bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hyaluronan in the Bone Marrow of Healthy Individuals and Patients with Acute Myeloid Leukaemia.
Authors: Sundstrom Gunnel M. , Dahl IngerMarie S. , Hultdin Magnus , Wahlin Anders , Engstrom-Laurent Anna 
Published: April 2020

Abstract
In the connective tissues the two major structural components are collagens and glycosaminoglycans (GAGs). When assessing pathological processes in the extracellular matrix, e.g. fibrosis, attention is primarily directed to the collagens. Hyaluronan (HYA) is a GAG of great interest not only as a tentative marker of early fibrosis but also of importance for the disease process in various malignancies.
Acute myeloid leukaemia (AML) is a clonal disorder characterised by abnormal proliferation of myeloid cell precursors. Research has mainly focused on the cellular events but the bone marrow matrix has attracted minor interest.
In this study bone marrow biopsies were obtained from 35 newly diagnosed AML patients and 30 healthy individuals. The bone marrow sections were analysed histochemically for HYA and reticulin (type III collagen).
The HYA staining was significantly stronger, p=0.003, in the AML patients compared to the healthy controls. Only one patient demonstrated abnormal reticulin staining score, but in the group of 8 patients with antecedent myelodysplastic syndrome (MDS), the reticulin staining score was significantly higher, p=0.003, compared to the patients with de novo AML. There was a significant correlation between the HYA and reticulin staining scores, p=0.005, in the AML patients as was seen in the control group, p=0.0005, indicating that the variables HYA and reticulin are not independent. No correlation was found between HYA grading and lactate dehydrogenase (LDH), number of blast cells, sex, age or antecedent blood disease before AML diagnosis. In the control group there was a significant correlation, p=0.042, between HYA and age.
Our findings establish that there is a deposition of HYA in bone marrow in healthy individuals and that HYA is increased in AML patients. It is discussed whether HYA could be an early marker of impending fibrosis and also exert important effects on cellular events in the disease process.
Tumor Necrosis Factor Alpha Inhibits Telomerase and Induces Senescence in Acute Myeloid Leukemia Cells.
Authors: Beyne-Rauzy Odile , Recher Christian , Dastugue Nicole , Prade-Houdellier Nais , Pottier Geraldine , Demur Cecile , Sabatier Laure , Laurent Guy , Mansat-DeMas Veronique 
Published: April 2020

Abstract
Tumor necrosis factor alpha (TNFα) is a multifunctional cytokine, which is overproduced in a series of hematological diseases, including acute myeloblastic leukemia (AML) and myelodysplasia (MDS). Apoptotic cell killing has been the most frequently documented cellular effect of TNFα in AML cells. Much little is known about TNFα effect in AML cells, which display an intrinsic defect in their apoptotic machinery. In this study, we describe that prolonged exposure to TNFα, but not Fas, resulted in senescence in the immature CD34+ CD38− KG1 cell line. Indeed, TNFα-treated KG1 cells displayed growth arrest, increased senescence-associated β-galactosidase activity, telomere shortening and additional chromosomal abberations. In these cells, as well as in fresh AML cells, treatment with TNFα resulted in decreased hTERT gene trancription and hTERT activity. Moreover, we found that ceramide production and JNK activation were critical signaling components in TNFα-induced hTERT gene inhibition. GM-CSF stimulation inhibited ceramide production, JNK activation, hTERT inhibition, and senescence markers induction. To conclude, our study suggests that, at least in some AML cells, TNFα is a regulator of hTERT with important functional consequences in terms of growth capacity and genetic stability. Moreover, the pro-senescent effect of TNFα is efficiently counter-regulated by stimulatory cytokines such as GM-CSF.
Involvement of Altered PML/RARalpha and RARbeta Expression in Delayed Restoration of Retinoic Acid Sensitivity in UF-1, an Acute Promyelocytic Leukemia Cell Line Carrying a Patient-Derived Mutant PML/RARalpha(Arg611Trp).
Authors: Hoshi Yoshiyuki , Imaizumi Masue , Iinuma Kazuie 
Published: April 2020

Abstract
[Introduction]
Mutations in the PML/retinoic acid receptor alpha (RARa) may be one mechanism of acquired resistance to all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL), but the molecular pathogenesis of this remains unclear. Recently, we reported the delayed restoration of ATRA sensitivity in UF-1, an APL cell line carrying a patient-derived mutant PML/RARa (Leukemia Res, 2004). In this study, we investigated the roles of the mutant PML/RARa and normal RARa in the restored ATRA sensitivity of UF-1.
[Methods]
After culture in the presence of ATRA or Am80 (RARa-selective RA), the differentiation and apoptosis of UF-1 were evaluated using FACS. RA-dependent transcriptional activity was examined using the luciferase assay. The expression of PML/RARa, RARa, and retinoic acid receptor beta(RARb)was analyzed using RT-PCR and Western-blotting.
[Results]
UF-1 had little response to ATRA up to day 4, but subsequently showed differentiation and apoptosis in response to ATRA or Am80 at 1 microM, but not 100 nM or lower. In the presence of Am80, UF-1 underwent differentiation similar to that in response to ATRA, while it showed apoptosis at lower degrees than that induced by ATRA. In the luciferase assay, the mutant PML/RARa had little RA-dependent transcriptional activity, but retained a dominant-negative action on normal RARa. Expression of the chimeric protein was decreased in the presence of 1 microM ATRA after day 4, while RARa was preserved. Interestingly, RARb expression was up-regulated in the presence of 1 microM ATRA.
[Discussion]
The mutant PML/RARa (Arg611Trp), with a reduced ATRA response and a preserved dominant-negative action, caused ATRA resistance of UF-1 during the initial culture period. However, an ATRA-induced decrease in the chimeric protein was thought to be the mechanism by which UF-1 restored ATRA sensitivity after 4 days of culture. Furthermore, the RA signaling that led to apoptosis of UF-1 may be transduced via RARb, which was up-regulated by 1 microM ATRA.
Apoptotic and Multi-Drug Resistance Profile in Elderly AML Patients.
Authors: Vidriales Maria-Belen , Suarez Lilia , García-Laraña José , López Antonio , Moreno María José , Martinez Rafael , Tormo Mar , Lavilla Esperanza , López-Berges Consuelo , de Santiago María , San Miguel Jesús F. , Orfao Alberto ,   for the Pethema Cooperative Group
Published: April 2020

Abstract
Elderly AML patients have an unfavorable prognosis with frequent resistance of leukemic cells to chemotherapy. The expression of proteins related with apoptosis and multi-drug resistance have been involved in chemotherapeutic resistance in AML; however, these proteins are not only expressed on leukemic but also on normal cells. Moreover, within leukemic cells, different stages of maturation may occur. The aim of the present study was to evaluate the expression of proteins related to apoptosis (APO 2.7, bax, and bcl-2), and drug resistance (P-gp, MRP, LRP) in a series of 117 elderly AML patients (median age of 70) uniformly treated according with the Spanish Pethema cooperative group protocol (LMA &gt;65). 63 patients (54%) achieved complete remission (CR), with a median relapse free survival (RFS) of 9.2 months. In the bone marrow (BM) pre-treatment, we performed a four-color staining technique (APO2.7, bax or bcl-2 with CD32/CD34/CD45; and P-gp, MRP, or LRP with CD34/CD19/CD33), allowing the identification of myeloid blast cells, and the discrimination between stages of maturation of blast cell subsets. Samples were acquired on a FACSCalibur flow cytometer (Becton/Dickinson), and appropriate controls were used in each individual sample and, accordingly, antigen expression in individual cell samples was quantified as relative fluorescence intensity (RFI) (ratio blast cell/control mean channel fluorescence value). Our results showed that the level of expression of MRP and LRP was significantly higher (mean±SD of MFI 2.0±0.75 vs 2.7±1.87 and 4.5±2.2 vs 7.0±6.2, respectively -p &lt;0.03-) in cases that did not achieved CR with one or two cycles of chemotherapy. Although different patterns of expression of apoptosis or drug resistance-associated proteins were detected according with the stage of maturation on myeloid blast cells, we did’t found any other correlation between levels of bcl-2, bax, APO 2.7, bcl-2/bax ratio or MDR and probability of achieving morphological CR. In addition, CD34 expression on blast cells had also significant influence on response (CR was achieved in 81% of CD34 negative cases vs only 46% of CD34 positive cases; p= 0.005). We didn’t found any influence of apoptosis and/or drug-resistance proteins expression in relapse rate nor RFS. Variables influencing RFS were age (p=0.04), and number of cycles to achieve CR (p=0.01); while only WBC count (p=0.05) influenced overall survival (OS). We conclude that MRP and LRP could have a role in the resistance to induction treatment in elderly AML patients but not in RFS or OS.
A Host Cell Reactivation Assay for DNA Repair System Analysis in Primary Hematopoietic Cells.
Authors: Baesecke Joerg , Thoms Kai , Roedling Tina , Aut Birgit , Viereck Volker , Griesinger Frank , Haase Detlef , Neumann Christine , Truemper Lorenz , Emmert Steffen 
Published: April 2020

Abstract
Therapy related acute myelogenous leukemia (t-AML) is frequently observed among patients who undergo a high dose chemotherapy and its incidence varies between 5 to 15% in non-myeloablative and myeloablative treatment protocols. Deficiencies in individual DNA-repair systems seem to be involved in t-AML leukemogenesis since indirect genetic markers of impaired DNA repair, e.g. microsatellite instability (mismatch repair) and polymorphisms of XRCC genes (base/nucleotide excision repair), are frequent in these patients. To directly determine the activity of different DNA repair systems we developed a modified host cell reactivation (HCR) assay which is applicable for the analysis of primary hematopoietic cells of clinical samples. This assay determines the ability of transfected host cells to repair damaged plasmid DNA as reflected in the recovery of luciferase activity. Depending on the type of DNA damage introduced to the plasmid prior to transfection, different DNA repair systems can be analysed, e.g. nucleotide excision repair (NER) or double strand break repair. We performed the HCR assay using 75 to 250 ng luciferase reporter gene plasmid (pCMV-Luc). Lymphocytes and cord blood CD34+-progenitor cells from healthy donors were collected according to the convention of Helsinki. 200,000 to 2,000,000 cells were cryopreserved, thawed and transfected using DEAE-dextran at a concentration of 0,1 mg/ml in a transfection volume of 250 μl. We obtained luciferase activities of 350-fold above background in CD34+ progenitor cells (1000-fold in lymphocytes) rendering these cells applicable for DNA repair analysis. In addition, we evaluated the normalized NER capacity (1000 J/m2 UVC irradiated plasmid vs. unirradiated control) of lymphocytes and two AML cell lineages, Kasumi-1 and HL60. Kasumi-1 and HL60 cells exhibited a significantly reduced NER capacity compared to lymphocytes (6.15% +/− 1.57% and 6.5% +/− 1.59% vs. 12.3% +/− 3.2%). Clinical AML samples are currently been investigated. Our modified HCR can be used for functional DNA repair analysis in fresh and cryopreserved patient samples of pre- and post-leukemic conditions as well as in leukemic blasts to elucidate the role of defective DNA repair during t-AML leukemogenesis. Furthermore, the modified HCR may also be used to determine the individual susceptibility for therapy related myeloid leukemia prior to chemotherapy.
Mimosine Induces Apoptosis through Metal Ion Chelation, Mitochondrial Activation and Reactive Oxygen Species Production in Human Leukemic Cells.
Authors: Hallak Maher , Dvilansky Alexander , Shpilberg Ofer , Levi Itai , Mazar Julia , Nathan Ilana 
Published: April 2020

Abstract
Mimosine, a non-protein amino acid, acts as a reversible inhibitor of DNA replication, and is widely used to synchronize cells at G1 phase of the cell cycle. We tested the possibility that mimosine might have an apoptotic effect on two types of AML cells: the monoblastic U-937 and the promyelocytic HL-60 cell lines. We show that mimosine induces apoptosis in both cell lines, with U-937 cells being more sensitive. The apoptotic effect of mimosine was antagonized by the addition of exogenous iron, indicating that it may act through iron chelation. Its mode of action was thus compared to that of desferrioxamine (DFO), a therapeutic iron chelating agent. Mimosine and DFO differed in their sensitivity to the suppressive effect of exogenous sources of iron in the form of hemin and ferrous sulfate suggesting different targets of action. Addition of another metal ion cupric sulfate was also able to antagonize the apoptotic effect of mimosine, undermining the notion that apoptosis is mediated through inhibition of ribonucleotide reductase, since this enzyme is solely dependent on iron for its activity. Moreover, when higher concentrations of iron were added to mimosine, cell death shifted from apoptosis to necrosis. Induction of apoptosis by both mimosine and DFO caused an early reduction in mitochondrial transmembrane potential and increase in caspase-3 activity, while only mimosine induced oxidative stress. In summary, our results imply that besides its known effect on DNA synthesis and G1 arrest, mimosine also activates apoptosis through an intrinsic pathway as well as reactive oxygen species production and thus elicits its anticancer effect by multiple pathways.
Degree of Concordance between Peripheral Blood Leukemic Blast Count and Mid Induction Bone Marrow in Childhood Acute Lymphoblastic Leukemia.
Authors: Al-Saleh Mahasen M. , Owaidah Tarek , Al-Daama Saad , Al-Humaidan Hind A. , Mousa Emad , Al-Asaad Tarek , Silo Ameurfina , Belgaumi Asim 
Published: April 2020

Abstract
While different Pediatric ALL study groups have used varying definitions of early response (BM vs. PB, prophase vs. day 7 vs. day 14), all agree that it provides critical prognostic information. Bone Marrow aspiration and biopsy (BMA/B) is an invasive procedure requiring sedation or anesthesia, and an early/mid induction specimen may be difficult to interpret even by experienced hematopathologists. In this study we attempted to determine if there was a concordance between peripheral blood blast (PBB) clearance and the findings of the day 14 BMA/B, and whether day 7 PBB count could reliably replace a mid induction BMA/B. Clinical data for newly diagnosed pediatric (&lt;14 years) ALL patients between January 1999 and December 2001 were retrieved from our prospective database. Day 14 BMA/B slides were reviewed independently by two hematopathologist. For the total 165 patients, median age was 4 years, 53.9% were boys. Complete information was available for 151 of these patients and further analysis is based on this number. 124 (82.1%) were treated with 4 agents while the remainder received a 3-drug induction. 23 (18.5%) had positive PBB on D7, and 21 (13.9%) had &gt;5% blasts in the D14 BMA/B. The D7 PBB count could positively and negatively predict the D14 BMA/B 71.9% and 89.4% of the times, respectively. In conclusion, when the D14 BMA/B is used as a measure of early response, an absence of D7 PBB can reliably predict a negative BM, however persistence of PBB does not necessarily predict a sub-optimal BM response to early therapy. Therefore, patients without PBB on D7 may not require BMA/B on D14, therefore avoiding an invasive procedure for this group of patients.
Scutellaria Baicalensis, a Herbal Medicine: Antitumor Activity Against Acute Lymphocytic Leukemia, Lymphoma and Myeloma in Vitro.
Authors: Kumagai Takashi , Muller Claudia , Desmond Julian C. , Imai Yasufumi , Heber David , Koeffler H. Phillip 
Published: April 2020

Abstract
Scutellaria baicalensis is a widely used Chinese herbal medicine for anti-inflammatory and anti-cancer therapy. The anticancer activity of Scutellaria baicalensis against prostate, breast, hepatocellular, colon and squamous cell carcinomas in vitro has been reported. In this study, we initially investigated its in vitro antitumor activities against 29 cancer cell lines including prostate, breast, ovarian, endometrial and pancreatic cancers as well as myeloid and lymphocytic leukemias, lymphomas, myelomas. The cells were cultured with Scutellaria baicalensis at a dose of 50 μg/ml for 4 days. The herb showed strong anti-proliferative activities against Blin-1 and Nalm-6 acute lymphocytic leukemia cells, Daudi Burkitt′s lymphoma cells and NCI-H929 myeloma cells as measured by MTT assays. Dose-response studies showed an ED50 of 8.32 μg/ml (Blin-1), 12.3 μg/ml (Nalm-6), 4.57 μg/ml (Daudi) and 5.01 μg/ml (NCI-H929) as measured by soft agar colony assay. Treatment with Scutellaria bacalensis at 50 μg/ml for 2 days induced apoptosis of 30% of Blin-1, 17% of Nalm-6, 20% of Daudi and 39% of NCI-H929 cells as measured by Annexin V assay. It also induced G2/M cell cycle arrest of Daudi cells. Scutellaria baicalensis also induced mitchondrial damage in 4 cell lines as measured by fluorescent emissions using the JC-1 assay. Protein expressions were examined by western blot using Blin-1 cells that were most sensitive to Scutellaria baicalensis. After treatment with 50 μg/ml of Scutellaria baicalensis for 2 days, levels of p27KIP1 increased by 152 % independently of p53, expression of the pro-apoptotic gene Bax increased by 208 %, and the anti-apoptotic proteins Bcl-2 and Bcl-XL decreased by 64 % and 38 %, respectively. Notably Scutellaria baicalensis decreased the expression of c-myc oncogene in a dose-dependent manner (80 % decrease at 50 μg/ml). Scutellaria baicalensis contains 21% of baicalin as measured by HPLC. The antiproliferative dose-response assays were repeated using baicalin and calculating the percent baicalin in the herb showed that the results nearly mirrored those of Scutellaria baicalensis, suggesting baicalin is the major anticancer component of this herb. We conclude that Scutellaria baicalensis inhibited the cell growth of B cell hematological malignancies including ALL, lymphoma, and myeloma in vitro by induction of apoptosis associated with mitchondrial damage and modulation of the Bcl family of genes. Thus, Scutellaria baicalensis and its major component, baicalin, should be tested in clinical trials for these hematological malignancies.
]Socioeconomic Factors May Select Adults Younger Than 60 Years of Age with “De Novo” Acute Myeloid Leukemia To Receive Intensive Treatment outside a Clinical Trial in Developing Countries. Experience of a Brazilian University Center.
Authors: Fagundes Evandro M. , Rocha Vanderson , Glória Ana Beatriz F. , Clementino Nelma Cristina D. , Quintão José S. , Guimaraes Joao Paulo O. , Pedroso Enio Roberto P. , Viana Marcos B. 
Published: April 2020

Abstract
Socioeconomic status (SES) is associated with treatment outcomes of ALL childhood. Whether this factor is associated with outcomes in adults AML in a developing country is not known. We have studied the impact of the human development index (HDI) of the United Nations as a SES factor for treatment outcomes of adults with “de novo” AML. Among 124 consecutive patients retrospectively analyzed, 46 (37 %) died during induction, 66 reached complete remission (53%) and 46 (37%) received high dose Ara-C (Hidac) consolidation. Five years-overall survival (OS) and leukemia free survival (LFS) were 17%±3% and 26%±6% respectively for all patients and 36%±7% and 30%±7% respectively for those receiving Hidac. In multivariate analysis, the HDI lower than 0.660 was associated with lower probability to receive Hidac (p=0.001), a trend for higher mortality in remission induction (p=0.062) and a decreased LFS (p&lt;0.0001), however it was not associated with outcomes for patients receiving Hidac. In conclusion, survival for patients who received Hidac consolidation is similar to those reported in developed countries, but results of overall outcomes are inferior, probably due to the influence of socio-economic factors before Hidac consolidation. Poor SES may be a factor associated with patient selection for intensive treatment and survival.
Folate Pathway Gene Expression Differs in Genetic Subtypes of Acute Lymphoblastic Leukemia and Influences Methotrexate Pharmacodynamics.
Authors: Kager Leo , Cheok Meyling H. , Yang Wenjian , Zaza Gianluigi , Pui Ching-Hon , Downing James R. , Relling Mary V. , Evans William E. 
Published: April 2020

Abstract
Methotrexate (MTX) is an essential treatment component for acute lymphoblastic leukemia (ALL). The ability of leukemia cells to accumulate MTX in its polyglutamylated form (MTXPG) is recognized as an important determinant of its antileukemic effect. We measured in vivo MTXPG accumulation in leukemia cells from 101 children with ALL, and established that blasts of B-lineage ALL with either the TEL-AML1 (n=24 patients, median 911, range 338 to 5906 pmol/109 blasts) or E2A-PBX1 gene fusion (n=5, median 553, range 364 to 800 pmol/109 blasts) or T-lineage ALL (n=14, median 572, range 284 to 1468 pmol/109 blasts) accumulate significantly lower MTXPG, compared to those of other B-lineage ALL (BNHD, n=39, median 2210, range 186 to 9722 pmol/109 blasts) or hyperdiploid ALL (BHD, n=19, median 4375, range 377 to 9206 pmol/109 blasts) (E2A-PBX1 versus BHD, p=0.008; E2A-PBX1 vs. BNHD, p=0.010; TEL-AML1 vs. BHD, p&lt;0.001; TEL-AML1 vs. BNHD, p=0.004; T-ALL vs. BHD and BNHD, p&lt;0.001; p-values are from pair-wise comparisons using Wilcoxon rank sum test, adjusted for multiple testing using Holm’s method). To elucidate mechanisms underlying these differences in MTXPG accumulation, we used oligonucleotide microarrays (Affymetrix® HG-U133A) to analyze expression of 32 folate pathway genes (53 probe sets) in diagnostic bone marrow blasts from 197 children with ALL. This revealed ALL subtype-specific patterns of folate metabolism gene expression and identified differences in gene expression that discriminated the MTXPG accumulation phenotype in ALL cells. We found significantly lower expression of the reduced folate carrier (SLC19A1, MTX uptake transporter) in E2A-PBX1 ALL; significantly higher expression of breast cancer resistance protein (ABCG2, MTX efflux transporter) in TEL-AML1 ALL; and lower expression of FPGS (catalyzes formation of MTXPG) in T-ALL; consistent with lower MTXPG accumulation in these ALL subtypes. These findings reveal distinct mechanisms of subtype-specific differences in MTXPG accumulation and point to new strategies to overcome this potential cause of treatment failure in childhood ALL.