bluuebunny/crossref_metadata_2025_split huggingface dataset:
MK886 Induced Apoptosis in HL-60 Cells Via Inhibition mPGES-1 Expression and Down-Regulation Prostaglandin E2 Synthesize.
Authors: Li Yiqing , Yin Songmei , Xie Shuangfeng , Nie Danian , Ma Liping , Wang Xiuju , Wu Yudan 
Published: October 2019

Abstract
Abstract 4824
Recent studies have shown that prostaglandin E2 (PGE2) may play a key role in the tumorigenesis and tumor development. Membrane-bound prostaglandin E2 synthase-1 (mPGES-1), an inducible enzyme that acts downstream of cyclooxygenase (COX) and specifically catalyzes the conversion of prostaglandin H2 (PGH2) to PGE2, was over-expression in a variety of solid tumor cells and tissues such as nonsmall-cell lung cancer, colon carcinoma, gastric carcinoma and breast cancer. MK886, a small molecular inhibitor, is a reasonable potency as an inhibitor of mPGES-1 in vitro experiment. In this study, we examined effects of MK886 on expression of mPGES-1 and PGE2 synthesis in human acute myeloid leukemia cell line (HL-60), observed cell proliferation and apoptosis after 24-h treatment with MK886, and tried to explore the possible mechanisms by checking some protein belong AKT cell singling pathway such as P-AKT, Bax and Bcl-2. We found that the expression levels of mPGES-1 mRNA and protein were higher in HL-60 cells than in normal mononuclearcells (MNC). MK886 inhibited mPGES-1 mRNA and protein expression and reduced PGE2 secretion in HL-60 cells in a dose-dependent manner. The cell proliferation was inhibited and the IC50 was 132.16μmol/L. With the increase of MK886 concentration, the cell apoptosis rate assayed by flow cytometry increased and the apparent apoptotic bodies increased when staining by Hoechst 33258. After treated with MK886 for 24h, protein was extracted and assayed by western blot. The results showed that the expression levels of P-AKT, Bcl-2 and c-myc decreased while the Bax protein expression increased in a dose-dependent manner. The caspase-3 activity, determined by colorimetric detection, also increased dose-dependently. These results indicated that mPGES-1 over-expressed in leukemia cell line HL-60, MK886 could induce apoptosis in HL-60 cells via reducing mPGES-1 expression and PGE2 synthesis dose-dependently, thereby regulate the AKT pathway including Bcl-2 family and the activity of caspase-3. It suggested that mPGES-1 inhibitor might emerge as an important therapeutic tool for leukemia treatment.

Disclosures:
No relevant conflicts of interest to declare.
Aspirin Induces Apoptosis in Human Leukemia Cells Independently of NF-κB and MAPKs through Alteration of the Mcl-1/Noxa Balance.
Authors: Cosialls Ana M , Iglesias-Serret Daniel , Piqué Maria , Barragán Montserrat , Santidrián Antonio F , González-Gironès Diana M , Coll-Mulet Llorenç , de Frias Mercè , Fernandez de Sevilla Alberto , Pons Gabriel , Gil Joan 
Published: October 2019

Abstract
Abstract 4825
Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) induce apoptosis in most cell types. We examined the mechanism of aspirin-induced apoptosis in human leukemia cells. Our results show that aspirin induced apoptosis in leukemia Jurkat T cells independently of NF-κB. Although aspirin induced p38 MAPK and c-Jun N-terminal kinase (JNK) activation, selective inhibitors of these kinases did not inhibit aspirin-induced apoptosis. We studied the regulation of Bcl-2 family members in aspirin-induced apoptosis. The mRNA levels of some pro-apoptotic members, such as BIM, NOXA, BMF or PUMA, were induced by aspirin. However, none of these pro-apoptotic proteins increased and the levels of Mcl-1 protein were reduced. Interestingly, in the presence of aspirin the protein levels of Noxa remained high. This alteration of the Mcl-1/Noxa balance was also found in other leukemia cell lines and primary chronic lymphocytic leukemia cells (CLL). Furthermore, in CLL cells aspirin induced an increase in the protein levels of Noxa. Knockdown of Noxa or Puma significantly attenuated aspirin-induced apoptosis. These results indicate that aspirin induces apoptosis through alteration of the Mcl-1/Noxa balance.

Disclosures
No relevant conflicts of interest to declare.
Reversal of Multidrug Resistance by Magnetic Fe3O4 Nanoparticle Copolymerizating Daunorubicin and mdr1-shRNA Expression Vetor in Leukemia Cells.
Authors: Chen Bao-An , Mao Peipei , Cheng Jian , Gao Feng , Ding Jia-Hua , Gao Chong , Zhang Wei , Xu Cui-Rong , Xu Wen-Lin , Sun Xin-Chen , Chen Ning-Na , Li Xiao-Mao , Wang Xue-Mei 
Published: October 2019

Abstract
Abstract 4829

Object
In many instances, Multidrug resistance (MDR) is mediated by increased expression at the cell surface of the MDR1 gene product, P-glycoprotein (P-gp), a 170-kD energy-dependent efflux pump. The aim of this study was to investigate the potential benefit of combination therapy with magnetic nanoparticle of Fe3O4 (MNP(Fe3O4)) and mdr1-shRNA Expression vetor.in K562/A02 leukemic cells.

Methods
To synthesis short hairpin RNA (shRNA)aiming divectly at the target sequence,we choice the 3491-3509,1539-1557and 3103-3121 nucleotide of mdr-1 mRNA as targets. Cloning in the plasmid vetor PGCSilencer-U6-neo-GFP, The recombinant plasmid vetors were called for PGY1-1,PGY1-2 and PGY1-3.The recombinant plasmid vetors were transfected into the cell 1ines K562/A02 by lipofection. After transfected 48 hours,the inhibition of mdr-1mRNA expression and the expression of P-gp was detected by realtime–PCR and Weston-blot, screening the recombinant plasmid vetor which has the most greatest mdr-1 gene inhibition ratio is PGY1-2.Analysis of the reveral ratio of multidrug resistance, the concentration of DNR and the content of mdr-1 gene and P-gp in K562/A02 cell line.

Results
The combination of daunorubicin (DNR) with either MNP(Fe3O4) or PGY1-2 exerted a potent cytotoxic effect on K562/A02 cells, while MNP(Fe3O4) and PGY1-2 cotreatment can synergistically down regulation the expression of mdr-1 gene and the expression of P-gp(P<0.05). The transfection efficiency was 20%; the concentration of DNR in K562/A02 cell line was obviously elevated (P<0.05);the multidrug resistance index of K562/A02 cell line was obviously decreased (P<0.05).

Conclusion
MNP(Fe3O4) and PGY1-2 cotreatment can synergistically reveral multidrug resistance. Thus our in vitro data strongly suggests a potential clinical application of MNP(Fe3O4) and PGY1-2 combination on CML.

Disclosures
No relevant conflicts of interest to declare.
Over-Expression of IGF-IR in Malignant Clonal Cells in Bone Marrow of Myelodysplastic Syndromes.
Authors: He Qi , Li Xiao , Zhang Zheng , Zhang Qingqiao , Xu Feng , Yang Lianping , Tao Ying , Liu Yizhi 
Published: October 2019

Abstract
Abstract 4832
To explore the expression level of insulin-like growth factor-1 receptor (IGF-IR) in malignant clone cells of myelodysplastic syndromes (MDS).

Method
Fluorescence in situ hybridization (FISH) and immunochemistry (APAAP, alkaline phosphatase anti-alkaline phosphatase) were used together to detect the expression of IGF-IR in the bone marrow cells of 26 MDS patients with known abnormal karyotypes.

Result
The average IGF-IR expression level on the surface of clone cells from the 26 MDS cases was markedly elevated compared to the corresponding level in normal cells (78.2±13.7% vs 14.1±14.0%,P <0.0001). The percentages of malignant clone cells in all 26 MDS cases were significantly correlated with the respective percentages of IGF-IR positive nucleated cells (r = 0.909; P <0.0001). No significant difference in the IGF-IR expression level on the clone cells were observed either between high- and low-risk MDS patients or among MDS patients with different abnormal karyotypes.

Conclusion
IGF-IR might be taken as a marker of clone cells in MDS because of its propensity to cause malignant proliferation.

Disclosures
No relevant conflicts of interest to declare.
Analysis of TCR Vgamma and Vdelta Repertoire and Clonality of T Cells in MDS Patients.
Authors: Geng SuXia , Du Xin , Li Yangqiu , Weng Jianyu , Zhong Liye , Wu Suijing , Guo Rong , Lu Zesheng 
Published: October 2019

Abstract
Abstract 4833
Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders characterized by ineffective hematopoiesis and frequent progression to acute myeloid leukemia. The pathophysiology of these syndromes remains poorly explained. The immune system also seems to contribute to the progressive cytopenias observed in MDS in some cases. We investigated the frequency and the discriminative value of TCR gamma and delta CDR3 clonality using RT-PCR and genescan technique in 40 MDS patients (24 male, 16 female),which included refractory anemia(n=1), refractory anemia with with ringed sideroblasts(n=6), refractory anemia with excess of blasts I (n=16)and II (n=17) respectively. The median age was 60 years (range 15-84).The results showed that 35(87.5%) MDS patients expressed all three TCR Vgamma subfamilies. Four(10%) and one(2.5%) MDS patients expressed two and one TCR Vgamma subfamilies respectively. Clonal expansion of T cells in some Vgamma subfamilies could be identified in 31 patients. The clonal expansion of Vgamma2 subfamily were identified most frequently. All the Vdelta subfamilies were absent in 2 MDS patients. The remaining 38 (95%) MDS cases expressed 0-6 Vdelta subfamilies. Vdelta1 and Vdelta2 were expressed most frequently followed by Vdelta8. While only 3(7.5%) patients expressed Vdelta5 subfamilies. Clonal expansion of Vdelta T cells were found in all MDS patients. The most frequent clonal expansion T cell was Vdelta3. In addition, 12 patients expressed monoclonal T cell Vdelta subfamily. Monoclonal expanded T cells were found in Vdelta3, Vdelta4, Vdelta6, Vdelta7 and Vdelta8 subfamilies. In summary,we found that MDS patients showed TCR Vgamma and delta skew distribution and clonal expansion. The absent of TCR Vdelta subfamily was more evident than TCR Vgamma subfamily. These findings provided further evidence that T cell mediated immune processes were a feature of MDS.

Disclosures
No relevant conflicts of interest to declare.
Polish Myelodysplastic Syndromes Registry- Report of 15 Months of Activity.
Authors: Dwilewicz-Trojaczek Jadwiga , Madry Krzysztof , Stella-Holowiecka Beata , Mital Andrzej , Szmigielska Anna , Obara Agata , Sikorska Anita , Nita Ewa , Mendrek Wlodzimierz , Wiater Elzbieta , Zalewska Magdalena , Biedron Monika , Jachalska Anna , Wasilewska Ewa , Wojciechowska Malgorzata , Kopacz Agnieszka , Nowicki Adam , Kolkowska Agnieszka , Guzicka-Kazimierczak Renata , Pedziwiatr Maria , Sedzimirska Mariola , Nowak Ewa , Blasiak Anna , Baranska Ewa , Soroka-Wojtaszko Maria , Gornik Slawomir , Kruger Witold , Katinas Katarzyna , Salamanczuk Zoriana , Sokolowska Bozena , Jedrzejczak Wieslaw W. , Deptala Andrzej 
Published: October 2019

Abstract
Abstract 4848

Background
Myelodysplastic syndrome(MDS) belong to the most common hematological diseases however epidemiological data on MDS are sparse. Until 2008 there were no data about epidemiology of MDS in Poland.

Methods
From 03.2008-05.2009 we have registered 966 patients in Polish MDS Registry. We have included only alive patients of various time of diagnosis. Patients from 22 centers were diagnosed according to WHO 2001 criteria.

Results
There were 508(53%)males and 458(47%) females. Median age at diagnosis was 70(range 19-99). Under 50 were 83(9%) cases with preponderance of females- 51 cases( males 32cases), between 50-70 there were 353(41%) cases, half of the patients-432(50%) were above 70( 247 males and 185 females).Prior chemotherapy and/or radiotherapy had 37((3,8%) patients. Distribution of MDS subtypes was as follows: RA-170(20%) cases, RARS-58(7%), RCMD-244(28%), RCMD-RS-18(2%), RAEB-1-120(14%), RAEB-2-169(19,5%), 5q- -40(4,6%), MDS-U-44(5%).In 103(10%) subtype was not done. Karyotype was available in 276(28%) cases. Cytogenetic risk groups were: low risk-182(68%), intermediate-52(20%) and high risk-33(12%). The most frequent cytogenetic results were: normal karyotype 44%, isolated 5q deletion 19%, complex karyotype 6%, 5q deletion + another one change 3% and 5q deletion with at least 2 changes 3%. According to IPSS risk groups low risk was found in 61( 22%) of cases, intermediate-1 -130(48%), intermediate-2-47(17%) and high risk in 31(11,5%). Median values of Hb was 9,1 g/dL, plts 129 G/L, ANC 1,7 G/L. RBC transfusion dependent were 429(44%) patients and platelet transfusion dependent were 100( 11%) pts. At least 2 U/month RBC transfusion requirement was 140(14%) patients. Serum ferritin level was assessed in 530 cases-171 of them( 32%) had higher than 1000μg/L level.

Conclusions
We have observed predominance of females among MDS patients under 50. Half of the patients had RA or RCMD subtype. Isolated 5 q deletion was the most frequent cytogenetic abnormality. Forty four percentage of patients was RBC transfusion dependant. Serum ferritin level was significantly elevated in 32% of assessed patients at the moment of MDS diagnosis.

Disclosures
No relevant conflicts of interest to declare.
Study On the Clonal Origin of Dysplastic Cells by Fluorescence in Situ Hybridization in Myelodysplastic Syndromes.
Authors: Zhang Jun , Xue Yongquan , Pan Jinlan , Wu Yafang , Shen Juan , Wang Yong , Liu Dandan , Chen Suning 
Published: October 2019

Abstract
Abstract 4858

Objective
To determining the clonal origin of dysplatic cells in Myelodysplastic syndromes (MDS) .

Methods
Karyotypic analyses of bone marrow cells using R-banding technique were carried out to determine the chromosomal abnormalities. Interphase fluorescence in situ hybridization (FISH) and morphologic analysis of bone marrow aspirates were performed in the same cells to investigate the clonal origin of dysplatic cells in 8 MDS patients.

Result
All patients had clonal karyotypic abnormalities: simple abnormality in 1 patient, complex abnormalities in 6 patients, coexistent of two unrelated clones in 1 patient. Most of dysplastic cells in 7 of 8 MDS patients derived from neoplasia clone while 1 patient had a reverse result,no matter what cell lineage was involved. Some of non-dysplastic cells of all patients derived from malignant clone; in 7 patients, the proportion of dysplastic cells in malignant clone were significantly higher than that of non- malignant clone.

Conclusion
Most of dysplastic cells in MDS derived from malignant clones, while the minority of them derived from non-malignant clones. Thus, it is reasonable to expect that in most cases myelodysplasia is present in malignant clone and can be taken as an important diagnostic evidence for MDS.

Disclosures
No relevant conflicts of interest to declare.
MD.
Authors: Gul Zartash , Galili Naomi , Tageja Nishant , Raza Azra 
Published: October 2019

Abstract
Abstract 4863
THE SECONDARY TRANSFORMATION OF MDS INTO MYELOFIBROSIS IS INDEPENDENT OF THE JAK2 MUTATION

Introduction
The exact significance of the JAK2 V617F mutation in MDS is unclear. It has previously been suggested that MF could be associated with MDS as one phenotype of myeloproliferative disorders. Ohyashiki et al in 2005 showed that two of six patients with MDS terminating in MF had the mutation at the time of MF, while no MDS patient without MF had the JAK2 V617F mutation, suggesting that MDS patients with the JAK2 V617F mutation may be responsible for secondary MF in MDS patients. We conducted the following experiments to further probe the role of JAK2 mutation in the pathology of MDS with myelofibrosis at our institution.

Methods
DNA samples of 8 patients in our institution who had MDS with subsequent myelofibrosis were isolated. Genomic DNA isolated using DN easy tissue kit(Qiagen) was amplified by PCR. After confirmation of DNA presence on 1 % agarose gel and purification using QIA quick PCR purification kit (Qiagen), gene sequencing was done. This sequencing was then analyzed for G to T mutation V617F in JAK2.

Results
We found no evidence of the JAK2 mutation in any of the eight samples.

Discussion
Given the fact that nearly half the patients with myelofibrosis carry the JAK2 V617F mutation, the possibility of an association between those patients who have myelodysplasia and subsequent myelofibrosis needs to researched. Our cohort which consisted of 8 patients showed no evidence for any such correlation. This evidence confirms the presence of different pathophysiological mechanisms for phenotypic expression of MDS and primary MF and also leads us to suggest that the expression of JAK2 is not the driving mutation in the pathogenesis of MDS progression to myelofibrosis.

Disclosures
No relevant conflicts of interest to declare.
Pulmonary Alveolar Proteinosis as a Terminal Complication in a Case of Myelodysplastic Syndrome with Idic(20q-).
Authors: Xue Yongquan , Han Yongsheng , Li Tianyu , Chen Suning , Zhang Jun , Pan Jinlan , Wu Yafang , Wang Yong , Shen Juan 
Published: October 2019

Abstract
Abstract 4864
Secondary pulmonary alveolar proteinosis (PAP) is a rare lung disease which was reported in 13 cases of myelodysplastic syndromes (MDS). A dicentric isochromosome of deleted chromosome 20q i.e., idic(20q-) is a newly recognized rare but recurrent cytogenetic anomaly which has been described in thirty cases of MDS. Recently we encounted an interesting MDS patient with idic(20q-) and secondary PAP. At presentation she was a forty-year-old women manifesting pancytopenia and dysplasia involving two cell lineages which were compatible with refractory cytopenia with multilineage desplasia. Chromosome analysis using R-banding technique showed a karyotype of 46,XX,-20,+a small metacentric chromosomal marker. FISH analysis proved this marker to be a dicentric isochromosome of a deleted 20q. Three yaeas after presentation her disease was complicated by secondary PAP which was confirmed by chest computed tomographic scan and the thoracoscopic lung biopsy which revealed the characteristic periodic acid Schiff stain-positive materials filling the alveoli. After prednisolone and intibiotics freatment, her symptoms had temporary improvement. At last she died of respiratory failure with a survival of 45 months. As we know, no MDS patients with idic(20q-) and secondary PAP have been reported in the literature. Thus, this patient is not only the thirty-first MDS case with idic(20q-), but also the first MDS case with idic(20q-) and secondary PAP.

Disclosures
No relevant conflicts of interest to declare.
Analysis of Familial Dysglobulinemia: a Multicenter IFM Study.
Authors: Dumontet Charles , Galia Perrine , Leleu Xavier , Avet-Loiseau Herve , Sobol Hagay 
Published: October 2019

Abstract
Abstract 4891
Multiple myeloma is a haematological malignancy which rarely occurs in a familial context. MGUS corresponds to the existence of a clone secreting a monoclonal immunoglobulin and can in some patients evolve to multiple myeloma. Although recurrent cytogenetic abnormalities have been described in tumor cells of sporadic cases of multiple myeloma, there are presently no identified genetic mechanisms which contribute to myelomagenesis, in particular in familial cases. The identification and study of families with several cases of dysglobulinemia should contribute to the determination of genetic factors predisposing to multiple myeloma. The aim of this study is to identify genetic factors predisposing to familial dysglobulinemia, thanks to the establishment of a DNA bank. Peripheral blood samples were collected both from patients with dysglobulinemia and from healthy family members and lymphoblastoid lines established for further studies. For this purpose, we have initiated a multicenter study aiming to identify families with several cases of dysglobulinemia, including both multiple myeloma and/or Monoclonal Gammapathy of Undetermined Significance (MGUS). This effort is supported by a French National Programme Hospitalier de Recherche Clinique (PHRC) and the French National Institute for Cancer Research (INCa)., and involves the French multicentric Myeloma groups, Intergroupe Francophone du Myélome (IFM) and Myeloma Autograft Group (MAG), in coordination with the Réseau des Hémopathies Familiales. This study was activated in Octobrer 2007 and as of April 2009, 72 families with at least two cases of dysglobulinemia (median 2, range 2-5) have been identified. Among 166 cases of dysglobulinemia, 100 were diagnosed as multiple myeloma, 49 as MGUS and the remainder as light chain amyloidosis or Waldenstrom's disease. The sex ratio was 1:1 for all groups. The median range at inclusion in this study was 64 years (range 33-85 years). The heavy chain subtype distribution was classical, with a majority of IgG cases. 42% of cases corresponded to cases involving parents and offspring and 54% corresponded to cases involving siblings. This study is ongoing in order to collect samples from 100 families and to initiate genetic analyses to identify predisposing factors.

Disclosures
No relevant conflicts of interest to declare.
Effect of Artesunate On Inhibiting Proliferation and Inducing Apoptosis of SP2/0 Myeloma Cells through Affecting NFκB p65.
Authors: LI Shihui , PAN Ling , Xue Fang , Cheng Zhiyong , Yang Xiaoyang , Guo Xiaoling , Wang Suyun 
Published: October 2019

Abstract
Abstract 4893
The initial treatment of multiple myeloma (MM) experienced a paradigm shift, in the past decade, with the introduction of novel agents such as thalidomide, lenalidomide and bortezomib, leading to improved outcomes. High dose therapy and autologous stem cell transplantation remains an important therapeutic option for patients with multiple myeloma eligible for the procedure. However, most of these treatment regimens are too expensive for Chinese patients. Therefore, we investigated the effects of artesunate, which is commonly used in the treatment of severe malaria, on inhibition of proliferation and induction of apoptosis of a mouse myeloma cell line SP2/0. The growth inhibition of SP2/0 cell proliferation induced by artesunate (ART) treatment was measured using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method and the rate of apoptosis and cell cycle changes induced by ART were analyzed by flow cytometry. ART induced morphology changes of apoptosis in SP2/0 cells, as observed by light and transmission electron microscopy. Additionally, DNA laddering, which is a hallmark of apoptosis, was observed by agarose gel electrophoresis of DNA harvested from SP2/0 cells treated with ART. The levels of nuclear factor kappa B p65 (NFκB p65) protein in nucleus and the inhibitor of NFκB (IκBα) in the cytoplasm were measured by western blot analysis and ELISA to evaluate NFκB p65 transcription activity indirectly. The results show that artesunate inhibited the proliferation and induced apoptosis of SP2/0 cells in a dose- and time-dependent manner. Artesunate also increased the proportion of SP2/0 cells in G0/G1 phase, while decreased the proportion of cells in G2/M or S phase. Additionally, artesunate treatment decreased the level of NFκB p65 protein in the nucleus, while increased the level of IκBα protein in the cytoplasm. The present result is the first report to show that artesunate may be useful in the treatment of multiple myeloma.

Disclosures
No relevant conflicts of interest to declare.