bluuebunny/crossref_metadata_2025_split huggingface dataset:
Risk Factors for Outcome after Haploidentical Hematopoietic Stem Cell Transplant in Children with Very High Risk Acute Lymphoblastic Leukemia: Impact of Centre Experience. A Survey on Behalf of the ALWP and PDWP of the EBMT.
Authors: Klingebiel Thomas , Cornish Jacqueline , Labopin Myriam , Locatelli Franco , Balduzzi Adriana , Owoc Joanne , Fagioli Franca , Engelhard Dan , Peters Christina , Dini Giorgio , Rocha Vanderson 
Published: April 2020

Abstract
In the absence of an HLA identical donor, T-cell depleted haploidentical hematopoietic stem cell transplantation (Haplo-HSCT) is an alternative option to treat children with very high risk acute lymphoblastic leukemia (ALL). However, little data is available in children. We have analyzed 118 children (≤16 years old) with ALL transplanted with a myeloablative Haplo-HSCT from 1995 to 2004 in Europe. Only transplants with 2 or more HLA disparities out of 6 (A, B and DRB1) were included. The median age was 8.5 years and median follow-up 56 months (8–116). At transplant, 21 (18%) were in CR1, 72 (61%) in CR2 or CR3 and 25 (21%) in more advanced phase. The 3-year leukemia free survival was 32±10%, 28±5% and 0%, respectively. Therefore we restricted the analysis to patients in remission (n=93) transplanted in 30 EBMT centers. Thirty-four (37%) patients were treated in centres performing more than 10 Haplo-HSCT in the study period (3 centres). The median age of recipient and donor was 8.7 and 37 years, respectively. Fifty four (65%) received a full Haplo-HSCT and 95% of the donors were parental. Twenty seven (29%) had t(9;21) or t(4;11). The majority of patients did not receive drugs for GVHD prophylaxis, ATG/ALG was used in conditioning in 74%, and 73% received TBI. The Clinimacs® device was used in 74% of selections. The median number of CD34+ cells infused was 12.8 106/Kg. Cumulative incidence with competing risk and KM estimates were used to calculate outcome probabilities. The median days of neutrophil recovery was 15 days (8–55) and 90% of patients had signs of engraftment. Acute GVHD II–IV was observed in 24% of the patients. In univariate analysis for LFS there was a trend towards better results for patients receiving higher CD34 cell dose (p=0.08) and a significant difference for patients transplanted in centres performing more Haplo-HSCT (49% versus 17%, p=0.002). Relapse incidence (RI) and non relapse mortality NRM) tended to be different between the experienced and less experienced centres. In less experienced centres NRM was 41% vs 27% (p=0.13) and RI 41% vs. 24% (p=0.10). There were patient, donor and transplant related differences between less and more experienced centres, specifically related to donor sex, Philadelphia positivity, year of transplantation, use of TBI, ATG and DLI and previous autograft. In conclusion, Haplo-HSCT is an alternative option to treat children with very high risk ALL in the absence of HLA identical donor. Centres with more experience have better LFS.
Ionizing Radiation Up-Regulates Telomerase Activity in Cancer Cell Lines; Mechanisms and Possible Clinical Relevance.
Authors: Lahav Meir , Ram Ron , Uziel Orit , Fenig Eyal , Beery Einat , Nordenberg Yardena 
Published: April 2020

Abstract
Background: Activation of telomerase has been recently recognized as one of the pivotal events in malignant transformation. Up-regulation of this enzyme is probably necessary for transformation and, more importantly, for perpetuation of the malignant clone. Down regulation of telomerase activity may compromise the viability of cancer cells. Therefore, telomerase is considered to be a central target for future anti cancer therapies. Indeed, others and we have shown that telomere shortening by inhibition of telomerase sensitizes malignant cells to several cytotoxic drugs. Very little is known about the effect of irradiation, an important anticancer modality, on telomerase activity. The available data is sketchy and controversial. In this study we characterize the effect of irradiation on telomerase activity in malignant cells and its molecular mechanism.
Methods: Several cancer cell lines were exposed to a range of radiation doses. Telomerase activity was assessed at various time points. All levels of telomerase regulation were evaluated: transcriptional, alternative splicing, posttranslational phosphorylation and dephosphorylation and intracellular compartmentalization of the enzyme. Subsequently, the involvement of several signal transduction pathways triggered by irradiation and relevant to telomerase regulation was evaluated by point inhibition of numerous signaling compounds.
Results: In all cell lines, irradiation caused a fourfold increase in telomerase activity with a maximal effect at 24 hours at a dose of 400 Rad. This elevation was mediated by posttranslational modification of the enzyme as phospho-AKT; the enzyme that phosphorylates telomerase was increased after irradiation. Transcriptional activity and intracellular compartmentalization of telomerase were not affected. PI3K/AKT pathway mediates the irradiation-induced upregulation of telomerase activity, as wortmanin decreased that effect. RAS oncogene was the upstream effector of PI3K, since its inhibition by FTS decreased irradiation dependent telomerase activity. PTEN was not involved in regulating that effect. In addition, several membrane receptors known to be activated by radiation including Erb1, Erb2 andIGF1R were not involved in the signaling cascade leading to the up regulation of telomerase.
Conclusions: Radiation causes posttranslational upregulation of telomerase in cancer cells lines. Telomerase activation probably enables non-specific “chromosomal healing” in certain low irradiation dosages. This activation was mediated via the PI3K/AKT signaling pathway activated by Ras. The membrane receptors classically activated by irradiation were not involved in this process. These finding have potential clinical implication, since the upregulation of telomerase by irradiation in cancer cells may interfere with future cytotoxic treatment and necessitate concomitant inhibition of the enzyme.
FoxO Are Critical Mediators of Hematopoietic Stem Cell Resistance to Physiologic Oxidative Stress.
Authors: Tothova Zuzana , Kollipara Ramya , Huntly Brian J. , Lee Benjamin H. , Castrillon Diego H. , Passegue Emmanuelle A. , Cullen Dana E. , McDowell Elizabeth P. , Lazo-Kallanian Suzan , Williams Ifor R. , DePinho Ronald A. , Gilliland D. Gary 
Published: April 2020

Abstract
Hematopoietic development and long-term homeostasis are tightly regulated by a dynamic balance of stem cell self-renewal and differentiation. To understand the role of the FoxO family of transcription factors in these processes, we studied the impact of somatic deletion of all FoxO genes in the adult hematopoietic system of mice engineered with the interferon-inducible Mx-Cre transgene and various conditional FoxO alleles: FoxO1L/L; FoxO3 L/L; and/or FoxO4 L/L. Cre-mediated excision of FoxO1, FoxO3 and FoxO4 (FoxO1/O3/O4L/L), resulted in myeloid lineage expansion, lymphoid developmental abnormalities and a marked decrease of the lineage-negative, Sca-1+, c-Kit+ (LSK) compartment, containing the hematopoietic stem cell (HSC) population, but normal numbers of myeloid progenitors. Furthermore, FoxO1/O3/O4L/L null bone marrow cells were defective in competitive and noncompetitive repopulation assays. This FoxO deficient defect correlated with enhanced cell cycling and increased apoptosis of HSC cells. Notably, there was an HSC-restricted elevation in the level of reactive oxygen species (ROS) that was not observed in committed progenitors, and was associated with decreased catalase and MnSOD expression. Furthermore, in vivo treatment with the anti-oxidative agent N-acetyl-cysteine (NAC) resulted in complete reversion of the FoxO deficient HSC phenotype. Taken together, these results demonstrate that, in the HSC compartment, FoxO proteins are mediators of quiescence and enhanced survival and play essential regulatory roles in the response to physiologic oxidative stress, a function that may contribute to the long-term regenerative potential of the hematopoietic stem cell compartment.
Histone Deacetylase Inhibitor, PCI-24781, Induces Growth Inhibition and Apoptosis in Hematopoietic Tumor-Derived Cell Lines and Primary Leukemia Cells.
Authors: Buggy Joseph , Balasubramanian Sriram , Ramos Jason , Sirisawad Mint , Naumovski Louie 
Published: April 2020

Abstract
Histone deacetylase (HDAC) inhibitors are a new class of anticancer drugs that have shown promising activity in clinical trials. PCI-24781 (formerly CRA-024781) is a novel, hydroxamic acid-based HDAC inhibitor that is currently under evaluation in phase I clinical trials in patients with refractory solid malignancies and lymphomas. In this study, we show that PCI-24781 inhibits growth and induces apoptosis in a variety of hematopoietic cell lines derived from B-, T- and myeloid malignancies. Growth inhibition and apoptosis were noted at drug concentrations &lt; 0.125 μM and were accompanied by known biochemical markers of HDAC inhibition including histone and tubulin hyperacetylation. PCI-24781 was also found to be active in animal xenograft models of hematopoietic disease displaying favorable drug-like pharmacokinetic and pharmacodynamic profiles, both intravenously and orally. To further establish the potential clinical utility of PCI-24781 in hematologic malignancies, primary leukemia samples were isolated from patients and screened for resistance to PCI-24781 in vitro. Of these 19 leukemia samples (10 acute myelogenous leukemia (AML) and 9 acute lymphocytic leukemia (ALL) some of which were derived from patients who had failed standard therapy), none were resistant to PCI-24781 at 0.5 μM and only 2 (1 AML and 1 ALL) were considered resistant at 50 nM. Gene expression analysis of PCI-24781 activity in these primary samples was consistent with HDAC inhibition and suggested potential downstream mechanisms of action for this compound in leukemia. These results demonstrate that PCI-24781 is active in hematopoietic tumor-derived cell lines in vitro as well as in vivo in preclinical models. Furthermore, the sensitivity of primary leukemic tumors to treatment with PCI-24781 in vitro, coupled with the predicted pharmacokinetics in humans suggests that PCI-24781 could be a valuable agent for the treatment of hematopoietic tumors.
Bortezomib Combined with Harringtonine or Arsenious Acid Induced Apoptosis in HL-60 Cells and Its Mechanism.
Authors: Meng Fan Yi , Fu Yun-bi , Sun Qi-xin , Xie Jun , Zhou Guang-biao 
Published: April 2020

Abstract
Objective: To explore the apoptosis effect induced by bortezomib combined with harringtonine or arsenious acid in HL60 cell line and the mechanism.
Methods: Cell’s apoptosis was demonstrated by MTT assay and Hoechst33342 staining. Expression of Bcl-2, Caspase-9, Caspase-3 and PARP protein was detected by western blotting.
Results: HL60 cells’ apoptosis could be induced by bortezomib, harringtonine and arsenious acid respectively, and the apoptosis effect was inhanced significantly when bortezomib combined with harringtonine or arsenious acid. Western blotting showed Bcl-2 protein was down-regulated and Caspase-9, Caspase-3 and PARP proteins were all cleaved activation when cells were treated by 15uM arsenious acid alone, but only cleaved activation of PARP and down-regulation of Bcl-2 protein be detected when cells were treated with 30nM harringtonine alone, expression of Caspase-9 and Caspase-3 has no change compared with the control. The changes of associated proteins were paralleled with the cell’s apoptosis when treated with combined drugs.
Conclusion: HL60 cells’ apoptosis could be inhanced significantly when treated by bortezomib combined with harringtonine or arsenious acid compared with treated by bortezomib alone. Arsenious acid and bortezomib can inhibit caspase signaling pathway and down-regulate the expression of Bcl-2 protein together, but harringtonine and bortezomib can only down-regulate the expression of Bcl-2 protein and induce cleaved activation of PARP together.
Soluble CD30 Can Distinguish Disease Progression from Acute GVHD in Patients with Adult T Cell Leukemia/Lymphoma Who Received Allogeneic Hematopoietic Stem Cell Transplantation.
Authors: Yoshimitsu Makoto , Fujiwara Hiroshi , Aoki Noriko , Ozaki Atsuo , Hamada Heiichiro , Matsushita Kakushi , Arima Naomichi , Tei Chuwa 
Published: April 2020

Abstract
At present, allogeneic hematopoietic stem cell transplantation (HCST) has been an only curative modality for the treatment of adult T cell leukemia/lymphoma (ATLL). Disease relapse and GVHD are the major causes of mortality after allo-HSCT for ATLL. To achieve better outcome, early detection of disease relapse after allo-HSCT is absolutely crucial for decision-making of interventions such as donor lymphocyte infusion and/or adjuvant chemotherapy, while tumor burden still remains in the level of minimal residual disease (MRD). Serum soluble interleukin-2 receptor alpha (sIL-2R) has been known as a marker of ATLL tumor burden in affected patients, however it increases in patients with acute and chronic GVHD as well. Here we propose a new strategy to distinguish disease progression of ATLL and GVHD at an early stage by measuring serum levels of soluble CD30 antigen (sCD30) and sIL-2R. The surface CD30 is normally expressed by activated B or T cells. It has been known that Hodgkin cells, anaplastic large cell lymphoma and ATLL cells also express surface CD30. The soluble form of CD30 is produced by metalloprotease cleavage. Acute type ATLL patients whose tumor cells express surface CD30 (CD30+ATLL), who underwent allo-HSCT, were included in this study. As control, the serum levels of sCD30 were measured in a healthy donor, an asymptomatic HTLV-I carrier and acute type ATLL patients whose tumor cell were negative for surface CD30 (CD30−ATLL), all were below measurable range. In addition, the level of sCD30 was undetectable in a CD30− ATLL patient with grade II gut acute GVHD as well. Confirming these low backgrounds, both of sCD30 and sIL2R levels were sequentially measured from induction chemotherapy and throughout allo-HSCT. During chemotherapy, the levels of sCD30 and sIL2R are well-correlated along with tumor burden as previously reported, and both markers increase at disease relapse after allo-HSCT as well. In contrast, during GVHD, sIL-2R levels increase along with GVHD status, while sCD30 remained lower or undetectable. In conclusion, serum levels of sCD30 and sIL-2R may predict not only disease progression at an early stage after allo-HSCT, but also distinguish that from GVHD. These findings may help to introduce an early intervention for ATLL progression with DLI and/or adjuvant chemotherapy at the level of minimal residual disease.
Figure Figure
Elevated Serum Neutrophil Elastase but Not Proteinase 3 Is Present in Patients with Myeloid Leukemia.
Authors: Sergeeva Anna , Ono Yoko , Molldrem Jeffrey J. 
Published: April 2020

Abstract
Proteinase 3 (P3) and neutrophil elastase (NE) are abnormally expressed in the cytoplasm of myeloid leukemia, and we have shown that the HLA-A2-restricted peptide PR1 is processed and cross-presented from both proteins by antigen-presenting cells (APC) to cytotoxic T lymphocytes (CTL). PR1-specific CTL kills leukemia cells and contributes to cytogenetic remission in patients with chronic myelogenous leukemia. Both exogenous P3 and NE can bind to monocytes and P3 promotes DC maturation in vitro. Since high levels of circulating P3 were found in patients with the ANCA-associated systemic vasculitis Wegener’s granulomatosis, modulation of DC by P3 has been implicated in reversal of tolerance. The role of extracellular P3 and NE in reversing tolerance in patients with myeloid leukemia is unknown. We used an ELISA assay to assess P3 and NE level in the sera of patients with AML and CML. Serum NE level was highly increased in all 15 AML patients studied (1045±149 ng/ml, n = 15) and in all 15 CML patients (1013±128, n = 15), compared to a control group of healthy donors (54±13 ng/ml, n = 4; p = 0.0038 and p = 0.0014, respectively). In contrast, serum P3 was increased in only 5 out of 18 (28%) AML patients (47 ± 18, n = 18 ng/ml) and in 8 out of 28 (29%) CML patients (95 ± 44 ng/ml, n = 28) compared to a group of 14 healthy donors (10 ± 2.2 ng/ml; p = 0.09 and p = 0.06, respectively). There was no relationship between elevated serum NE and P3 levels (r=0.16, n=35). P3 level in untreated patients and healthy donors did not change within at least 13 months, although P3 decreased after allogeneic BMT in 5 out of 5 patients (p &lt; 0.05) with high serum levels of P3 pre-BMT. Because P3 is expressed by myeloid progenitor cells in the bone marrow, we studied the concentration of P3 in bone marrow-derived serum (BMS). To our surprise, BMS P3 concentration in patients with myeloid leukemia (23 ± 9.5 ng/ml, n = 9) was similar to that of a control group of patients with non-myeloid hematological malignancies (27 ± 11.8, n = 5) (p = 0.08), and BMS P3 concentration was similar to sera P3 concentration in the same patient (p = 0.52). Interestingly, BMS P3 level correlated with the level of BMS GM-CSF (quantified by ELISA) in a small group of patients with AML and CML (r = 0.94, n = 9), suggesting that P3 secretion by leukemia cells may be downstream of GM-CSF. We also analyzed membrane expression of P3 and NE in 5 AML patients using flow cytometry and found that P3, but not NE, was expressed on circulating cells in 3 of 5 patients. This unique expression of P3 and NE suggests that circulating NE might be the predominant source of cross-presented PR1 antigen by APC or myeloid leukemia cells.
Global Proteomics in AML: Using SELDI-TOF MS on Diagnostic Samples To Identify Spectra and Protein Biomarkers Indicative of Prognosis.
Authors: Stenke Leif , Pernemalm Maria , Forshed Jenny , Pawitan Yodi , Lagergren-Lindberg Marita , Kanter Lena , Lehtiö Janne 
Published: April 2020

Abstract
With the object to identify key proteins related to treatment response in acute myeloid leukemia (AML), and to eventually elucidate new targets for therapy, we have investigated protein spectra from diagnostic AML samples. Surface-enhanced laser desorption ionization time-of-flight mass spectrometry (SELDI-TOF MS) was used to spot proteins in the molecular weight area of 2–40 kDa. The samples were applied to two different chip surfaces (CM10 and Q10) for selective protein binding, avoiding the necessity of extensive purification and separation procedures prior to analysis. Peripheral blood samples from a total of 67 acute leukemia patients at diagnosis were analyzed. The cells were collected, frozen and stored in biobanks between 1988 and 2003. This provided a good basis for correlating detected protein peaks to a large number of clinical diagnostic and therapeutic variables and outcomes. Among the patients, aged 18 to 86 yrs, response to induction therapy was observed with complete remission (CR) durations ranging between 12 and 3701 days. The duration of first CR was used as a dichotomic variable in order to compare protein spectra from groups of patients with “good” and “bad” response, respectively, to chemotherapy. A peak detection and annotation software was developed in-house1,2 and employed. The software will be presented and a comparison to commercially available MS-spectral analysis methods will be provided. Initial results from MS profiling of the two response groups showed 18 significantly (p&gt;0.01) differently expressed peaks on anion exchange chips and 22 peaks on cation exchange surfaces. Ongoing work is focused on further development of the RS peak detection method, including the influence of normalisation and filtering of the SELDI data and supervised linear and non-linear modelling. In addition, identification of selected peaks and their relation to various clinical variables is in progress.
Gene Expression Profiling of Pediatric MLL-Rearranged Leukemia: Relation between Acute Lymphoblastic Leukemia, Acute Myeloid Leukemia, and Leukemic Cell Lines.
Authors: Ishii Masami , Tsutsumi Shuichi , Taki Tomohiko , Nishimura Kunihiro , Ge Xijin , Tsuchida Masahiro , Ohki Misao , Bessho Fumio , Sugita Kanji , Ishii Eiichi , Ichikawa Hitoshi , Aburatani Hiroyuki , Hayashi Yasuhide 
Published: April 2020

Abstract
Although most patients with acute lymphoblastic leukemia (ALL) having MLL rearrangements suffer poor treatment outcome, there exists a subgroup of patients with this disease who enjoy long-term disease-free survival. In order to verify our previously reported new classification of this type of leukemia predicting treatment outcome, we analyzed gene expression profiles of MLL-rearranged leukemic cell lines and acute myeloid leukemia (AML) samples along with the previously reported ALL samples. Hierarchical clustering and the weighted vote method showed that cell line samples formed a strong association with the poorer prognosis subgroup in the classification, and that AML samples had some relationship with the better prognosis subgroup. Highly expressed genes in the poorer prognosis subgroup combined with cell line samples compared with the better prognosis subgroup include genes related to tumor aggressiveness, such as SNCG, GRM4, and EDG4. These results support the significance of the previously described classification associated with prognosis. Large-scale clinical studies, therefore, may be worth trying on the basis of this classification.
Elevated Serum Ras Levels in Patients with LGL Leukemia.
Authors: Nelli Erin M. , Loughran Thomas P. , Leitzel Kim , Ali Suhail M. , Demers Lawrence , Carney Walter P. , Hamer Peter J. , Lipton Allan 
Published: April 2020

Abstract
Background: Ras is a GDP/GTP binding G protein that acts as a molecular switch converting signals from the cell membrane to the nucleus to regulate cell proliferation, differentiation, and protein synthesis. Activation of ras oncogenes has been identified in a variety of cancers, including 30% of patients with acute myelogenous leukemia (AML). Large granular lymphocyte (LGL) leukemia is a clonal T-cell lymphoproliferative disorder associated with chronic neutropenia, anemia, or autoimmune diseases, particularly rheumatoid arthritis. The purpose of this study was to evaluate serum ras levels in patients with LGL leukemia.
Methods: A novel ras p21 ELISA (Oncogene Science/Bayer HealthCare) employing two monoclonal antibodies was utilized to quantify ras levels in baseline serum obtained from 32 patients with LGL leukemia. A control group of 48 healthy subjects was also used to establish a cutoff for the upper limit of normal for serum ras levels. A 95% non-parametric cut-off was used to determine significant differences in the frequency of elevated serum ras levels in control vs. LGL leukemia patients.
Results: The median serum ras level in the 48 healthy control subjects was 125 pg/mL, with a 5% to 95% range of 50–422 pg/mL. The upper limit of normal for serum ras was defined as 422 pg/mL, as determined using the 95 % non-parametric cut-off. In the LGL leukemia patient group, 19 of 32 patients (59 %) had elevated baseline serum ras levels (median 484 pg/mL) (p=0.0001) when utilizing the healthy control upper limit of normal cut-off value.
Conclusions: The results of this study indicate that the majority of LGL leukemia patients have significantly elevated serum ras levels when compared to healthy controls. Serum ras should be evaluated as a potential biomarker in larger leukemia trials, especially for response to treatment with inhibitors of the ras signaling pathway.