bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acute Lymphoblastic Leukemia in Adolescents and Young Adults in Finland.
Authors: Usvasalo Anu , Saarinen-Pihkala Ulla , Elonen Erkki , Raty Riikka , Vettenranta Kim 
Published: October 2019

Abstract
Background: Long-term survival in pediatric acute lymphoblastic leukemia has dramatically improved during the past three decades through intensification of therapy. Progress has also been made regarding therapy of adult ALL. Recent reports in the literature suggest better outcome on pediatric protocols, as compared with adult ones. In pediatric ALL, age over 10 years is a high-risk factor in many protocols. The arbitrary age limit of 16 years may not truly reflect the biologic differences in ALL between adolescents vs. young adults. The purpose of the present work was to evaluate the outcome of adolescents with ALL in Finland, treated on pediatric vs. adult ALL protocols.
Materials and methods: All patients aged 10–25 years diagnosed with ALL during 1990–2005 in Finland were included. There were 120 patients (aged 10–16 yrs) treated on pediatric common Nordic (NOPHO) protocols with a total duration of 2 yrs, and 100 patients (aged 17–25 yrs) treated on Finnish National ALL adult protocols with a total duration of 3.5 yrs. In total 15 underwent allo-SCT in first remission. Data had been collected to the pediatric Nordic NOPHO database, as well as to the Finnish Leukemia Group ALL database. Events were defined as death, relapse, or second malignancy.
Results: The 5-year EFS was 68 % for children (n=62) and 55% for adults (n=72) (p=0.04), and the 5-year OS was 75 % for children and 68 % for adults (p=0.075), respectively. When only patients treated with conventional chemotherapy were included (stem cell transplant recipients in 1CR excluded), the 5-year EFS was 65 % for children (n=53) and 55 % for adults (n=66) (p=0.09), and the 5-year OS was 80 % for children and 65 % for adults (p=0.09), respectively. Regardless of protocol, EFS in the age group of 10–15 years was 74 % and in the group 15–25 years 57 % (p=0,06).
Conclusions: EFS regarding all patients was better on pediatric than on adult protocols. All the other comparisons reached statistically only a trend level. The difference in outcome between pediatric and adult protocols in Finland is less clear than reported elsewhere. Age seems to be a prognostic factor also in the adolescent age groups. The non-transplanted patients seemed to have a better outcome, suggesting that those with higher risk probably ended up with transplant. Although therapy is an important risk factor, our further analysis of cytogenetic features including CGH array may reveal other risk factors that may turn out to be even more powerful.
EFS, pediatric vs. adult treatment group EFS, pediatric vs. adult treatment group
Curcumin Inhibits Proliferation of Leukemic Cells Expressing P210BCR-ABL or BCR-ABL-T315I and Prolongs Survival of Mice with B-Cell Acute Lymphoblastic Leukemia (B-ALL).
Authors: William Basem M. , Goodrich Ami , Peng Cong , Li Shaoguang 
Published: October 2019

Abstract
The prognosis of BCR-ABL-induced B-ALL remains dismal with no effective chemotherapies currently available. Curcumin, a natural compound derived from tumeric, has been shown to induce apoptosis in the leukemic cell line K562 and in many solid tumor cells. We tested whether curcumin has an inhibitory effect on B-lymphoid transformation by wild type BCR-ABL or BCR-ABL-T315I mutant. We first used BCR-ABL-expressing pre-B cells isolated from B-ALL mice and BCR-ABL-expressing BaF/3 cells. We treated these cells with different concentrations of curcumin (10, 30, or 50 uM), and found that proliferation of the cells was significantly inhibited at concentrations as low as 10 uM. Curcumin also induced apoptosis of the cells, as shown by increased Annexin V-positive cells detected by FACS. Western blot analysis showed that Curcumin treatment resulted in decreased JNK2 activation and a significant increase in IKKa/b expression. To further investigate the underlying mechanisms for cellular apoptosis induced by curcumin, we screened for apoptosis related transcription factors that were activated or inactivated in curcumin-treated BCR-ABL-expressing pre-B cells isolated from B-ALL mice. To do so, we probed nuclear extracts of these cells onto a commercial DNA oligonucleotide arrays (Panomics) representing the canonical binding sites for 52 transcription factors. We observed decreased expression of NFkB at 48 hours and a significant increase in expression of AP-2, p53, and vitamin D receptor 3 (VDR3) at 24 hours. The p53 induction by curcumin was further demonstrated by Western blotting. To examine the efficacy of curcumin on B-ALL, we induced B-ALL in BALB/c mice by transplanting BCR-ABL-transduced donor bone marrow cells into lethally irradiated recipient mice. The B-ALL mice were treated with intraperitoneally injected curcumin (40 mg/kg, once a day), and the treated mice survived significantly longer than the vehicle-treated B-ALL mice (p=0.04; Peto-Wilcoxon test). Taken together, our results suggest a potential use of curcumin in treating BCR-ABL-induced B-ALL.
Lyn Is an Important Component of the Signal Transduction Pathway Specific to FLT3/ITD and Can Be a Therapeutic Target in the Treatment of AML with FLT3/ITD.
Authors: Hayakawa Fumihiko , Okamoto Mitsunori , Abe Akihiro , Kiyoi Hitoshi , Naoe Tomoki 
Published: October 2019

Abstract
Fms-like tyrosine kinase 3 (FLT3) is expressed in hematopoietic progenitor cells. An internal tandem duplication (ITD) of the FLT3 juxtamembrane domain (FLT3/ITD) is the most frequent mutation in human adult acute myeloid leukemia (AML). Being transfected into IL-3 dependent cell line, 32D, FLT3/ITD causes constitutive activation of FLT3 itself and its downstream signal components, which leads to IL-3 independent cell growth. In particular, STAT5 activation is thought to be a key signaling event since it is induced only by FLT3/ITD not by wild type FLT3. However the signal component which mediates FLT3/ITD to STAT5 is yet to be clarified. In the present study, we showed the mutant- specific association of FLT3/ITD with Lyn, which led to the phosphorylation of Lyn in vivo. We also demonstrated that Lyn directly bound to FLT3 through its SH2 domain in vitro and that the association depended on tyrosyl-phosphorylation at juxtamembrane domain of FLT3. We revealed the critical role of Lyn for STAT5 activation and the autonomous cell growth in FLT3/ITD transfectant of 32D by using anti-Lyn siRNA and the Src family kinase inhibitor PP2. More importantly, we demonstrated successful treatment of FLT3/ITD induced tumors with PP2 in the mice model. These results demonstrate that Lyn is a critical component of the signal transduction pathway specific to FLT3/ITD and can be a therapeutic target in the treatment of AML with FLT3/ITD.
High Expression of ENPP2/Autotaxin in Patients with FLT3-ITD Positive Acute Myeloid Leukemia.
Authors: Ortlepp Claudia , Steudel Christine , Koch Sina , Ryser Martin , Ehninger Gerhard , Thiede Christian 
Published: October 2019

Abstract
The Fms-like tyrosine kinase 3 (FLT-3) receptor tyrosine kinase acts as an important player in controlling the growth and differentiation of haematopoietic progenitor cells. It was shown that activating mutations of FLT-3 are involved in the pathogenesis of acute myeloid leukemia (AML). The most frequent aberration is an internal tandem duplication (ITD) of the juxtamembrane domain coding sequence, which is present in up to 27% of the patients with AML and has been associated with poorer prognosis. To further understand the factors involved, we performed microarray analysis to identify genes specifically upregulated in cases with FLT3-ITD mutations. One gene we identified was ENPP2/Autotaxin (ENPP2/ATX). The ENPP2/ATX protein acts as a lysophospholipase D through generating lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P). These two bioactive small lipids have crucial functions in cell migration and proliferation and act via G-protein coupled receptors. ENPP2/ATX has been associated with tumor cell migration in several solid tumors, expression has not been reported in myeloid cells before. The aim of the current study was to investigate the expression pattern of ENPP2/ATX in normal haematopoiesis and leukemia as well as its role in the pathogenesis of AML. Real-Time PCR analysis of 215 primary AML samples from all major cytogenetic risk groups confirmed a significant upregulation in FLT3-ITD patients. High expression was also found in cases with complex karyotype and −5 and −7, but not in cases with good risk cytogenetics. To explore the function of ENPP2/ATX in the haematopoietic system, we stably overexpressed two different splice variants of ENPP2/ATX in several leukemic cell lines. The expression was detected at both, mRNA and protein level by RT-PCR and Western blot analyses, respectively. The lysophospholipase D activity of the protein could be measured by a functional assay using an artificial substrate for ENPP2/ATX. Transwell migration assays showed an increased migration capacity of cells with high expression of ENPP2, which indicates that the overexpressed protein is functional. Based on our results, we suggest that ENPP2/ATX is involved in leukemic cell migration. Our findings point to a close link between ENPP2/ATX and FLT3 in the pathogenesis of AML. Current work focuses on its role in cell survival and prognosis.
Common Leukemic Signaling Pathways Identified by Comparative Analysis of GM-CSF and FLT3 Activated Receptor Mutations.
Authors: D’Andrea Richard , Perugini Michelle , Kok Chung , Wilkinson Christopher , Brown Anna , Gonda Thomas 
Published: October 2019

Abstract
As a strategy to identify key targets in myeloid leukemia we examined directly the overlap in signaling and downstream events induced by several activated receptor mutants associated with AML. We compared the events induced by a leukemic mutant (V449E) of the GM-CSF receptor with events associated with the activating FLT3 internal tandem duplication mutant (FLT3-ITD) and the D835Y kinase domain mutant (FLT3-TKD). Receptor mutants were introduced by retroviral transduction into the FDB-1 bi-potential myeloid cell line model (McCormack MP et al., Blood.95:120–127, 2000). We used biochemical analysis and pathway inhibitors to demonstrate that the GMR V449E mutant selectively activates the JAK2-STAT5 and p44/42 MAPK pathways which are central to the ability of this mutant to confer continued growth and arrested differentiation in the absence of growth factor. Like the GMR V449E mutant, the FLT3-ITD and -TKD mutants arrest granulocyte-macrophage differentiation and support continued growth in the absence of added growth factor. For both of these mutants we also observed constitutive JAK2 and STAT5 phosphorylation and sensitivity to a selective JAK2 inhibitor (JAK2 Inhibitor II, Merck) suggesting a potential key role for JAK2 in signalling from FLT3 activating mutants. Both FLT3 mutants activated the p44/42 MAPK pathway, resulted in Akt phosphorylation and were sensitive to PI3-kinase and MEK inhibitors. As activation of the p44/42 MAPK pathway is common to all mutants, and has recently been associated with suppressed differentiation in AML (Radomska HS et al, J Exp Med. 203:371–381, 2006), we used the selective MEK inhibitor, U0126 (Merck), to investigate the contribution of this pathway to maintenance of the differentiation block. Treatment of factor-independent FDB-1 cells expressing the GMR V449E mutant, or either FLT3 mutant, with U0126 for 48 hours induced morphological differentiation suggesting that the sustained activation of p44/42 MAPK contributes to maintaining the arrest in myeloid differentiation. To explore further the overlapping nature of signalling by the GMRV449E and FLT3-ITD activated mutants we utilised the Wilcoxan rank sum test to perform gene-set enrichment analysis. Analysis of 119 FLT3-ITD associated genes (126 probes) (Mizuki M et al, Blood101: 3164–3173, 2003) revealed that this gene-set shows evidence of differential expression in response to GMR V449E signaling (p=2.8x10−7). In particular, we identify the tumor suppressor gene, Gadd45α, as a common gene, down-regulated in response to signalling via the FLT3-ITD, FLT3-TKD and GMR V449E activated receptors. Analysis of AML gene expression data (Valk PJ et al, New Engl. J. Med: 350:1617–1628, 2004) indicates that activation of Gadd45α maybe suppressed by multiple pathways in AML blasts.
Antioxidants Improve Factor VIII Secretion in the Liver by Preventing Oxidative Stress, Activation of the Unfolded Protein Response, and Apoptosis.
Authors: Malhotra Jyoti D. , Zhang Kezhong , Miao Hongzi , Pipe Steven W. , Kaufman Randal J. 
Published: October 2019

Abstract
Factor V (FV) and Factor VIII (FVIII) are homologous glycoproteins that provide essential functions in hemostasis. Previous studies demonstrated that compared to FV, the FVIII polypeptide folds inefficiently, accumulates in the endoplasmic reticulum (ER) and activates the Unfolded Protein Response (UPR). The UPR, mediated by the proximal sensors PERK and IRE1, is a signaling pathway leading to either adaptive survival or apoptotic demise upon accumulation of unfolded proteins in the ER. Here we show that FVIII expression in hepatocytes in vivo mediated by hydrodynamic tail-vein injection of plasmid DNA into fviii −/ − mice produces between 0.5 to 1.0 Unit/ml of FVIII in the plasma. This level of FVIII expression activated PERK and IRE1 to signal the UPR and induced both markers of oxidative stress and apoptosis in hepatocytes. In contrast, injection of DNA encoding either FV or a FVIII molecule engineered for improved secretion did not induce oxidative stress, activate the UPR or induce apoptosis. Gene expression analysis demonstrated that FVIII expression induced expression of the proapoptotic transcription factor CHOP. Injection of FVIII expression plasmids into chop−/ − mice did not induce oxidative stress or apoptosis, indicating that these stress responses require CHOP. Feeding of mice with the lipid soluble antioxidant, butylated hydroxy anisole (BHA), reduced oxidative stress and apoptosis and increased expression of FVIII in the plasma, demonstrating a pivotal role of oxidative stress in limiting FVIII expression and triggering apoptosis. Finally, overexpression of the anti-apoptotic protein Bcl2 also significantly suppressed oxidative stress and apoptosis and increased FVIII expression. The results demonstrate that 1) misfolding of an ER luminal protein, FVIII, is sufficient to induce oxidative stress and apoptosis in vivo, 2) oxidative stress limits protein secretion and activates apoptosis through a mechanism that requires CHOP, and 3) intervention to prevent oxidative stress by antioxidant feeding or Bcl2 overexpression preserves ER function, improves secretion and prevents apoptosis. The findings raise the possibility to treat diseases of protein misfolding, such as certain mutations that cause hemophilia A, by treatment with antioxidants.
Effects of Initial Treatment on Survival among Elderly AML Patients: Findings from the SEER-Medicare Database.
Authors: Menzin Joseph , Boulanger Luke , Karsten Verena , Cahill Ann L. , Earle Craig E. 
Published: October 2019

Abstract
Background: Acute myeloid leukemia (AML) is the most common type of leukemia among adults in the U.S. However, data on the effects of treatment on survival for large numbers of AML patients in clinical practice are limited.
Methods: Using the linked SEER-Medicare database, we evaluated mortality for AML patients 65+ years of age diagnosed between 1999 and 2002 who received chemotherapy versus no chemotherapy. Patients were followed from diagnosis until death or the database cut-off (December 31, 2003). The presence of chemotherapy treatment was identified based on procedure codes and diagnosis-related groups. The two study cohorts were matched on age, sex, comorbidity (Deyo adaptation of the Charlson Comorbidity Index), geographical region, teaching hospital status, and myelodysplastic syndrome (MDS) in the prior 12 months. Mortality rates were estimated via the Kaplan-Meier technique. Subgroup analyses were performed by level of comorbidity, age group, and teaching hospital status.
Results: A total of 3,317 elderly patients with AML who were eligible for fee-for-service Medicare coverage were identified. Of these, 1,193 (36%) received chemotherapy and 2,124 did not receive treatment. Treated patients were found to be younger and had fewer comorbidities compared to untreated patients. After matching, there were 888 patients in both cohorts. Mean age was 75 years and 59% were male. Fifty-three percent of patients received care at teaching hospitals. The median Charlson score was 1.0 and 24% were diagnosed with prior MDS. Median survival was 4.4 months longer for the treated cohort than for the untreated cohort (6.1 versus 1.7 months; P<0.0001) (see Figure).
Conclusions: This large observational study of elderly patients with AML illustrates that chemotherapy treatment is associated with improved survival. This survival gain is slightly less than that observed in other population-based AML studies that did not match on key prognostic factors, such as age and comorbidity levels.
Survival rates for treated and untreated patients Survival rates for treated and untreated patients
Treatment of AML in the Elderly: Who Is “Fit” for Intensive Chemotherapy?.
Authors: Hills Robert K. , Kell William J. , Burnett Alan K. 
Published: October 2019

Abstract
Currently, increasing attention is being focused on the older patient with AML who is deemed “unfit” for intensive chemotherapy. Indeed a recent population-based study (Juliusson et al, Leukemia 2006 (20), 42–7) showed that only around one half of patients between the ages of 70 and 79 were offered remission induction chemotherapy. Typically the unfit patients are treated with supportive care, low doses of cytosine arabinoside (Ara-C) or with investigational agents. However, there is no strict definition of what constitutes a patient unfit for intensive chemotherapy. The NCRI AML14 trial offered patients the choice of entering an intensive chemotherapy randomisation (where patients received daunorubicin/Ara-C based therapy, n=1273), or a non-intensive randomisation between low dose Ara-C and hydroxyurea (n=217). A randomisation between intensive and non-intensive chemotherapy was attempted but recruited only 8 patients, indicating that clinicians did not appear to be uncertain about which patients should receive which type of treatment. In order to identify which factors were significantly associated with the decision to enter either the intensive or non-intensive approach we performed analyses of the AML14 data. The two principal factors associated with fitness for intensive chemotherapy were age and performance status (both p<0.0001). Other factors influencing the decision were presence of comorbidities (p=0.007), diagnosis (de novo v secondary, p=0.01), lower weight (p=0.04) and heart disease (p=0.04). However, even after adjusting for these factors, clinician was a highly significant predictive variable (p<0.0001), and this significance was retained even if analyses were restricted to those doctors who had entered patients into both parts of the trial. While it is unsurprising that patients deemed unfit for intensive chemotherapy are older, less fit, thinner and with more comorbidities, the high level of significance of clinician as a variable indicates that this characterisation is insufficient. It is likely that clinician is a surrogate variable for other factors currently not routinely collected, although there is also a suggestion that clinicians may not be consistent in who receives intensive treatment. Comparisons of patients treated intensively and those treated non-intensively, even when stratified for prognostic factors, tend to show that intensively treated patients perform better (Wheatley et al., Blood 2005 (106(11)) 199a (Abstract 674)) but it is unclear whether even this stratified comparison is confounded.
Conclusion: This study defines factors which differ between patients allocated to an intensive or non-intensive approach. However we identify the clear influence of which physician is involved in the choice as an independent factor. To identify factors (which may be components of the physician’s choice) reliably a more comprehensive index is needed for which a prototype will be presented.
Effectiveness of Clofarabine in Elderly AML Patients with Adverse Cytogenetics Unfit for Intensive Chemotherapy.
Authors: Burnett Alan K. , Baccarani M. , Johnson Peter , Yin John , Saunders Andrew , Russell Nigel , Hills Robert 
Published: October 2019

Abstract
Outcomes for elderly patients with AML are almost uniformly poor, and it has been shown (Wheatley et al., Blood2005, 106(11) 199a) that patients with adverse cytogenetics have a particularly poor prognosis. Additionally, a large proportion of such patients are considered not to be fit for intensive chemotherapy (Juliusson et al, Leukemia, 2006 (20): 42–7), and given best supportive care, or low-dose Ara-C. The NCRI AML14 trial observed no remissions in 18 patients with adverse cytogenetics treated with Ara-C, and no remissions in 20 patients treated with hydroxyurea. We present here a combined analysis of the BIOV-121 Study, and the UWCM-0001 study. Both studies were for untreated patients over 65 years of age who were not considered fit for chemotherapy. The treatment comprised clofarabine 30mg/m2 on days 1–5 repeated after 28–42 days for up to 3 courses. The primary endpoints were overall response (CR, CRi or PR) and safety.
Patients: A total of 95 patients were recruited, of whom 95 received clofarabine 30mg/m2. Twenty-six patients (27%) had adverse cytogenetics.
Results: 10/26 patients (38%) achieved either CR or CRi. With a median follow-up of 10 months (range 2–17 months), 1 year survival is 20%, with 19/26 patients having died. At most recent follow-up, 4/10 patients achieving CR or CRi are still alive in remission.
Discussion: The remission rate of 38% seen with clofarabine compares favourably, not only with traditional non-intensive approaches (which have failed to induce any remissions in similar sized cohorts), but also to the 42% remission rate seen in patients treated with intensive daunorubicin/Ara-C based chemotherapy in the NCRI AML14 trial. One year survival rates are also encouraging, at 20% compared to 0%, 5% and 23% for patients treated with Ara-C, supportive care, and intensive chemotherapy respectively. Exploratory comparisons of survival between the 30mg clofarabine patients and the three treatment regimens give highly significant survival advantages compared to Ara-C and HU (p=0.0001, p=0.004 respectively) and no significant difference between clofarabine and DA (p=1.0), although confidence intervals in this case are wide.
Conclusions: Clofarabine has the ability to induce remissions in patients with adverse cytogenetics, unlike Ara-C and supportive care, and survival in this group is improved. Remission rates and survival are similar to those seen for patients treated with intensive chemotherapy. Clofarabine is clearly worthy of further investigation, and may provide an important treatment option for high risk patients with AML.