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Huang J.,Aurora University | Huang J.,Institute of Hematology and Blood Disease Hospital | Wang S.,Aurora University | Wang S.,Xiamen University | And 5 more authors.
Molecular Cancer | Year: 2013

Background: Elevated expression of erbB3 receptor has been reported to induce resistance to therapeutic agents, including trastuzumab in erbB2-overexpressing breast cancer. Our recent studies indicate that erbB3 interacts with both erbB2 and IGF-1 receptor to form a heterotrimeric complex in trastuzumab-resistant breast cancer cells. Herein, we investigate the antitumor activity of MM-121/SAR256212, a fully human anti-erbB3 antibody (Ab), against two erbB2-overexpressing breast cancer cell lines resistant to trastuzumab.Methods: MTS-based proliferation assays were used to determine cell viability upon treatment of trastuzumab and/or MM-121/SAR256212. Cell cycle progression was examined by flow cytometric analysis. Western blot analyses were performed to determine the expression and activation of proteins. Tumor xenografts were established by inoculation of the trastuzumab-resistant BT474-HR20 cells into nude mice. The tumor-bearing mice were treated with trastuzumab and/or MM-121/SAR256212 via i.p injection to determine the Abs' antitumor activity. Immunohistochemical analyses were carried out to study the Abs' inhibitory effects on tumor cell proliferation and induction of apoptosis in vivo.Results: MM-121 significantly enhanced trastuzumab-induced growth inhibition in two sensitive and two resistant breast cancer cell lines. MM-121 in combination with trastuzumab resulted in a dramatic reduction of phosphorylated erbB3 (P-erbB3) and Akt (P-Akt) in the in vitro studies. MM-121 combined with trastuzumab did not induce apoptosis in the trastuzumab-resistant cell lines under our cell culture condition, rather induced cell cycle G1 arrest mainly associated with the upregulation of p27kip1. Interestingly, in the tumor xenograft model established from the trastuzumab-resistant cells, MM-121 in combination with trastuzumab as compared to either agent alone dramatically inhibited tumor growth correlated with a significant reduction of Ki67 staining and increase of cleaved caspase-3 in the tumor tissues.Conclusions: The combination of MM-121 and trastuzumab not only inhibits erbB2-overexpressing breast cancer cell proliferation, but also promotes the otherwise trastuzumab-resistant cells undergoing apoptosis in an in vivo xenografts model. Thus, MM-121 exhibits potent antitumor activity when combined with trastuzumab under the studied conditions. Our data suggest that further studies regarding the suitability of MM-121 for treatment of breast cancer patients whose tumors overexpress erbB2 and become resistant to trastuzumab may be warranted. © 2013 Huang et al.; licensee BioMed Central Ltd.

Yang L.,Chinese Academy of Sciences | Liu L.,Chinese Academy of Sciences | Wang J.,Chinese Academy of Sciences | Wang J.,Institute of Hematology and Blood Disease Hospital | And 6 more authors.
Leukemia and Lymphoma | Year: 2011

Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCRrestriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.193.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.064.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.250.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.410.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.400.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.9740.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.120.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate-related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese. © 2011 Informa UK, Ltd.

Li B.,Institute of Hematology and Blood Disease Hospital
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2012

To analyze the clinical features and survival time in primary myelodysplastic syndromes (MDS) patients accompanied with immunological abnormalities. The clinical information, laboratory findings and survival time in 194 untreated primary MDS patients with complete immunological laboratory tests or a past history of autoimmune disease were analyzed retrospectively. There were 37/194 cases (19.07%) with autoimmune abnormalities, including 16/194 (8.25%) with autoimmune disease and 21/194 asymptomatic cases (10.82%) with serologic immunological abnormalities only. There was significant differences in the distribution of age < 60 years old, female, CD4(+)T-cell/CD8(+)T-cell ration < 1 and trisomy 8 (P < 0.05) between the cases with autoimmune disease and without autoimmune abnormalities. The former had a higher 2-year OS, but there was no significance (P = 0.065). There was no significant differences in the distribution of age, MDS-subtype, IPSS risk groups, haemoglobin, absolute neutrophil count, platelets count, the severity of anemia and neutropenia, high level of serologic TNF, chromosomal abnormalities, cytogenetic risk groups and bone marrow cellularity (P > 0.05). MDS patients with autoimmune disease are mainly female and younger than 60 years old, with high proportion of trisomy 8 and better prognosis.

Liu X.,Institute of Hematology and Blood Disease Hospital
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2013

To evaluate the efficacy and safety of antifungal prophylaxis of itraconazole in patients with acute myeloid leukemia (AML) to probe the relationship of the antifungal effect and the adverse events with serum concentration. From April 2009 to May 2011, a total of 310 courses from 112 patients referred to our institute were enrolled in this study; of them, 297 courses were eligible for analysis. Eligible cases were randomized into oral group and injection/oral group according to different chemotherapy of induction and consolidation. Blood samples were collected at different time points for measurements of serum itraconazole levels. The morbidity of IFI and the adverse events were analyzed. The morbidities of IFI in injection/oral and oral groups were 10.1% and 20.9%, respectively (P=0.010). 7 and 9 cases in injection/oral and oral groups, respectively were withdrawn from the study because of adverse events, and the difference between these two groups was of no significance. Serum itraconazole levels of injection/oral and oral groups were 672(299-1097) μg/L and 534(210-936) μg/L, respectively (P<0.01). Antifungal prophylaxis with itraconazole in AML patients was effective and safe. Prophylactic effect with injection/oral itraconazole was superior to oral itraconazole solution; moreover, prophylactic effect of itraconazole was highly correlated with its serum level.

Ruan M.,Institute of Hematology and Blood Disease Hospital
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2012

Acute myeloblastic leukemia (AML) accounts for 15 to 25 percent of childhood acute leukemias. Cytogenetic information is important for diagnosis, classification and prognosis of AML. Our aim was to analyze the relationship between karyotypic characteristics and prognosis of childhood AML. According to karyotypic characteristics, 128 newly diagnosed children AML were separated into 4 subgroups: patients with t(15;17) (group APL), patients with t(8;21)/inv(16) (group A), patients with -7/t(9;22)/complex karyotypes (group C) and the others (group B). Prognoses of these patients were analyzed. The ages ranged from 1 to 16 years with the mean age of 7 years. 85 boys and 43 girls were included in this study. The 4-year event-free survival (EFS) and overall survival (OS) rates were (55.9 ± 4.7)% and (69.3% ± 4.5)%, respectively. The 4-year EFS and OS of non-M(3)-AML patients were (49.9 ± 5.2)% and (57.1 ± 6.0)%, respectively. The probabilities of 4-year EFS of the four subgroups were (72.2 ± 1.1)%, (66.3 ± 7.7)%, (38.5 ± 9.1)% and (20.1 ± 12.3)%, respectively (P = 0.000). The probabilities of 4-year OS were (92.6 ± 5.1)%, (69.4 ± 7.9)%, (55.6 ± 8.6)% and (30.0 ± 12.3)%, respectively (P = 0.000). Cytogenetic aberrations seen in pediatric AML had a significant impact on prognosis.

Li Z.Q.,Institute of Hematology and Blood Disease Hospital
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2012

To explore the diagnosis and differential diagnosis of refractory cytopenia of children (RCC) according to WHO classification, and discuss the relationship between the cytology reviewed by hematologists and histology reviewed by pathologists. We selected 50 non-severe aplastic anemia cases from 2007 - 2010 in our hospital and collected clinical data. Experienced hematologists and pathologists evaluated bone marrow biopsy and smear respectively. Of 50 cases, 23 were male and 27 female (M:F = 1:1.17), the median age at diagnosis was 9 years (ranged from 3 to 14 years). 5 patients had disagreement of diagnosis between hematologists and pathologists. In 3 cases hematologists diagnosed as aplastic anemia (AA) and pathologists as RCC, 2 cases vice versa. The final diagnoses of 50 patients reached consensus between hematologists and pathologists were AA 16 cases, RCC 34 cases including 8 refractory cytopenias with multilineage dysplasia (RCMD) cases. All 16 cases AA showed severe hypocellularity. Only 4 cases (25.00%) RCC showed severe hypocellularity, 19 cases (73.08%) RCC showed mild hypocellularity and 3 cases (11.54%) RCC were normal hypocellularity. Our results suggests that RCC was not rare in China. The main feature of RCC was dysplasia because of absence of increased blast. RCC was easily confused with AA. The main points of differential were present dysplastic changes of megakaryocyte best appreciated by the hematologists and morphologists and abnormal location of hematopoietic easily observed by pathologists. Overall, cytology and histology were complementary in the investigation of RCC and AA, because of sometimes one might give information that not be given from the other.

PubMed | Institute of Hematology and Blood Disease Hospital
Type: Journal Article | Journal: Zhongguo yi xue ke xue yuan xue bao. Acta Academiae Medicinae Sinicae | Year: 2016

TET2 gene is a member of TET oncogene family. It has been reported as a tumor suppressor gene with important roles in myelopiesis. Recent studies have shown that TET2 protein takes part in demethylation by converting 5-methylcytosine (5-mc) into 5-hydroxymethylcytosine (5-hmc). Somatic TET2 inactivation leads to abnormal myelopiesis and myeloid malignancies. In this review,the structure and function of TET2 and the relationship between TET gene mutation and myeloid malignancies are summarized.

Han M.,Institute of Hematology and Blood Disease Hospital
Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2015

OBJECTIVE: To observe the clinical characteristics of infections in adult acute leukemia (AL)patients during chemotherapy in hospital, and identify the risk factors for infections.METHODS: A retrospective study of patients with AL who underwent chemotherapy between July 2010 and Dec 2014 in the First Affiliated Hospital of Xiamen University was conducted. Clinical features and risk factors for infections were analyzed.RESULTS: 191 patients with AL received a total of 728 courses of chemotherapies. During these admissions, 385(52.9%) infections episodes occurred. The common infections sites were lower respiratory tract infection(36.3%,153/374), bloodstream infection(17.1%, 64/374), oral infection(13.6%,51/374), and perianal infection(13.4%, 50/374). 164 strains of pathogenic bacteria were detected. Gram- negative bacteria were recorded in 59.1% of documented pathogens, and Gram- positive bacteria were responsible for 32.9% of infections. Multivariate unconditioned logistic analysis of factors identified consistent independent risk factors for no completely remission(OR=0.142, P< 0.001), duration of neutropenia longer than 7 days(OR=12.764, P<0.001), general wards(OR=1.821, P< 0.001), and hospitalization interval longer than 10 days(OR=0.720, P=0.039).CONCLUSION: Infections after chemotherapy for AL continues to be common. AL patients with induction chemotherapy or severe neutropenia faced an increased risk of infections by multivariate analysis. And patients with short-term stay or laminar flow wards seem to be less susceptible to infections.

PubMed | Institute of Hematology and Blood Disease Hospital
Type: Journal Article | Journal: Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2015

To investigate the myeloperoxidase (cMPO) expression pattern by flow cytometry (FCM) in patients with acute myeloid leukemia (AML) and its role in classifying AML.Eight- color multiparametric FCM with CD45/SSC gating was used to determine the cMPO expression in 502 AML patients.The positive rate of cMPO in all patients was 58.0%, in which the proportion of normal positivity, dim positivity and partial positivity was 21.5%, 34.1% and 2.4%, respectively. The remaining case (42.0%) were all negative. In AML with t (15;17(q22;q12)/PMLRAR, the positive rate was the highest (100%) and the intensity was similar to that of the normal granular leukocytes, followed by AML with t (8;21q22;q22/RUNX1-RUNX1T1, the positive rate was 91.4% and the intensity was mostly dim. AML with minimal differentiation and acute megakaryoblastic leukemia were all cMPO negative. The positive rates of cMPO in the remaining subtypes were between 22.7% and 76.2%.The positive rate and intensity of cMPO were significantly different among different subtypes of AML.

PubMed | Institute of Hematology and Blood Disease Hospital
Type: Journal Article | Journal: Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi | Year: 2015

To investigate the long- term outcome of cyclosporin A (CsA) combined with thalidomide regime for Chinese patients with IPSS low/intermediate- 1 myelodysplastic syndromes (MDS) without del5qand the predictive variables which could impact the response to the therapy.Seventy-six MDS patients who were treated with these drugs at a single institute in China were retrospectively analyzed. The polymorphism of cereblon gene, rs1672753, was detected in patients of this cohort by PCR and direct sequencing.A total of 53% of patients showed hematological improvementHIto the therapy. Thirty-one patients31/73, 43%achieved erythrocyte responseHI-E; 15 patients15/50, 30%achieved neutrophil responseHI-N); 18 patients18/58, 31%achieved platelet responseHI-P). Twenty-seven of the 50 patients46%who were dependent on red blood cell transfusion achieved HI- E and became independent of transfusion. The median duration of response among the responders was 22 months (range, 1- 131 + months). Bone marrow blasts 2% was the only factor associated with longer response duration in univariate analysis P=0.010. There was no significant difference between the two groups of celeblon gene rs1672753 polymorphism either on the response rate or the response duration. The median survival of 67 patients without stem cell transplantation was 82 months. In multivariate analyses, factors significantly correlated with survival were IPSS-RHR=3.461, 95%CI 1.126-10.639, P=0.030), age 60 yHR=4.120, 95%CI 1.070-15.867, P=0.040and HI-NHR=7.733, 95%CI 1.007-59.396, P=0.049).CsA combined with thalidomide regime could improve the anemia symptom in low/int-1 risk MDS patients without del5q. The predictive value of cereblon gene polymorphism, rs1672753, could not be verified in this study.

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