bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long Term Data on Anthracycline Cardiotoxicity in 547 Children with AML.
Authors: Creutzig Ursula , Diekamp Sylke , Zimmermann Martin , Reinhardt Dirk 
Published: October 2019

Abstract
Anthracyclines are effective antineoplastic drugs in acute mylogenous leukemia (AML) and dose intensity and cumulative doses are especially important. However, the use of anthracyclines is limited by cardiotoxicity, which occurs already at 300 mg/m2 cumulative doses (given as daunorubicin dosage) in children. To evaluate anthracycline-associated cardiomyopathy in pediatric AML-patients, the incidence of late clinical and subclinical cardiotoxicity (using echocardiography) was analysed in studies AML-BFM 93 and 98. Out of a total of 1,207 patients under 18 years, 547 (45%) patients were eligible for the analysis of late cardiotoxicity - de novo AML: 470 of 1,010 (46%), AML-Down syndrome: 69 of 121 (57%), secondary AML 8 of 76 (11%) -, median follow-up 5.3 years (0.8–11.7 years) after diagnosis. The cumulative dose of anthracyclines was risk-adapted between 300 and 450 mg/m2 or even higher in patients with secondary AML.
Results: Late cardiomyopathy was seen in 16 patients, cumulative incidence (CI) after 11 years 5±1% (de novo patients: 4±1%), including 4 of 38 patients (10.5%) who suffered already from early cardiomyopathy. Nine of these 16 patients (CI 2.5±1%) showed clinical symptoms, with persistent abnormal shortening fraction in 5 of them, which led to death in one AML-Down syndrome patient. Late subclinical cardiomyopathy occurred temporarily in 7 patients. Late clinical cardiomyopathy mainly effected patients with a second anthracycline therapy (3 of 8 with AML as secondary malignancy) and those with early cardiotoxicity. Using anthracyclines risk-adapted or administering long-term infusion might have contributed to the low rate of cardiomyopathy in AML de novo patients.
NPM Mutations and Not FLT3 Mutations Are a Potential Marker for Monitoring Minimal Residual Disease in Acute Myeloid Leukemia.
Authors: Palmisano Michela , Grafone Tiziana , Ottaviani Emanuela , Testoni Nicoletta , Paolini Stefania , Papayannidis Cristina , Rondoni Michela , Baccarani Michele , Martinelli Giovanni 
Published: October 2019

Abstract
Nucleophosmin (NPM) is a multifunctional phosphoprotein that acts as nucleocytoplasmic shuttling protein, with tumour suppressor and oncogenic functions. Recently, NPM mutations have been found in a subset of adults with de novo acute myeloid leukemia (AML). These mutations occur in the last coding exon (exon 12), causing a frameshift and the formation of novel C-termini. The abnormal mutated NPM protein shows aberrant cytoplasmic localization and is frequently associated with FLT3 mutation.
These observations provide basis for studies of the pathogenesis in AML. We did sequential analysis on patient samples during the clinical course to investigate the stability and pathogenetic role of NPM mutation in AML and the association with FLT3 mutations. The NPM mutations were determined by D-HPLC analysis; samples exhibiting an abnormal D-HPLC profile were confirmed by direct sequencing. We investigated 28 patients of de novo AML. Eleven samples were sequenced since they showed an heteroduplex D-HPLC profile. Type A mutation (960_963dupTCTG) was the commonest observed change, occurring in 9/11 samples, followed by type B mutation (960_963insCATG) in 1 case and type D mutation (960_963insCCTG) in 1 case. Furthermore, we observed that 5/11 patients harboring NPM mutation presented also mutant FLT3 at diagnosis. Analyzing NPM mutations during progression of disease, we observed that NPM mutation disappeared at complete remission and the same mutation reappeared at relapse. No differences were found in wild type NPM.
Instead, we found a modification of FLT3 status associated to evolution of disease in 7/28 patients: 2 patients lost the mutation at relapse, 4 patients acquired the mutation at relapse and 1 patient modified the mutation from D835 to ITD (Table 1). Together these results suggest that NPM mutations and not FLT3 mutations may have utility as a potential marker for monitoring minimal residual disease. Studies on the biological effects of NPM mutations will contribute to disclose the role of NPM mutations in the pathogenesis of AML and their interactions with other genetic alterations such as FLT3.
Sonic Hedgehog Signaling in Mantle Cell Lymphoma.
Authors: Hegde Ganapati V. , Emanuel Katy , Joshi Avadhut D. , Munger Corey M. , Weisenburger Dennis D. , Vose Julie M. , Joshi Shantaram S. 
Published: October 2019

Abstract
Mantle cell lymphoma (MCL) is associated with poor clinical outcome among all the B-cell malignancies. MCL cells have a characteristic phenotype including IgM+, IgD+, CD5+, CD10−, CD19+, CD20+, Bcl2+, CD23−, CD24+, and have a (11:14) (q13:q32) translocation, involving the Bcl-1 locus and the IgH heavy chain joining region, resulting in up-regulation of Bcl-1/PRAD-1 with increased Cyclin D1 expression. In spite of our understanding of B cell development, we do not have effective therapeutic approach to treat MCL. This warrants an immediate understanding of the biology MCL cells, and key signaling pathways underlying the disease progression. Further, these key signaling pathways involved in MCL could be specifically targeted, which may have potential therapeutic value.
Emerging evidences have revealed that sonic hedgehog (Shh) signaling promotes tumor cell proliferation, and protects them from apoptosis in different cancers such as pancreatic cancer, prostate cancer, gastric cancer, medulloblastoma, basal cell carcinoma, breast cancer, etc. In addition, targeting the Shh signaling has been shown as a potential therapeutic approach to treat some of these cancers. However, the role of Shh signaling has not been reported in any of B cell malignancies including MCL. Therefore, we studied the status of Shh signaling molecules in the proliferation and survival of MCL cells in vitro using JVM-2, Granta-519, Jeko-1 and Z138 cell lines and human primary MCL cells. Our results demonstrate that the molecules involved in the Shh signaling like patched and smoothened receptors, and the target transcription factors, GLI were over expressed in Granta-519, Jeko-1, Z-138 and JVM-2 MCL cell lines, and patients primary MCL cells compared to normal human B lymphocytes. Addition of exogenous Shh increased the proliferation of JVM-2 cells in vitro. There was an increased transcripts level of GLI1, BCL2 and Cyclin D1 (CCND1) in JVM-2 cells following the addition of Shh. Addition of Shh-signaling inhibitor Cyclopamine abrogated the increased proliferation and transcription of the above genes induced by Shh in JVM-2 cells (figure 1). Furthermore, the Gli2 anti-sense oligonucleotide decreased CCND1 and BCL2 transcript expression, as well as decreased the proliferation of JVM2 cells in vitro (figure 2). Taken together, these results suggest that Shh-Gli signaling may be one of the pathways that regulate the Bcl-2 and Cyclin D1 activation and thereby regulate the proliferation and apoptosis of MCL cells. Therefore, further dissecting of the Shh-Gli mediated regulation of Bcl2 signaling may have potential implications in advancing the treatment for MCL.
Figure 1: Figure 1:. Figure 2: Figure 2:.
aUPD in the Clonal Evolution of Follicular Lymphoma.
Authors: O’Shea Derville , Iqbal Sameena , Carlotti Emanuela , Davies Andrew , Chaplin Tracy , Matthews Janet , Raghavan Manoj , Norton Andrew , Lister T. Andrew , Young Bryan D. , Fitzgibbon Jude 
Published: October 2019

Abstract
The use of Single Nucleotide Polymorphism (SNP) array profiling has uncovered extensive regions of acquired uniparental disomy (aUPD) in the cancer genome that go undetected using cytogenetics or array-CGH platforms. These regions usually arise by mitotic recombination and can render a cell homozygous for a pre-existing abnormality. SNP array analysis was performed using the Affymetrix 10K Gene-chip mapping array on DNA extracted from a series of Follicular Lymphoma (FL) lymph nodes biopsies from 42 patients, taken at time of diagnosis (n=20), progression (n=16) and transformation (t-FL) (n=32), and the t(14;18) positive lymphoma cell lines DoHH2 and RL 2261. Analysis was performed using the genome oriented laboratory file system, a software package designed to interpret SNP data. The criteria of > 96% homozygosity in at least 50 contiguous SNPs was found to detect no abnormalities in 24 normal remission bone marrows and was therefore adopted for the detection of abnormal runs of homozygosity. Abnormalities were detected in 53/68 primary specimens; these were non-random with recurring sites of aUPD on several chromosomes including 6p, 9p, 12q and 17p. This panel included 26 paired FL and t-FL samples; in 9 FL cases regions of homozygosity were identified which were not present in the subsequent t-FL sample, suggesting that t-FL may arise in a proportion of patients by a mechanism other than a process of direct clonal evolution. Homozygosity of 9p and 17p was seen primarily in the transformation samples and in three cases rendered the cell homozygous for a pre-existing mutation of either CDKN2A or TP53. Thus mutation precedes mitotic recombination which leads to the removal of the remaining wild-type allele. Nine out of 42 patients studied (21%) have aUPD of chromosome 6p. This appears to be an early event in lymphomagenesis as it was present in both FL and t-FL samples obtained from the same patient. The sites of mitotic recombination cluster in a region immediately proximal to the MHC complex at 6p21-12 in 8/9 cases. Mutations in CCND3, CDKN1A, and two translocation partners of BCL6: SRP20 and HIST1H4I, which are all located within or just distal of this cluster, were excluded by direct sequence analysis. Loss of MHC class II expression has been frequently observed in Diffuse Large B-cell lymphoma and a selective advantage gained by the lymphoma cell here would have implications in tumour surveillance. This study highlights the frequency of aUPD in follicular lymphoma and ongoing studies will elucidate the selective basis of a UPD at this location in the pathogenesis of lymphoma.
PVRL2 Is Translocated to the TCRA Locus in t(14;19)(q11;13) Positive Peripheral T-Cell Lymphoma.
Authors: Almire Carole , Ruminy Philippe , Bertrand Philippe , Wlodarska Iwona , Subero Jose I. Martin , Siebert Reiner , Tilly Herve , Bastard Christian 
Published: October 2019

Abstract
T-cell non-Hodgkin lymphomas (NHLs) are uncommon malignancies that represent approximately 15% of aggressive lymphomas in Western countries. Contrasting with B-cell lymphomas, very few recurrent chromosomal abnormalities have been identified. Nevertheless, the TCR loci and preferentially the TCRAD at chromosome band 14q11 could be involved in up to 15% of cases. We recently reported a novel and recurrent t(14;19)(q11;q13) chromosomal translocation in peripheral T-cell lymphoma (PTCL). FISH analysis performed in three cases suggested an implication of the TCRAD locus at 14q11 and of BCL3 at 19q13. We now report the molecular cloning of the genomic junctions for these three patients. Sequence analysis confirmed the involvement of the TCRAD on 14q11 and assessed the breakpoint’s localisation to the TCRA variable region for all cases. In the first, the chromosomal break occurred between the J30 and the J31 segments while in the second it was in the J58 segment. Thus, both translocations probably occurred after an illegitimate V(D)J recombination. Remarkably, for the third patient, junctions with the deltaRec and psi(J)alpha elements were identified on the der(14) and der(19) respectively. Consequently this translocation probably results from an illegitimate deltarec-Psi(J)alpha rearrangement (TCRD deletion) during thymopoiesis before Valpha-Jalpha rearrangements. On chromosome 19, our results indicated a new clustering of breakpoints outside the region documented in t(14;19)(q32;q13) in chronic lymphocytic leukemia. Remarkably, all three breaks occurred ~130kb downstream from BCL3, in the PVRL2 gene. Consequently, the TCRA locus enhancer is juxtaposed to PVRL2 and BCL3 on the derivative chromosome 19. For two patients, mRNA expression levels were investigated by real time RT-PCR experiments, which confirmed a high expression of both PVRL2 and BCL3. In conclusion, we identified PVRL2 as the recurrent translocation partner of the TCRA locus in PTCL. Whether this clustering results from an important instability of the PVRL2 gene during thymopoiesis remains to be investigated. The PVRL2 overexpression itself may be an important step for T-cell lymphomagenesis.
FTY720 (2-Amino-2-[2-(4-octylphenyl) ethyl] Propane 1, 3-diol hydrochloride), Mediates Cytotoxicity through Caspase Independent and Protein Phosphatase 2A Dependent Mechanisms in Chronic Lymphocytic Leukemia and Lymphoblastic Leukemia/Lymphoma.
Authors: Liu Qing , Zhao Xiaobin , Frissora Frank , Ma Yihui , Santhanam Ramasamy , Perrotti Danilo , Chen Ching-Shih , Dalton James T. , Byrd John C. , Muthusamy Natarajan 
Published: October 2019

Abstract
FTY720 (2-Amino-2-[2-(4-octylphenyl) ethyl] propane 1, 3-diol hydrochloride) is a synthetic compound produced by modification of a natural immunosuppressant, ISP-1. It is an immunosuppressive agent that is being developed to prevent organ transplant rejection. Recent studies indicate additional role for FTY720 in inducing cell apoptosis. We demonstrate here a novel mechanism by which FTY720 mediates cytotoxic effects in cell lines representing different B cell malignancies and primary B cells from chronic lymphocytic leukemia (CLL) patients. FTY720 induced apoptosis as detected by annexin V/ propidium iodide staining in representative B cell lines and CLL patient derived CD19+ B cells in time and dose dependent manner (p<0.0001, untreated vs 10mM-treated CLL cells, n=15). In contrast to previous reports in T cell lines, FTY720 induced cytotoxicity in Raji cell line and primary CLL cells is independent of activation of caspase 3, 8 and 9 or poly-ADP ribose polymerase cleavage. Further, pan-caspase inhibitor Z-VAD-fmk rescued these cells from fludarabine but not FTY720 induced apoptosis (p=0.001 fludarabine vs fludarabine+z-VAD-fmk; p=0.99 FTY720 vs FTY720+z-VAD-fmk, n=5). Over-expression of Bcl-2 failed to protect transformed B-cells from FTY720 induced apoptosis suggesting Bcl-2 independent cytotoxic effect. Interestingly, FTY720 induced consistent increase in protein phosphatase 2a (PP2a) activity and concentrations of okadaic acid that inhibited the FTY720-induced PP2A activity also resulted in inhibition of FTY720-mediated cytotoxicity in B cell lines and primary CLL cells, indicating a role for PP2A activation in FTY720 induced cytotoxicity. Consistent with its activation of PP2A, FTY720 induced dephosphorylation of of Erk1/2 in CLL B cells. Further, FTY720 treatment resulted in significant in-vivo therapeutic efficacy associated with prolonged survival in a xenograft SCID mouse model of disseminated B cell lymphoma/leukemia (median survival time for FTY720 treated mice was 47 days (95 %CI 39–53) compared to 18 days in placebo controls (95% CI 17–19) P<0.0001-FTY720 vs placebo). These results provide first evidence for a PP2A dependent and caspase independent cytotoxicity of FTY720 in B cells. The novel caspase and Bcl-2 independent mechanism of cytotoxicity concurrent with identification of PP2a activation as a surrogate marker of cell killing provide further justification for clinical development of this agent in lymphoid leukemia.
Ethacrynic Acid Can Inhibit Wnt/β-Catenin Signaling and Induce Apoptosis in Chronic Lymphocytic Leukemia Cells.
Authors: Liu Jerry X. , Endo Tomoyuki , Kipps Thomas J. , Dennis Carson A. , Desheng Lu 
Published: October 2019

Abstract
Chronic lymphocytic leukemia (CLL) is caused by an abnormal balance in signals for survival and cell death. Recently, CLL cells are shown to have an activated Wnt/β-catenin pathway, which may contribute to the apoptosis-resistant state characteristic of this disease. Accordingly, inhibitors of the Wnt/β-catenin pathway may compromise the viability of CLL cells in vitro and in vivo. To identify potential inhibitors of the Wnt/β-catenin pathway, we screened the Gen-Plus drug library using a Wnt/β-catenin TOPflash reporter plasmid in HEK293 cells. Although 99% of the 960 drugs screened with this assay, including many clinically used alkylating agents and anti-metabolites, did not inhibit the Wnt/β-catenin pathway, ethacrynic acid (EA), a once commonly used diuretic agent, displayed potent inhibition of Wnt/β-catenin signaling. EA has an unsaturated lactone nucleophile that can react with sulfhydryl groups in proteins. N-acetyl-L-cysteine (NAC), but not other anti-oxidants, prevented EA from inhibiting the trans-activation function of β-catenin. Treatment of CLL cells with EA caused a time-dependent decrease in protein levels of the Wnt/β-catenin regulated LEF-1 transcription factor, which is overexpressed in CLL cells, compared to normal blood lymphocytes. Treatment with EA also caused a concentration dependent decrease in cyclin D1 and fibronectin levels in CLL cells as detected by Q-PCR. Collectively, these results suggest that EA can inhibit Wnt/β-catenin signaling in CLL cells, and this effect is mediated by the ability of EA to modify sulfhydryl groups on key proteins, rather than by non-specific nucleophilic attack or increased cellular oxidative stress alone. Cell viability assays showed that EA induced cell death in primary CLL cells with a mean IC50 of 3 uM, a concentration achieved in previous clinical trials with the drug in patients with solid tumors. EA at 3 uM also enhanced by 6–10 fold the cytotoxicity of fludarabine in CLL cells from both fludarabine sensitive and resistant patients. At the same concentration, EA did not cause significant cell death of normal blood mononuclear cells. These results, therefore, suggest the therapeutic potential of EA in CLL, based on a novel mechanism of targeting the Wnt/β-catenin signaling pathway.
Apoptotic Death of Bcr-Abl-Expressing Myeloid Progenitors in Response to the m-Tor Inhibitor RAD001 (Everolimus) Is Promoted by the Nuclear Import of c-Abl.
Authors: Mancini Manuela , Zuffa Elisa , Corrado Patrizia , Brusa Gianluca , Petta Sara , Pagnotta Eleonora , Santucci Maria Alessandra 
Published: October 2019

Abstract
Nuclear accumulation of c-Abl protein in response to genotoxic damage addresses apoptotic cell death. The process, driven by the disruption of its binding to 14-3-3 scaffolding proteins, is independent from c-Abl catalytic state and conditional upon 14-3-3 phosphorylation by the c-jun N-terminal kinase (JNK) (Yoshida et al Nat Cell Biol 7,278,2005). Our work moved from the observation that the constitutive activation of Abl tyrosine kinase (TK) by juxtaposed Bcr sequences in p210 fusion protein Bcr-Abl precludes c-Abl nuclear import in response to gamma irradiation, advancing a role for residual c-Abl protein “loss of function” in the apoptosis-resistant phenotype of Chronic Myeloid Leukemia (CML) progenitors. In 32D cell clones transducing a temperature-conditional Bcr-Abl mutant, active p210 TK is associated with the overexpression of 14-3-3sigma mostly driven by transcriptional events involving histone H4 acetylation (but not methylation) status of the gene promoter. P210 TK inhibition in response to 24 hour exposure to imatinib mesylate (IM) is associated with an early downregulation of 14-3-3sigma followed by c-Abl nuclear import and cell commitment to apoptotic death. The two last events are further enhanced by complementary inhibition of the 14-3-3 binding site by R18 peptide, supporting that the negative impact of p210 TK on pro-apoptotic function of residual normal c-Abl arises from its effects on 14-3-3sigma. Previous studies proved that the activation of p38 MAP kinase contributes to IM effects in CML (Parmar et al, J Biol Chem279,25345,2004). Interestingly, p38 MAP kinase is also involved in tuberous sclerosis 2 gene protein (TSC2, also known as tuberin) phosphorylation and enhanced binding to 14-3-3 possibly promoting the activation of IM-compensatory signals, including m-Tor (Li et al, J Biol Chem278,13663,2003). Here we show that the m-Tor inhibitor RAD001 (everolimus; kindly provided by Novartis Pharma AG) at 100 nM concentration induces c-Abl nuclear import and apoptotic cell death in 32D cell clones expressing active p210 TK. Both events are further and significantly enhanced by combination with IM. C-Abl nuclear shuttling in response to the RAD001 and IM combination procedes from Akt and p38 MAP kinase inactivating dephosphorylation and 14-3-3 phosphorylation at serine residues critical for client protein binding including the apoptotic death effectors Bad, Bax and Ask1. In conclusion, our work supports the advantage of TK and m-Tor inhibitor association for CML treatment.
Trough Plasma Imatinib Concentrations Are Associated with Both Cytogenetic and Molecular Responses to Standard-Dose Imatinib in Chronic Myeloid Leukemia.
Authors: Picard Stephane , Titier Karine , Etienne Gabriel , Lassalle Regis , Marit Gerald , Reiffers Josy , Begaud Bernard , Moore Nicholas , Molimard Mathieu , Mahon Francois-Xavier 
Published: October 2019

Abstract
BACKGROUND
Variable responses to imatinib, in the treatment of chronic myeloid leukemia (CML), are incompletely understood. Previous studies focused on cellular mechanisms of resistance to imatinib. Another hypothesis for variable response lies in pharmacokinetic variability that may reduce drug exposure in patients receiving imatinib.
METHODS
Using high-performance liquid chromatography-tandem mass spectrometry, we assessed trough plasma imatinib concentrations in CML patients who responded or not to standard-dose imatinib, after at least one year’s treatment. Complete cytogenetic response (CCR) was defined as 0 percent Philadelphia-chromosome-positive cells in bone marrow. Major molecular response (MMR) was defined as a 3 logarithm reduction of BCR-ABL transcripts, quantified from peripheral blood using real-time quantitative reverse-transcriptase polymerase chain reaction.
RESULTS
Sixty-eight patients were included. Mean trough plasma imatinib concentrations were significantly higher in the group with CCR (56 patients) than in the group without (P=0.02). Mean (±SD) trough plasma imatinib concentrations were significantly higher in the group with MMR (34 patients) than in the group without (1452.1±649.1 ng per milliliter vs. 869.3±427.5 ng per milliliter, P<0.001) whereas there was no difference in the imatinib daily dose. For trough plasma imatinib concentrations and their discrimination potential for MMR, the area under receiver-operating characteristic curve was 0.775, with best sensitivity (76.5 percent) and specificity (70.6 percent) at a plasma threshold of 1002 ng per milliliter.
CONCLUSIONS
Monitoring of plasma imatinib concentrations may become part of standard management of CML patients, or should at the very least be checked in the case of treatment failure or suboptimal response.