bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Treatment of STI571 (Glivec) and Curcumin Synergistically Suppresses the Growth of K562 Cells Via Inhibition of Bcr-Abl Pathway.
Authors: Park Juwon , Bae Eunkyung , Yoon Sung-Soo , Kim Byoung K. 
Published: November 2019

Abstract
Curcumin, biologically active compound extracted from rhizomes of Curcuma species, has been shown to possess potent anti-inflammatory and anti-tumor properties. As such, curcumin caused dose-dependent apoptosis of K562 cells, which is preceded by the activation of caspase 3. In addition, phosphorylation of Erk was effectively inhibited by curcumin. These findings leaded us to investigate the effects of combined treatment of curcumin and STI571 on K562 cells. With combined treatments, expression of Bcl-2, -XL, and Bid were dramatically down-regulated. In addition, the activity of caspase-3 was 2 fold higher than compared with either treatment alone. Cyclin D1 and its related proteins were down-regulated. In addition, combined treatment of curcumin and STI571 dramatically inhibited phoryphorylation of abl and its downstream proteins such as Src kinases and MAPK in K562 cells stimulated by IL-3. Taken together, our data suggested that curcumin potentiated the effects of STI571 in CML.
Quantitative Monitoring of T315I BCR-ABL Mutation by the Invader Assay.
Authors: Kakihana Kazuhiko , Ohashi Kazuteru , Najima Yuho , Kikuchi Taku , Nagata Yasunobu , Ueki Toshimitsu , Kobayashi Takeshi , Yamashita Takuya , Akiyama Hideki , Yamaguchi Toshikazu , Sakamaki Hisashi 
Published: November 2019

Abstract
Although imatinib mesylate has a highly inhibitory effect against BCR-ABL kinase, primary and secondary refractoriness have been observed. Point mutation within the kinase domain of BCR-ABL is one of the most important drug-resistant mechanisms. Of 25 reported point mutations, T315I BCR-ABL mutation might be dismal in clinical settings because it mediates clinical resistance to imatinib, nilotinib, and dasatinib, and the only established therapeutic option is hematopoietic stem cell transplantation at this moment. However, there is no information about the kinetics of this mutated clone. Here we developed quantitative Invader assay to monitor T315I BCR-ABL transcript. By using fluorescent resonance energy transfer system, the amount of released 5′ flap is measured as signal intensity, which enables us to calculate the percentage of T315I products with standard curve. Using this assay, we serially monitored T315I BCR-ABL transcript in a CML patient whose BCR-ABL transcript was still detectable (more than 100 copies/microgram RNA) 3 months after starting imatinib therapy. Although we have continued to monitor T315I BCR-ABL transcripts in 13 patients (chronic phase) up to 10 months, there was no patients who appear to be apparently resistant to imatinib due to a given T315I mutant, so far. In contrast, in a case of Ph+ ALL was being treated with chemotherapy including imatinib, we serially monitored both wild type and T315I BCR-ABL transcripts and observed the increased level of T315I transcript during relapse (0%at the time of diagnosis and 54.8% at relapse). Thus, our new strategy could be a useful tool to study the kinetics of the mutant clone and the pharmacokinetics of the drug resistant to T315I mutation.
BCR-ABL Induces Autocrine IGF-1 Signaling.
Authors: Kumarylakshmikuttyamma Asha , Pastural Elodie , DeCoteau John F. , Geyer C. Ronald 
Published: November 2019

Abstract
BCR-ABL is responsible for the initial phase of chronic myelogenous leukemia (CML), which is effectively treated by the BCR-ABL tyrosine kinase inhibitor imatinib. Over time, patients become resistant to treatment and progress to blast crisis, an event that is driven by additional genetic and epigenetic aberrations. Recently, we showed that RIZ1 expression decreases in blast crisis and that re-expression of RIZ1 inhibits IGF-1 expression. IGF-1 signaling is required in many stages of hematopoiesis and inappropriate activation of autocrine IGF-1 signaling may facilitate transformation to blast crisis. In this study, we examined mechanisms used by CML blast crisis cells to activate IGF-1 expression. We monitored the effects of small molecule inhibitors and shRNAs of BCR-ABL, HCK, and STAT5b on IGF-1 expression, proliferation, and apoptosis in CML blast crisis cell lines. We used chromatin immunoprecipitation assays to confirm that STAT5b associates with the IGF-1 promoter in a BCR-ABL-dependent manner. We found that BCR-ABL activates autocrine IGF-1 signaling using HCK and STAT5b. Imatinib blocks HCK phosphorylation, STAT5b phosphorylation, and the association of STAT5b with the IGF-1 promoter. Inhibition of these signaling components using small molecule drugs or shRNA inhibits IGF-1 expression, decreases proliferation, and enhances apoptosis. The effects of imatinib are partially reversed by the addition of exogenous IGF-1. Furthermore, treatment of CML blast crisis cell lines with the IGF-1 receptor inhibitor AG1024 decreases proliferation and enhances apoptosis and this activity correlates with IGF-1 expression levels. Our study highlights autocrine IGF-1 signaling as an important event in the transformation to blast crisis and provides a novel mechanism to explain the activity of IGF-1R and HCK inhibitors in blocking blast crisis phenotypes. Together, our results provide further support for the therapeutic potential of IGF-1 signaling components in treating CML, especially in cases associated with elevated autocrine IGF-1 expression.
Nordic CML Study Group Quality and Standardization Rounds for Quantitative RT-PCR of BCR-ABL To Facilitate Reporting on the International Scale.
Authors: Boström Hans , Lundan Tuija , Andersen Morten Tolstrup , Barbany Gisela , Fioretos Thoas , Golovleva Irina , Jonasson Jon , Juvonen Vesa , Lindlöf Mikael , Olsen Mats Irgen , Pallisgaard Niels , Savolainen Eeva-Riitta , Schaffer Marie , Silye Aleksandra , Hjorth-Hansen Henrik , Magnusson Magnus K. , Nielsen Johann Lanng , Porkka Kimmo , Simonsson Bengt , Kairisto Veli 
Published: November 2019

Abstract
Measuring the level of BCR-ABL transcripts by real-time quantitative polymerase chain reaction (RQ-PCR) has been shown to be a highly sensitive and specific method for evaluating residual disease burden in chronic myeloid leukemia (CML). In the IRIS trial, a 3-log reduction of BCR-ABL transcripts from a baseline median pre-treatment level was termed a “major molecular response”, and achieving this degree of minimal residual disease (MRD) was related to a more favorable prognosis. Recently it was proposed that the residual disease scale used in the IRIS trial should be named “International Scale” (IS) and this scale is recommended to be used in future studies of CML treatment. Since the baseline in the IRIS trial can no longer be reproduced, a project for distributing reference material has been initiated by the original IRIS study reference laboratory in Adelaide and by a secondary European reference laboratory in Mannheim. Within the framework of the Nordic CML Study Group, RQ-PCR for BCR-ABL is routinely performed in 13 clinical laboratories located in Finland, Sweden, Norway and Denmark. Only two Nordic laboratories had an opportunity to receive reference material from Mannheim. Therefore it was necessary to complement this effort by performing a Nordic quality and standardization round based not only on the external reference material but also on local pre-treatment samples from CML patients. Thus each of the participating laboratories prepared samples representing minimal residual disease and also additional pre-treatment CML samples. These samples were divided into 13 identical aliquots and distributed to all other participants this summer. By this approach we can not only check reproducibility of measurements, but also evaluate different laboratory specific steps in the procedures, such as the importance of source cell material, RNA isolation method, control genes, model of thermocycler and methods/enzymes used in reverse-transcription and RQ-PCR. Based on the results, provisional conversion factors for adjustment of the BCR-ABL transcript levels to the International Scale will be produced for all participating laboratories. This work is an example on successful international RQ-PCR standardization, which is essential for clinical and research estimation of MRD in CML patients.
Mechanisms of 2-Methoxyestradiol-Induced Apoptosis on Myelodysplastic Syndrome MUTZ-1 Cell Lines.
Authors: Chen Bao-An , Xia Guo-Hua , Lu Hui-Xia , Shao Ze-Ye , Gao Chong , Ding Hua-Jia , Xiao Ping-Pei , Chen Ning-Na , Zhao Gang , Gao Feng , Chen Jian , Wang Jun 
Published: November 2019

Objective: To study the mechanism of proliferation inhibition and apoptosis of MDS-RAEB MUTZ-1 cells by 2-methoxyestradiol(2-ME).
Methods: MUTZ-1 cells were treated with different concentrations of 2-ME;cellular proliferation was determined by MTT assay;apoptosis rate was determined with annexinV-FITC/PI double staining and cell cycle was analyzed by flow cytometry (FCM);the changes of morphologic features of MUTZ-1 cells were investigated by cytomorphology with Wright-Giemsa’s staining; lactate dehydrogenises (LD) was determined by Beckman Counter and agarose gel electrophoresis was used to verify whether 2-ME could induce apoptosis in MUTZ-1 cells. Moreover, the activity of telomerase in MUTZ-1 cells was examined by TRAP-ELISA.
Results: The results showed that 1∼4μmol/L 2-ME inhibited the proliferation of MUTZ-1 cells in a dose-and time-dependent manner; the typical apoptotic morphological features appeared in MUTZ-1 cells after being treated with 4μmol/L 2-ME for 12hours; the marked DNA ladder pattern of internucleosomal fragmentation was observed after being treated with 4μmol/L 2-ME for 24hours and the up-regulated production of LD was assayed after treatment of 2-ME for 36hours. The number of MUTZ-1 cells of G0/G1 phase and S phase decreased, while the number of G2/M phase increased after MUTZ-1 cells were incubated with 1,2 and 4μmol/L2-ME for 12 hours, respectively(P<0.05). The inhibition effect of telomerase activity was enhanced in a dose- and time- dependent manner. Moreover, telomerase activity was significant negatively correlated with increased apoptosis (r =−0.954, p=0.046) and the number of sustained G2/M phase(r=−0.979, p=0.021) at the corresponding time point, respectively.
Conclusions :It is concluded that the mechanism of proliferation inhibition and apoptosis of MUTZ-1 cells induced by 2-ME is probably related with inhibition of telomerase activity and G2/M cell cycle arrest; 2-ME may be a potentially useful, adjunctive anticancer drug in treating myelodysplastic syndrome.
Cyclosporine A without or with Thalidomide for the Treatment of Patients with Myelodysplastic Syndromes.
Authors: Xiao Zhijian , Xu Zefeng , Wang Jianxiang , Hao Yushu 
Published: November 2019

Abstract
The myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal hematopoietic stem cell disorders, while, immunological abnormalities are frequently observed in patients with MDS. Recently immunosuppressive therapies including prednisolone, antithymocyte globulin, and cyclosporin A (CsA) are used to treat cytopenia in some patients with MDS. Recent clinical trials have also confirmed that thalidomide may improve anemia and, less frequently, other cytopenias, in a proportion of younger patients with low-riskMDS (11–56%, on intention-to-treat analysis). In the current study, we report the outcome and side-effects in patients with MDS treated with cyclosporine A without or with thalidomide. From October 2000 to October 2005, 32 patients with MDS (RCMD 22 cases, RCMD-RARS 3 cases, RAEB-I6 cases, 5q- symdrome,1 case)were treated with cyclosporine A(CSA)(3mg/Kg.d) as single agents (n=14, group A) or CSA combined with thalidomide (200mg–400mg/d)(n=18, group B). There were no significant difference in hematologic or clinical features, Karyotype anomalies, classification of FAB or WHO, International Prognostic Scoring System(IPSS) score between the two group patients. Four patients of group A(28.5%) and twelve of group B (66.7%, P=0.011) achieved hematologic improvement. Three patients achieved a HI-E (three major), three patients HI-P(two major, one minor)and three patients HI-N(two major, one minor)within the group A. Twelve patients achieved a HI-E (eleven major, one minor), seven patients HI-P(five major, two minor)and six patients HI-N(three major, three minor)within group B. Two patients(2/11 cases,18.2%) became transfusion independence within group A, nine patients(9/14 cases, 64.3%)became transfusion independence within group B. There was statistic difference between two groups(P=0.021). Nine patients emerged hepatic lesion(three in group A(21.4%), six in group B(33.3%), P=0.457), Three patients emerged nephrotoxicity(one in group A(7.1%), two in group B(11.1%), P=0.702). These patients all made a recovery by treatment. Our primary results showed that CSA combined thalidomide is highly effective and relatively well-tolerated treatment for patients with MDS.
A Comparison of Stem Cell Source in Recipients of T-Cell Depleted Myeloablative Transplants for Leukaemia: No Difference in Mortality Using BM or PBSC.
Authors: Shaw B.E. , Russell Nigel H. , Pagliuca A. , Apperley J. , Cook G. , Mackinnon S. , Madrigal J.A. , Marks D. , Morgan G.J. , Peggs K. , Potter M.N. , Towlson K. , Byrne J.L. 
Published: November 2019

Abstract
The use of GSCF-mobilised Peripheral Blood Stem Cells (PBSC) for unrelated donor (UD) transplantation has increased dramatically since 2000. The association of PBSC with more rapid engraftment and with an increase in chronic Graft versus Host Disease (GvHD), compared to bone marrow (BM) has been reported in a number of studies. More recently the use of PBSC has been associated with an increase in transplant related mortality (TRM) and decrease in survival (OS) in T-cell replete transplants. We sought to analyse the impact of PBSC compared to BM in a cohort of UD transplant recipients, where T-cell depleting agents (in-vivo campath in >90%) were included in the transplant conditioning. The study included 145 patients transplanted between January 2000 and March 2006: CML- 35 in 1CP; acute leukaemia (AML in 61, ALL in 49)-110 in CR1 or 2. All had myeloablative conditioning regimens and received grafts with 9–10/10 matched HLA alleles. 86 patients received BM and 59 PBSC. There were no associations between the stem cell source and any transplant variable (including disease and stage). There was a trend to an increased use of PBSC in patients with a single antigen mismatch (p=0.052). All evaluable patients achieved neutrophil engraftment, with a significantly faster time to engraft in recipients of PBSC compared to BM (16 vs 20 days; p=0.0003). The incidence of acute GvHD was 46% (grade I in 50%, II in 41%, III in 8%, IV in 2%). This was significantly higher in recipients of PBSC (60%) compared to BM (36%; p=0.006), however there was no increase in either II/IV (p=0.69) or III/IV (p=0.18) disease in PBSC recipients. In univariate analysis, the presence of a single HLA mismatch (p=0.026) was the only other variable to be associated with an increase in acute GvHD. In a logistic regression model including both these variables, the use of PBSC remained significantly associated with an increase in aGvHD (OR=2.3; 95% CI 1.1,4.7;p=0.020). The TRM was 14%, 27% and 39% at 100 days, 1 and 5 years respectively. At none of these time points was the stem cell source associated with a significant difference in TRM. The 5-year incidence of chronic GvHD was 58% (BM 55%, PBSC 60%; NS), extensive disease in one third, and of relapse was 61% (BM 60%, PBSC 62%; NS). The 5-years OS was 41% with a median follow-up of 3.4 years (0.5–7.1). This was 44% using PBSC and 40% using BM (NS). In conclusion, although we observed an increase in acute GVHD with PBSC this was only of grade 1 disease. We found no association between the use of PBSC and an increased risk of chronic GVHD or of a worse transplant outcome, when compared to BM, in recipients of T-cell depleted myeloablative transplants for leukaemia.
Treatment of Myelodysplastic Syndrome with Azacitidine and Erythropoietin.
Authors: Limaye Sewanti , Lipshitz Jay , Dulala Renuka , Patel Dilip 
Published: November 2019

Abstract
PURPOSE: Myelodysplastic syndrome (MDS) is a group of clonal bone marrow disorders leading to bone marrow failure and acute myeloid leukemia. With better understanding of the biology of MDS, newer treatment options like therapy with the hypomethylating agents, azacitidine and decitabine have proven beneficial. Major randomized controlled trials by CALGB and others have demonstrated the efficacy of azacitidine. Growth factor use was prohibited in these trials. However, in the community, most patients have continued to get growth factor support along with azacitidine therapy. Since there is lack of evidence backing such clinical practice, we attempted to review response to therapy in patients receiving combination therapy with azacitidine and erythropoietin.
METHODS: We identified MDS patients treated with concomitant azacitidine and erythropoietin at our institution over the last five years. Data collected from retrospective chart review of these patients was statistically analyzed.
RESULTS: Sixteen patients with concomitant azacitidine and erythropoietin therapy were identified. Complete remissions were seen in 31%(5/16) of the patients. Induction of partial remissions in our study was 25% (4/16). Thirty one percent (5/16) of patients had hematologic improvement not meeting criteria for partial remission. Thirteen percent of patients (2/16) did not benefit at all from azacitidine and erythropoietin support. The median number of cycles received for adequate response was six. A total response (complete remission, partial remission and hematological improvement) of 87%(14/16,) was seen with combination therapy, which is significantly higher than previously published total response of 44–60%.
CONCLUSION: Azacitidine with erythropoietin support provides important clinical benefits for patients with MDS. There was a trend towards a higher rate of complete and partial responses in these patients than reported earlier in patients who received azacitidine alone. Randomized controlled studies will be needed to validate this further.
Comparison of response to therapy in high risk MDS: Responses *CALGB-9221(azacitidine) **Combined analysis(azacitidine) Study patients treated with azacitidine and growth factors *JCO May 15 2002: 2429–2440.**JCO Aug 20 2006: 3895–3903. Complete Remission 7% 10–17% 31% Partial Remission 16% Rare 25% Hematological Improvement 37% 23–36% 31% Total response 60% 44% 87%
No Reversal of Demethylation after Azacitidine Treatment in Concordance with Poor Clinical Response.
Authors: Tran Huong Thi Thanh , Kim Hee Nam , Ahn JaeSook , Lee Il-Kwon , Yang Deok-Hwan , Kim Yeo-Kyeoung , Lee Je-Jung , Park Kyeong-Soo , Kim HyeoungJoon 
Published: November 2019

Abstract
The epigenetic gene silencing associated with promoter DNA methylation is as powerful as gene mutations in functionally inactivating tumor suppressor genes. Thus, a non-intensive treatment may be changed the natural history of MDS for the first time by the demethylating agent, 5-aza-deoxycytidine (Decitabine) with silenced gene expression by reversal of p15 hypermethylation and protein expression in the bone marrow in MDS. The MS-MLPA (methylation-specific multiplex ligation-dependent probe amplification) ME-001B probemix (MRC-Holland) containing 25 tumor suppressor genes has been used to detect the methylation level in the peripheral blood samples of 29 MDS before azacitidine (Vidaza) and only 6 MDS after 3–5 courses of therapy. Patients that hypermethylated at least 1 gene were 7 of 29, either the common hypermethylating genes as p15, ESR1 or the previously known FHIT in MDS also have occurred. Only two patients except one patient related to either methylation level-reducing gene or removal methylated gene (putative demethylation reversal) have in concordance with clinical response in hematological evidence. Interestingly, three other patients were high methylation level persistently or additional methylated gene after treatment (putative demethylation no reversal or more severe), two patients of these are correspond with no clinical response and one is propensity to progressing leukemia. With IGSF4 gene hypermethylation, to the best of our knowledge, there was no report in MDS. Our results suggest that methylation level possibly contributes to the dignosistic, prognosistic and a molecular monitoring marker after treatment of Azacitidine.
Pediatric Myelodysplastic Syndrome and Juvenile Myelomonocytic Leukemia in Korea: A Nation-Wide, Multicenter, Retrospective Study.
Authors: Kook Hoon , Han Dong Kyun , Kang Hyeong Jin , Cho Bin , Chung Nak Gyun , Im Ho Jun , Park Hyeon Jin , Park Jun Eun , Yoo Keon Hee ,   for MDS Committee of the Korean Society of Pediatric Hematology Oncology
Published: November 2019

Abstract
Recent advances in the diagnosis, molecular pathogenesis, classification and therapy have been made in the field of myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML) in childhood. We report a retrospective analysis of children with MDS and JMML diagnosed between 2001 and 2006 in Korea. In total, 135 patients were enrolled from 19 major hospitals with pediatric hematology oncology clinics: MDS, 96 (primary MDS, 77; constitutional anomalies with MDS, 13; treatment-related MDS, 6) and JMML, 39. The incidence of MDS/JMML was around 22.5/year, which is about 6% of childhood leukemia. Various classification systems including FAB, WHO, IPSS, CCC system, and pediatric adjustment of the WHO classification were applied. The median ages at diagnosis were 68 and 10 months in MDS, and JMML, respectively. Males dominated in JMML. Cytogenetic abnormalities were observed in 43% of MDS (monosomy 7, 5; trisomy 8, 3) and in 10% of JMML. Treatment was chosen by each institute’s preference: 34 patients with MDS received AML-type intensive chemotherapy, with complete remission rate of 82.0%. The 5-year Kaplan-Meier overall survival rate was 54% each for MDS and JMML. Survival of MDS patients was influenced by the marrow blast % (P = 0.007) and disease category (P= 0.006). Stem cell transplantations (SCT) were undertaken in 56 patients (MDS, 29; JMML, 27). The sources of stem cells were: bone marrow, 36; umbilical cord, 18; peripheral blood, 2). Matched related transplants were 9 cases. Conditioning was various, but BuCy based regimen was used in 68.4%. Acute GvHD ≥ Grade II was found in 43.8% and chronic GvHD in 35.1%. The 5-year Kaplan-Meier overall survival rate was 55% for MDS, and 57% for JMML. Survival after unrelated transplant was comparable with that of matched related transplants. This analysis inspired the necessity of nation-wide prospective studies in Korea, including morphologic study by a central pathology review board, epidemiologic study, molecular pathophysiologic study, and therapeutic trials incorporating SCTs, or new drugs.