004); The percentage of patients with no postoperative risk factor in group 1 was 52.0%, much higher than 32.2% in group 2 (P=0.006) and 35.4% in group 3 (P=0.019); The occurrence rate of surgery-related complications in groups 1, 2 and 3 were 29.4%, 28.7%, and 33.3%, respectively, with no statistical differences among the groups (P=0.981). Regarding preoperative neoadjuvant complications, none were obvious in group 3, while occurrence rates of myelosuppression in groups 1 and 2 were 89.1% and 86.6%, of nausea and vomitting were 78.4% and 78.2%, but without significant differences (all P>0.05). Among 166 patients who received postoperative adjuvant therapy in the three groups, the occurrence rates were: 65.4%, 64.3% and 61.1% respectively for myelosuppression; 42.3%, 38.1%, and 38.9% for nausea and vomiting; 9.6%, 9.5% and 9.7% for urocystitis; and 63.5%, 69.0% and 65.3% enteritis and rectitis. There were no statistically significant differences among them (all P>0.05). The five-year disease-free survival rates (DFS) in groups 1, 2, 3 were 78.3%, 75.1%, 80.9%, respectively; the five-year overall survival rates (OS) were 81.4%, 78.2%, and 81.1%, respectively. The five-year OS of 166 patients receiving postoperative in the three groups were 72.4%, 69.5%, and 71.8%, respectively, with no significant variation (all P>0.05). Although there were no differences among three groups in DFS and OS, preoperative neoadjuvant chemotherapy combined with intracavitary radiotherapy may increase the effective rate and the percentage of patients with no postoperative risk factors and decrease the percentage of patients receiving postoperative adjuvant therapy, thereby decreasing complications indirectly and increasing quality of life.