bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Study of Bortezomib Alone or in Combination with Harringtonine or Arsenic Trioxide on Proliferation and Apoptosis of Multidrug Resistant Leukemic Cells.
Authors: Meng Fan Yi , Cai Yan Xia , Sun Qi Xin , Fu Yun Bi , Li Li 
Published: October 2019

Abstract
To investigate the effect of bortezomib alone or combined with harringtonine (HT) or arsenic trioxide (As2O3) on the proliferation activity and apoptosis of HL60/ADM cell line and refractory/relapse acute leukemia primary cell. HL60/ADM cells or refractory/relapse acute leukemia primary cells were incubated with bortezomib at different doses alone and in combination with HT or As2O3. The proliferation activity was abserved by MTT assay, cell apoptosis was studied by fluorescence microscopy and flow cytometry. Intracellular concentration of daunorubicin (DNR) was determined by flow cytometry. In bortezomib-treated tumor cells, inhibition rate enhanced and apoptotic cells increased in mumber time- and dose-dependently. 40nM Bortezomib can best inhibit the proliferation activity of HL60/ADM cells when incubated for 48 hours. 15uM As2O3 or 752nM HT combined with different doses of bortezomib can inhibit the proliferation and induce the apoptosis of HL60/ADM cells, The dual inhibition of As2O3 plus bortezomib or HT plus bortezomib may present a superior anticancer efficancy to either inhibition of the drugs above alone (P<0.05;<0.01). Bortezomib (10nM) can markedly enhance the intraceflular accumulation of DNR in HL60/ADM cells(P=0.000). Bortezomib can inhibits proliferation and induces apoptosis of HL60/ADM cells and refactory/ relapse acute leukemic primary cells. When combined with HT or As2O3 appear to have synergistic effects, and the mechanisms might be associated with the ability of reversing multidrug resisitant of Bortezomib.
RARα-Specific Retinoid Am-80 Prevents SDF-1-Mediated Chemotaxis in CXCR4 Expressing Tumor Cells.
Authors: Matsumoto Taichi , Jimi Shiro , Suzumiya Junji , Hara Shuji , Tamura Kazuo 
Published: October 2019

Abstract
Chemokine (C-X-C motif) receptor 4 (CXCR4) plays an important role on hematogenous metastasis of tumor cells to the organs comprising constitutively stromal cell-derived facter-1 (SDF-1). Retinoids have been utilized as a drug for treatment of acute promyelocytic leukemia (APL), in which tumor cells give rise to differentiation and cell death by activation of retinoic acid receptors (RARs). However, the effects of retinoid on chemokine-mediated cell motility are totally unknown. In this study, we examined the effects of retinoids, including all-trans retinoic acid (ATRA) and RARα-specific retinoid Am-80, on CXCR4-mediated chemotactic activity using five myeloid and lymphoid leukemia cells (HL-60, K562, MOLT-3, Jurkat, and U266B1). When cells were incubated with ATRA or Am-80 at doses up to 10 mM for 3 days, comparable effects were found; cytotoxic effect occurred only in HL-60, and growth inhibition was albeit detected in all of other cells. The extents of cell surface CXCR4 in all of the cells detected by flow cytometric analysis tended to be correlated with SDF-1-induced migration activity. Cell surface CXCR4 was slightly decreased by ATRA treatment, while it was significantly decreased by Am-80 treatment, and the alterations were in time- and dose-dependent fashions. In terms of CXCR4 expression, Jurkat was the most sensitive cells. Cell migration in response to SDF-1, was monitored by a modified Boyden chamber method. SDF-1 induced significant chemotaxis in HL-60, MOLT-3 and Jurkat cells, but did not in K562 and U266B1 cells. After treatment with the retinoids, HL-60 was only a cell type increasing random cell motility, however in retinoids-pretreated MOLT-3 and Jurkat cells, no such effect was found, and therefore suggesting that up-regulation of the motility in HL-60 is maybe due to a response by dyeing cells. However, in a case of pretreatment with not ATRA but Am-80, SDF-1-induced chemotaxis of MOLT-3 and Jurkat cells was dose-dependently repressed in accordance with decrease in cell surface CXCR4 expression. This was also confirmed by a time-laps horizontal migration system, indicated that pseudopodia formation accompanied with F-actin rearrangement by SDF-1 was strongly inhibited by Am-80-pretreatment. These results indicate that RARα-specific retinoid Am-80 may induce not only growth inhibition, but also prevention of SDF-1/CXCR4-mediated hematogenous metastasis in CXCR4 expressing tumor cells.
Pharmacogenetic Study of Methotrexate and 6-Mercaptopurine Related Genes in Korean Pediatric Patients with Acute Lymphoblastic Leukemia.
Authors: Kang Hyoung Jin , Seo Young-Jin , Lee Chang Jin , Kim Hyery , Jang Mi Kyung , Koh Sang Hyeok , Oh Yongtaek , Han Byoung-Don , Kim Chul Woo , Kim Eun Kyung , Shin Hee Young , Ahn Hyo Seop 
Published: October 2019

Abstract
The cure rate of pediatric acute lymphoblastic leukemia (ALL) has dramatically improved after the introduction of maintenance therapy. But many Korean patients could not tolerate the planned dose of methotrexate (MTX) and 6-mercaptopurine (MP) from Western protocols. Recently, tailored therapy based on individual pharmacogenetic background is introduced to improve the survival with the reduction of complication. To establish the basis for the tailored therapy, genes associated with MTX and MP metabolism were analyzed in Korean children with ALL. The dose percent to the planned dose of MTX (20 mg/m2) and MP (50 mg/m2) at final maintenance cycle were analyzed with the 7 polymorphism site (MTHFR 677 C>T, MTHFR 1298 A>C, RFC 80 G>A, TYMS enhancer repeat, TPMT 238 G>C, TPMT 460 G>A, TPMT 719 A>G) in 96 ALL patient using TotalPlex PCR method (except TYMS). The median dose percent of MTX and MP of all patients were 57.5% and 49%, respectively. Only 31/96 and 22/96 patients tolerated more than 75% of planned MTX and MP doses, respectively. Variant TPMT was found in 6 patients (one *1/*3B and five *1/*3C). The mean dose percent of MP in patients with variant TPMT (33.2%) was lower than that of others (53.5%), significantly (P=0.04). MTHFR 677, MTHFR 1298, RFC 80, and TYMS enhancer repeat were not associated with the dose percent of MTX. But the dose percent of MTX was correlated with the dose percent of MP significantly (R2=0.64, P=0.00). The 5 year event free survival of all patients was 93.7%. Although 16/96 patients received less than 25% of full MP dose, there was no event in these patients. Dose reduction of MP is recommended for the patients with 3 major variant types of TPMT but many others with wild type could not tolerate the planned dose of MP. Study of novel polymorphism is necessary for the basis of tailored therapy in Korean pediatric ALL patients.
Carbonyl-Substituted Titanocenes as New Cytostatic Agents Against Lymphoma and Leukemia in Childhood.
Authors: Selig Anja , Wagner Laura , Winkler Iris , Lauterbach Thorsten , Gansaeuer Andreas , Prokop Aram 
Published: October 2019

Abstract
Acute lymphoblastic leukemia (ALL) is the most common malignant disease in childhood. Despite a relatively good prognosis approximately one fourth of the patients suffers from relapse and, consequently, a worse prognosis. Only 40% of these children with relapsed ALL will survive. Patients who fail to achieve a complete remission in chemotherapy do not survive. This explains the need for new compounds that may overcome resistance against clinically employed cytostatic drugs. In the present study we examined novel titan-containing agents concerning their cytotoxic potential with great success in vitro, ex vivo in primary leukemia cells from children with primary and relapsed ALL and in vivo in a lymphoma model in mice. We could show anti-leukemic and anti-lymphoma activity in various established cell lines, like Nalm6, Reh, SupB15 and BJAB. By Casy Counter we detected a decrease of proliferation and vitality in cell culture. That the cell death is effected by apotosis induction we investigated by flowcytometric measurement of DNA-fragmentation after propidiumiodid staining (LC50 = 5–10 μM) and phosphatidylserin-staining on cell membrane surface. Via western blotting we could show titanocene-induced caspase-processing and PARP cleavage. To characterize the titanocene apoptosis pathway we used cellular model systems with deficiencies in different molecular parts of the apoptosis cascade. The induced apoptosis reveals to be independent of CD95 receptor, the pro-apoptotic factor SMAC and the anti-apoptotic protein Bcl-2. Even in mamma carcinoma cells (MCF-7) with Caspase 3- deficiency titanocenes were able to induce apoptosis significantly. We also investigated a loss of mitochondrial membrane potential, which indicates the involvement of the mitochondrial apoptosis machinery in titanocene-induced cell death. Unspecific cytotoxic effects, like necrosis, could be excluded by lactatdehydrogenase-release assay. Ex vivo we tested isolated primary lymphoblasts of children with primary and relapsed ALL. We could demonstrate, that even lymphoblasts with resistance against doxorubicin (p < 0.005) and cytarabine (p < 0.01) are sensitive to titanocenes. In vivo tests in a mouse model with human lymphoma cells (BJAB) show significant reduce of tumor progression effected by oral treatment with carbonyl-substituted titanocenes compared with a control group. These experiments in mice show a good tolerability of titanocenes. Taken together, carbonyl-substituted titanocenes comprise a totally new, very promising class of cytostatic agents for lymphoma and leukemia therapy, especially for the therapy of relapsed ALL in childhood.
Clinical Significance of PML/RAR Isoform in Patients of Acute Promyelocytic Leukemia.
Authors: Kim Ki-Hyang , Lee Won-Sik , Lee Kyoo-Hyung , Lee Je-Hwan , Choi Seong-Jun , Lee Jung-Hee , Park Jae-Hoo , Min Young-Joo , Kim Hawk , Bae Sung-Hwa , Ryoo Hun-Mo , Hyun Myung-Soo , Kim Min-Kyung , Zang Dae-Young , Kim Hyo-Jung , Ahn Jin-Seok , Jung Chul-Won , Lee Kyeong-Won , Lee Jung-Lim , Joo Young-Don 
Published: October 2019

Abstract
Background: Three types of PML-RARα mRNA fusion transcripts in acute promyelocytic leukemia (APL) could be existed: a short (S)-form type, a long (L)-form type or a variable (V)-form type. Whether 3 types of PML-RARα mRNA fusion transcripts associated with different manifestations and outcomes in individual APL cases are unclear. Recently, some studies reported the controversial results for the relationship between the types of PML-RARα mRNA fusion transcripts and clinical outcomes. But, there was no data about the types of PML-RARα mRNA fusion transcripts especially for the APL patients who were received remission induction therapy with AIDA.
Methods: We performed a retrospective analysis for the data of 94 patients with APL, whose isoform data was available. We evaluated the differences of therapeutic outcome of remission induction chemotherapy in terms of response rate, relapse-free survival (RFS), overall survival (OS) and the association of pretreatment clinical parameter characteristics according to the PML-RARα isoforms.
Results: The median age of the patients was 41 years (15–85). CR rate following remission induction treatment was 84.9% (AIDA 87.0% vs. non-AIDA 80.0%). Among 94 patients, there were 58 L-form cases (62.1%), 32 S-form cases (34.0%), 4 V-form cases (4.3%). There was no significant difference at any patient’s pretreatment characteristic according to PML-RARα isoform type. CR rate was higher in the group of initial WBC <10,000/ul (93.5% vs. 65.4%, p=0.001). But there was no difference within the isoform L/S subgroup (84.2% vs. 87.2%). And OS and RFS were not different between isoform L/S subgroup (5yr 74.3% vs. 83.1%, 84.2% vs. 85.1%). AIDA induction group was better than non-AIDA induction group regarding OS and RFS (5yr 84.4% vs 55.7%, p=0.026, 90.0% vs 65.7%, p=0.007), but not significant in the multivariate analysis. And also, it was not significantly different in the OS and RFS between isoform L/S subgroup of the AIDA induction group (5yr 80.5% vs. 92.0%, 95.7% vs. 97.0%).
Conclusion: This study suggests that
high initial WBC count is associated with low CR rate, AIDA induction group has a trend of better OS and RFS, treatment outcomes according to PML-RARα isoform type are not different.
Prospective study will be needed to confirm the meaningful significance of PML-RARα isoform type.
Prognostic Significance of Molecular-Cytogenetic Abnormalities in Pediatric T-ALL Is Not Explained by Immunophenotypic Differences.
Authors: van Grotel Martine , Langerak Anton W. , Beverloo H. Berna , Buijs-Gladdines Jessica G.C.A.M. , Burger Nicole B. , van Noesel Max M. , Pieters Rob , Meijerink Jules P.P. 
Published: October 2019

Abstract
Pediatric T-cell acute lymphoblastic leukemia (T-ALL) is characterized by recurrent chromosomal rearrangements that may have prognostic significance. T-ALL cases with specific aberrations may arrest at specific T-cell development stages. Two classification systems were developed to classify T-ALL into developmental subgroups, i.e. the European Group for the Immunological Characterization of Leukemias (EGIL) and the T-cell receptor (TCR) classification system. In this study, we investigated the relationship between molecular-cytogenetic abnormalities and T-cell development stage. We investigated whether arrest at specific T-cell stages explains the prognostic significance of molecular-cytogenetic abnormalities. To this aim, we extensively studied 72 pediatric T-ALL cases by FISH and RQ-PCR for the presence of genetic abnormalities and expression of transcription factors, by PCR and sequencing for NOTCH1 mutations and by flow-cytometry to determine the T-cell receptor status as well as CD marker expression. The median clinical follow-up was 5 years. HOX11 rearranged cases were CD1 positive consistent with a cortical stage, but as 4 out of 5 cases lacked cytoplasmatic-beta expression, developmental arrest may precede beta-selection. HOX11L2 was especially confined to immature and pre-AB developmental stages, but 3 out of 17 HOX11L2 mature cases were restricted to the γδ-lineage. TAL1 rearrangements were restricted to the αβ-lineage with most cases being TCRαβ positive. NOTCH1 mutations were present in all molecular-cytogenetic subgroups without restriction to a specific developmental stage. The CALM-AF10 translocation as detected in 3 T-ALL patients was significantly associated with early relapse. TAL1 or HOX11L2 rearrangements were associated with trends to good and poor outcome, respectively. Cases with high TAL1 expression levels also demonstrated a trend towards good outcome, whereas cases with the lowest TAL1 levels had a poor outcome and were mostly HOX11L2 or CALM-AF10 positive. NOTCH1 mutations did not predict for poor outcome. Classification into T-cell developmental subgroups did not predict for outcome. In conclusion, the present study shows that differences in outcome for various molecular-cytogenetic subgroups cannot be attributed to differences in T-cell maturation stage.
Myeloid-Associated Antigen Expression Is an Adverse Factor for Complete Remission Following Induction Chemotherapy of Adult Precursor T-Lymphoblastic Leukemia/Lymphoma (T-ALL).
Authors: Al-Khabori Murtadha , Samiee Samira , Fung Sharon , Xu Wei , Brandwein Joseph , Brien William , Patterson Bruce , Chang Hong 
Published: October 2019

Abstract
We retrospectively reviewed our experience of 63 adult T-ALL patients to identify clinical and pathologic prognostic factors and build a risk-stratification model for induction chemotherapy. At presentation, the patients’ median age was 30, 49 were male and 14 female, 69% had lymphadenopathy, 38% a mediastinal mass, 24% CNS involvement and 21% splenomegaly. The median initial WBC was 17.9 x 109/L (range 0.10–510.0). Blasts expressed CD34 in 42% of cases, CD10 in 33% and at least one myeloid-associated antigen (CD13 or CD33) in 27%. Karyotypes were abnormal in 34% of cases. Fifty-three of 61 patients (87%) who underwent induction chemotherapy achieved complete remission (CR) on protocols including vinca alkaloids, anthracyclines and corticosteroids. On univariate analysis; age, gender, initial WBC, CD10, CD34 and abnormal karyotype did not predict CR but patients expressing at least one myeloid-associated antigen had a CR of 71% compared to 93% (P=0.03) for patients not expressing myeloid antigens. The median follow-up was 19.2 months (95% CI: 0.1–172.8). Twenty-three patients relapsed with a median relapse-free survival (RFS) of 41.6 months (95%CI: 21.6–55.9). The RFS was longer for patients with an initial WBC of 3–50 x 109 and for cases expressing CD10 but neither was statistically significant (P=0.19, P=0.14). On follow-up, 34 patients died with a median overall survival (OS) of 31.3 months (95%CI: 16.8–56.8). Patients with CD10 expression had a longer median OS at 44.7 months (versus 19.2 months for CD10 negative patients) but again, the difference was not statistically significant (P=0.11). Age, gender, CD34, myeloid-associated antigen expression and karyotype did not influence RFS or OS. Our study indicates that expression of myeloid-associated antigens is an adverse prognostic factor for complete remission of adult T-ALL and should be considered for induction chemotherapy risk-stratification.
Crosslineage T-Cell Receptor Genes Rearrangements and Active Receptor Editing in B-Cell Acute Lymphoblastic Leukemia.
Authors: Makuch-Lasica Hanna , Majewski Miroslaw , Nowak Grazyna , Kania Iwona , Lewandowska Monika , Konopka Lech , Warzocha Krzysztof 
Published: October 2019

Abstract
B-cell acute lymphoblastic leukemia (B-ALL) results from clonal expansion of B-lymphocytes derived at different stage of differentiation. Immunoglobulin (Ig) heavy chain genes (IGH), light chain kappa (IGK) and lambda (IGL) genes rearrange during early B-lymphocyte differentiation. T-cell receptor (TCR) genes are considered to rearrange exclusively in normal T lymphocytes, but malignant B lymphoblasts often contain crosslineage rearranged TCR genes. The clonal leukemic cell population, carrying identical copies of rearranged Ig and/or TCR genes, can be identified above 95% of B-ALL patients. In our study Ig/TCR genes rearrangements were detected by multiplex PCR with heteroduplex analysis according to BIOMED-2 protocol. DNA was isolated by column method from mononuclear cells isolated from the peripheral blood/bone marrow samples obtained at initial diagnosis from 36 B-ALL patients. Monoclonal rearrangements of Ig genes were detected in 100% (36/36) of patients. The most frequent rearrangements were observed in IGH genes (94%), including complete IGHV-IGHJ in 83% (30/36) and incomplete IGHD-IGHJ in 22% (8/36) of patients. Among complete IGH rearrangements 2 biallelic rearrangements in IGHV1-7 and IGHJ genes (FR3) were found. Ig light chain genes rearrangements were identified in 26 patients (72%) (including 64% of IGKV-IGKJ, 47% IGKV/intron-Kde, and 22% IGLV-IGLJ) what indicates active receptor editing occurring during B lymphoblasts leukemogenesis. Crosslineage TCR genes rearrangements were found in 97% (35/36) of patients. TCR beta genes rearrangements were detected in 47% (17/36) of patients (complete TRBV-TRBJ in 25% (9/36), TRBD-TRBJ in 6/36 patients - 17%). TRGV-TRGV in 58% (21/36), TRDV-TRDJ in 58% (21/36); 17 monoallelic and 4 biallelic were found. The inactivation of potentially functional IGKV-IGKJ by secondary rearrangements indicates active receptor editing. Our data describe IGK and IGL genes rearrangements incidence, present allelic exclusion and active receptor editing in B-ALL patients. B-ALL lymphoblast undergoes rearrangement on the same IGK allele before IGL genes rearrangement occur. The data may suggest the possible of antigens in B-ALL immunopathogenesis. The results indicate also rearranged IGK, IGL and TCR genes as stable molecular marker for monitoring MRD in B-ALL.
Clinical Characteristics and Outcomes in Patients with t(8;21) Acute Myeloid Leukemia in Japan.
Authors: Narimatsu Hiroto , Yokozawa Toshiya , Iida Hiroatsu , Tsuzuki Motohiro , Hayakawa Masaya , Takeo Takaaki , Iino Masaki , Ichihashi Takuji , Kato Chiaki , Sawamoto Akiyo , Sao Hiroshi , Yanada Masamitsu , Emi Nobuhiko , Kiyoi Hitoshi , Yamaguchi Tetsushi , Naoe Tomoki , Suzuki Ritsuro , Sugiura Isamu 
Published: October 2019

Abstract
Clinical characteristics of Japanese patients with t(8;21) acute myeloid leukemia (AML) have not been well described. From January 2000 to December 2005, a total of 147 Japanese adult de novo AML (FAB: M2) patients were newly diagnosed with t(8;21) AML (n=46) or without t(8;21) AML (n=101) in collaborating hospitals. Patients with t(8;21) (median age, 49.5 years; range, 18–86 years) were significantly younger than AML(M2) patients without t(8;21) (median age, 60 years; range 17–90 years) (p<0.001). Three-year overall survival rate in patients with t(8;21) was 70% (95% confidence interval (CI), 51–83%), significantly better than that in AML (M2) patients without t(8;21) (log-rank test, p=0.005) (Figure). Among patients <60-years-old, overall survival rates of patients with t(8;21) AML and patients with non-t(8;21) AML(M2) were 71% (95%CI, 47–86%) and 58% (95%CI, 41–72%), respectively (log-rank test, p=0.28). Of the 40 patients who achieved complete remission, 21 patients received high-dose cytarabine-containing consolidation therapy. Event-free survival rates at 3 years after diagnosis in patients with and without high-dose cytarabine were 60% (95%CI, 36–78%) and 57% (95%CI, 26–79%), respectively (log-rank, p=0.87). In multivariate analysis, age and white blood cell count at diagnosis represented significant predictors of overall survival. For the 147 AML(M2) patients, presence of t(8;21) was not a significant predictor of overall survival after adjusting for age (hazard ratio, 0.65; 95%CI, 0.34–1.24; p=0.19). Japanese patients with t(8;21) AML display more favorable survival rates than those in Western countries. Efficacy of high-dose cytarabine might differ between Japanese and Western patients. Clinicians must be aware of potential differences among different ethnicities.
Figure Figure
Immunohistochemical Staining for p16 in Acute Lymphoblastic Leukemia.
Authors: Kim Sun Young , Jeong Dae-Chul , Lee Mee Jeong 
Published: October 2019

Abstract
Purpose: p16 gene, mapped to the 9p21 chromosomal region, has emerged as a candidate tumor suppressor gene in human neoplasm. It is an inhibitor of cyclin-dependent kinase and inhibits Rb phosphorylation. In a variety of tumors, deletion and/or mutation of the p16 gene has been found including childhood acute lymphoblastic leukemia (ALL). Despite their high frequency, the prognostic importance of p16 alterations is still controversial in ALL and has been reported to be either unfavorable or similar to that of other patients. We studied the correlation between p16 and clinical outcomes of patients diagnosed as ALL.
Methods: We performed an immunohistochemical staining for protein p16 in 74 cases of bone marrow biopsy slide initially diagnosed as ALL between January 1998 and December 2006. We reviewed the clinical manifestations, laboratory findings, treatment outcomes retrospectively.
Results: Of 74 slides, 12 were negative for p16. Seven were males and 5 were females with a median age at diagnosis was 5.8(1.3–18.8) years. Initial WBC were 17,225(500–403,300)/μl and by immunologic surface marker analysis, 7 patients were early pre-B CALLA(+) and 5 patients were T-cell ALL. Two patients of intermediate risk group had relapsed and died. Three patients had family history of breast cancer. Four patients died and overall survival rates were 53.5±18.7%.
Conclusion: p16 is supposed to be an independent risk factor of childhood ALL associated with poor outcomes. In clinical setting, the clinician must take into account p16 status, not only at the genomic but also at the protein level. Further clinical experience on thoroughly investigated cases will help a better understanding between p16 and clinical outcomes.