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- [Clinical Analysis of Acute Myeloid Leukemia with CBFB-MYH11-Positive]. [English Abstract, Journal Article]
- Zhongguo Shi Yan Xue Ye Xue Za Zhi 2013 Mar; 21(2):305-10.
The study was aimed to investigate the clinical characteristics of acute myeloid leukemia (AML) with CBFB-MYH11 gene. The clinical data of 12 cases were analyzed retrospectively, including age, clinical characteristics, immunophenotype, treatment protocols and efficacy as well as the prognosis. The results indicated that 12 patients with CBFB-MYH11 were detected in 293 AML patients. The median age of the 12 patients was 32.5 (21 - 57) years old. According to French-American-British (FAB) classification, 66.7% (8/12) patients was diagnosed as M4Eo and 33.3% patients was diagnosed as M4. At new diagnosis, the median WBC count was 19.8×10(9)/L (2.46 - 164.30×10(9)/L). The WBC count > 100×10(9) was found in 16.7% patients (2/12). The complete remission (CR) rate after 1 and 2 cycles of induction chemotherapy were 83.3% and 16.7% respectively, so the total CR rate was 100%. Estimated 5-year relapse-free survival (RFS) and overall survival (OS) were 80% and 83%, respectively. It is concluded that patients with CBFB-MYH11 are usually M4Eo and M4. Patients with this fusion gene are often associated with high frequency of CD33, CD34, CD117, HLA-DR, CD15, CD64 and CD14 expression. Patients with CBFB-MYH11 have a tendency of higher CR rate, longer RFS and OS.
- [Overexpression of eIF4E Gene in Acute Myeloid Leukemia and Its Relation with Disease Progression]. [English Abstract, Journal Article]
- Zhongguo Shi Yan Xue Ye Xue Za Zhi 2013 Mar; 21(2):296-9.
The aim of this study was to detect the expression level of eIF4E gene in patients with non-treated, remission and non-remission/relapse acute myeloid leukemia (AML), and other non-malignant haematologic diseases so as to analyze and reveal the relationship of eIF4E gene expression with AML progression. SYBR Green I RT-PCR was used to assay the expression level of eIF4E mRNA extracted from bone marrow mononuclear cells in 30 patients with AML (6 in M2, 5 in M3, 8 in M4, 10 in M5, 1 in M6) and 20 patients with non-malignant hematologic diseases. The β2-microglubin(β2M) was used as internal reference and the formula 2(-ΔCt)×100% was applied to calculate the expression level of eIF4E gene. The results showed that the eIF4E expression level (7.098 ± 5.544)% in patients with non-treated and non-remitted/relapsed AML was significantly higher than that in patients with remission (0.964 ± 0.312)% (P < 0.01) and non-malignant hematologic diseases (0.248 ± 0.163)% (P < 0.01). There was no difference between latter two group patients, even though the expression level of eIF4E gene in patients with M4 and M5 was higher. As compared with non-malignant hematologic diseases, the expression level of eIF4E gene of patients with remission patients showed no significant difference. It is concluded that the over-expression of eIF4E gene has been found in patients with AML, and its level obviously decreases along with remission of disease, thus the eIF4E gene may be a surveillance parameter for disease progression.
- Association between Tumorigenic Potential and the Fate of Cancer Cells in a Syngeneic Melanoma Model. [Journal Article]
- PLoS One 2013; 8(4):e62124.
The self-renewal potential of a cancer cell can be estimated by using particular assays, which include xenotransplantation in immunocompromised animals or culturing in non-adherent serum-free stem-cells media (SCM). However, whether cells with self-renewal potential actually contribute to disease is unknown. Here we investigated the tumorigenic potential and fate of cancer cells in an in-vivo melanoma model. We examined cell lines which were derived from the same parental line: a non-metastatic cell line (K1735/16), a metastatic cell line (K1735/M4) and a cell line which was selected in non-adherent conditions (K1735/16S). All cell lines exhibited similar proliferation kinetics when grown on culture plates. K1735/16 cells grown in soft agar or in suspension non-adherent conditions failed to form colonies or spheroids, whereas the other cell lines showed prominent colonogenicity and spheroid formation capacity. By using sphere limiting dilution analysis (SLDA) in serum-free media, K1735/16S and K1735/M4 cells grown in suspension were capable of forming spheroids even in low frequencies of concentrations, as opposed to K1735/16 cells. The tumorigenic potential of the cell lines was determined in SCID mice using intra footpad injections. Palpable tumors were evident in all mice. In agreement with the in-vitro studies, the K1735/M4 cell line exhibited the highest growth kinetics, followed by the K1735/16S cell line, whereas the K1735/16 cell line had the lowest tumor growth potential (P<0.001). In contrast, when we repeated the experiments in syngeneic C3H/HeN mice, the K1735/16 cell line produced macroscopic tumors 30-100 days after injection, whereas K1735/M4 and K1735/16S derived tumors regressed spontaneously in 90-100% of mice. TUNEL analysis revealed significantly higher number of apoptotic cells in K1735/16S and K1735/M4 cell line-derived tumors compared to K1735/16 tumors (P<0.001). The models we have examined here raised the possibility, that cells with high-tumorigenic activity may be more immunogenic and hence are more susceptible to immune-regulation.
- Inhibitory Effects of Ginsenoside Metabolites, Compound K and Protopanaxatriol, on GABAC Receptor-Mediated Ion Currents. [Journal Article]
- Korean J Physiol Pharmacol 2013 Apr; 17(2):127-32.
Ginsenosides, one of the active ingredients of Panax ginseng, show various pharmacological and physiological effects, and they are converted into compound K (CK) or protopanaxatriol (M4) by intestinal microorganisms. CK is a metabolite derived from protopanaxadiol (PD) ginsenosides, whereas M4 is a metabolite derived from protopanaxatriol (PT) ginsenosides. The γ-aminobutyric acid receptorC (GABAC) is primarily expressed in retinal bipolar cells and several regions of the brain. However, little is known of the effects of ginsenoside metabolites on GABAC receptor channel activity. In the present study, we examined the effects of CK and M4 on the activity of human recombinant GABAC receptor (ρ1) channels expressed in Xenopus oocytes by using a 2-electrode voltage clamp technique. In oocytes expressing GABAC receptor cRNA, we found that CK or M4 alone had no effect in oocytes. However, co-application of either CK or M4 with GABA inhibited the GABA-induced inward peak current (IGABA ). Interestingly, pre-application of M4 inhibited IGABA more potently than CK in a dose-dependent and reversible manner. The half-inhibitory concentration (IC50) values of CK and M4 were 52.1±2.3 and 45.7±3.9 µM, respectively. Inhibition of IGABA by CK and M4 was voltage-independent and non-competitive. This study implies that ginsenoside metabolites may regulate GABAC receptor channel activity in the brain, including in the eyes.
- Metabolism of bromopride in mouse, rat, rabbit, dog, monkey, and human hepatocytes. [JOURNAL ARTICLE]
- Drug Metab Pharmacokinet 2013 Apr 23.
Bromopride (BRP) has been utilized clinically for treatment of nausea, vomiting and gastro-intestinal motility disorders. The pharmacokinetics of BRP have been characterized in dogs and humans, however, the metabolic profile of BRP has not been well studied. The present study was aimed at better understanding BRP metabolism across species. We investigated biotransformation of BRP in mouse, rat, rabbit, dog, monkey, and human hepatocytes with the help of LC-MS(n) and accurate mass measurement. Mouse, rat, dog, and monkey are relevant in drug discovery and development as pre-clinical species to be compared with human, whereas rabbits were efficacy models for BRP. Overall, 20 metabolites of BRP were identified across hepatocytes from six species. Monkey offered the most coverage for human, in terms of number of metabolites identified. Interestingly, M14, an N-sulfate metabolite of BRP was identified as a human-specific metabolite. BRP metabolism had only been reported in dog plasma and urine, historically. Our investigation is the first documentation of in vitro metabolism of BRP in six the species reported here. Metabolites M1, M2, M4-M10, M12, M13, and M15-M20 have not been previously reported. In summary, this report documents seventeen metabolites of BRP for the first time, thus providing a deeper insight into the biotransformation of BRP.
- [The immunophenotypic and clinical characteristics of NPM1 mutated acute myeloid leukemia patients]. [English Abstract, Journal Article]
- Zhonghua Xue Ye Xue Za Zhi 2013 Feb; 34(2):98-103.
To compare the immunophenotypic and clinical characteristics between NPM1 mutated acute myeloid leukemia (AML) (NPM1m(+)AML) and unmutated AML(NPM1m(-)AML) not otherwise characterized (NOS) under similar FAB subtypes constituent ratio.Immunophenotyping and NPM1 gene mutation type-A, B and D and other leukemic related fusion genes were detected by multiparamter flow cytometry and real time RT-PCR or PCR, respectively. 104 AML patients with NPM1m(+)AML and performed immunophenotyping assay were included, 97 with NPM1m(-)AML.There were significant difference between the two groups at presentation in terms of sex, white blood count(WBC), platelet counts (PLT), blast ratio, normal karyotype ratio, WT1 expression level, FLT3-ITD mutation positive rate and remission rate of first course of induction therapy (P < 0.05). On the immunophenotype, the expression of early differentiation antigens (CD34, HLA-DR, CD117, CD38), lymphocytic antigens (CD7, CD4, CD19, CD2), myeloid and monocytic differentiation-associated antigens (CD13, CD14, CD15) were lower, and that of CD33 as well as CD123 were higher in NPM1m(+)AML patients. Among them, only CD34, HLA-DR, CD7, and CD4 positive cases were significantly lower in NPM1m(+)AML group than in NPM1m(-)AML group (P < 0.05), the rest of them had significant difference in the number of positive cells (P < 0.05). Above features were further analyzed between the M1/M2 and M4/M5 subgroups. M1/M2 cases retained the women prominent and had a higher WT1 expression level (P < 0.05). The expression of monocytic differentiation-associated antigens including HLA-DR and lymphocytic antigens were higher and that of CD117 were lower in M4/M5 subtype (P < 0.05). Among them, the positive rates of HLA-DR, CD64, CD11b, CD10, CD15, and CD4 were significantly higher in M4/M5 than in M1/M2 in NPM1m(+)AML group (P < 0.05).The most clinical characteristics in NPM1m(+)AML patients are consistent with reports, but some immunophenotype are different to the previous reports under similar FAB subtypes constituent ratio. The major immunophenotypic features of NPM1m(+)AML patients are lower expression of progenitor, myeloid and lymphoid lineage antigens. Monocytic differentiation-associated antigens are only higher expression in M4/M5 cases when comparison with M1/M2 cases within NPM1m(+)AML group.
- [Expression of homeobox gene HOXA9 in childhood acute leukemia, and its clinical significance]. [English Abstract, Journal Article]
- Zhongguo Dang Dai Er Ke Za Zhi 2013 Apr; 15(4):268-72.
To investigate the expression of homeobox gene HOXA9 in the bone marrow mononuclear cells of children with acute leukemia (AL) and its clinical significance.Forty-six children with AL were divided into acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) groups. Fifteen children with idiopathic thrombocytopenic purpura were selected as a control group. The mRNA expression of HOXA9 was measured by reverse transcription polymerase chain reaction (RT-PCR).HOXA9 expression was detected in 63% of the 52 bone marrow samples from 46 AL children. The positive HOXA9 expression rate in the AML group was significantly higher than in the ALL and control groups (86% vs 35% and 13%; P<0.05). The mRNA expression of HOXA9 in the AML group was significantly higher than in the ALL and control groups (P<0.05). Among the children with AML, those with M5 AML had the highest HOXA9 mRNA level, followed by children with M4 AML and children with M1 and/or M2 AML, but HOXA9 expression was not detected in children with M3 AML. The high-risk subgroup of AML children had relatively high levels of HOXA9 expression. In the children with AML, the initial treatment subgroup had significantly higher positive HOXA9 expression rate and HOXA9 mRNA levels than in the remission subgroup and control group (P<0.05), but there were no significant differences between the latter two groups (P>0.05). The non-remission subgroup had significantly higher HOXA9 expression than the remission subgroup and control group (P<0.05). CONCLISONS: High expression of HOXA9 is associated with the occurrence of AL, and its expression level is significantly higher in children with AML than in those with ALL. There is a positive correlation between the expression level of HOXA9 and the risk of childhood leukemia, and high expression of HOXA9 suggests poor prognosis. Therefore, HOXA9 can be used as one of the indices in the diagnosis, treatment and prognosis prediction of childhood AL.
- Interdigitating dendritic cell sarcoma presenting simultaneously with acute myelomonocytic leukemia: report of a rare case and literature review. [Journal Article]
- Int J Hematol 2013 May; 97(5):657-66.
Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare tumor derived from interdigitating dendritic cells. We report the first case of a 64-year-old Chinese woman who was diagnosed with simultaneous IDCS and acute myelomonocytic leukemia (AML-M4). The patient had undergone chemotherapy for breast cancer 6 years previously. Based on the laboratory results, both the IDCS and the AML-M4 in this patient were determined to be of myelogenous origination. Furthermore, a review of 62 IDCS cases (Medline database, key word: IDCS) reported to date revealed that as many as 17 % of the patients had malignant disease and received radiotherapy and/or chemotherapy prior to developing IDCS, and that this group of patients showed worse prognosis compared with counterparts. The patient in the present report showed poor response to four cycles of sequential chemotherapy, and died 6 months after the initial diagnosis.
- Molecular analysis of the site for 2-arachidonylglycerol (2-AG) on the β2 subunit of GABAA receptors. [JOURNAL ARTICLE]
- J Neurochem 2013 Apr 20.
2-arachidonyl glycerol (2-AG) allosterically potentiates GABAA receptors via a binding site located in transmembrane segment M4 of the β2 subunit. Two amino acid residues have been described that are essential for this effect. With the aim to further describe this potential drug target, we performed a cysteine scanning of the entire M4 and part of M3. All four residues in M4 affecting the potentiation here and the two already identified residues locate to the same side of the α-helix. This side is exposed to M3, where further residues were identified. From the fact that the important residues span > 18 Å, we conclude that the hydrophobic tail of the bound 2-AG molecule must be near linear and that the site mainly locates to the inner leaflet but stretches far into the membrane. The influence of the structure of the head group of the ligand molecule on the activity of the molecule was also investigated. We present a model of 2-AG docked to the GABAA receptor.
- The functional results of acute nerve grafting in traumatic sciatic nerve injuries. [Journal Article]
- Ulus Travma Acil Cerrahi Derg 2013 Mar; 19(2):109-14.
The sciatic and peroneal nerves are the most frequently injured in lower extremities, followed by tibial and femoral nerves. The aim of this study is to evaluate the functional results of acute nerve grafting in traumatic sciatic nerve injuries.A total of 9 patients with sciatic nerve defect were treated with primary nerve grafting. The mean age was 31.7 years. The etiologic factors were gunshot wounds, traffic accident, and penetrating trauma.All of the patients had sciatic nerve defects ranging from 3.4 to 13.6 cm. The follow-up period ranged between 25 and 84 months. The tibial nerve motor function was "good" or "very good" (M3-M4) in 5 patients (55.6%). The plantar flexion was not sufficient for the rest of the patients. The peroneal nerve motor function was also "good" and "very good" in 3 patients (33.3%).The functional results of the acute nerve grafting of the sciatic nerve within the first week after the injury are poorer than reported in the related literature. This protocol should only be applied to select patients who have adequate soft tissue coverage and healthy nerve endings.