bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Significance of MicroRNA-155 in Lymphocytic Malignancy.
Authors: Banerjee Arnob , Reiner Steven 
Published: October 2019

Abstract
Oncogenes and tumor suppressor genes implicated in lymphocytic malignancy mainly encode proteins, but more recent studies have identified specific micro-RNA (miR) molecules that also have an important role in the transformation of lymphocytes. MiRs are non-coding RNA molecules of approximately 22 nucleotides that regulate gene expression by targeting specific mRNAs for silencing or degradation. Certain miR’s, termed oncomiRs, have been shown to play a role in malignant transformation. MiR-155 is one of the first described onco-miRs, with high levels of expression observed in biopsy samples from patients with Hodgkin’s lymphoma, primary mediastinal B cell lymphoma, and diffuse large B cell lymphoma. MiR-155 was demonstrated to have a causal role in B cell transformation in transgenic mice with forced overexpression of miR-155 in the B cell lineage. The transgenic mice develop fatal aggressive B cell malignancies in the first six months of life. The mechanism of miR-155 in lymphocytic transformation remains unclear. Some insight into the physiologic function of miR-155 was gained using mice with a deletion of the gene encoding miR-155. The mice have defects in germinal center formation and in cytokine production by B and T cell lineages. We have used combined gain and loss of function approaches to study the function of miR-155 in T helper cells. Our experiments have demonstrated effects on T helper cell differentiation that are dependent on both the level and the timing of miR-155 expression. The cellular phenotypes we have observed, in combination with computational target prediction have allowed us to identify several promising mRNA targets which are expressed in both T cells and B cells. Currently we are investigating whether any of the target mRNA candidates we have identified contribute to the oncogenic potential of miR-155. We have screened several lymphocyte cell lines for levels of miR-155 expression, and have identified lines in which miR-155 is highly expressed. We are using a loss of function approach to test the dependence of these lines on miR-155 expression. The relative contribution of each candidate target mRNA from our previous studies is being assessed by forced expression of the mRNA in the presence of miR-155 expression and by knockdown in the presence of miR-155 antagonism. Further functional studies and investigation of mRNA targets will help to elucidate both the physiologic role of miR-155 in lymphocytes and its role in lymphocytic malignancy.
Variation of Sorcin’s Expression in the Reversion of Multidrug Resistance of K562/A02 Leukemic Line with Tetrandrine.
Authors: Chen Bao-An Chen , Li Jing , Ding Jia-Hua , Gao Chong , Sun Yun-Yu , Gao Feng , Wang Jun , Zhao Gang , Chen Ning-Na , Chen Jian , Pei Xiao-Ping 
Published: October 2019

Objective This paper aims to investigate the reversal multiple of daunomycin(DNR) with different concentration of tetrandrine(tet) at different time, to study the variation of Soluble resistance related calcium binding protein (sorcin)’s expression in the reversion of multidrug resistance of K562/A02 leukemic line with different concentration of tet at different time, and to provide new theoretic evidence for the clinical application of tet as resistence modifying agents.
Method
The reversal multiple of DNR with different concentration of tet at different time was assayed by MTT (concentration of tet is 0.5mg/l or1mg/l or 2mg/l, incubation time is 48h or 72h). The variation of the gene’s expression of sorcin with different concentration of tet at different time wasassayed by RT-PCR(grouping like MTT).
Result
MTT analysis demonstrated that the reversal concentration was 1.81(0.5mg/l,48h),3.62(1.0mg/l,48h),6.14(2.0mg/l,48h),2.8(0.5mg/l,72h),(1.0mg/l,48h),7.12(2.0mg/l,72h) respectively. RT-PCR analysis demonstrated that sorcin gene was lowly displayed in K562 cells and highly displayed in K562/A02 cells.
The variation was first accentuation and then attenuation with the concentration accrescence of tet, this tendency had no obviously difference between 48h and 72h.
Conclusion
1 The result of the experiment shows that tet may reverse multidrug resistance of K562/A02 cells by the down regulation of the expression of sorcin gene and proteinum;
2. It may have the concentration dependence and the time dependence in the reversion of multidrug resistance of K562/A02 cells with tet.
Lycorine Inhibits the Proliferation of HL-60 Cell Line through Up-Regulation of p21.
Authors: Liu Jing , Shi Bi-Wei , Hu Ji-Liang , Hu Wei-Xin 
Published: October 2019

Abstract
In previous studies we found that lycorine had broad antitumor effects and tumor cells were more sensitive to lycorine than non-tumor cells. We also showed that the mitochondrial and cell death receptor pathways were involved in lycorine-induced apoptosis of HL-60 cells. To further explore the molecular mechanism by which lycorine inhibits cell proliferation, the gene chip technique was used to detect the difference of gene expression patterns between 5.0 μM lycorine-treated HL-60 cells and control. The chip included 494 genes associated with apoptosis and proliferation. This data set revealed a significant change of 91 genes in expression, with 79 being up-regulated and 12 down-regulated. In particular the tumor suppressor gene p21 was up-regulated 9.3 folds in the lycorine-treated group. Consistent with this finding, RT-PCR and Western blotting confirmed the up-regulation of p21 gene and its protein in HL-60 cells treated with 5.0 μM lycorine for 24 h. The levels of p21 protein and its downstream cell cycle molecules Cdc2, Cdk2 and cyclin E were assessed after HL-60 cells were incubated with 0, 1.25, 2.5 and 5.0 μM lycorine. The results showed that the expression of Cdc2, Cdk2 and cyclin E was down-regulated, while that of p21 was up-regulated. Thus, lycorine could induce cell cycle arrest by interfering with cell cycle signaling pathways through up-regulation of p21 and concomitant down-regulation of Cdc2, Cdk2 and cyclin E in HL-60 cells.
P-Glycoprotein Is Downregulated in KG1a Primitive Leukaemia Cells by LDL Cholesterol Deprivation and by HMG-CoA Reductase Inhibitors.
Authors: Connelly-Smith Laura , Pattinson Joanne , Grundy Martin , Shang Shili , Seedhouse Claire , Russell Nigel , Pallis Monica 
Published: October 2019

Abstract
P-glycoprotein (pgp) is a membrane transporter encoded by the multidrug resistance (MDR1, ABCB1) gene. Pgp is a poor prognostic factor in elderly patients with acute myeloid leukaemia (AML). In addition to its role in drug efflux, pgp has been implicated in cellular cholesterol homeostasis. We investigated the effects of exogenous cholesterol removal on pgp expression and function. KG1a drug-naïve, primitive leukaemia cells were cultured in serum free medium with or without the addition of low density lipoprotein (LDL) cholesterol. After 72 hours pgp expression and function was assessed by flow cytometry and total cholesterol content of the KG1a cells was determined by the Amplex Red® cholesterol assay. The addition of clinically available cholesterol lowering agents, HMG-CoA (3-hydroxy-3-methylglutaryl coenzyme A) reductase inhibitors to KG1a cells was also assessed. There was a 39% (SEM 8.3% P=0.03) decrease in pgp protein expression after 3 days of serum free culture without HMG-CoA reductase inhibitors. Message was decreased by 40% (P=0.01) and pgp function was also reduced by 40% (P=0.005). The addition of low density lipoprotein (LDL) cholesterol restored pgp expression to 86% of the basal value. The addition of a HMG-CoA reductase inhibitor to KG1a cells in serum free culture resulted in a further 26% (lovastatin, P=0.03) and 16% (pravastatin, P=0.05) reduction in pgp respectively. Lovastatin also significantly reduced cellular cholesterol levels by 47% (P=0.002) under serum free conditions. Furthermore, the toxicity of the pgp substrate drug daunorubicin was significantly enhanced following lovastatin pre-culture (P=0.04). We conclude that LDL/cholesterol contributes to pgp expression and chemoresistance in primitive leukaemia cells. The use of HMG-CoA reductase inhibitors may be of clinical value in lowering pgp expression in AML.
Synergistic Anti-Leukemic Effect of Protein Kinase A Activator and PPARγ Agonist Is Independent of Bcl-2 Status.
Authors: Erikstein Bjarte S. , Tronstad Karl J. , McCormack Emmet , Schwede Frank , Bergen Rolf , Gjertsen Bjorn T. 
Published: October 2019

Abstract
The fatty acid derivate tetradecylthioacetic acid (TTA) and 8-CPT-cAMP have previously been shown to have anti-proliferative activities through activation of PPARγ and effects on the mitochondrial metabolism, respectively. Based on our previous work, we hypothesized that these two agents have a converging point of action. The combined effect of these two compounds was investigated in acute myelogenous cell lines (IPC-81 and HL-60), including IPC-81 clones over expressing either Bcl-2 or inducible cAMP early transcription repressors (ICER). Brown Norwegian rat leukaemia (BNML) was used as an in vivo model system. 8-CPT-cAMP- and TTAs anti-leukemic activity was assessed in vivo and in vitro. The compounds were able to synergistically induce a decrease in viability in promyelocytic IPC-81 cells when measured by combinational index. Enforced expression of ICER could partially protect the cell from TTA induced apoptosis. Bcl-2 over expression did not prevent additive apoptosis induction of the two compounds. An additive proliferation inhibition of the two compounds was detected in HL-60 cells at a 8-CPT-cAMP concentration that did not affect viability in itself. TTA and 8-CPT-cAMP had a spleen anti-leukaemic activity in vivo but the schedule of administration will have to be further investigated. In conclusion there seems to be a converging point in the action of 8-CPT-cAMP and TTA since they synergistically decrease in vitro viability of acute leukemic cells.
Pharmacokinetic and Pharmacodynamic Properties of SB1317, a Potent and Orally Active Multi-Kinase Inhibitor.
Authors: Yeo Pauline , Venkatesh P. , Goh Evelyn , Zeng Peizi , New Lee S. , Hu Changyong , Sangthongpitag Kanda , William Anthony D. , Goh Kee C. , Wood Jeanette M. , Kantharaj Ethirajulu 
Published: October 2019

Abstract
Key physicochemical properties such as solubility, lipophilicity (logD7.4, logP) and pKa (the negative log of the acid dissociation constant) can be used to predict protein binding, tissue distribution, and gastrointestinal (GI) absorption. More recent application of computational methods allows even better prediction of compound oral bioavailability from in vitro and/or in silico properties. During the lead optimization process in our multi-kinase inhibitor program a good correlation between physicochemical properties like logD and solubility (determined experimentally at pH 7) versus AUC(0-inf) (Area Under the Curve) was observed for a series of kinase inhibitors. A calculated logD*solubility value between 200 to 400 predicted a reasonably high oral AUC(0-inf) in mouse PharmacoKinetic (PK) studies for this series of compounds, with correlation coefficient of >0.9. The correlation of logD*solubility vs. AUC(0-inf) enabled us to prioritize compounds for PK studies. SB1317, a novel pyrimidine derivative, is an orally active multi-kinase inhibitor that evolved as a lead drug candidate from in vitro and in vivo pharmacokinetic studies. SB1317 is a highly permeable compound, does not undergo active P-glycoprotein transport, and has a solubility of 75 μg/ml. It is metabolically stable in dog and human liver microsomes and unstable in rodent liver microsomes. No P450 inhibition was observed up to 10 μM towards CYP3A4, CYP1A2, CYP2C9 and CYP2C19. In vivo pharmacokinetics in nude mice and Beagle dogs resulted in %F of 12 and 37% respectively. Tumor pharmacokinetics of SB1317 shows increased exposure in tumor than in plasma with a AUC(0-t) tumor/plasma ratio of 3. Excellent oral dose proportionality (10, 20 and 40mg/kg) was observed in both plasma and tumor. SB1317 has exhibited uniformly high plasma protein binding (>99%) across the preclinical species and human. It is the free or unbound portion of the compound in the plasma or at the tissue level that would yield effective anti-tumor activity. (AUC0-inf)unbound/GI50 and Cmax-unbound/GI50 were used as PK/PD surrogates for the measure of SB1317 efficacy. A factor of SB1317 unbound AUC (0-inf)/GI50 above 0.5 results in significant pharmacodynamic (PD) effects in hematological tumor models (MV4-11 and HL-60 engraft model). Linear pharmacokinetic extrapolation from preclinical species to human was determined by allometric scaling (predicted human % F = 36). PK/PD relationships established for SB1317 in preclinical species could form the basis of a PK/PD-driven clinical development program.
Iv Vitro Modeling of the Use of FLT3 Inhibitors To Reduce Chemotherapy Doses for Elderly Patients with AML.
Authors: Schittenhelm Marcus M. , Kampa Kerstin M. , Yee Kevin W.H. , Kanz Lothar , Heinrich Michael C. 
Published: October 2019

Abstract
Among the expanding population of elderly AML patients, aggressive therapy options are often limited due to other medical conditions and the decreased tolerance of these patients to conventional chemotherapy. Internal tandem duplications (ITD) of the FLT3 juxtamembrane domain occur in 20–30% of AML patients and predict poor outcome. Monotherapy with FLT3-tyrosine kinase inhibitors (TKIs) has produced biological and some clinical responses. Side effects of TKI and chemoagents are only moderately overlapping. We hypothesized that the use of FLT3 inhibitors may allow dose reduction of chemotherapy with resultant decreased side effects, but without loss of antileukemic activity. Using primary AML blasts, we found that combination of the TKI tandutinib (Tn) (or sunitinib (Sn)) with cytarabine (Cy) and/or daunorubicin (Dn) has a favorable growth inhibitory activity compared to Cy/Dn alone. Of note, the effects were only seen in cells expressing a FLT3 ITD mutation. In order to perform more detailed mathematical analyses, we utilized three cell lines containing FLT3 ITD mutations: a BaF3 cell line transduced with an ITD mutant FLT3 as well as MV4-11 and MOLM14 cell lines which have naturally occurring FLT3 ITD mutations. Dilution series were set up with the single agents as well as different drug combinations to create isobolograms using the method of Chou and Talalay. Next, dose reduction indices (DRI) were computed using calcusyn® software. DRI for the combination of Tn with Cy demonstrated a 6 (MV4:11) - 19 (Ba/F3 FLT3 ITD) fold potential dose reduction of Cy at ED90 for induction of apoptosis. In addition, the DRI of cytarabine in combination with Sn would allow a 2–145 fold cytarabine dose reduction for the various cell lines. The combination of Dn with Tn or Sn demonstrated a DRI up to 6 fold. Similar DRI were seen when inhibition of cellular proliferation was the final endpoint. Of note, Sn plus Cn or Dn displayed a - moderate but beneficial - DRI of 2 in Ba/F3 cells expressing the FLT3 wildtype isoform. Also, triple-combination allowed up to 10 fold dose reduction of the chemoagents - in cell lines as well as native blasts. We conclude that dose reduction strategies by adding TKI may be clinically useful, particularly for elderly AML patients or patients with co-existent illnesses that would predict for a poor tolerance of standard chemotherapy regimens.
Expression Analysis and Prognostic Significance of the PHLPP Gene in Acute Leukemias and Myelodysplastic Syndromes.
Authors: Ono Takaaki , Nakamura Satoki , Kazuyuki Shigeno , Takeshita Kaori , Keiji Okinaka , Hirano Isao , Fujisawa Shinya , Ohnishi Kazunori 
Published: October 2019

Abstract
[Background] The proto-oncogene Akt/PKB is activated in many human cancers including leukemias, and regulates the cell survival and apoptosis. Akt/PKB is activated by growth factors or the phosphatidylinositol-3,4,5-triphosphate via PI3K, phosphorylates many substrates for cell survival or proliferation. The tumor suppressor PTEN prevents Akt/PKB phosphorylation and activation. On the other hand, the PH domain leucine-rich repeat protein phosphatase (PHLPP) dephosphorylates Akt/PKB, induces apoptosis, and suppresses tumor growth. It has been reported that the expression levels of PHLPP are significantly reduced in several colon cancer and glioblastoma cell lines, and Akt/PKB phosphorylation is elevated. However, we found that PHLPP gene was overexpressed in MNCs derived from patients with acute leukemias and MDS. In this study, we have investigated the expression analysis and prognostic significance of the PHLPP gene in patients with acute leukemias and MDS.
[Methods] The cells used in this study were human acute leukemia cell lines, HL60, U937, YRK2, CEM, and MOLT4 cells. Primary acute lymphoblastic leukemia (8 ALL (8 L2)), myelodysplastic syndromes (32 MDS (18 RAEB-I, 14 REAB-II)), and acute myeloblastic (25 AML (4 M1, 11 M2, 6 M4, 4 M5)) cells were obtained from the peripheral blood. Human normal mononuclear cells (MNCs) were isolated from peripheral blood (PB) of healthy volunteers after obtaining informed consents. For analysis of PHLPP mRNA, quantitative RT-PCR was performed in all cell lines and clinical samples.
[Results] In all cell lines, the expressions of PHLPP mRNA were significantly increased more than normal MNCs. In HL60, U937, YRK2, CEM and MOLT4 cells transfected with the siRNA PHLPP, it is shown that the phosphorylation state of Akt was markedly increased compared to the untransfected cells. In the clinical samples obtained from patients with acute leukemias and myelodisplastic syndromes, the PHLPP gene was overexpressed in 7/8 (87.5%) of ALL, 14/25 (56%) of AML, and 26/32 (81.3%) of MDS. This higher expression was not associated to the counts of blasts of PB (P < 0.01). The relative folds of PHLPP gene expression were for AML: 3.02, MDS: 4.16, and ALL 3.62 compared to normal MNCs. Kaplan-Meier survival analysis revealed that lower PHLPP expression increases the probability of the longer overall and the progression free survival of the patients. Moreover, when CR status after chemotherapy, mean PHLPP expression levels were significantly reduced compared to unCR status after chemotherapy in MNCs derived from PB of patients with acute leukemias and myelodysplastic syndromes.
[Conclusions] Our results suggest that the PHLPP gene was overexpressed in MNCs derived from the patients with acute leukemias and myelodysplastic syndromes and may possibly be characterized as a new marker of unfavorable prognosis for ALL, AML, and MDS.
Telomerase Activity and Telomere Length in APL: May Be Proliferative and Prognostic Markers.
Authors: Ghaffari Seyed Hamidolah , Shayan-Asl Nilofar , Jamialahmadi Abdolhamid , Ghavamzadeh Ardeshir , Alimoghaddam Kamran 
Published: October 2019

Abstract
Introduction: The telomeric DNA together with its associated proteins protects the chromosome ends from degradation or aberrant recombination. Telomerase and telomere are extensively investigated as potential diagnostic and prognostic markers in human tumors. In this study, we aim to investigate the significance of telomerase activity (TA) and telomere length (TL) in patients with acute promyelocytic leukemia (APL).
Methods: About 300 sequential peripheral blood mononuclear cell (PBMC) samples were collected from 40 patients with APL (32 newly diagnosed and 8 relapsed), at diagnosis, during and after therapy with Arsenic Trioxide. TA was assessed by TRAP-ELISA and -PAGE procedures. Terminal restriction fragment (TRF) length was determined by Southern blot analysis, using a Chemiluminescence-based assay. Quantification of PML-RARα/G6PDH transcripts was carried out by real-time PCR assay.
Results: About 90% of the APL patients had a significant reduction in TRF length (median 3.5, ranged 2.3 to 6.7 kbp) relative to the age-matched control or to that at the time of CR (median 11.37; ranged 8.90 to 14.70 kbp) from the same patients (P<0.0001). A significance positive correlation between telomere length and PML-RARα expression was found in the APL patients (P=0.001). In all the APL patients, telomerase activity was elevated in comparison with normal individuals (P<0.001). The telomerase activity levels were significantly higher in patients with short TRF. The group of patients with shortened TRF and elevated TA had a significantly poorer overall survival. The levels of TA were even significantly higher and the TL size difference of leukemic from non-leukemic was significantly longer in relapsed patients than patients with the primary APL.
Conclusion: Short telomere and high telomerase levels in the APL patients are mainly a consequence of extensive proliferative histories and they correlate with the disease progression. The shortened telomere length and the elevated telomerase activity may serve as prognostic factors for a subset of APL patients with more aggressive disease and poor outcome, and who may not respond favourably to arsenic therapy.
CD56+ AML Is Strongly Associated with AML1/ETO Rearrangement and CNS Involvement in Childhood AML.
Authors: Lee Hye Ryun , Lee Dong Soon , Kim Inho , Yoon Sung-Soo , Park Seonyang , Kim Byoung Kook , Kang Hyoung Jin , Shin Hee Young , Ahn Hyo Seop , Kim Hyun Kyung , Park Myoung Hee , Cho Han Ik 
Published: October 2019

Abstract
Introduction: To investigate the clinical difference between CD56+AML and CD56−AML, we examined the incidence of CD56+AML and analyzed several clinical and biological characteristics, cytogenetic features, immunophenotypic features, and clinical prognosis of CD56+AML.
Method: 213 patients (177 adults, 36 children) with de novo AML in Seoul National University Hospital were enrolled. FAB subtypes were 4 M0 (2.3%), 26 M1, (12.2%), 78 M2 (36.6%), 27 M3 (12.8%), 43 M4 (20.2%), 15 M5 (7.1%), 14 M6 (6.6%), and 5 M7 (2.4%). Immunophenotyping was performed by immunohistochemical stain or multiparameter flow cytometry. The association between CD 56 expression and variables (age, sex, WBC count, blast, cytogenetic features, extramedullary involvement, disease free survival, and overall survival) was analyzed by the fisher’s exact test, chi-square test and T test, and Kaplan-Meier method. All statistical calculation were performed using SPSS system.
Results: CD56 was detected in 6 of 177 adults (3.4%) and in 9 (25.0%) of children, showing significantly higher in children group (p = 0.000). The CD56 expression was significantly frequent in M7 subtype (p=0.003). The other clinical characteristics, such as sex, WBC count, % blasts in peripheral blood was not significantly associated with CD56 positivity. Frequency of extramedullary involvement did not differ between CD56+AML and CD56−AML. However, the frequency of CNS involvement at initial diagnosis or relapse were significantly higher in CD56+AML (p=0.018). (Table 1) Among cytogenetic changes, AML1/ETO rearrangement was significantly associated with CD56 expression (p=0.024). Aberrant expression of one or more lymphoid markers was observed in 42.9% (6/15 CD56+AML) and 45.2% (80/198 CD56+AML), showing no difference between CD56+AML and CD56−AML. Median disease free survival was 7 months in CD56+AML and 19 months in CD56−AML, showing no significant difference in two groups (p=0.2466). Median overall survival was not reached in CD56+AML and 25 months in CD56−AML (p=0.1591).
Conclusion: The incidence of CD56 positive AML was higher in childhood AML and association of CD56+AML with AML1/ETO rearrangement, CNS involvement and M7 subtype was observed, suggesting the different biologic behavior of CD56+AML. Furthermore, we suggest that 3rd lineage of leukemic cells, would be taken into consideration for the biphenotypic leukemia.
Extramedullary involvement of CD56+ vs. CD56− CD56+ CD56- p * chi-square test or fisher’s exact test (level of significance: p<0.05) n=15 (7.0%) n=198 (93.0%) Extramedullary involvement 3 (20.0%) 27 (13.6%) 0.450 Adult 0 19 Child 3 8 CNS involvement 3 (20.0%) 7 (3.5%) 0.025 Adult 0 4 Child 3 3