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Sample records for leukaemia gene tel

  1. Gene therapy for paediatric leukaemia.

    PubMed

    Rousseau, R F; Bollard, C M; Heslop, H E

    2001-07-01

    Improvements in the chemotherapeutic and transplant regimens have had a significant impact in improving survival rates for paediatric leukaemia. However, there are still important problems to address including what options are available for patients with chemoresistant disease and what strategies are available to avoid the concerns regarding the toxicity associated with highly cytotoxic treatment regimens. Gene therapy and immunotherapy protocols hold great promise. Using gene transfer of a marker gene, a number of biological issues in the therapy of leukaemia have been addressed. For example, by gene marking autologous bone marrow grafts it has been possible to demonstrate that infused marrow contributes to relapse in acute and chronic myeloid leukaemias. In the allogeneic transplant setting, genetically modified T-cells have proven valuable for the prophylaxis and treatment of viral diseases and may have an important role in preventing or treating disease relapse. Gene transfer is also being used to modify tumour function, enhance immunogenicity, and confer drug-resistance to normal haematopoietic stem cells. With the continued scientific advancements in this field, gene therapy will almost certainly have a major impact on the treatment of paediatric leukaemia in the future. PMID:11727502

  2. Gene profiling of the erythro- and megakaryoblastic leukaemias induced by the Graffi murine retrovirus

    PubMed Central

    2010-01-01

    Background Acute erythro- and megakaryoblastic leukaemias are associated with very poor prognoses and the mechanism of blastic transformation is insufficiently elucidated. The murine Graffi leukaemia retrovirus induces erythro- and megakaryoblastic leukaemias when inoculated into NFS mice and represents a good model to study these leukaemias. Methods To expand our understanding of genes specific to these leukaemias, we compared gene expression profiles, measured by microarray and RT-PCR, of all leukaemia types induced by this virus. Results The transcriptome level changes, present between the different leukaemias, led to the identification of specific cancerous signatures. We reported numerous genes that may be potential oncogenes, may have a function related to erythropoiesis or megakaryopoiesis or have a poorly elucidated physiological role. The expression pattern of these genes has been further tested by RT-PCR in different samples, in a Friend erythroleukaemic model and in human leukaemic cell lines. We also screened the megakaryoblastic leukaemias for viral integrations and identified genes targeted by these integrations and potentially implicated in the onset of the disease. Conclusions Taken as a whole, the data obtained from this global gene profiling experiment have provided a detailed characterization of Graffi virus induced erythro- and megakaryoblastic leukaemias with many genes reported specific to the transcriptome of these leukaemias for the first time. PMID:20102610

  3. Identification of novel Notch target genes in T cell leukaemia

    PubMed Central

    Chadwick, Nicholas; Zeef, Leo; Portillo, Virginia; Fennessy, Carl; Warrander, Fiona; Hoyle, Sarah; Buckle, Anne-Marie

    2009-01-01

    Background Dysregulated Notch signalling is believed to play an important role in the development and maintenance of T cell leukaemia. At a cellular level, Notch signalling promotes proliferation and inhibits apoptosis of T cell acute lymphoblastic leukaemia (T-ALL) cells. In this study we aimed to identify novel transcriptional targets of Notch signalling in the T-ALL cell line, Jurkat. Results RNA was prepared from Jurkat cells retrovirally transduced with an empty vector (GFP-alone) or vectors containing constitutively active forms of Notch (N1ΔE or N3ΔE), and used for Affymetrix microarray analysis. A subset of genes found to be regulated by Notch was chosen for real-time PCR validation and in some cases, validation at the protein level, using several Notch-transduced T-ALL and non-T-ALL leukaemic cell lines. As expected, several known transcriptional target of Notch, such as HES1 and Deltex, were found to be overexpressed in Notch-transduced cells, however, many novel transcriptional targets of Notch signalling were identified using this approach. These included the T cell costimulatory molecule CD28, the anti-apoptotic protein GIMAP5, and inhibitor of DNA binding 1 (1D1). Conclusion The identification of such downstream Notch target genes provides insights into the mechanisms of Notch function in T cell leukaemia, and may help identify novel therapeutic targets in this disease. PMID:19508709

  4. Mutational analysis of the candidate tumor suppressor genes TEL and KIP1 in childhood acute lymphoblastic leukemia.

    PubMed

    Stegmaier, K; Takeuchi, S; Golub, T R; Bohlander, S K; Bartram, C R; Koeffler, H P

    1996-03-15

    We have shown previously that loss of heterozygosity at chromosome band 12p13 is among the most frequent genetic abnormalities identified in acute lymphoblastic leukemia (ALL) of childhood. Two known genes map within the critically deleted region of 12p: TEL, the gene encoding a new member of the ETS family of transcription factors, which is rearranged in a variety of hematological malignancies; and KIP1, the gene encoding the cyclin-dependent kinase inhibitor p27. Both genes are, therefore, excellent candidate tumor suppressor genes. In this report, we determined the exon organization of the TEL gene and performed mutational analysis of TEL and KIP1 in 33 childhood ALL patients known to have loss of heterozygosity at this locus. No mutations in either TEL or KIP1 were found; this suggest that neither TEL nor KIP1 is the critical 12p tumor suppressor gene in childhood ALL. PMID:8640833

  5. The clinical implications of gene mutations in chronic lymphocytic leukaemia.

    PubMed

    Rossi, Davide; Gaidano, Gianluca

    2016-04-12

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  6. The clinical implications of gene mutations in chronic lymphocytic leukaemia

    PubMed Central

    Rossi, Davide; Gaidano, Gianluca

    2016-01-01

    Chronic lymphocytic leukaemia (CLL) is a molecularly heterogeneous disease as revealed by recent genomic studies. Among genetic lesions that are recurrent in CLL, few clinically validated prognostic markers, such as TP53 mutations and 17p deletion, are available for the use in clinical practice to guide treatment decisions. Recently, several novel molecular markers have been identified in CLL. Though these mutations have not yet gained the qualification of predictive factors for treatment tailoring, they have shown to be promising to refine the prognostic stratification of patients. The introduction of targeted drugs is changing the genetics of CLL, and has disclosed the acquisition of previously unexpected drug resistant mutations in signalling pathway genes. Ultra-deep next generation sequencing has allowed to reach deep levels of resolution of the genetic portrait of CLL providing a precise definition of its subclonal genetic architecture. This approach has shown that small subclones harbouring drug resistant mutations anticipate the development of a chemorefractory phenotype. Here we review the recent advances in the definition of the genomic landscape of CLL and the ongoing research to characterise the clinical implications of old and new molecular lesions in the setting of both conventional chemo-immunotherapy and targeted drugs. PMID:27031852

  7. Subcellular localization of EEN/endophilin A2, a fusion partner gene in leukaemia

    PubMed Central

    2004-01-01

    EEN (extra eleven nineteen), also known as EA2 (endophilin A2), a fusion partner of the MLL (mixed-lineage leukaemia) gene in human acute leukaemia, is a member of the endophilin A family, involved in the formation of endocytic vesicles. We present evidence to show that EEN/EA2 is localized predominantly in nuclei of various cell lines of haemopoietic, fibroblast and epithelial origin, in contrast with its reported cytoplasmic localization in neurons and osteoclasts, and that EEN/EA2 exhibits nucleocytoplasmic shuttling. During the cell cycle, EEN/EA2 shows dynamic localization: it is perichromosomal in prometaphase, co-localizes with the bipolar spindle in metaphase and anaphase and redistributes to the midzone and midbody in telophase. This pattern of distribution coincides with changes in protein levels of EEN/EA2, with the highest levels being observed in G2/M-phase. Our results suggest that distinct subcellular localization of the endophilin A family members probably underpins their diverse cellular functions and indicates a role for EEN/EA2 in the cell cycle. PMID:15214844

  8. Fusion of platelet-derived growth receptor {beta} to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation

    SciTech Connect

    Golub, T.; Barker, G.; Gilliland, D.G.

    1994-09-01

    Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome characterized by abnormal clonal myeloid proliferation, and by progression to acute myelogenous leukemia (AML). A recently recognized subgroup of CMML has a t(5;12) (q33;p13) balanced translocation. Fluorescence in situ hybridization (FISH) localized the translocation breakpoint near the CSF1 receptor (CSF1R) locus on chromosome 5q. Pulsed-field gel electrophoresis confirmed rearrangements near CSF1R, but involvement of CSF1R itself was excluded. Southern blotting showed a rearrangement within the closely linked PDGF receptor {beta} (PDGFR{beta}) gene. Ribonuclease protection assays localized the translocation breakpoint to nucleotide 1766 in PDGFR{beta} RNA. Anchored PCR was used to identify the chromosome 12 fusion partner, a novel ets-like protein, tel. Tel contains a highly conserved carboxy terminal ets-like DNA-binding domain, and an amino terminal domain with a predicted helix-loop-helix (HLH) secondary structure. The consequence of the t(5;12) translocation is fusion of the tel HLH domain to the PDGFR{beta} transmembrane and tyrosine kinase domains. The tel HLH domain may contribute a dimerization motif which serves to constitutively activate PDGFR{beta} tyrosine kinase activity. The tel-PDGFR{beta} fusion demonstrates the oncogenic potential of PDGFR{beta}, and may provide a paradigm for early events in the pathogenesis of AML.

  9. Perspectives for therapeutic targeting of gene mutations in acute myeloid leukaemia with normal cytogenetics.

    PubMed

    Falini, Brunangelo; Sportoletti, Paolo; Brunetti, Lorenzo; Martelli, Maria Paola

    2015-08-01

    The acute myeloid leukaemia (AML) genome contains more than 20 driver recurrent mutations. Here, we review the potential for therapeutic targeting of the most common mutations associated with normal cytogenetics AML, focusing on those affecting the FLT3, NPM1 and epigenetic modifier genes (DNMT3A, IDH1/2, TET2). As compared to early compounds, second generation FLT3 inhibitors are more specific and have better pharmacokinetics. They also show higher anti-leukaemic activity, leading to about 50% of composite complete remissions in refractory/relapsed FLT3-internal tandem duplication-mutated AML. However, rapid relapses invariably occur due to various mechanisms of resistance to FLT3 inhibitors. This issue and the best way for using FLT3 inhibitors in combination with other therapeutic modalities are discussed. Potential approaches for therapeutic targeting of NPM1-mutated AML include: (i) reverting the aberrant nuclear export of NPM1 mutant using exportin-1 inhibitors; (ii) disruption of the nucleolus with drugs blocking the oligomerization of wild-type nucleophosmin or inducing nucleolar stress; and (iii) immunotherapeutic targeting of highly expressed CD33 and IL3RA (CD123) antigens. Finally, we discuss the role of demethylating agents (decitabine and azacitidine) and IDH1/2 inhibitors in the treatment of AML patients carrying mutations of genes (DNMT3A, IDH1/2 and TET2) involved in the epigenetic regulation of transcription. PMID:25891481

  10. Trisomy 19 is associated with trisomy 12 and mutated IGHV genes in B-chronic lymphocytic leukaemia.

    PubMed

    Sellmann, Ludger; Gesk, Stefan; Walter, Christoph; Ritgen, Matthias; Harder, Lana; Martín-Subero, José I; Schroers, Roland; Siemer, Dörte; Nückel, Holger; Dyer, Martin J S; Dührsen, Ulrich; Siebert, Reiner; Dürig, Jan; Küppers, Ralf

    2007-07-01

    The occurrence of trisomy 19 was investigated in 705 cases of B-chronic lymphocytic leukaemia (CLL) by metaphase cytogenetic and/or fluorescence in situ hybridisation analyses. Trisomy 19 was detected in 11 cases (1.6%), all of which also carried a trisomy 12; nine of 10 had mutated IGHV genes. In contrast, B-CLL cases with trisomy 12 lacking trisomy 19 mostly had unmutated IGHV genes. Karyotypes of the present study and the literature identified a strong correlation to trisomy 18 in addition to trisomy 12. Trisomy 19 seems to be a secondary event in B-CLL with trisomy 12, mostly originating from mutated B cells. PMID:17593029

  11. Validation of a mouse xenograft model system for gene expression analysis of human acute lymphoblastic leukaemia

    PubMed Central

    2010-01-01

    Background Pre-clinical models that effectively recapitulate human disease are critical for expanding our knowledge of cancer biology and drug resistance mechanisms. For haematological malignancies, the non-obese diabetic/severe combined immunodeficient (NOD/SCID) mouse is one of the most successful models to study paediatric acute lymphoblastic leukaemia (ALL). However, for this model to be effective for studying engraftment and therapy responses at the whole genome level, careful molecular characterisation is essential. Results Here, we sought to validate species-specific gene expression profiling in the high engraftment continuous ALL NOD/SCID xenograft. Using the human Affymetrix whole transcript platform we analysed transcriptional profiles from engrafted tissues without prior cell separation of mouse cells and found it to return highly reproducible profiles in xenografts from individual mice. The model was further tested with experimental mixtures of human and mouse cells, demonstrating that the presence of mouse cells does not significantly skew expression profiles when xenografts contain 90% or more human cells. In addition, we present a novel in silico and experimental masking approach to identify probes and transcript clusters susceptible to cross-species hybridisation. Conclusions We demonstrate species-specific transcriptional profiles can be obtained from xenografts when high levels of engraftment are achieved or with the application of transcript cluster masks. Importantly, this masking approach can be applied and adapted to other xenograft models where human tissue infiltration is lower. This model provides a powerful platform for identifying genes and pathways associated with ALL disease progression and response to therapy in vivo. PMID:20406497

  12. Targeted gene transfer to lymphocytes using murine leukaemia virus vectors pseudotyped with spleen necrosis virus envelope proteins.

    PubMed

    Engelstädter, M; Buchholz, C J; Bobkova, M; Steidl, S; Merget-Millitzer, H; Willemsen, R A; Stitz, J; Cichutek, K

    2001-08-01

    In contrast to murine leukaemia virus (MLV)-derived vector systems, vector particles derived from the avian spleen necrosis virus (SNV) have been successfully targeted to subsets of human cells by envelope modification with antibody fragments (scFv). However, an in vivo application of the SNV vector system in gene transfer protocols is hampered by its lack of resistance against human complement. To overcome this limitation we established pseudotyping of MLV vector particles produced in human packaging cell lines with the SNV envelope (Env) protein. Three variants of SNV Env proteins differing in the length of their cytoplasmic domains were all efficiently incorporated into MLV core particles. These pseudotype particles infected the SNV permissive cell line D17 at titers of up to 10(5) IU/ml. A stable packaging cell line (MS4) of human origin released MLV(SNV) pseudotype vectors that were resistant against human complement inactivation. To redirect their tropism to human T cells, MS4 cells were transfected with the expression gene encoding the scFv 7A5 in fusion with the transmembrane domain (TM) of the SNV Env protein, previously shown to retarget SNV vector particles to human lymphocytes. MLV(SNV-7A5)-vector particles released from these cells were selectively infectious for human T cell lines. The data provide a proof of principle for targeting MLV-derived vectors to subpopulations of human cells through pseudotyping with SNV targeting envelopes. PMID:11509952

  13. The methylenetetrahydrofolate reductase C677T gene polymorphism decreases the risk of childhood acute lymphocytic leukaemia.

    PubMed

    Franco, R F; Simões, B P; Tone, L G; Gabellini, S M; Zago, M A; Falcão, R P

    2001-12-01

    We have determined the prevalence of methylenetetrahydrofolate reductase (MTHFR) mutations C677T and A1298C in 71 children (< or = 15 years) with acute lymphoblastic leukaemia (ALL) and in 71 control subjects. Odds ratio (OR) for ALL linked to MTHFR C677T was 0.4 (95% CI 0.2-0.8); for heterozygotes it was 0.5 (95% CI 0.2-0.9) and for homozygotes it was 0.3 (95%CI 0.09-0.8). MTHFR A1298C yielded an overall OR for ALL of 1.3 (95% CI: 0.7-2.6); for heterozygotes it was 1.3 (95% CI: 0.7-7.6) and for homozygotes it was 2.8 (95% CI 0.5-15.6). In conclusion, MTHFR C677T was linked to a significant 2.4-fold decreased risk of developing childhood ALL, whereas MTHFR A1298C did not significantly affect the risk of ALL in our population. PMID:11736945

  14. The genetic landscape of paediatric de novo acute myeloid leukaemia as defined by single nucleotide polymorphism array and exon sequencing of 100 candidate genes.

    PubMed

    Olsson, Linda; Zettermark, Sofia; Biloglav, Andrea; Castor, Anders; Behrendtz, Mikael; Forestier, Erik; Paulsson, Kajsa; Johansson, Bertil

    2016-07-01

    Cytogenetic analyses of a consecutive series of 67 paediatric (median age 8 years; range 0-17) de novo acute myeloid leukaemia (AML) patients revealed aberrations in 55 (82%) cases. The most common subgroups were KMT2A rearrangement (29%), normal karyotype (15%), RUNX1-RUNX1T1 (10%), deletions of 5q, 7q and/or 17p (9%), myeloid leukaemia associated with Down syndrome (7%), PML-RARA (7%) and CBFB-MYH11 (5%). Single nucleotide polymorphism array (SNP-A) analysis and exon sequencing of 100 genes, performed in 52 and 40 cases, respectively (39 overlapping), revealed ≥1 aberration in 89%; when adding cytogenetic data, this frequency increased to 98%. Uniparental isodisomies (UPIDs) were detected in 13% and copy number aberrations (CNAs) in 63% (median 2/case); three UPIDs and 22 CNAs were recurrent. Twenty-two genes were targeted by focal CNAs, including AEBP2 and PHF6 deletions and genes involved in AML-associated gene fusions. Deep sequencing identified mutations in 65% of cases (median 1/case). In total, 60 mutations were found in 30 genes, primarily those encoding signalling proteins (47%), transcription factors (25%), or epigenetic modifiers (13%). Twelve genes (BCOR, CEBPA, FLT3, GATA1, KIT, KRAS, NOTCH1, NPM1, NRAS, PTPN11, SMC3 and TP53) were recurrently mutated. We conclude that SNP-A and deep sequencing analyses complement the cytogenetic diagnosis of paediatric AML. PMID:27022003

  15. C1236T polymorphism in MDR1 gene correlates with therapeutic response to imatinib mesylate in Indian patients with chronic myeloid leukaemia.

    PubMed

    Chhikara, Sunita; Sazawal, Sudha; Mishra, Pravas; Chaubey, Rekha; Mahapatra, Manoranjan; Saxena, Renu

    2015-01-01

    Patients with chronic myeloid leukaemia show an excellent response to treatment with imatinib. However, in some patients, the disease is resistant to imatinib. This resistance may be related to the presence of genetic variations on the drug's pharmacokinetics and metabolism. We therefore studied three polymorphisms (C1236T, G2677T and C3435T) in the human multidrug-resistance gene (MDR1) in 86 patients with chronic myeloid leukaemia treated with imatinib. Imatinib resistance was more frequent in patients with TT genotype at locus 1236 than in those with CT/CC genotypes (p=0.003). For the other two loci (G2677T and C3435T), resistance was seen to be higher for TT genotype when compared to GG/GT and CT/CC but it was not statistically significant (p=0.13 and p=0.099). In conclusion, determination of C1236T MDR1 genotype may help to predict response to imatinib therapy in patients with chronic myeloid leukaemia. PMID:27294449

  16. Quantitative multiplex quantum dot in-situ hybridisation based gene expression profiling in tissue microarrays identifies prognostic genes in acute myeloid leukaemia

    SciTech Connect

    Tholouli, Eleni; MacDermott, Sarah; Hoyland, Judith; Yin, John Liu; Byers, Richard

    2012-08-24

    Highlights: Black-Right-Pointing-Pointer Development of a quantitative high throughput in situ expression profiling method. Black-Right-Pointing-Pointer Application to a tissue microarray of 242 AML bone marrow samples. Black-Right-Pointing-Pointer Identification of HOXA4, HOXA9, Meis1 and DNMT3A as prognostic markers in AML. -- Abstract: Measurement and validation of microarray gene signatures in routine clinical samples is problematic and a rate limiting step in translational research. In order to facilitate measurement of microarray identified gene signatures in routine clinical tissue a novel method combining quantum dot based oligonucleotide in situ hybridisation (QD-ISH) and post-hybridisation spectral image analysis was used for multiplex in-situ transcript detection in archival bone marrow trephine samples from patients with acute myeloid leukaemia (AML). Tissue-microarrays were prepared into which white cell pellets were spiked as a standard. Tissue microarrays were made using routinely processed bone marrow trephines from 242 patients with AML. QD-ISH was performed for six candidate prognostic genes using triplex QD-ISH for DNMT1, DNMT3A, DNMT3B, and for HOXA4, HOXA9, Meis1. Scrambled oligonucleotides were used to correct for background staining followed by normalisation of expression against the expression values for the white cell pellet standard. Survival analysis demonstrated that low expression of HOXA4 was associated with poorer overall survival (p = 0.009), whilst high expression of HOXA9 (p < 0.0001), Meis1 (p = 0.005) and DNMT3A (p = 0.04) were associated with early treatment failure. These results demonstrate application of a standardised, quantitative multiplex QD-ISH method for identification of prognostic markers in formalin-fixed paraffin-embedded clinical samples, facilitating measurement of gene expression signatures in routine clinical samples.

  17. Ovarian cancer has frequent loss of heterozygosity at chromosome 12p12.3-13.1 (region of TEL and Kip1 loci) and chromosome 12q23-ter: evidence for two new tumour-suppressor genes.

    PubMed Central

    Hatta, Y.; Takeuchi, S.; Yokota, J.; Koeffler, H. P.

    1997-01-01

    Identification of the key genetic alterations leading to ovarian cancer is in its infancy. Polymerase chain reaction (PCR)-based analysis of loss of heterozygosity (LOH) is a powerful method for detecting regions of altered tumour-suppressor genes. Focusing on chromosome 12, we examined 23 ovarian cancer samples for LOH using 31 highly polymorphic microsatellite markers and found the chromosomal localization of two putative tumour-suppressor genes. Two commonly deleted regions were 12p12.3-13.1 in 6/23 (26%) and 12q23-ter in 7/23 (30%) samples. LOH on chromosome 12 was more common in late-stage ovarian carcinomas. The region of LOH at 12p12.3-13.1 includes the genes that code for the ETS-family transcriptional factor, known as TEL, and the cyclin-dependent kinase inhibitor, known as p27Kip1. Mutational analysis of both TEL and p27Kip1 using single-strand conformation polymorphism (SSCP) showed no abnormalities, suggesting that the altered gene in this region is neither of these genes. Taken together, our data suggest that new tumour-suppressor genes in the region of chromosomes 12p12.3-13.1 and 12q23-ter may be involved in the development of ovarian cancer. Images Figure 1 Figure 2 Figure 4 PMID:9155043

  18. Myristicin from nutmeg induces apoptosis via the mitochondrial pathway and down regulates genes of the DNA damage response pathways in human leukaemia K562 cells.

    PubMed

    Martins, Célia; Doran, Carolina; Silva, Inês C; Miranda, Claudia; Rueff, José; Rodrigues, António S

    2014-07-25

    Myristicin, an allylbenzene, is a major active component of various spices, such as nutmeg and cinnamon, plants from the Umbelliferae family or in some essential oils, such as oils of clove or marjoram. Human exposure to myristicin is low but widespread due to consumption of these spices and essential oils, added to food (e.g. cola drinks) or in traditional medicine. Occasionally high dose exposure occurs, leading to various clinical symptoms, however the molecular mechanisms underlying them are unknown. Our previous studies revealed that myristicin is not genotoxic and yet presented apoptotic activity. Therefore, in this work we assessed the apoptotic mechanisms induced by myristicin in human leukaemia cells. In order to gain further insight on the potential of myristicin to modulate gene expression we also analysed alterations in expression of 84 genes associated with the DNA damage response pathway. The results obtained show that myristicin can induce apoptosis as characterised by alterations in the mitochondrial membrane potential, cytochrome c release, caspase-3 activation, PARP-cleavage and DNA fragmentation. The gene expression profile revealed an overall down regulation of DNA damage response genes after exposure to myristicin, with significant under-expression of genes associated with nucleotide excision repair (ERCC1), double strand break repair (RAD50, RAD51) and DNA damage signalling (ATM) and stress response (GADD45A, GADD45G). On the whole, we demonstrate that myristicin can alter mitochondrial membrane function, induce apoptosis and modulate gene expression in human leukaemia K562 cells. This study provides further detail on the molecular mechanisms underlying the biological activity of myristicin. PMID:24792648

  19. In utero origins of childhood leukaemia.

    PubMed

    Greaves, Mel

    2005-01-01

    Chimaeric fusion genes derived by chromosome translocation are common molecular abnormalities in paediatric leukaemia and provide unique markers for the malignant clone. They have been especially informative in studies with twins concordant for leukaemia and in retrospective scrutiny of archived neonatal blood spots. These data have indicated that, in paediatric leukaemia, the majority of chromosome translocations arise in utero during foetal haemopoiesis. Chromosomal translocations and preleukaemic clones arise at a substantially higher frequency ( approximately 100x) before birth than the cumulative incidence or risk of disease, reflecting the requirement for complementary and secondary genetic events that occur postnatally. A consequence of the latter is a very variable and occasionally protracted postnatal latency of disease (1-15 years). These natural histories provide an important framework for consideration of key aetiological events in paediatric leukaemia. PMID:15707724

  20. Genes encoding members of the JAK-STAT pathway or epigenetic regulators are recurrently mutated in T-cell prolymphocytic leukaemia.

    PubMed

    López, Cristina; Bergmann, Anke K; Paul, Ulrike; Murga Penas, Eva M; Nagel, Inga; Betts, Matthew J; Johansson, Patricia; Ritgen, Matthias; Baumann, Tycho; Aymerich, Marta; Jayne, Sandrine; Russell, Robert B; Campo, Elias; Dyer, Martin Js; Dürig, Jan; Siebert, Reiner

    2016-04-01

    T-cell prolymphocytic leukaemia (T-PLL) is an aggressive leukaemia. The primary genetic alteration in T-PLL are the inv(14)(q11q32)/t(14;14)(q11;q32) leading to TRD/TRA-TCL1A fusion, or the t(X;14)(q28;q11) associated with TRD/TRA-MTCP1 fusion. However, additional cooperating abnormalities are necessary for emergence of the full neoplastic phenotype. Though the pattern of secondary chromosomal aberrations is remarkably conserved, targets of the changes are largely unknown. We analysed a cohort of 43 well-characterized T-PLL for hotspot mutations in the genes JAK3, STAT5B and RHOA. Additionally, we selected a subset of 23 T-PLL cases for mutational screening of 54 genes known to be recurrently mutated in T-cell and other haematological neoplasms. Activating mutations in the investigated regions of the JAK3 and STAT5B genes were detected in 30% (13/43) and 21% (8/39) of the cases, respectively, and were mutually exclusive. Further, we identified mutations in the genes encoding the epigenetic regulators EZH2 in 13% (3/23), TET2 in 17% (4/23) and BCOR in 9% (2/23) of the cases. We confirmed that the JAK-STAT pathway is a major mutational target, and identified epigenetic regulators recurrently mutated in T-PLL. These findings complement the mutational spectrum of secondary aberrations in T-PLL and underscore the potential therapeutical relevance of epigenetic regulators in T-PLL. PMID:26917488

  1. The t(8;9)(p22;p24) translocation in atypical chronic myeloid leukaemia yields a new PCM1-JAK2 fusion gene.

    PubMed

    Bousquet, Marina; Quelen, Cathy; De Mas, Véronique; Duchayne, Eliane; Roquefeuil, Blandine; Delsol, Georges; Laurent, Guy; Dastugue, Nicole; Brousset, Pierre

    2005-11-01

    Several tyrosine kinase genes are involved in chromosomal translocations in chronic myeloproliferative disorders, but there are still uncharacterized translocations in some cases. We report two such cases corresponding to atypical chronic myeloid leukaemia with a t(8;9)(p22;p24) translocation. By fluorescence in situ hybridisation (FISH) on the corresponding metaphases with a bacterial artificial chromosome probe encompassing the janus kinase 2 (JAK2) gene at 9p24, we observed a split for both patients, suggesting that this gene was rearranged. The locus at 8p22 contains different candidate genes including the pericentriolar material 1 gene (PCM1), already implicated in reciprocal translocations. The rearrangement of the PCM1 gene was demonstrated by FISH, for both patients. By RT-PCR, we confirmed the fusion of 3' part of JAK2 with the 5' part of PCM1. Sequence analysis of the chimeric PCM1-JAK2 mRNA suggests that the putative protein displays the coiled-coil domains of PCM1 and the tyrosine kinase domain of JAK2. This new translocation identifies JAK2 as a possible therapeutic target for compounds with anti-tyrosine kinase activity. PMID:16091753

  2. The outcome of Chronic lymphocytic leukaemia patients with 97% IGHV gene identity to germline is distinct from cases with <97% identity and similar to those with 98% identity.

    PubMed

    Davis, Zadie; Forconi, Francesco; Parker, Anton; Gardiner, Anne; Thomas, Peter; Catovsky, Daniel; Rose-Zerilli, Matthew; Strefford, Jonathan C; Oscier, David

    2016-04-01

    IGHV gene mutational status has prognostic significance in chronic lymphocytic leukaemia (CLL) but the percentage of mutations that correlates best with clinical outcome remains controversial. We initially studied 558 patients from diagnosis and found significant differences in median time to first treatment (TTFT) among Stage A patients and in overall survival (OS) for the whole cohort, between cases with <97% and 97-98·99% identity and between cases with 97-98·99% and ≥99% identity, when cases from the IGHV3-21 Stereotype Subset #2 were excluded. A significant difference in progression-free survival (PFS) and OS between those with <97% and 97-98·99% identity, but not between those with 97-98·99% and ≥99% identity was also observed in a validation cohort comprising 460 patients in the UK CLL4 trial. Cox Regression analyses in the Stage A cohort revealed that a model which incorporated <97%, 97-98·99% and ≥99% identity as subgroups, was a better predictor of TTFT in CLL than using the 98% cut-off. Multivariate analysis selected the three mutational subgroups as independent predictors of TTFT in Stage A patients, and of OS in the diagnostic cohort. This study highlights that cases with 97% identity should not be considered to have the same prognosis as other cases with mutated IGHV genes defined as <98% identity to germline. PMID:26846718

  3. Aberrant expression of aldehyde dehydrogenase 1A (ALDH1A) subfamily genes in acute lymphoblastic leukaemia is a common feature of T-lineage tumours.

    PubMed

    Longville, Brooke A C; Anderson, Denise; Welch, Mathew D; Kees, Ursula R; Greene, Wayne K

    2015-01-01

    The class 1A aldehyde dehydrogenase (ALDH1A) subfamily of genes encode enzymes that function at the apex of the retinoic acid (RA) signalling pathway. We detected aberrant expression of ALDH1A genes, particularly ALDH1A2, in a majority (72%) of primary paediatric T cell acute lymphoblastic leukaemia (T-ALL) specimens. ALDH1A expression was almost exclusive to T-lineage, but not B-lineage, ALL. To determine whether ALDH1A expression may have relevance to T-ALL cell growth and survival, the effect of inhibiting ALDH1A function was measured on a panel of human ALL cell lines. This revealed that T-ALL proliferation had a higher sensitivity to modulation of ALDH1A activity and RA signalling as compared to ALL cell lines of B-lineage. Consistent with these findings, the genes most highly correlated with ALDH1A2 expression were involved in cell proliferation and apoptosis. Evidence that such genes may be targets of regulation via RA signalling initiated by ALDH1A activity was provided by the TNFRSF10B gene, encoding the apoptotic death receptor TNFRSF10B (also termed TRAIL-R2), which negatively correlated with ALDH1A2 and showed elevated transcription following treatment of T-ALL cell lines with the ALDH1A inhibitor citral (3,7-dimethyl-2,6-octadienal). These data indicate that ALDH1A expression is a common event in T-ALL and supports a role for these enzymes in the pathobiology of this disease. PMID:25208926

  4. Acute myeloid leukaemia.

    PubMed

    Khwaja, Asim; Bjorkholm, Magnus; Gale, Rosemary E; Levine, Ross L; Jordan, Craig T; Ehninger, Gerhard; Bloomfield, Clara D; Estey, Eli; Burnett, Alan; Cornelissen, Jan J; Scheinberg, David A; Bouscary, Didier; Linch, David C

    2016-01-01

    Acute myeloid leukaemia (AML) is a disorder characterized by a clonal proliferation derived from primitive haematopoietic stem cells or progenitor cells. Abnormal differentiation of myeloid cells results in a high level of immature malignant cells and fewer differentiated red blood cells, platelets and white blood cells. The disease occurs at all ages, but predominantly occurs in older people (>60 years of age). AML typically presents with a rapid onset of symptoms that are attributable to bone marrow failure and may be fatal within weeks or months when left untreated. The genomic landscape of AML has been determined and genetic instability is infrequent with a relatively small number of driver mutations. Mutations in genes involved in epigenetic regulation are common and are early events in leukaemogenesis. The subclassification of AML has been dependent on the morphology and cytogenetics of blood and bone marrow cells, but specific mutational analysis is now being incorporated. Improvements in treatment in younger patients over the past 35 years has largely been due to dose escalation and better supportive care. Allogeneic haematopoietic stem cell transplantation may be used to consolidate remission in those patients who are deemed to be at high risk of relapse. A plethora of new agents - including those targeted at specific biochemical pathways and immunotherapeutic approaches - are now in trial based on improved understanding of disease pathophysiology. These advances provide good grounds for optimism, although mortality remains high especially in older patients. PMID:27159408

  5. Molecular expression of l-asparaginase gene from Nocardiopsis alba NIOT-VKMA08 in Escherichia coli: A prospective recombinant enzyme for leukaemia chemotherapy.

    PubMed

    Meena, Balakrishnan; Anburajan, Lawrance; Vinithkumar, Nambali Valsalan; Shridhar, Divya; Raghavan, Rangamaran Vijaya; Dharani, Gopal; Kirubagaran, Ramalingam

    2016-09-30

    l-Asparaginase is an antineoplastic agent that selectively reduces the level of l-asparagine in blood and diminishes the proliferation of cancerous cells. Studies were carried out on the cloning and heterologous expression of l-asparaginase biosynthesis gene (ansA) from Nocardiopsis alba NIOT-VKMA08 to achieve the stable inducible system that overproduces the glutaminase-free recombinant l-asparaginase. Overexpression of recombinant l-asparaginase was achieved with an optimized final concentration of 1.5mM of isopropyl-β-d-thiogalactoside (IPTG) and the enzyme was expressed as a soluble protein. The recombinant enzyme was purified using nickel-nitrilotriacetic acid (Ni-NTA) chromatography and the purified enzyme disclosed an elevated level of asparaginase activity (158.1IU/mL). Optimum pH and temperature of the purified l-asparaginase for the hydrolysis of l-asparagine were 8.0 and 37°C and it was very specific for its natural substrate, l-asparagine. Detailed studies were carried out on the kinetics of enzyme reaction, catalytic activity, temperature and ionic strength and the thermostability of the l-asparaginase enzyme. The functional characterisation of the recombinant l-asparaginase was studied through Fourier transform infrared spectroscopy (FT-IR), nuclear magnetic resonance (NMR), in silico sequence analysis and protein structural modelling. Glutaminase activity was not detected in the recombinant l-asparaginase, which could reduce the probable side effects during leukaemia therapy. PMID:27155523

  6. Mutation Analysis of IDH1/2 Genes in Unselected De novo Acute Myeloid Leukaemia Patients in India - Identification of A Novel IDH2 Mutation.

    PubMed

    Raveendran, Sureshkumar; Sarojam, Santhi; Vijay, Sangeetha; Geetha, Aswathy Chandran; Sreedharan, Jayadevan; Narayanan, Geetha; Sreedharan, Hariharan

    2015-01-01

    IDH1/2 mutations which result in alternation in DNA methylation pattern are one of the most common methylation associated mutations in Acute myeloid leukaemia. IDH1/2 mutations frequently associated with higher platelet level, normal cytogentics and NPM1 mutations. Here we analyzed IDH1/2 mutations in 200 newly diagnosed unselected Indian adult AML patients and investigated their correlation with clinical, cytogenetic parameters along with cooperating NPM1 mutation. We detected 5.5% and 4% mutations in IDH1/2 genes, respectively. Except IDH2 c.515_516GG>AA mutation, all the other identified mutations were reported mutations. Similar to reported c.515G>A mutation, the novel c.515_516GG>AA mutation replaces 172nd arginine to lysine in the active site of the enzyme. Even though there was a preponderance of IDH1/2 mutations in NK-AML, cytogenetically abnormal patients also harboured IDH1/2 mutations. IDH1 mutations showed significant higher platelet count and NPM1 mutations. IDH2 mutated patients displayed infrequent NPM1 mutations and lower WBC count. All the NPM1 mutations in the IDH1/2 mutated cases showed type A mutation. The present data suggest that IDH1/2 mutations are associated with normal cytogenetics and type A NPM1 mutations in adult Indian AML patients. PMID:25987093

  7. The variability of RR Tel

    NASA Astrophysics Data System (ADS)

    Heck, A.; Manfroid, J.

    1982-12-01

    Photometric measurements of RR Tel performed at ESO are discussed. RR Tel is a galactic nova which has been associated with a sole outburst, observed in 1944. The photometric observations were made in the ubvy system in August 1981, when a strong brightening was detected in V. IUE data subjected to a Fourier analysis indicate that the object has a period within 5 days of 395 days. Measurements of brightening of the J component also yield a period of 390 days. The presence of a Mira variable is considered, noting the supporting evidence from H2O and TiO spectral bands, but equally the lack of IR data until after 1960. It is suggested that data from before 1944 indicate that modulated bursts of mass transfer and accompanying accretion events preceeded the outburst of the underlying binary star, which could be a link between dwarf novae, classical novae, and symbiotic stars.

  8. TEL/ETV6 induces apoptosis in 32D cells through p53-dependent pathways

    SciTech Connect

    Yamagata, Tetsuya; Maki, Kazuhiro; Waga, Kazuo; Mitani, Kinuko . E-mail: kinukom-tky@umin.ac.jp

    2006-08-25

    TEL is an ETS family transcription factor that is critical for maintaining hematopoietic stem cells in adult bone marrow. To investigate the roles of TEL in myeloid proliferation and differentiation, we introduced TEL cDNA into mouse myeloid 32Dcl3 cells. Overexpression of TEL repressed interleukin-3-dependent proliferation through blocking cell cycle progression. Also, the presence of TEL triggered apoptosis through the mitochondrial intrinsic pathway on exposure to granulocyte colony-stimulating factor. We found an increase in p53 protein and its DNA binding in the TEL-overexpressing cells. Forced expression of TEL stimulated transcription via the p53-responsive element and increased the expression of cellular target genes for p53 such as cell cycle regulator p21 and apoptosis inducer Puma. Consistently, induction of apoptosis was delayed by pifithrin-{alpha} treatment and completely blocked by increased expression of Bcl-2 in the TEL-overexpressing cells. These data collectively suggest that TEL exerts a tumor suppressive function through augmenting the p53 pathway and facilitates normal development of myelopoiesis.

  9. Configuration of immunoglobulin and T cell receptor beta and gamma genes in acute myeloid leukaemia: pitfalls in the analysis of 40 cases.

    PubMed Central

    Parreira, L.; Carvalho, C.; Moura, H.; Melo, A.; Santos, P.; Guimarães, J. E.; Parreira, A.

    1992-01-01

    AIMS: To evaluate the overall incidence of immunoglobulin (Ig) and T cell receptor (TCR) beta and gamma gene rearrangements in a series of 40 cases of acute myeloid leukaemia (AML) and to determine whether structural modifications of these genes could be correlated with the abnormal expression of lymphoid markers in malignant cells. METHODS: All cases were classified according to the criteria of the FAB group and immunophenotyped with a panel of monoclonal antibodies reactive with myeloid and lymphoid differentiation antigens. DNA analysis was performed by the method of Southern using probes for the Ig JH, TCR-C beta 1, and TCR-J tau 1 regions. RESULTS: Phenotypic analysis showed that in addition to myeloid markers, 10 cases expressed lymphoid antigens: CD7 in seven (of which three were TdT positive, one CD2 positive, and one CD19 positive) and CD19 in three. Southern blot analysis showed that bands with sizes different from the germ line control were present in the TCR beta genes in 11 cases: in six of 30 with pure myeloid phenotype and in five of 10 of those expressing lymphoid markers. A close observation of the size and patterns of those bands, however, showed that they could be artefactual. Indeed, further analysis showed that they were either due to resistant Eco RI/Hind III sites at the beta locus or to plasmid contamination. Rearranged genes were eventually found in only two of the 40 cases: at the Ig JH region in one of the 30 with pure myeloid phenotype (3.3%) and at the TCR gamma genes in one of 10 with lymphoid markers (10%). CONCLUSIONS: These observations showed that Ig/TCR gene rearrangements were rare in this AML series (overall incidence of 5%) and that they were not significantly more common in cases with aberrant expression of lymphoid markers. The size and pattern of the potential non-germline bands that can be found in these loci must be carefully evaluated. Images PMID:1372916

  10. Cytogenetic findings in acute leukaemias of infants.

    PubMed Central

    Lampert, F.; Harbott, J.; Ritterbach, J.

    1992-01-01

    Of 706 children, 528 with acute lymphoblastic leukaemia (ALL) and 178 with acute myelocytic leukaemia (AML), whose leukaemia karyotypes could be successfully analysed, 48 were infants less than 1 year of age, 28 with ALL (5% of ALL patients) and 20 with AML (11% of AML patients). In contrast to older children. ALL-leukaemocytogenetics in infants was characterised by lack of hyperdiploidy with over 50 chromosomes and higher incidence of pseudodiploidy. Thirteen (= 46%) infants had an 11q23 aberration, and 11 of them had t(4;11). In AML, nine (= 45%) infants also had an 11q23 abnormality, e.g. t(9;11). Thus, the 11q23 aberration was present in almost 50% of all leukaemia karyotypes of infants. In ALL of infants, the CALLA negative, pre-pre-B immunophenotype prevailed. In AML of infants, the monocytic subtype dominated. A biphenotypic morphology (lymphoid-monocytic) with the expression of lymphoid and myeloid antigens was seen in several ALL and AML cases. In conclusion, leukaemogenesis in infants is a rare event, arising in stem cells of very early hematopoietic differentiation (probably due to gene rearrangement errors, most frequently at FRA11B), and differs from leukaemogenesis in older age groups by unique clinical and cellular features. PMID:1503922

  11. C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase gene: effect on methotrexate-related toxicity in adult acute lymphoblastic leukaemia.

    PubMed

    Eissa, Deena Samir; Ahmed, Tamer Mohamed

    2013-03-01

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme involved in folate metabolism. Two polymorphisms, C677T and A1298C, were described leading to reduced enzyme activity. Methotrexate (MTX) is an antifolate agent of consolidation and maintenance therapy of acute lymphoblastic leukaemia (ALL). Despite its clinical success, MTX can be associated with serious toxicities resulting in treatment interruption or discontinuation, impacting disease outcome. There is evidence that MTX toxicity can be affected by polymorphisms in genes encoding for drug-metabolizing enzymes such as MTHFR. Therefore, we aimed to investigate the influence of MTHFR C677T and A1298C polymorphisms on the frequency of MTX-related toxicity, disease outcome and patients' survival. MTHFR polymorphisms were assessed in 50 adult patients with de novo ALL using real-time PCR. Patients were followed-up for the development of haematologic and/or nonhaematologic toxicity and assessment of clinical outcome. Frequency of C677T polymorphisms was 42% for TT, 24% for CT and 34% for CC; A1298C polymorphisms were 28, 6 and 66% for CC, AC and AA, respectively. MTX therapy was significantly associated with neutropaenia, hepatic and gastrointestinal toxicities, unfavourable response at day 14 of induction therapy, increased relapse and mortality rates and shorter survival in patients with 677 TT genotype than in those with CC and CT, whereas 1298 CC genotype patients had lower frequency of neutropaenia, hepatic toxicity and relapse than in those with AA and AC. Our study suggests MTHFR polymorphism as an attractive predictor of MTX-related toxicity in adult ALL, considering it a potential prognostic factor influencing disease outcome. PMID:23183238

  12. The yeast telomere length regulator TEL2 encodes a protein that binds to telomeric DNA.

    PubMed Central

    Kota, R S; Runge, K W

    1998-01-01

    TEL2 is required for telomere length regulation and viability in Saccharomyces cerevisiae. To investigate the mechanism by which Tel2p regulates telomere length, the majority (65%) of the TEL2 ORF was fused to the 3'-end of the gene for maltose binding protein, expressed in bacteria and the purified protein used in DNA binding studies. Rap1p, the major yeast telomere binding protein, recognizes a 13 bp duplex site 5'-GGTGTGTGGGTGT-3' in yeast telomeric DNA with high affinity. Gel shift experiments revealed that the MBP-Tel2p fusion binds the double-stranded yeast telomeric Rap1p site in a sequence-specific manner. Analysis of mutated sites showed that MBP-Tel2p could bind 5'-GTGTGTGG-3' within this 13 bp site. Methylation interference analysis revealed that Tel2p contacts the 5'-terminal guanine in the major groove. MBP-Tel2p did not bind duplex telomeric DNA repeats from vertebrates, Tetrahymena or Oxytricha. These results suggest that Tel2p is a DNA binding protein that recognizes yeast telomeric DNA. PMID:9490802

  13. The SAM domain of human TEL2 can abrogate transcriptional output from TEL1 (ETV-6) and ETS1/ETS2.

    PubMed

    Vivekanand, Pavithra; Rebay, Ilaria

    2012-01-01

    Regulation of gene expression downstream of the Receptor Tyrosine Kinase signaling pathway in Drosophila relies on a transcriptional effector network featuring two conserved Ets family proteins, Yan and Pointed, known as TEL1 (ETV6) and ETS1/ETS2, respectively, in mammals. As in Drosophila, both TEL1 and ETS1/ETS2 operate as Ras pathway transcriptional effectors and misregulated activity of either factor has been implicated in many human leukemias and solid tumors. Providing essential regulation to the Drosophila network, direct interactions with the SAM domain protein Mae attenuate both Yan-mediated repression and PointedP2-mediated transcriptional activation. Given the critical contributions of Mae to the Drosophila circuitry, we investigated whether the human Ets factors TEL1 and ETS1/ETS2 could be subject to analogous regulation. Here we demonstrate that the SAM domain of human TEL2 can inhibit the transcriptional activities of ETS1/2 and TEL1. Drosophila Mae can also attenuate human ETS1/ETS2 function, suggesting there could be cross-species conservation of underlying mechanism. In contrast, Mae is not an effective inhibitor of TEL1, suggesting the mode of TEL2SAM-mediated inhibition of TEL1 may be distinct from how Drosophila Mae antagonizes Yan. Together our results reveal both further similarities and new differences between the mammalian and Drosophila networks and more broadly suggest that SAM domain-mediated interactions could provide an effective mechanism for modulating output from the TEL1 and ETS1/2 oncogenes. PMID:22615925

  14. Silencing of TESTIN by dense biallelic promoter methylation is the most common molecular event in childhood acute lymphoblastic leukaemia

    PubMed Central

    2010-01-01

    Background Aberrant promoter DNA methylation has been reported in childhood acute lymphoblastic leukaemia (ALL) and has the potential to contribute to its onset and outcome. However, few reports demonstrate consistent, prevalent and dense promoter methylation, associated with tumour-specific gene silencing. By screening candidate genes, we have detected frequent and dense methylation of the TESTIN (TES) promoter. Results Bisulfite sequencing showed that 100% of the ALL samples (n = 20) were methylated at the TES promoter, whereas the matched remission (n = 5), normal bone marrow (n = 6) and normal PBL (n = 5) samples were unmethylated. Expression of TES in hyperdiploid, TEL-AML+, BCR-ABL+, and E2A-PBX+ subtypes of B lineage ALL was markedly reduced compared to that in normal bone marrow progenitor cells and in B cells. In addition TES methylation and silencing was demonstrated in nine out of ten independent B ALL propagated as xenografts in NOD/SCID mice. Conclusion In total, 93% of B ALL samples (93 of 100) demonstrated methylation with silencing or reduced expression of the TES gene. Thus, TES is the most frequently methylated and silenced gene yet reported in ALL. TES, a LIM domain-containing tumour suppressor gene and component of the focal adhesion complex, is involved in adhesion, motility, cell-to-cell interactions and cell signalling. Our data implicate TES methylation in ALL and provide additional evidence for the involvement of LIM domain proteins in leukaemogenesis. PMID:20573277

  15. Genetic susceptibility in childhood acute leukaemias: a systematic review

    PubMed Central

    Brisson, Gisele D; Alves, Liliane R; Pombo-de-Oliveira, Maria S

    2015-01-01

    Acute leukaemias (AL) correspond to 25–35% of all cancer cases in children. The aetiology is still sheltered, although several factors are implicated in causality of AL subtypes. Childhood acute leukaemias are associated with genetic syndromes (5%) and ionising radiation as risk factors. Somatic genomic alterations occur during fetal life and are initiating events to childhood leukaemia. Genetic susceptibility has been explored as a risk factor, since environmental exposure of the child to xenobiotics, direct or indirectly, can contribute to the accumulation of somatic mutations. Hence, a systematic review was conducted in order to understand the association between gene polymorphisms and childhood leukaemia risk. The search was performed in the electronic databases PubMed, Lilacs, and Scielo, selecting articles published between 1995 and 2013. This review included 90 case-control publications, which were classified into four groups: xenobiotic system (n = 50), DNA repair (n = 16), regulatory genes (n = 15), and genome wide association studies (GWAS) (n = 9). We observed that the most frequently investigated genes were: NQO1, GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, CYP2D6, CYP2E1, MDR1 (ABCB1), XRCC1, ARID5B, and IKZF1. The collected evidence suggests that genetic polymorphisms in CYP2E1, GSTM1, NQO1, NAT2, MDR1, and XRCC1 are capable of modulating leukaemia risk, mainly when associated with environmental exposures, such as domestic pesticides and insecticides, smoking, trihalomethanes, alcohol consumption, and x-rays. More recently, genome wide association studies identified significant associations between genetic polymorphisms in ARID5B e IKZF1 and acute lymphoblastic leukaemia, but only a few studies have replicated these results until now. In conclusion, genetic susceptibility contributes to the risk of childhood leukaemia through the effects of gene–gene and gene–environment interactions. PMID:26045716

  16. Chronic lymphocytic leukaemia.

    PubMed

    Scarfò, Lydia; Ferreri, Andrés J M; Ghia, Paolo

    2016-08-01

    Chronic lymphocytic leukaemia (CLL) is the most common leukaemia among the adults in the Western World. CLL (and the corresponding nodal entity small lymphocytic lymphoma, SLL) is classified as a lymphoproliferative disorder characterised by the relentless accumulation of mature B-lymphocytes showing a peculiar immunophenotype in the peripheral blood, bone marrow, lymph nodes and spleen. CLL clinical course is very heterogeneous: the majority of patients follow an indolent clinical course with no or delayed treatment need and with a prolonged survival, while others experience aggressive disease requiring early treatment followed by frequent relapses. In the last decade, the improved understanding of CLL pathogenesis shed light on premalignant conditions (i.e., monoclonal B-cell lymphocytosis, MBL), defined new prognostic and predictive markers, improving patient stratification, but also broadened the therapeutic armamentarium with novel agents, targeting fundamental signaling pathways. PMID:27370174

  17. Chilblain-like leukaemia cutis.

    PubMed

    Tran, Chi; McEwen, Gary; Fraga, Garth Robert

    2016-01-01

    Chilblain, also known as pernio, is an abnormal inflammatory response to cold, moist environmental conditions. Persistent or atypical lesions should prompt investigation to exclude underlying systemic illness. We describe a case of acute myeloid leukaemia that presented with chilblain-like leukaemia cutis. PMID:27095810

  18. Lymphoid leukaemia in a cow.

    PubMed

    Johnstone, A C

    1982-10-01

    An 18-month old Friesian heifer which had lost condition and had diarrhoea for several weeks was diagnosed by haematological and pathological examinations as having lymphocytic leukaemia. True lymphatic leukaemia has not previously been described in cattle and does not readily fit into presently accepted classifications of bovine leukosis. PMID:16030823

  19. Leucapheresis for management of retinopathy in chronic myeloid leukaemia.

    PubMed

    Mohamed, Muhajir; Oakley, Carmen; McEwen, Fiona; Connelley, Georgina

    2015-01-01

    Chronic myeloid leukaemia is a myeloproliferative neoplasm characterised by granulocytic hyperplasia in the bone marrow and the presence of a specific cytogenetic abnormality known as Philadelphia chromosome with fusion of breakpoint cluster region (BCR) and ableson (ABL) genes. Retinopathy is a rare sight-threatening complication of chronic myeloid leukaemia, which occurs due to leucostasis in retinal blood vessels. We report a case of a patient who presented with visual impairment due to leucostasis, who was successfully managed by leucapheresis along with BCR-ABL tyrosine kinase inhibitor. PMID:26628310

  20. Childhood leukaemia in Ireland.

    PubMed

    Herity, B; Daly, L; Breatnach, F; Buttimer, J; Egan, E; Fennelly, J; McCann, S; Walsh, J H

    1992-06-01

    In response to professional and public concern about health consequences, in particular cancer risk, from previous and current levels of ionising radiation in the Irish Sea, a study of incidence and mortality from acute lymphoid leukaemia (ALL) and other lymphoid malignancies in children was undertaken. Overall rates were similar to those found in other western populations and distribution of high rates was quite random over the country as a whole. There was a small but significant excess in incidence of ALL for the years 1974-76 in a narrow three mile wide strip along the east coast. It is not possible in the context of this study to postulate aetiological factors which might explain this finding. PMID:1628939

  1. Acute lymphoblastic leukaemia

    PubMed Central

    Inaba, Hiroto; Greaves, Mel; Mullighan, Charles G.

    2013-01-01

    Summary Acute lymphoblastic leukaemia (ALL) is seen in both children and adults, but its incidence peaks between ages 2 and 5 years. The causation of ALL is considered to be multi-factorial, including exogenous or endogenous exposures, genetic susceptibility, and chance. The survival rate of paediatric ALL has improved to approximately 90% in recent trials with risk stratification by biologic features of leukaemic cells and response to therapy, therapy modification based on patient pharmacodynamics and pharmacogenomics, and improved supportive care. However, innovative approaches are needed to further improve survival while reducing adverse effects. While most children can be cured, the prognosis of infants and adults with ALL remains poor. Recent genome-wide profiling of germline and leukaemic cell DNA has identified novel submicroscopic structural genetic alterations and sequence mutations that contribute to leukaemogenesis, define new ALL subtypes, influence responsiveness to treatment, and may provide novel prognostic markers and therapeutic targets for personalized medicine. PMID:23523389

  2. Eosinophilic leukaemia in a cat.

    PubMed

    Sharifi, Hassan; Nassiri, Seyed Mahdi; Esmaelli, Hossein; Khoshnegah, Javad

    2007-12-01

    A 14-year-old female domestic shorthair cat was presented to Tehran University Veterinary Teaching Hospital for a persistent fever, anorexia, intermittent vomiting, weight loss and weakness. The main clinical signs were pale mucous membranes, dehydration and splenomegaly. The complete blood count and serum biochemistry tests revealed non-regenerative anaemia, thrombocytopenia and increased alkaline phosphatase (ALP) activity. An enzyme-linked immunosorbent assay (ELISA) test for feline leukaemia virus was negative. Blood film and bone marrow examination revealed a large number of immature eosinophils with variable sizes and numbers of faintly azurophilic granules. Cytochemical staining of blood film demonstrated 70% positive cells for ALP activity. Four percent CD34 positive cells were detected by flow cytometry. As eosinophilic leukaemia is difficult to identify by light microscopy, well-defined diagnostic criteria and the use of flow cytometry and cytochemical staining can improve the ability to correctly diagnose this type of leukaemia in cats. PMID:17669677

  3. The prognostic value of FISH as an adjunct to conventional cytogenetics for the detection of cryptic gene rearrangements on chromosome 16. A retrospective investigation of 13 patients from Northern Ireland diagnosed with M4Eo acute myeloid leukaemia.

    PubMed

    McGrattan, P; Humphreys, M W

    2003-05-01

    M4Eo acute myeloid leukaemia (AML) patients with the typical chromosome 16 abnormalities have a favourable prognosis. These subtle 16q22 gene rearrangements can be difficult to detect by conventional cytogenetic methods and if missed could lead to the incorrect assignment of prognostic group and hence subsequent treatment strategies. We retrospectively studied 13 patients diagnosed with M4Eo AML for such chromosome 16 abnormalities comparing conventional cytogenetic (G-banding) and molecular (FISH) methods. G-banded analysis detected only 2 patients with definite chromosome 16 abnormalities whereas FISH detected 4 patients, one with the typical inversion and three with the typical chromosome 16 translocation. FISH analysis also confirmed a false +ve G-banded result in one patient and a false -ve G-banded result in another patient. Finally, FISH confirmed a deletion of one chromosome 16 homologue in another patient indicating a poor prognosis. The overall survival of patients with the typical 16q22 rearrangements (n=4) was also significantly better (P=0.007) than patients with normal chromosome 16 homologues or having other numerical and/or structural abnormalities (n=9). This set of data shows that FISH is a more accurate method for the detection of cryptic 16q22 gene rearrangements and because of the prognostic implications has become a mandatory test along with conventional cytogenetics for all newly diagnosed M4Eo AML patients in Northern Ireland. PMID:12868698

  4. Comparative analysis between RQ-PCR and digital-droplet-PCR of immunoglobulin/T-cell receptor gene rearrangements to monitor minimal residual disease in acute lymphoblastic leukaemia.

    PubMed

    Della Starza, Irene; Nunes, Vittorio; Cavalli, Marzia; De Novi, Lucia Anna; Ilari, Caterina; Apicella, Valerio; Vitale, Antonella; Testi, Anna Maria; Del Giudice, Ilaria; Chiaretti, Sabina; Foà, Robin; Guarini, Anna

    2016-08-01

    Real-time quantitative polymerase chain reaction (RQ-PCR) is a standardized tool for minimal residual disease (MRD) monitoring in acute lymphoblastic leukaemia (ALL). The applicability of this technology is limited by the need of a standard curve based on diagnostic DNA. The digital droplet PCR (ddPCR) technology has been recently applied to various medical fields, but its use in MRD monitoring is under investigation. In this study, we analysed 50 ALL cases by both methods in two phases: in the first, we established analytical parameters to investigate the applicability of this new technique; in the second, we analysed MRD levels in 141 follow-up (FU) samples to investigate the possible use of ddPCR for MRD monitoring in ALL patients. We documented that ddPCR has sensitivity and accuracy at least comparable to those of RQ-PCR. Overall, the two methods gave concordant results in 124 of the 141 analysed MRD samples (88%, P = 0·94). Discordant results were found in 12% borderline cases. The results obtained prove that ddPCR is a reliable method for MRD monitoring in ALL, with the advantage of quantifying without the need of the calibration curves. Its application in a cohort of patients with a longer FU will conclusively define its clinical predictive value. PMID:27172403

  5. TEL2 suppresses metastasis by down-regulating SERPINE1 in nasopharyngeal carcinoma

    PubMed Central

    Zhang, Ru-Hua; Wang, Li; Li, Mei; Luo, Rongzhen; Qian, Chao-Nan; Shao, Jian-Yong; Zeng, Yi-Xin; Kang, Tiebang

    2015-01-01

    Metastasis is the major cause of treatment failure in patients with nasopharyngeal carcinoma (NPC). However, the molecular mechanisms of NPC metastasis are poorly understood. Here, using our customized gene microarray containing all of the known human transcription factors and the current markers for epithelial-mesenchymal transition, we report that TEL2 was down-regulated in highly metastatic NPC cells and the metastatic tissues in lymph node. Mechanistically, TEL2 inhibits the cell migration and invasion in vitro and metastasis in vivo by releasing its direct suppression on the SERPINE1 promoter in NPC. Consistently, an inverse correlation was observed between the protein levels of TEL2 and SERPINE1 using clinical NPC samples. Collectively, we have provided the first evidence that TEL2 plays a key role in NPC metastasis by directly down-regulating SERPINE1, and that this novel axis of TEL2 / SERPINE1 may be valuable to develop new strategies for treating NPC patients with metastasis. PMID:26335051

  6. The function of the RNA-binding protein TEL1 in moss reveals ancient regulatory mechanisms of shoot development.

    PubMed

    Vivancos, Julien; Spinner, Lara; Mazubert, Christelle; Charlot, Florence; Paquet, Nicolas; Thareau, Vincent; Dron, Michel; Nogué, Fabien; Charon, Céline

    2012-03-01

    The shoot represents the basic body plan in land plants. It consists of a repeated structure composed of stems and leaves. Whereas vascular plants generate a shoot in their diploid phase, non-vascular plants such as mosses form a shoot (called the gametophore) in their haploid generation. The evolution of regulatory mechanisms or genetic networks used in the development of these two kinds of shoots is unclear. TERMINAL EAR1-like genes have been involved in diploid shoot development in vascular plants. Here, we show that disruption of PpTEL1 from the moss Physcomitrella patens, causes reduced protonema growth and gametophore initiation, as well as defects in gametophore development. Leafy shoots formed on ΔTEL1 mutants exhibit shorter stems with more leaves per shoot, suggesting an accelerated leaf initiation (shortened plastochron), a phenotype shared with the Poaceae vascular plants TE1 and PLA2/LHD2 mutants. Moreover, the positive correlation between plastochron length and leaf size observed in ΔTEL1 mutants suggests a conserved compensatory mechanism correlating leaf growth and leaf initiation rate that would minimize overall changes in plant biomass. The RNA-binding protein encoded by PpTEL1 contains two N-terminus RNA-recognition motifs, and a third C-terminus non-canonical RRM, specific to TEL proteins. Removal of the PpTEL1 C-terminus (including this third RRM) or only 16-18 amino acids within it seriously impairs PpTEL1 function, suggesting a critical role for this third RRM. These results show a conserved function of the RNA-binding PpTEL1 protein in the regulation of shoot development, from early ancestors to vascular plants, that depends on the third TEL-specific RRM. PMID:22170036

  7. Reanalysis Of The PZ Tel System: Arguments For The Reality Of PZ Tel B To Be PZ Tel b

    NASA Astrophysics Data System (ADS)

    Jenkins, James

    2011-09-01

    I will present some new analysis of the PZ Tel system, which has recently been shown to host a young companion with a mass of around 30 Jupiter-masses, along with a debris disk of around 0.3 Lunar-masses. We have reanalyzed the iron abundance of the host star using our new spectral synthesis method, and contrary to previous results, we find the star to be super metal-rich, with a metallicity ([Fe/H]) of 0.2 dex. We also find the age of the system from chromospheric activities and pre-main sequence evolutionary models to be around 25Myrs. I will show some comparisons between the companion's bulk properties, such as broadband colours, and some of the latest evolutionary models as a function of metallicity. Finally, I will use these results to show how the companion to PZ Tel could be the first directly imaged extreme-Jovian extrasolar planet and not a low-mass brown dwarf. I acknowledge funding by Fondecyt through grant 3110004 and partial support from Centro de Astrofisica FONDAP 15010003, the GEMINI-CONICYT FUND and from the Comite Mixto ESO-GOBIERNO DE CHILE.

  8. Mira's role in RR Tel revisited

    NASA Astrophysics Data System (ADS)

    Heck, A.; Manfroid, J.

    The present uvby data, IUE FES measurements and American Association of Variable Star Observers visual estimates of the very slow nova RR Tel show that the object has gone through periodic variations in visual light since it started fading in 1949 after the outburst it incurred in 1944. The period is, however, not constant, and varies between 350 and 410 days, confirming Mayall's (1957) statement and contradicting the conclusions of later investigators. Synchronized variations of a Mira in the infrared and of a blue component indicate that the Mira mass outflow probably varies in a phase with its pulsations. Large variations occur in visual light on a time scale of a few weeks.

  9. Haemophagocytic syndrome complicating acute lymphoblastic leukaemia.

    PubMed Central

    Stark, R.; Manoharan, A.

    1989-01-01

    A 41 year old female developed reactive haemophagocytic histiocytosis secondary to herpes simplex infection, during remission induction for acute lymphoblastic leukaemia. She recovered fully with acyclovir and supportive treatment. Previous publications on the association between acute lymphoblastic leukaemia and haemophagocytic syndrome are reviewed, and the nature of the haemophagocytic disorder is discussed. Images Figure 1 PMID:2687829

  10. Genetic variegation of clonal architecture and propagating cells in leukaemia.

    PubMed

    Anderson, Kristina; Lutz, Christoph; van Delft, Frederik W; Bateman, Caroline M; Guo, Yanping; Colman, Susan M; Kempski, Helena; Moorman, Anthony V; Titley, Ian; Swansbury, John; Kearney, Lyndal; Enver, Tariq; Greaves, Mel

    2011-01-20

    Little is known of the genetic architecture of cancer at the subclonal and single-cell level or in the cells responsible for cancer clone maintenance and propagation. Here we have examined this issue in childhood acute lymphoblastic leukaemia in which the ETV6-RUNX1 gene fusion is an early or initiating genetic lesion followed by a modest number of recurrent or 'driver' copy number alterations. By multiplexing fluorescence in situ hybridization probes for these mutations, up to eight genetic abnormalities can be detected in single cells, a genetic signature of subclones identified and a composite picture of subclonal architecture and putative ancestral trees assembled. Subclones in acute lymphoblastic leukaemia have variegated genetics and complex, nonlinear or branching evolutionary histories. Copy number alterations are independently and reiteratively acquired in subclones of individual patients, and in no preferential order. Clonal architecture is dynamic and is subject to change in the lead-up to a diagnosis and in relapse. Leukaemia propagating cells, assayed by serial transplantation in NOD/SCID IL2Rγ(null) mice, are also genetically variegated, mirroring subclonal patterns, and vary in competitive regenerative capacity in vivo. These data have implications for cancer genomics and for the targeted therapy of cancer. PMID:21160474

  11. Ferritinaemia in Leukaemia and Hodgkin's Disease

    PubMed Central

    Jones, P. A. E.; Miller, F. M.; Worwood, M.; Jacobs, A.

    1973-01-01

    The serum ferritin concentration is increased in both acute myeloblastic leukaemia and Hodgkin's disease. In acute leukaemia the mean concentration is about ten times the normal level and is associated with a high concentration of transferrin-bound iron. In Hodgkin's disease abnormal ferritinaemia is associated with a low concentration of transferrin-bound iron and appears to result from a block of reticuloendothelial iron release. Increased concentrations of circulating ferritin have also been observed in a few cases of chronic leukaemia and myelomatosis. PMID:4511989

  12. TAUVEX - Tel Aviv University UV Explorer

    NASA Astrophysics Data System (ADS)

    Leibowitz, Elia M.

    1995-06-01

    TAUVEX - Tel Aviv University UV Explorer is a space telescope that is currently being built in Israel, to be flown on board the Russian international sattelite SRG - Spectrum Roentgen Gamma, in late 1995 or early 1996. TAUVEX is an imager in the near UV spectral window. Its major goal is to make a survey of about 10% of the UV sky, in the range λ = 1350 - 3500Å. A successful operation of TAUVEX will partially fill an important gap in our recognition of the sky, namely the distribution and the nature of the celestial UV sources, which are still mostly unknown. TAUVEX will also operate as a fast multicolor photometer in its UV range of operation. TAUVEX is aligned in parallel to the common optical axix of all the other instruments on board SRG, most of which are telescopes and monitors for high energy radiation. SRG will be thus able to perform for the first time in history simultaneous astronomical observations in one and the same celestial body, that cover together 7 order of magnitude of the recorded radiation. The observations of TAUVEX can be greatly enhanced by ground base observations.

  13. Design and kinetic analysis of hammerhead ribozyme and DNAzyme that specifically cleave TEL-AML1 chimeric mRNA

    SciTech Connect

    Choi, Woo-Hyung; Choi, Bo-Ra; Kim, Jae Hyun; Yeo, Woon-Seok; Oh, Sangtaek; Kim, Dong-Eun

    2008-09-12

    In order to develop the oligonucleotides to abolish an expression of TEL-AML1 chimeric RNA, which is a genetic aberration that causes the acute lymphoblastic leukemia (ALL), hammerhead ribozymes and deoxyoligoribozymes that can specifically cleave TEL-AML1 fusion RNA were designed. Constructs of the deoxyribozyme with an asymmetric substrate binding arm (Dz26) and the hammerhead ribozyme with a 4 nt-bulged substrate binding arm in the stem III (buRz28) were able to cleave TEL-AML1 chimeric RNA specifically at sites close to the junction in vitro, without cleaving the normal TEL and AML1 RNA. Single-turnover kinetic analysis under enzyme-excess condition revealed that the buRz28 is superior to the Dz26 in terms of substrate binding and RNA-cleavage. In conjunction with current progress in a gene-delivery technology, the designed oligonucleotides that specifically cleave the TEL-AML1 chimeric mRNA are hoped to be applicable for the treatment of ALL in vivo.

  14. Acute myelogenous leukaemia in Hurler's syndrome.

    PubMed

    Chen, K T; McKenna, R W; Desnick, R J

    1978-06-01

    The occurrence of the Hurler syndrome and acute myelogenous leukaemia in a 2 1/2-year-old girl is described. This represents the first published report of the concurrence of these two diseases. PMID:97385

  15. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia

    PubMed Central

    Ceccacci, Elena; Minucci, Saverio

    2016-01-01

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  16. Inhibition of histone deacetylases in cancer therapy: lessons from leukaemia.

    PubMed

    Ceccacci, Elena; Minucci, Saverio

    2016-03-15

    Histone deacetylases (HDACs) are a key component of the epigenetic machinery regulating gene expression, and behave as oncogenes in several cancer types, spurring the development of HDAC inhibitors (HDACi) as anticancer drugs. This review discusses new results regarding the role of HDACs in cancer and the effect of HDACi on tumour cells, focusing on haematological malignancies, particularly acute myeloid leukaemia. Histone deacetylases may have opposite roles at different stages of tumour progression and in different tumour cell sub-populations (cancer stem cells), highlighting the importance of investigating these aspects for further improving the clinical use of HDACi in treating cancer. PMID:26908329

  17. Genome sequencing and annotation of Serratia sp. strain TEL.

    PubMed

    Lephoto, Tiisetso E; Gray, Vincent M

    2015-12-01

    We present the annotation of the draft genome sequence of Serratia sp. strain TEL (GenBank accession number KP711410). This organism was isolated from entomopathogenic nematode Oscheius sp. strain TEL (GenBank accession number KM492926) collected from grassland soil and has a genome size of 5,000,541 bp and 542 subsystems. The genome sequence can be accessed at DDBJ/EMBL/GenBank under the accession number LDEG00000000. PMID:26697332

  18. Synergistic targeted therapy for acute promyelocytic leukaemia: a model of translational research in human cancer.

    PubMed

    Mi, J-Q; Chen, S-J; Zhou, G-B; Yan, X-J; Chen, Z

    2015-12-01

    Acute promyelocytic leukaemia (APL), the M3 subtype of acute myeloid leukaemia, was once a lethal disease, yet nowadays the majority of patients with APL can be successfully cured by molecularly targeted therapy. This dramatic improvement in the survival rate is an example of the advantage of modern medicine. APL is characterized by a balanced reciprocal chromosomal translocation fusing the promyelocytic leukaemia (PML) gene on chromosome 15 with the retinoic acid receptor α (RARα) gene on chromosome 17. It has been found that all-trans-retinoic acid (ATRA) or arsenic trioxide (ATO) alone exerts therapeutic effect on APL patients with the PML-RARα fusion gene, and the combination of both drugs can act synergistically to further enhance the cure rate of the patients. Here, we provide an insight into the pathogenesis of APL and the mechanisms underlying the respective roles of ATRA and ATO. In addition, treatments that lead to more effective differentiation and apoptosis of APL cells, including leukaemia-initiating cells, and more thorough eradication of the disease will be discussed. Moreover, as a model of translational research, the development of a cure for APL has followed a bidirectional approach of 'bench to bedside' and 'bedside to bench', which can serve as a valuable example for the diagnosis and treatment of other malignancies. PMID:26058416

  19. Significance of Phi bodies in acute leukaemia.

    PubMed Central

    Cardullo, L de S; Morilla, R; Catovsky, D

    1981-01-01

    Material from 39 patients with acute leukaemia was investigated with the peroxidase cytochemical reaction using 3,3'diaminobenzidine (DAB) and other substrates in order to test their sensitivity in detecting myeloid differentiation. The proportion of positive blasts and of cases with Auer rods in acute myeloid leukaemia (AML) was significantly greater with DAB than with benzidine. In addition, Phi bodies were demonstrated in AML blasts only when DAB was used; Phi bodies were also observed in two out of seven cases of chronic granulocytic leukaemia in "myeloid" blast crisis but were not seen in any case of acute lymphoblastic leukaemia. Phi bodies were more numerous when the reaction was carried out at pH 9.7, and their number was significantly reduced in the presence of 3-amino 1,2,4-triazole. Both findings suggest that the Phi bodies derive from catalase-containing granules (microperoxisomes) and are distinct from Auer rods, which derive from peroxidase-containing (primary) granules. Like Auer rods, Phi bodies appear to be characteristics of immature myeloid cells in leukaemia but are seen with a higher frequency than Auer rods in acute myeloid leukemia. Images p154-a PMID:6262384

  20. Single Molecule Measurements of Protelomerase TelK-DNA Complexes

    NASA Astrophysics Data System (ADS)

    Landry, Markita; Khafizov, Rustem; Huang, Wai Mun; Chemla, Yann

    2008-10-01

    Protein-DNA interactions lie at the heart of many essential cellular processes such as replication, recombination, and repair. Recent advances in optical ``tweezers'' have made it possible to resolve motions on the scale of a single base pair of DNA, 3.4å. High-resolution optical traps have the potential to reveal these interactions at their fundamental length scales and should reveal how certain proteins bind to DNA or recognize target sequences. Telomerases are enzymes that have been actively studied in various organisms because of their fundamental involvement with both cancer and aging^1. Protelomerase TelK is an enzyme responsible for forming closed DNA hairpin ends in linear DNA. TelK is not an ATP dependant enzyme, which is surprising given the degree of DNA distortion accomplished by the enzyme, and the large energy barrier intrinsic in DNA hairpin formation. Therefore, our focus is on TelK mutants lacking their c-terminal domain, and TelK YF mutants lacking their tyrosine active site amino acid. Preliminary data have shown remarkable differences in protein binding and unbinding forces caused by the removal of a single oxygen atom from a 73 kDa protein. Further measurements using high-resolution optical tweezers should provide fundamental insights into the nature and importance of the electrostatic interactions between TelK and its DNA substrate. 1. Shay, J. et al. Rad. Res. 155, 188 (2001) [1] Huang, W. et al. Mol. Cell. 27, 901 (2007).

  1. Leukaemia mortality around French nuclear sites.

    PubMed Central

    Hattchouel, J. M.; Laplanche, A.; Hill, C.

    1995-01-01

    This study was designed to investigate leukaemia mortality in the population under the age of 25 residing around the 13 French nuclear sites operating in 1985. In four geographical zones defined according to the distance from the site, 503 exposed communes were identified and followed up between 1968 and 1989. A total of 4,132,000 person-years of observation were accumulated. The number of leukaemia deaths observed (69) did not differ from the expected number (86.15) estimated according to national mortality statistics. There was no difference in the risks of leukaemia mortality according to sex, age, type of installation and no trend with an increasing distance from installations. PMID:7880754

  2. Stem cell origins of leukaemia and curability.

    PubMed Central

    Greaves, M. F.

    1993-01-01

    It is suggested that most childhood acute lymphoblastic leukaemias and some other paediatric cancers are chemo-curable because they arise in stem cell populations that are functionally transient, chemosensitive and programmed for apoptosis. Most adult acute leukaemias are chemo-incurable at least in part because they originate in relatively drug resistant stem cells with extensive self-renewal capacity. The latter property in turn increases the probability of clones evolving with multi-drug resistance. Particular mutations may superimpose additional adverse features on leukaemic cells. PMID:8439493

  3. HOX-mediated LMO2 expression in embryonic mesoderm is recapitulated in acute leukaemias.

    PubMed

    Calero-Nieto, F J; Joshi, A; Bonadies, N; Kinston, S; Chan, W-I; Gudgin, E; Pridans, C; Landry, J-R; Kikuchi, J; Huntly, B J; Gottgens, B

    2013-11-28

    The Lim Domain Only 2 (LMO2) leukaemia oncogene encodes an LIM domain transcriptional cofactor required for early haematopoiesis. During embryogenesis, LMO2 is also expressed in developing tail and limb buds, an expression pattern we now show to be recapitulated in transgenic mice by an enhancer in LMO2 intron 4. Limb bud expression depended on a cluster of HOX binding sites, while posterior tail expression required the HOX sites and two E-boxes. Given the importance of both LMO2 and HOX genes in acute leukaemias, we further demonstrated that the regulatory hierarchy of HOX control of LMO2 is activated in leukaemia mouse models as well as in patient samples. Moreover, Lmo2 knock-down impaired the growth of leukaemic cells, and high LMO2 expression at diagnosis correlated with poor survival in cytogenetically normal AML patients. Taken together, these results establish a regulatory hierarchy of HOX control of LMO2 in normal development, which can be resurrected during leukaemia development. Redeployment of embryonic regulatory hierarchies in an aberrant context is likely to be relevant in human pathologies beyond the specific example of ectopic activation of LMO2. PMID:23708655

  4. An algorithm for leukaemia immunophenotype pattern recognition.

    PubMed

    Petrovecki, M; Marusić, M; Dezelić, G

    1993-01-01

    Since leukaemia-specific leucocyte antigen has not been identified to date, the immunological diagnosis of leukaemia is achieved through the application of a wide set of monoclonal antibodies specific for surface markers on leukaemic cells. Thus, the interpretation of leukaemia immunophenotype seems to be a mathematically determined comparison of 'what we found' and 'what we know' about it. The objective of this study was to establish an algorithm for transformation of empirical rules into mathematical values to achieve proper decisions. Recognition of leukaemia phenotype was performed by comparison of phenotyping data with reference data, followed by scoring of such comparisons. Systematic scoring resulted in the formation of new numerical variables allocated to each state, whereas a most significant variable was described as a complex measure of compatibility. A system of recognized states was described by mathematical variables measuring the confidence of information systems, i.e. maximal, total and relative entropy. The entire algorithm was derived by matrix algebra and coded in a high-level program language. The list of the states recognized appeared to be especially helpful in differential diagnosis, occasionally pointing to states that had not been in the scientist's mind at the start of the analysis. PMID:8366688

  5. New TEL Environments for Vocational Education--Teacher's Instructional Perspective

    ERIC Educational Resources Information Center

    Hämäläinen, Raija; Cattaneo, Alberto

    2015-01-01

    Modern vocational education is increasingly taking place in new technology-enhanced learning (TEL) settings. On the one hand, vocational education can benefit from the opportunities of technological development. On the other hand, such technologies may create new challenges for teachers. Therefore, there is a particular need to pay more attention…

  6. Teaching Gender in Israel: Experiences at the Tel Aviv University

    ERIC Educational Resources Information Center

    Fenster, Tovi

    2011-01-01

    This paper examines the ways in which neoliberal economic policies are affecting academic work in Israeli universities, prioritizing programs that can generate their own funding, External philanthropic support from North America has enabled creation of an interdisciplinary Women and Gender Studies Program at Tel Aviv University that draws…

  7. SWI/SNF Subunits SMARCA4, SMARCD2 and DPF2 Collaborate in MLL-Rearranged Leukaemia Maintenance

    PubMed Central

    Sankar, Aditya; Miyagi, Satoru; Rundsten, Carsten Friis; Johansen, Jens Vilstrup; Helin, Kristian

    2015-01-01

    Alterations in chromatin structure caused by deregulated epigenetic mechanisms collaborate with underlying genetic lesions to promote cancer. SMARCA4/BRG1, a core component of the SWI/SNF ATP-dependent chromatin-remodelling complex, has been implicated by its mutational spectrum as exerting a tumour-suppressor function in many solid tumours; recently however, it has been reported to sustain leukaemogenic transformation in MLL-rearranged leukaemia in mice. Here we further explore the role of SMARCA4 and the two SWI/SNF subunits SMARCD2/BAF60B and DPF2/BAF45D in leukaemia. We observed the selective requirement for these proteins for leukaemic cell expansion and self-renewal in-vitro as well as in leukaemia. Gene expression profiling in human cells of each of these three factors suggests that they have overlapping functions in leukaemia. The gene expression changes induced by loss of the three proteins demonstrate that they are required for the expression of haematopoietic stem cell associated genes but in contrast to previous results obtained in mouse cells, the three proteins are not required for the expression of c-MYC regulated genes. PMID:26571505

  8. [History of the Hôtel-Dieu of Bourges].

    PubMed

    Albou, P

    1996-01-01

    Bourges hospital (Hôtel-Dieu de Bourges, 1527) is one of the last to be built in France modeled in the Beaune style (1443) with chapel and wards linked in one line. The former gothic part, built between 1510 and 1527, was later completed by two Renaissance doors (1511 and 1533) and by two classical style wings built after the 1628 plague. Following the Revolution, the gothic part was divided by a floor which somewhat alters the interior appearance of the whole construction. The closing of the general care unit in November 1994 (and transfer of the Bourges General Hospital to new premises) now renders feasible the restoration of the former hospital (Hôtel-Dieu) almost unknown until now, thereby giving it the place it might fully desserve in the architectural and tourist heritage of Bourges. PMID:11624983

  9. Rhinocerebral zygomycosis in acute lymphoblastic leukaemia.

    PubMed

    Sica, S; Morace, G; La Rocca, L M; Etuk, B; Di Mario, A; Pagano, L; Zini, G; Rutella, S; Leone, G

    1993-01-01

    We describe a patient with acute lymphoblastic leukaemia who developed rhinocerebral zygomycosis during the aplastic phase induced by antineoplastic chemotherapy. The patient was treated with fluconazole intravenously (400 mg daily) for 30 days and underwent surgical debridement. As a result of this treatment a complete remission of the zygomycosis-associated symptoms was observed. The possibility of treating zygomycosis with fluconazole is discussed. PMID:8015558

  10. Structure of the intact ATM/Tel1 kinase

    PubMed Central

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-01-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID:27229179

  11. Structure of the intact ATM/Tel1 kinase

    NASA Astrophysics Data System (ADS)

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-05-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents.

  12. Structure of the intact ATM/Tel1 kinase.

    PubMed

    Wang, Xuejuan; Chu, Huanyu; Lv, Mengjuan; Zhang, Zhihui; Qiu, Shuwan; Liu, Haiyan; Shen, Xuetong; Wang, Weiwu; Cai, Gang

    2016-01-01

    The ataxia-telangiectasia mutated (ATM) protein is an apical kinase that orchestrates the multifaceted DNA-damage response. Normally, ATM kinase is in an inactive, homodimer form and is transformed into monomers upon activation. Besides a conserved kinase domain at the C terminus, ATM contains three other structural modules, referred to as FAT, FATC and N-terminal helical solenoid. Here we report the first cryo-EM structure of ATM kinase, which is an intact homodimeric ATM/Tel1 from Schizosaccharomyces pombe. We show that two monomers directly contact head-to-head through the FAT and kinase domains. The tandem N-terminal helical solenoid tightly packs against the FAT and kinase domains. The structure suggests that ATM/Tel1 dimer interface and the consecutive HEAT repeats inhibit the binding of kinase substrates and regulators by steric hindrance. Our study provides a structural framework for understanding the mechanisms of ATM/Tel1 regulation as well as the development of new therapeutic agents. PMID:27229179

  13. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome

    PubMed Central

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2014-01-01

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress. PMID:24932421

  14. Acute myeloid leukaemia after treatment for acute lymphoblastic leukaemia in girl with Bloom syndrome.

    PubMed

    Adams, Madeleine; Jenney, Meriel; Lazarou, Laz; White, Rhian; Birdsall, Sanda; Staab, Timo; Schindler, Detlev; Meyer, Stefan

    2013-09-18

    Bloom syndrome (BS) is an inherited genomic instability disorder caused by disruption of the BLM helicase and confers an extreme cancer predisposition. Here we report on a girl with BS who developed acute lymphoblastic leukaemia (ALL) at age nine, and treatment-related acute myeloid leukaemia (t-AML) aged 12. She was compound heterozygous for the novel BLM frameshift deletion c.1624delG and the previously described c.3415C>T nonsense mutation. Two haematological malignancies in a child with BS imply a fundamental role for BLM for normal haematopoiesis, in particular in the presence of genotoxic stress. PMID:24932421

  15. Large geomagnetic field anomalies revealed in Bronze to Iron Age archeomagnetic data from Tel Megiddo and Tel Hazor, Israel

    NASA Astrophysics Data System (ADS)

    Shaar, Ron; Tauxe, Lisa; Ron, Hagai; Ebert, Yael; Zuckerman, Sharon; Finkelstein, Israel; Agnon, Amotz

    2016-05-01

    Geomagnetic field measurements from the past few centuries show heightened secular variation activity in the southern hemisphere associated with the south Atlantic anomaly (SAA). It is uncertain whether geomagnetic anomalies at a similar scale have existed in the past owing to limited coverage and uncertainties in the paleomagnetic database. Here we provide new evidence from archaeological sources in the Levant suggesting a large positive northern hemisphere anomaly, similar in magnitude to the SAA during the 9th-8th centuries BCE, called "Levantine Iron Age anomaly". We also report an additional geomagnetic spike in the 8th century. The new dataset comprises 73 high precision paleointensity estimates from ca. 3000 BCE to 732 BCE, and five directional measurements between the 14th and the 9th centuries BCE. Well-dated pottery and cooking ovens were collected from twenty archaeological strata in two large contemporaneous stratigraphical mounds (tells) in Israel: Tel Megiddo and Tel Hazor. The new data are combined with previously published data and interpreted automatically using the PmagPy Thellier GUI program. The Tel Megiddo and Tel Hazor data sets demonstrate excellent internal consistency and remarkable agreement with published data from Mesopotamia (Syria). The data illustrate the evolution of an extreme geomagnetic high that culminated in at least two spikes between the 11th and the 8th centuries BCE (Iron Age in the Levant). The paleomagnetic directional data of the 9th century BCE show positive inclination anomalies, and deviations of up to 22° from the averaged geocentric axial dipole (GAD) direction. From comparison of the Levantine archaeomagnetic data with IGRF model for 2015 we infer the "Levantine Iron Age anomaly" between the 10th and the 8th centuries BCE is a local positive anomaly. The eastward extent of the anomaly is currently unknown.

  16. Immunization against primary, transplanted and spontaneous murine leukaemia using a live Moloney sarcoma virus vaccine.

    PubMed Central

    Mayer, A. M.; Basombrio, M. A.; Pasqualini, C. D.

    1980-01-01

    The purpose of this study was to use an immunization protocol with Moloney sarcoma virus (MSV-M) as active immunogen against exogenous and endogenous leukaemia. The s.c. route was chosen since it offered advantages over the i.m. route: the primary sarcomas were smaller, the regression faster, there were fewer recurrences and there was good persistent immunity. Strong protection was obtained against primary leukaemias induced by Friend leukaemia virus (FLV), Moloney leukaemia virus (MLV), Rauscher leukaemia virus (RLV), Precerutti-Law leukaemia virus (PLLV/T2), and H179A leukaemia virus. It was not possible to protect against leukaemia induced by Gross leukaemia virus (GLV). With transplantable leukaemias the results varied: partial protection was observed against H110 leukaemia (induced with human material) and R14 leukaemia (induced by X-irradiation) whilst no protection was obtained against P277 leukaemia (induced by Moloney leukaemia virus). As for spontaneous leukaemias, immunized BALB/c mice showed an increased incidence over the controls, while in F1 (Swiss x AKR) mice the incidence was similar but the latent period was shorter. Furthermore, in long-term observations the MSV-M-immunized mice showed an increased mortaltiy, which could be related to (1) new phenotypic mixtures between MSV-M and leukaemia viruses; (2) reactivation of MSV-M sarcoma-genesis with age, and (3) genotype susceptibility to MSV-M. PMID:6252923

  17. Time space distribution of childhood leukaemia in the Netherlands.

    PubMed Central

    van Steensel-Moll, H A; Valkenburg, H A; Vandenbroucke, J P; van Zanen, G E

    1983-01-01

    In the western part of the Netherlands during 1973-80 leukaemia was diagnosed in 293 patients aged under 15 years. An overall incidence rate of 2.91 per 100000 person years was calculated. No seasonal influence on months of birth or months of diagnosis of these patients could be traced by the method of Edwards. Time space clustering was looked for by both methods of Mantel and Knox. No significant time space clustering of date and place of diagnosis of childhood leukaemia was found in all types of leukaemia, acute lymphocytic leukaemia (ALL), ALL in boys and girls, ALL in children under 6 years at diagnosis, and in acute non-lymphocytic leukaemia. PMID:6577127

  18. A solid state Marx generator for TEL2

    SciTech Connect

    Kamerdzhiev, V.; Pfeffer, H.; Saewert, G.; Shiltsev, V.; /Fermilab

    2007-06-01

    The solid-state Marx generator modulates the anode of the electron gun to produce the electron beam pulses in the second Tevatron Electron Lens (TEL2). It is capable of driving the 60 pF terminal with 600 ns pulses of up to 6 kV with a p.r.r. of 50 kHz. The rise and fall times are 150 ns. Stangenes Industries developed the unit and is working on a second version which will go to higher voltage and have the ability to vary its output in 396 ns intervals over a 5 {micro}s pulse.

  19. Requirement of the FATC domain of protein kinase Tel1 for localization to DNA ends and target protein recognition

    PubMed Central

    Ogi, Hiroo; Goto, Greicy H.; Ghosh, Avik; Zencir, Sevil; Henry, Everett; Sugimoto, Katsunori

    2015-01-01

    Two large phosphatidylinositol 3-kinase–related protein kinases (PIKKs), ATM and ATR, play a central role in the DNA damage response pathway. PIKKs contain a highly conserved extreme C-terminus called the FRAP-ATM-TRRAP-C-terminal (FATC) domain. In budding yeast, ATM and ATR correspond to Tel1 and Mec1, respectively. In this study, we characterized functions of the FATC domain of Tel1 by introducing substitution or truncation mutations. One substitution mutation, termed tel1-21, and a truncation mutation, called tel1-ΔC, did not significantly affect the expression level. The tel1-21 mutation impaired the cellular response to DNA damage and conferred moderate telomere maintenance defect. In contrast, the tel1-ΔC mutation behaved like a null mutation, conferring defects in both DNA damage response and telomere maintenance. Tel1-21 protein localized to DNA ends as effectively as wild-type Tel1 protein, whereas Tel1-ΔC protein failed. Introduction of a hyperactive TEL1-hy mutation suppressed the tel1-21 mutation but not the tel1-ΔC mutation. In vitro analyses revealed that both Tel1-21 and Tel1-ΔC proteins undergo efficient autophosphorylation but exhibit decreased kinase activities toward the exogenous substrate protein, Rad53. Our results show that the FATC domain of Tel1 mediates localization to DNA ends and contributes to phosphorylation of target proteins. PMID:26246601

  20. Intravenous immune globulin in chronic lymphocytic leukaemia.

    PubMed Central

    Gamm, H; Huber, C; Chapel, H; Lee, M; Ries, F; Dicato, M A

    1994-01-01

    The most common complication of chronic lymphocytic leukaemia (CLL) is infection, which occurs mainly in advanced stages of disease or in those patients with hypogammaglobulinaemia. Intravenous immune globulin (IVIG) has been shown to be a useful prophylactic therapy against infections in such patients. A randomized, double-blind study on 36 patients receiving either 500 mg/kg or 250 mg/kg IVIG every 4 weeks was undertaken to determine the dose regimen required. There was no significant difference in the two treatment groups and we found that CLL patients were equally protected with low-dose IVIG. PMID:8033428

  1. Childhood leukaemia, nuclear sites, and population mixing.

    PubMed

    Kinlen, L

    2011-01-01

    The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated. PMID:21063418

  2. Childhood leukaemia, nuclear sites, and population mixing

    PubMed Central

    Kinlen, L

    2011-01-01

    The excess of childhood leukaemia (CL) in Seascale, near the Sellafield nuclear reprocessing site in rural NW England, suggested that an epidemic of an underlying infection, to which CL is a rare response, is promoted by marked population mixing (PM) in rural areas, in which the prevalence of susceptibles is higher than average. This hypothesis has been confirmed by 12 studies in non-radiation situations. Of the five established CL excesses near nuclear sites, four are associated with significant PM; in the fifth, the Krummel power station in Germany, the subject has not been thoroughly investigated. PMID:21063418

  3. Belinostat, a potent HDACi, exerts antileukaemic effect in human acute promyelocytic leukaemia cells via chromatin remodelling

    PubMed Central

    Valiuliene, Giedre; Stirblyte, Ieva; Cicenaite, Dovile; Kaupinis, Algirdas; Valius, Mindaugas; Navakauskiene, Ruta

    2015-01-01

    Epigenetic changes play a significant role in leukaemia pathogenesis, therefore histone deacetylases (HDACis) are widely accepted as an attractive strategy for acute promyelocytic leukaemia (APL) treatment. Belinostat (Bel, PXD101), a hydroxamate-type HDACi, has proved to be a promising cure in clinical trials for solid tumours and haematological malignancies. However, insight into molecular effects of Bel on APL, is still lacking. In this study, we investigated the effect of Bel alone and in combination with differentiation inducer retinoic acid (RA) on human promyelocytic leukaemia NB4 and HL-60 cells. We found that treatment with Bel, depending on the dosage used, inhibits cell proliferation, whereas in combination with RA enhances and accelerates granulocytic leukaemia cell differentiation. We also evaluated the effect of used treatments with Bel and RA on certain epigenetic modifiers (HDAC1, HDAC2, PCAF) as well as cell cycle regulators (p27) gene expression and protein level modulation. We showed that Bel in combination with RA up-regulates basal histone H4 hyperacetylation level more strongly compared to Bel or RA alone. Furthermore, chromatin immunoprecipitation assay indicated that Bel induces the accumulation of hyperacetylated histone H4 at the p27 promoter region. Mass spectrometry analysis revealed that in control NB4 cells, hyperacetylated histone H4 is mainly found in association with proteins involved in DNA replication and transcription, whereas after Bel treatment it is found with proteins implicated in pro-apoptotic processes, in defence against oxidative stress and tumour suppression. Summarizing, our study provides some novel insights into the molecular mechanisms of HDACi Bel action on APL cells. PMID:25864732

  4. Yeast Pol4 Promotes Tel1-Regulated Chromosomal Translocations

    PubMed Central

    Sastre-Moreno, Guillermo; Aguilera, Andrés; Blanco, Luis

    2013-01-01

    DNA double-strand breaks (DSBs) are one of the most dangerous DNA lesions, since their erroneous repair by nonhomologous end-joining (NHEJ) can generate harmful chromosomal rearrangements. PolX DNA polymerases are well suited to extend DSB ends that cannot be directly ligated due to their particular ability to bind to and insert nucleotides at the imperfect template-primer structures formed during NHEJ. Herein, we have devised genetic assays in yeast to induce simultaneous DSBs in different chromosomes in vivo. The repair of these breaks in trans could result in reciprocal chromosomal translocations that were dependent on classical Ku-dependent NHEJ. End-joining events leading to translocations were mainly based on the formation of short base pairing between 3′-overhanging DNA ends coupled to gap-filling DNA synthesis. A major proportion of these events were specifically dependent on yeast DNA polymerase Pol4 activity. In addition, we have discovered that Pol4-Thr540 amino acid residue can be phosphorylated by Tel1/ATM kinase, which could modulate Pol4 activity during NHEJ. Our data suggest that the role of Tel1 in preventing break-induced chromosomal translocations can, to some extent, be due to its stimulating effect on gap-filling activity of Pol4 to repair DSBs in cis. Overall, this work provides further insight to the molecular mechanisms of DSB repair by NHEJ and presents a new perspective to the understanding of how chromosomal translocations are formed in eukaryotic cells. PMID:23874240

  5. RR Tel: Getting Under the Flux Limit: An Observation with FUSE

    NASA Technical Reports Server (NTRS)

    Sonnenborn, George (Technical Monitor); Kenyon, Scott J.

    2004-01-01

    The goal of this program is to acquire a FUSE spectrum of the symbiotic binary RR Tel. With these data, we plan to derive improved constraints on the hot component, the nebula, and perhaps the red giant wind. Based on results from AG Dra, we should also be able to use some line detections to improve atomic parameters for high ionization emission lines. This results would benefit the general FUSE community. As of this writing, the FUSE observation of RR Tel has not been made. Because RR Tel is a very bright UV source, the FUSE team is assessing the likelihood that RR Tel will have an adverse affect on the instrument.

  6. Distribution of ABO blood groups in acute leukaemias and lymphomas.

    PubMed

    Vadivelu, Murali K; Damodaran, Senthilkumar; Solomon, John; Rajaseharan, Annabelle

    2004-09-01

    We studied the distribution of ABO blood groups in Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, in children up to the age of 12 years, in a hospital-based retrospective study. Blood group data were recorded from the case records of all the patients in a tertiary care centre with the diagnosis of Hodgkin's lymphoma, non-Hodgkin's lymphoma, acute myeloid leukaemia and acute lymphoblastic leukaemia, during the period 1987-1997. There were 63 Hodgkin's lymphoma, 78 non-Hodgkin's lymphoma, 116 acute myeloid leukaemia and 522 acute lymphoblastic leukaemia patients. We assessed the distribution of ABO blood groups and the difference in the distribution from the source population. In Hodgkin's lymphoma, there were 45.6% [95% confidence interval (CI): 6.8-84.5] more patients with B blood group. In acute lymphoblastic leukaemia, there were 14.3% (95% CI: 3.2-25.2) more patients with O blood group. In Hodgkin's lymphoma and non-Hodgkin's lymphoma patients, there were 56.5% (95% CI: 19.9-85.4) and 52.9% (95% CI: 18.1-82.6) less patients with A blood group, respectively. This shows that the relationship between the ABO blood groups and haematological malignancies merits further investigation in a population-based prospective study. This is the first study of its kind in any Indian population. PMID:15175895

  7. Whole-genome sequencing identifies recurrent mutations in chronic lymphocytic leukaemia

    PubMed Central

    Puente, Xose S.; Pinyol, Magda; Quesada, Víctor; Conde, Laura; Ordóñez, Gonzalo R.; Villamor, Neus; Escaramis, Georgia; Jares, Pedro; Beà, Sílvia; González-Díaz, Marcos; Bassaganyas, Laia; Baumann, Tycho; Juan, Manel; López-Guerra, Mónica; Colomer, Dolors; Tubío, José M. C.; López, Cristina; Navarro, Alba; Tornador, Cristian; Aymerich, Marta; Rozman, María; Hernández, Jesús M.; Puente, Diana A.; Freije, José M. P.; Velasco, Gloria; Gutiérrez-Fernández, Ana; Costa, Dolors; Carrió, Anna; Guijarro, Sara; Enjuanes, Anna; Hernández, Lluís; Yagüe, Jordi; Nicolás, Pilar; Romeo-Casabona, Carlos M.; Himmelbauer, Heinz; Castillo, Ester; Dohm, Juliane C.; de Sanjosé, Silvia; Piris, Miguel A.; de Alava, Enrique; Miguel, Jesús San; Royo, Romina; Gelpí, Josep L.; Torrents, David; Orozco, Modesto; Pisano, David G.; Valencia, Alfonso; Guigó, Roderic; Bayés, Mónica; Heath, Simon; Gut, Marta; Klatt, Peter; Marshall, John; Raine, Keiran; Stebbings, Lucy A.; Futreal, P. Andrew; Stratton, Michael R.; Campbell, Peter J.; Gut, Ivo; López-Guillermo, Armando; Estivill, Xavier; Montserrat, Emili; López-Otín, Carlos; Campo, Elías

    2012-01-01

    Chronic lymphocytic leukaemia (CLL), the most frequent leukaemia in adults in Western countries, is a heterogeneous disease with variable clinical presentation and evolution1,2. Two major molecular subtypes can be distinguished, characterized respectively by a high or low number of somatic hypermutations in the variable region of immunoglobulin genes3,4. The molecular changes leading to the pathogenesis of the disease are still poorly understood. Here we performed whole-genome sequencing of four cases of CLL and identified 46 somatic mutations that potentially affect gene function. Further analysis of these mutations in 363 patients with CLL identified four genes that are recurrently mutated: notch 1 (NOTCH1), exportin 1 (XPO1), myeloid differentiation primary response gene 88 (MYD88) and kelch-like 6 (KLHL6). Mutations in MYD88 and KLHL6 are predominant in cases of CLL with mutated immunoglobulin genes, whereas NOTCH1 and XPO1 mutations are mainly detected in patients with unmutated immunoglobulins. The patterns of somatic mutation, supported by functional and clinical analyses, strongly indicate that the recurrent NOTCH1, MYD88 and XPO1 mutations are oncogenic changes that contribute to the clinical evolution of the disease. To our knowledge, this is the first comprehensive analysis of CLL combining whole-genome sequencing with clinical characteristics and clinical outcomes. It highlights the usefulness of this approach for the identification of clinically relevant mutations in cancer. PMID:21642962

  8. Late relapses in acute promyelocytic leukaemia.

    PubMed

    Latagliata, Roberto; Carmosino, Ida; Breccia, Massimo; Minni, Antonio; Testi, Anna; Iorio, Nicol; Lo-Coco, Francesco; Avvisati, Giuseppe; Petti, Maria Concetta; Mandelli, Franco; Cimino, Giuseppe

    2007-01-01

    From January 1988 to December 1997, among 53 acute promyelocytic leukaemia patients in 1st complete remission (CR) after 5 years from diagnosis, we observed 5 late relapses (9.4%) after 60, 61, 71, 101 and 155 months from diagnosis; 3 of those late relapses (7.7%) occurred among 39 patients previously treated with all-trans-retinoic acid. An involvement of the mastoid occurred in 3/5 patients (60%), compared with 2/32 patients (6.3%) at an early relapse (p < 0.02). As to the treatment of the late relapse, 1 patient received all-trans-retinoic acid alone followed by allogeneic transplantation and 4 patients were treated according to the GIMEMA 0191 protocol. All patients achieved a 2nd CR and are still alive: 4 in the 2nd molecular CR after 6, 33, 34 and 115 months; 1 relapsed after 15 months and is now in the 3rd CR. In conclusion, a late relapse occurred in a sizeable fraction of acute promyelocytic leukaemia patients: the high rate of ear involvement might be explained considering the ear as a 'disease sanctuary'. PMID:17135723

  9. Maxillo-ethmoidal chloroma in acute myeloid leukaemia: Case report

    PubMed Central

    Ferri, E; Minotto, C; Ianniello, F; Cavaleri, S; Armato, E; Capuzzo, P

    2005-01-01

    Summary Chloroma, also called Granulocytic Sarcoma or Myeloid Sarcoma, is a rare malignant extra-medullary neoplasm of myeloid precursor cells. It is usually associated with myeloproliferative disorders but its appearance may precede the onset of leukaemia. Chloroma may be found in several extracranial sites. Involvement of the head and neck region is uncommon. Differential diagnosis is often difficult and includes acute lymphoblastic leukaemia, large cell NHL, lymphoblastic lymphoma and Ewing’s sarcoma. The case is presented of a maxillo-ethmoidal chloroma occurring in a case of poor prognosis acute myeloid leukaemia, emphasizing the clinical and cyto-histological features and problems concerning differential diagnosis. PMID:16450777

  10. Acute myeloid leukaemia (M6B: pure acute erythroid leukaemia) in a Thoroughbred foal.

    PubMed

    Forbes, G; Feary, D J; Savage, C J; Nath, L; Church, S; Lording, P

    2011-07-01

    A 10-week-old Thoroughbred filly was referred for anaemia of 4 weeks' duration. Haematology revealed severe anaemia and panleucopenia. Cytological examination of bone marrow smears revealed a myeloid to erythroid ratio <0.02:1 (reference range 0.5-2.4:1.0) and an abundance of erythroid precursor cells. The erythroid cell population included rubriblasts, prorubricytes and rubricytes, with only scant numbers of metarubricytes present. There were numerous mitotic erythroid cells, some of which were atypical and megaloblastic. These cytomorphological changes are consistent with pure acute erythroid leukaemia. No treatment was instituted and the filly died three days after presentation. This case illustrates the need to consider both haematology and bone marrow findings to establish a diagnosis of pure erythroid leukaemia. To our knowledge, there is no documented case of acute myeloproliferative disease in horses involving cells of erythroid lineage, but this condition should be considered a differential diagnosis for horses presenting with anaemia. PMID:21696377

  11. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling

    PubMed Central

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S.; Costa, Magdaline; Ghahremani, Morvarid Farhang; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J. Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S.; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W.; Janzen, Viktor; McCormack, Matthew P.; Lock, Richard B.; Curtis, David J.; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P. P.; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J.

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  12. ZEB2 drives immature T-cell lymphoblastic leukaemia development via enhanced tumour-initiating potential and IL-7 receptor signalling.

    PubMed

    Goossens, Steven; Radaelli, Enrico; Blanchet, Odile; Durinck, Kaat; Van der Meulen, Joni; Peirs, Sofie; Taghon, Tom; Tremblay, Cedric S; Costa, Magdaline; Farhang Ghahremani, Morvarid; De Medts, Jelle; Bartunkova, Sonia; Haigh, Katharina; Schwab, Claire; Farla, Natalie; Pieters, Tim; Matthijssens, Filip; Van Roy, Nadine; Best, J Adam; Deswarte, Kim; Bogaert, Pieter; Carmichael, Catherine; Rickard, Adam; Suryani, Santi; Bracken, Lauryn S; Alserihi, Raed; Canté-Barrett, Kirsten; Haenebalcke, Lieven; Clappier, Emmanuelle; Rondou, Pieter; Slowicka, Karolina; Huylebroeck, Danny; Goldrath, Ananda W; Janzen, Viktor; McCormack, Matthew P; Lock, Richard B; Curtis, David J; Harrison, Christine; Berx, Geert; Speleman, Frank; Meijerink, Jules P P; Soulier, Jean; Van Vlierberghe, Pieter; Haigh, Jody J

    2015-01-01

    Early T-cell precursor leukaemia (ETP-ALL) is a high-risk subtype of human leukaemia that is poorly understood at the molecular level. Here we report translocations targeting the zinc finger E-box-binding transcription factor ZEB2 as a recurrent genetic lesion in immature/ETP-ALL. Using a conditional gain-of-function mouse model, we demonstrate that sustained Zeb2 expression initiates T-cell leukaemia. Moreover, Zeb2-driven mouse leukaemia exhibit some features of the human immature/ETP-ALL gene expression signature, as well as an enhanced leukaemia-initiation potential and activated Janus kinase (JAK)/signal transducers and activators of transcription (STAT) signalling through transcriptional activation of IL7R. This study reveals ZEB2 as an oncogene in the biology of immature/ETP-ALL and paves the way towards pre-clinical studies of novel compounds for the treatment of this aggressive subtype of human T-ALL using our Zeb2-driven mouse model. PMID:25565005

  13. Epidemiological Evidence of Childhood Leukaemia Around Nuclear Power Plants

    PubMed Central

    Janiak, Marek K.

    2014-01-01

    A few reports of increased numbers of leukaemia cases (clusters) in children living in the vicinity of nuclear power plants (NPP) and other nuclear installations have triggered a heated debate over the possible causes of the disease. In this review the most important cases of childhood leukaemia clusters around NPPs are described and analyzed with special emphasis on the relationship between the environmental exposure to ionizing radiation and the risk of leukaemia. Since, as indicated, a lifetime residency in the proximity of an NPP does not pose any specific health risk to people and the emitted ionizing radiation is too small to cause cancer, a number of hypotheses have been proposed to explain the childhood leukaemia clusters. The most likely explanation for the clusters is ‘population mixing’, i.e., the influx of outside workers to rural regions where nuclear installations are being set up and where local people are not immune to pathogens brought along with the incomers. PMID:25249830

  14. Leukaemia cutis after starting bendamustine: cause or coincidence?

    PubMed

    Mawri, Sagger; Nabi, Shahzaib; Jallad, Bassel; Won, Joseph

    2015-01-01

    A 55-year-old man with a history of chronic lymphocytic leukaemia presented with diffuse skin lesions that began 1 week after starting a new chemotherapy regimen with bendamustine and rituximab. The lesions appeared as erythematous papules that were neither itchy nor tender, and did not blanch with pressure. Initially, they began on his scalp and flanks and, over the next few days, spread diffusely throughout his body, becoming darker in colour. Skin biopsy showed atypical clonal B-cell proliferation in a perivascular, periadnexal and dermal band-like distribution, which was further characterised by immunohistochemical evaluation. These findings were suggestive of leukaemia cutis and consistent with the patient's chronic lymphocytic leukaemia, which was previously confirmed by bone marrow biopsy. The bendamustine was stopped and the patient's chemotherapy regimen was switched to fludarabine, cyclophosphamide and rituximab. Shortly thereafter, the leukaemia cutis regressed significantly. PMID:26392439

  15. Acute myelomonocytic leukaemia presenting as xanthomatous skin eruption

    PubMed Central

    O'Donnell, JR; Tansey, P; Chung, P; Burnett, AK; Thomson, J; McDonald, GA

    1982-01-01

    A case of acute myelomonocytic leukaemia (AMMOL) is reported in which skin infiltration with xanthomatous nodules was the presenting feature. The histological, including ultrastructural, appearances are described. Images PMID:6958680

  16. Critical Perspectives on TEL: Art and Design Education, Theory, Communities and Space

    ERIC Educational Resources Information Center

    Sclater, Madeleine; Lally, Vic

    2016-01-01

    This paper explores three themes, emerging from the Inter-Life project, an Art and Design education and social skills project set in a virtual world. We argue that they connect with the concerns raised by critical Technology-Enhanced Learning (TEL) researchers at the Alpine Rendezvous workshop entitled "TEL: the Crisis and the Response."…

  17. Framework of Quality Assurance of TEL Integration into an Educational Organization

    ERIC Educational Resources Information Center

    Volungeviciene, Airina; Tereseviciene, Margarita; Tait, Alan

    2014-01-01

    This research paper addresses the issues of integration of technology enhanced learning (TEL) into an educational organization. Good practice experience cannot be directly transferred to new organisations due to different contextual conditions. The TEL integration depends significantly upon a very rapid development of services and information…

  18. Adult T-cell leukaemia lymphoma in an aborigine.

    PubMed

    Kirkland, M A; Frasca, J; Bastian, I

    1991-10-01

    A 44-year-old Aborigine with Adult T-cell Leukaemia/Lymphoma (ATLL) due to HTLV-I is reported. He presented with transverse myelitis of subacute onset, and subsequently developed frank T-cell leukaemia complicated by splenomegaly and hypercalcaemia. Cell surface marker studies showed a phenotype of CD3+ CD4+ CD8- CD25+, and serological and molecular studies confirmed HTLV-I infection. This is the first report of ATLL in an Australian Aborigine. PMID:1759923

  19. Immunotherapy in Chronic Lymphocytic Leukaemia (CLL).

    PubMed

    Freeman, Ciara L; Gribben, John G

    2016-02-01

    Chronic lymphocytic leukaemia (CLL) is well known to generate impaired immune responses in the host, with the malignant clone residing in well-vascularized tissues and circulating in peripheral blood but also in close proximity to effector cells that are capable, if activated appropriately, of eliciting a cytotoxic response. These, combined with the fact that this is frequently a condition affecting older patients with co-morbidities often unfit for many "traditional" cytotoxic agents with their significant associated toxicities, make CLL an ideal candidate for the development of immunotherapy. The impressive results seen with the addition of a monoclonal antibody, rituximab, to a chemotherapy backbone, for example, is testament to how effective harnessing an immune-mediated response in CLL can be. This review serves to outline the available arsenal of immunotherapies-past and present-demonstrated to have potential in CLL with some perspectives on how the landscape in this disease may evolve in the future. PMID:26857283

  20. Sexuality of young women surviving leukaemia

    PubMed Central

    Puukko, L; Hirvonen, E; Aalberg, V; Hovi, L; Rautonen, J; Siimes, M

    1997-01-01

    Accepted 7 December 1996
 This study was designed to assess the sexuality of young women surviving acute leukaemia in childhood or early adolescence. Thirty of 31 survivors were compared with 50 healthy age matched controls. Three methods were used: a self report questionnaire, a face to face interview conducted by a psychiatrist, and a projective psychological test. The age at initiation of dating and sexual activity, the frequency of sexual intercourse, and opinions on sexual behaviour were similar in the two groups. With regard to inner sexuality, however, the survivors differed significantly from the healthy controls. Their images of sexuality were more restrictive, and their attitudes, especially those concerning sexual pleasure, were more negative than those of the controls. Sexual identity among the survivors was less often feminine and more often infantile as compared with the controls. The findings obtained with the three methods of assessment were concordant.

 PMID:9135258

  1. Incidence of childhood leukaemia in The Netherlands (1973-1980).

    PubMed Central

    van Steensel-Moll, H. A.; Valkenburg, H. A.; van Zanen, G. E.

    1983-01-01

    The childhood leukaemia incidence rate for the Netherlands was estimated at 3.11 per 100.000 children (aged 0-15 year) per year, based on a complete nation-wide childhood leukaemia registry comprising the period 1973-1980. Acute lymphocytic leukaemia (ALL) accounted for 82.4% of the patients, acute non-lymphocytic leukaemia for 13.6% and chronic myeloid leukaemia for 2.9%. ALL occurred more frequently in boys (sex ratio 1.2). The highest ALL rate was observed in the 3-4 year age group. These figures corresponded with the data of the Manchester Children's Tumour Registry. Neither the incidence rates according to year of diagnosis nor the incidence rates according to year of birth showed a significant trend with time. The total leukaemia incidence rate in urban areas was somewhat higher than in rural areas. While the direct comparison of the incidence rate between these areas is not significant, the trend over the three categories of urbanisation is significant. PMID:6573905

  2. Leukaemia incidence in the Techa River Cohort: 1953–2007

    PubMed Central

    Krestinina, L Y; Davis, F G; Schonfeld, S; Preston, D L; Degteva, M; Epifanova, S; Akleyev, A V

    2013-01-01

    Background: Little is known about leukaemia risk following chronic radiation exposures at low dose rates. The Techa River Cohort of individuals residing in riverside villages between 1950 and 1961 when releases from the Mayak plutonium production complex contaminated the river allows quantification of leukaemia risks associated with chronic low-dose-rate internal and external exposures. Methods: Excess relative risk models described the dose–response relationship between radiation dose on the basis of updated dose estimates and the incidence of haematological malignancies ascertained between 1953 and 2007 among 28 223 cohort members, adjusted for attained age, sex, and other factors. Results: Almost half of the 72 leukaemia cases (excluding chronic lymphocytic leukaemia (CLL)) were estimated to be associated with radiation exposure. These data are consistent with a linear dose response with no evidence of modification. The excess relative risk estimate was 0.22 per 100 mGy. There was no evidence of significant dose effect for CLL or other haematopoietic malignancies. Conclusion: These analyses demonstrate that radiation exposures, similar to those received by populations exposed as a consequence of nuclear accidents, are associated with long-term dose-related increases in leukaemia risks. Using updated dose estimates, the leukaemia risk per unit dose is about half of that based on previous dosimetry. PMID:24129230

  3. Hoyeraal-Hreidarsson syndrome caused by a germline mutation in the TEL patch of the telomere protein TPP1.

    PubMed

    Kocak, Hande; Ballew, Bari J; Bisht, Kamlesh; Eggebeen, Rebecca; Hicks, Belynda D; Suman, Shalabh; O'Neil, Adri; Giri, Neelam; Maillard, Ivan; Alter, Blanche P; Keegan, Catherine E; Nandakumar, Jayakrishnan; Savage, Sharon A

    2014-10-01

    Germline mutations in telomere biology genes cause dyskeratosis congenita (DC), an inherited bone marrow failure and cancer predisposition syndrome. DC is a clinically heterogeneous disorder diagnosed by the triad of dysplastic nails, abnormal skin pigmentation, and oral leukoplakia; Hoyeraal-Hreidarsson syndrome (HH), a clinically severe variant of DC, also includes cerebellar hypoplasia, immunodeficiency, and intrauterine growth retardation. Approximately 70% of DC cases are associated with a germline mutation in one of nine genes, the products of which are all involved in telomere biology. Using exome sequencing, we identified mutations in Adrenocortical Dysplasia Homolog (ACD) (encoding TPP1), a component of the telomeric shelterin complex, in one family affected by HH. The proband inherited a deletion from his father and a missense mutation from his mother, resulting in extremely short telomeres and a severe clinical phenotype. Characterization of the mutations revealed that the single-amino-acid deletion affecting the TEL patch surface of the TPP1 protein significantly compromises both telomerase recruitment and processivity, while the missense mutation in the TIN2-binding region of TPP1 is not as clearly deleterious to TPP1 function. Our results emphasize the critical roles of the TEL patch in proper stem cell function and demonstrate that TPP1 is the second shelterin component (in addition to TIN2) to be implicated in DC. PMID:25233904

  4. Tel2 structure and function in the Hsp90-dependent maturation of mTOR and ATR complexes

    SciTech Connect

    Takai, Hiroyuki; Xie, Yihu; de Lange, Titia; Pavletich, Nikola P.

    2010-09-20

    We reported previously that the stability of all mammalian phosphatidylinositol 3-kinase-related protein kinases (PIKKs) depends on their interaction with Tel2, the ortholog of yeast Tel2 and Caenorhabditis elegans Clk-2. Here we provide evidence that Tel2 acts with Hsp90 in the maturation of PIKK complexes. Quantitative immunoblotting showed that the abundance of Tel2 is low compared with the PIKKs, and Tel2 preferentially bound newly synthesized ATM, ATR, mTOR, and DNA-PKcs. Tel2 complexes contained, in addition to Tti1-Tti2, the Hsp90 chaperone, and inhibition of Hsp90 interfered with the interaction of Tel2 with the PIKKs. Analysis of in vivo labeled nascent protein complexes showed that Tel2 and Hsp90 mediate the formation of the mTOR TORC1 and TORC2 complexes and the association of ATR with ATRIP. The structure of yeast Tel2, reported here, shows that Tel2 consists of HEAT-like helical repeats that assemble into two separate {alpha}-solenoids. Through mutagenesis, we identify a surface patch of conserved residues involved in binding to the Tti1-Tti2 complex in vitro. In vivo, mutation of this conserved patch affects cell growth, levels of PIKKs, and ATM/ATR-mediated checkpoint signaling, highlighting the importance of Tti1-Tti2 binding to the function of Tel2. Taken together, our data suggest that the Tel2-Tti1-Tti2 complex is a PIKK-specific cochaperone for Hsp90.

  5. Mortality from brain cancer and leukaemia among electrical workers.

    PubMed Central

    Loomis, D P; Savitz, D A

    1990-01-01

    The relation of brain cancer and mortality from leukaemia to electrical occupations was investigated in a case-control study based on all deaths in 1985 and 1986 in the 16 states in the United States that report occupational data from death certificates to the national vital statistics registry. The case series comprised all 2173 men who died of primary brain cancer (International Classification of Diseases-9 ((ICD-9) code 191) and all 3400 who died of leukaemia (ICD-9 codes 204-208). Each was matched with 10 controls who died of other causes in the same year. Men employed in any electrical occupation had age race adjusted odds ratios (ORs) of 1.4 (95% confidence interval (CI) 1.1-1.7) for brain cancer and 1.0 (95% CI 0.8-1.2) for leukaemia, compared with men in all other occupations. Brain cancer odds ratios were larger for electrical engineers and technicians (OR 2.7, 95% CI 2.1-3.4), telephone workers (OR 1.6, 95% CI 1.1-2.4), electric power workers (OR 1.7, 95% CI 1.1-2.7), and electrical workers in manufacturing industries (OR 2.1, 95% CI 1.3-3.4). There was some evidence of excess leukaemia among the same groups (ORs of 1.1-1.5) despite absence of an association for all electrical workers. The excess of deaths from brain cancer was concentrated among men aged 65 or older, whereas leukaemia was associated with electrical work only among younger decedents and those with acute lymphocytic leukaemia. These results from a large and geographically diverse population corroborate reports of increased mortality from brain cancer among electrical workers, but gives only limited support to suggestions of excess deaths from leukaemia. PMID:2207035

  6. Maternal and birth characteristics in relation to childhood leukaemia.

    PubMed

    Podvin, Danise; Kuehn, Carrie M; Mueller, Beth A; Williams, Michelle

    2006-07-01

    Our objective was to investigate the association of childhood leukaemia with selected maternal and birth characteristics by conducting a population-based case-control study using linked cancer registry and birth certificate records for Washington State. We compared maternal and infant characteristics of 595 Washington-born residents <20 years old with leukaemia diagnosed during 1981-2003, and 5,950 control children, using stratified analysis and logistic regression. Maternal age 35+ years (odds ratio [OR] 1.5; 95% confidence interval [CI] 1.1, 2.0), infant birthweight 4,000+ g (OR 1.4; 95% CI 1.1, 1.8), neonatal jaundice (OR 1.5; 95% CI 1.1, 2.1), and Down's syndrome (OR 31.3; 95% CI 6.4, 153.4) were associated with an increased risk of leukaemia. Among women with 2+ pregnancies, having at least two prior early (<20 weeks' gestation) fetal deaths was also associated with an increased risk (OR 1.5; 95% CI 0.97, 2.1). Maternal unmarried status (OR 0.7; 95% CI 0.6, 0.9) and African American race (OR 0.5; 95% CI 0.3, 0.9) were associated with a decreased risk. These results were more marked for acute lymphocytic leukaemia (ALL) than for acute myeloid leukaemia (AML), and for leukaemia diagnosed <5 years of age. These results may provide clues to the aetiology of childhood leukaemia. Genetic epidemiological studies are needed to expand our knowledge of inherent and possibly prenatal influences on the occurrence of this disease. PMID:16879503

  7. Mixed lineage leukaemia histone methylases 1 collaborate with ERα to regulate HOXA10 expression in AML

    PubMed Central

    Yao, Jie; Fang, Li-Chao; Yang, Zai-Lin; Huang, Hui; Li, Yan; Deng, Jun; Zheng, Junsong

    2014-01-01

    HOXA10, a homeobox-containing gene involved in definitive haematopoiesis, which implicated in the pathogenesis of AML (acute myeloid leukaemia), has been studied extensively. But the regulatory mechanism that drives HOXA10 expression is still unclear. In the present paper, HOXA10 regulated by MLL1 (mixed lineage leukaemia histone methylase 1) with an epigenetic way has been demonstrated. The HOXA10 promoter contains several EREs (oestrogen response elements), including ERE1 and ERE2, which are close to the transcription start site, and are associated with E2-mediated activation of HOXA10. It has been shown that knockdown of the ERα (oestrogen receptor α) suppresses E2-mediated activation of HOXA10. Similarly, knockdown of MLL1 suppresses activation of HOXA10 and is bound to the ERE of HOXA10 promoter in an E2-dependent manner by forming complex with ERα. Knockdown of ERα affects the E2-dependent binding of MLL1 into HOXA10 EREs, suggesting critical roles of ERα in recruiting MLL on the HOXA10 promoter. More interestingly, the methylation status of histone protein H3K4 (H3 at lysine 4) with E2 is much higher than without E2 treatment in leukaemia cell. On the contrary, the methylation status of HOXA10 promoter with E2 treatment is much lower, which elevate the HOXA10 expression. Moreover, with ERα knockdown, the H3K4 methylation level is also decrease in myeloid cell. Overall, it has been clearly demonstrated that HOXA10 is transcriptionally regulated by MLL1, which, in coordination with ERα, plays a critical role in this process with epigenetic way and suggests a potential anti-E2 treatment of AML. PMID:25307539

  8. Heterogeneity of T cell lymphoblastic leukaemias.

    PubMed Central

    Gómez, E; San Miguel, J F; González, M; Orfao, A; López-Berges, C; Ríos, A; López Borrasca, A

    1991-01-01

    Twenty eight out of 170 consecutive cases of acute lymphoblastic leukaemia (ALL) were examined. They were of T cell origin, with the following distribution: seven (28%) cases had pre-T or prothymic features; nine (36%) cases showed early thymocytic features, six (24%) had cortical features; and three (12%) had a "mature" phenotype. The remaining three cases could not be sub-classified. A striking finding was that pre-T ALL differed from intrathymic ALL not only in the absence of both E rosettes and intrathymic differentiation antigens, but also in the expression of two non-lineage specific antigens HLA-DR and CD10. Both antigens appear in the bone marrow from the very first stages of lymphoid differentiation, implying that the origin for pre-T ALL is bone marrow. A comparison of the clinical features of pre-T and thymic ALL showed that pre-T ALL disease showed a pattern more similar to non-T ALL disease: a lower incidence of mediastinal mass, absence of extrahaematopoietic disease, lower white cell counts and haemoglobin concentrations, and a higher incidence of bone pain. No obvious difference in response to treatment was apparent. The results show that T-ALL is not only a heterogeneous immunological group but also suggest that it may have different origins: bone marrow for pre-T ALL and the thymus for thymic ALL. PMID:1890194

  9. Molecular therapy for acute myeloid leukaemia.

    PubMed

    Coombs, Catherine C; Tallman, Martin S; Levine, Ross L

    2016-05-01

    Acute myeloid leukaemia (AML) is a heterogeneous disease that is, in general, associated with a very poor prognosis. Multiple cytogenetic and molecular abnormalities that characterize different forms of AML have been used to better prognosticate patients and inform treatment decisions. Indeed, risk status in patients with this disease has classically been based on cytogenetic findings; however, additional molecular characteristics have been shown to inform risk assessment, including FLT3, NPM1, KIT, and CEBPA mutation status. Advances in sequencing technology have led to the discovery of novel somatic mutations in tissue samples from patients with AML, providing deeper insight into the mutational landscape of the disease. The majority of patients with AML (>97%) are found to have a clonal somatic abnormality on mutational profiling. Nevertheless, our understanding of the utility of mutation profiling in clinical practice remains incomplete and is continually evolving, and evidence-based approaches to application of these data are needed. In this Review, we discuss the evidence-base for integrating mutational data into treatment decisions for patients with AML, and propose novel therapeutic algorithms in the era of molecular medicine. PMID:26620272

  10. Epidemiology of chronic myeloid leukaemia: an update.

    PubMed

    Höglund, Martin; Sandin, Fredrik; Simonsson, Bengt

    2015-04-01

    National and regional population-based registries are, provided diagnostic accuracy and full coverage of the target population, indispensible tools for epidemiological research. Chronic myeloid leukaemia (CML) registries with more comprehensive reporting may also provide complementary data on treatment outcome to those obtained from clinical trials. Reports from several European CML registries consistently show a crude annual incidence of 0.7-1.0/100,000, a median age at diagnosis of 57-60 years and a male/female ratio of 1.2-1.7. The incidence of CML has been stable over time. Worldwide, variations in the reported incidence of CML may be due to methodological issues, but a true difference between different geographical areas and/or ethnical subgroups cannot be excluded. The prevalence of CML is not well known but has been estimated to be 10-12/100,000 inhabitants with a steady increase due to the dramatic improvement in survival of these patients. In recent population-based studies, CML patients have an overall survival that is comparable to that shown in large clinical trials, though relative survival in patients >70 years is still decreased. The importance of socio-economic factors and health-care setting for outcome and the possible increased risk of secondary cancer in CML are areas of ongoing research. PMID:25814090

  11. Structural studies on leukaemia inhibitory factor

    SciTech Connect

    Norton, R.S.; Maurer, T.; Smith, D.K.; Nicola, N.A.

    1994-12-01

    Leukaemia Inhibitory Factor (LIF) is a pleiotropic cytokine that acts on a wide range of target cells, including mega-karyocytes, osteoblasts, hepatocytes, adipocytes, neurons, embryonic stem cells, and primordial germ cells. Many of its activities are shared with other cytokines, particularly interleukin-6, oncostatin-M, ciliary neurotrophic factor, and granulocyte colony-stimulating factor (G-CSF). Although secreted in vivo as a glycoprotein, nonglycosylated recombinant protein expressed in E. coli is fully active and has been used in our nuclear magnetic resonance (NMR) studies of the three-dimensional structure and structure-function relationships of LIF. With 180 amino acids and a molecular mass of about 20 kDa, OF is too large for direct structure determination by two-dimensional and three-dimensional {sup 1}HNMR. It is necessary to label the protein with the stable isotopes {sup 15}N and {sup 13}C and employ heteronuclear three-dimensional NMR in order to resolve and interpret the spectral information required for three-dimensional structure determination. This work has been undertaken with both human LIF and a mouse-human chimaera that binds to the human LIF receptor with the same affinity as the human protein and yet expresses in E. coli at much higher levels. Sequence-specific resonance assignments and secondary structure elements for these proteins will be presented and progress towards determination of their three-dimensional structures described.

  12. Use and reported effectiveness of Tel-Med: a telephone health information system.

    PubMed Central

    Diseker, R A; Michielutte, R; Morrison, V

    1980-01-01

    In January 1977, a Telephone Information System (Tel-Med) was begun in Winston-Salem, North Carolina. A survey was conducted to determine how Tel-Med was meeting the community's need for health information and to see if program objectives were being met. Respondents in 3,005 randomly selected households were interviewed by telephone to determine user characteristics, user motivation, action taken, knowledge and information gained, and system improvements. A key finding indicated that larger percentages of adults with lower income and educational levels were not aware of the service than were the adults in upper income and educational levels. However, income and education are not related to use of Tel-Med among individuals who know of this service. This finding suggests that the poorer and lesser educated would use Tel-Med in a way similar to that of their more fortunate peers if efforts were made to inform them of the service. PMID:7356084

  13. Whole genome sequence of Oscheius sp. TEL-2014 entomopathogenic nematodes isolated from South Africa

    PubMed Central

    Lephoto, Tiisetso E.; Mpangase, Phelelani T.; Aron, Shaun; Gray, Vincent M.

    2016-01-01

    We present the annotation of the draft genome sequence of Oscheius sp. TEL-2014 (Genbank accession number KM492926). This entomopathogenic nematode was isolated from grassland in Suikerbosrand Nature Reserve near Johannesburg in South Africa. Oscheius sp. Strain TEL has a genome size of 110,599,558 bp and a GC content of 42.24%. The genome sequence can be accessed at DDBJ/EMBL/GenBank under the accession number LNBV00000000. PMID:27054091

  14. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia

    PubMed Central

    Irvine, David A.; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L.; Moka, Hothri A.; Ho, Yinwei; Nixon, Colin; Manley, Paul W.; Wheadon, Helen; Goodlad, John R.; Holyoake, Tessa L.; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34+ CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34+ CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34+ CP-CML cell engraftment in NSG mice and, upon administration to EGFP+ /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  15. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation.

    PubMed

    Steffen, Leta S; Bacher, Jeffery W; Peng, Yuanlin; Le, Phuong N; Ding, Liang-Hao; Genik, Paula C; Ray, F Andrew; Bedford, Joel S; Fallgren, Christina M; Bailey, Susan M; Ullrich, Robert L; Weil, Michael M; Story, Michael D

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML. PMID:22987027

  16. Molecular characterisation of murine acute myeloid leukaemia induced by 56Fe ion and 137Cs gamma ray irradiation

    PubMed Central

    Bacher, Jeffery W.

    2013-01-01

    Exposure to sparsely ionising gamma- or X-ray irradiation is known to increase the risk of leukaemia in humans. However, heavy ion radiotherapy and extended space exploration will expose humans to densely ionising high linear energy transfer (LET) radiation for which there is currently no understanding of leukaemia risk. Murine models have implicated chromosomal deletion that includes the hematopoietic transcription factor gene, PU.1 (Sfpi1), and point mutation of the second PU.1 allele as the primary cause of low-LET radiation-induced murine acute myeloid leukaemia (rAML). Using array comparative genomic hybridisation, fluorescence in situ hybridisation and high resolution melt analysis, we have confirmed that biallelic PU.1 mutations are common in low-LET rAML, occurring in 88% of samples. Biallelic PU.1 mutations were also detected in the majority of high-LET rAML samples. Microsatellite instability was identified in 42% of all rAML samples, and 89% of samples carried increased microsatellite mutant frequencies at the single-cell level, indicative of ongoing instability. Instability was also observed cytogenetically as a 2-fold increase in chromatid-type aberrations. These data highlight the similarities in molecular characteristics of high-LET and low-LET rAML and confirm the presence of ongoing chromosomal and microsatellite instability in murine rAML. PMID:22987027

  17. Deregulated hedgehog pathway signaling is inhibited by the smoothened antagonist LDE225 (Sonidegib) in chronic phase chronic myeloid leukaemia.

    PubMed

    Irvine, David A; Zhang, Bin; Kinstrie, Ross; Tarafdar, Anuradha; Morrison, Heather; Campbell, Victoria L; Moka, Hothri A; Ho, Yinwei; Nixon, Colin; Manley, Paul W; Wheadon, Helen; Goodlad, John R; Holyoake, Tessa L; Bhatia, Ravi; Copland, Mhairi

    2016-01-01

    Targeting the Hedgehog (Hh) pathway represents a potential leukaemia stem cell (LSC)-directed therapy which may compliment tyrosine kinase inhibitors (TKIs) to eradicate LSC in chronic phase (CP) chronic myeloid leukaemia (CML). We set out to elucidate the role of Hh signaling in CP-CML and determine if inhibition of Hh signaling, through inhibition of smoothened (SMO), was an effective strategy to target CP-CML LSC. Assessment of Hh pathway gene and protein expression demonstrated that the Hh pathway is activated in CD34(+) CP-CML stem/progenitor cells. LDE225 (Sonidegib), a small molecule, clinically investigated SMO inhibitor, used alone and in combination with nilotinib, inhibited the Hh pathway in CD34(+) CP-CML cells, reducing the number and self-renewal capacity of CML LSC in vitro. The combination had no effect on normal haemopoietic stem cells. When combined, LDE225 + nilotinib reduced CD34(+) CP-CML cell engraftment in NSG mice and, upon administration to EGFP(+) /SCLtTA/TRE-BCR-ABL mice, the combination enhanced survival with reduced leukaemia development in secondary transplant recipients. In conclusion, the Hh pathway is deregulated in CML stem and progenitor cells. We identify Hh pathway inhibition, in combination with nilotinib, as a potentially effective therapeutic strategy to improve responses in CP-CML by targeting both stem and progenitor cells. PMID:27157927

  18. Leukaemia cell of origin identified by chromatin landscape of bulk tumour cells.

    PubMed

    George, Joshy; Uyar, Asli; Young, Kira; Kuffler, Lauren; Waldron-Francis, Kaiden; Marquez, Eladio; Ucar, Duygu; Trowbridge, Jennifer J

    2016-01-01

    The precise identity of a tumour's cell of origin can influence disease prognosis and outcome. Methods to reliably define tumour cell of origin from primary, bulk tumour cell samples has been a challenge. Here we use a well-defined model of MLL-rearranged acute myeloid leukaemia (AML) to demonstrate that transforming haematopoietic stem cells (HSCs) and multipotent progenitors results in more aggressive AML than transforming committed progenitor cells. Transcriptome profiling reveals a gene expression signature broadly distinguishing stem cell-derived versus progenitor cell-derived AML, including genes involved in immune escape, extravasation and small GTPase signal transduction. However, whole-genome profiling of open chromatin reveals precise and robust biomarkers reflecting each cell of origin tested, from bulk AML tumour cell sampling. We find that bulk AML tumour cells exhibit distinct open chromatin loci that reflect the transformed cell of origin and suggest that open chromatin patterns may be leveraged as prognostic signatures in human AML. PMID:27397025

  19. Genetic Aberrations in Childhood Acute Lymphoblastic Leukaemia: Application of High-Density Single Nucleotide Polymorphism Array

    PubMed Central

    Sulong, Sarina

    2010-01-01

    Screening of the entire human genome using high-density single nucleotide polymorphism array (SNPA) has become a powerful technique used in cancer genetics and population genetics studies. The GeneChip® Mapping Array, introduced by Affymetrix, is one SNPA platform utilised for genotyping studies. This GeneChip system allows researchers to gain a comprehensive view of cancer biology on a single platform for the quantification of chromosomal amplifications, deletions, and loss of heterozygosity or for allelic imbalance studies. Importantly, this array analysis has the potential to reveal novel genetic findings involved in the multistep development of cancer. Given the importance of genetic factors in leukaemogenesis and the usefulness of screening the whole genome, SNPA analysis has been utilised in many studies to characterise genetic aberrations in childhood acute lymphoblastic leukaemia. PMID:22135543

  20. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation.

    PubMed

    Hartmann, Luise; Dutta, Sayantanee; Opatz, Sabrina; Vosberg, Sebastian; Reiter, Katrin; Leubolt, Georg; Metzeler, Klaus H; Herold, Tobias; Bamopoulos, Stefanos A; Bräundl, Kathrin; Zellmeier, Evelyn; Ksienzyk, Bianka; Konstandin, Nikola P; Schneider, Stephanie; Hopfner, Karl-Peter; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Middeke, Jan Moritz; Stölzel, Friedrich; Thiede, Christian; Wolf, Stephan; Bohlander, Stefan K; Preiss, Caroline; Chen-Wichmann, Linping; Wichmann, Christian; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E; Wörmann, Bernhard J; Braess, Jan; Hiddemann, Wolfgang; Spiekermann, Karsten; Greif, Philipp A

    2016-01-01

    The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. PMID:27252013

  1. ZBTB7A mutations in acute myeloid leukaemia with t(8;21) translocation

    PubMed Central

    Hartmann, Luise; Dutta, Sayantanee; Opatz, Sabrina; Vosberg, Sebastian; Reiter, Katrin; Leubolt, Georg; Metzeler, Klaus H.; Herold, Tobias; Bamopoulos, Stefanos A.; Bräundl, Kathrin; Zellmeier, Evelyn; Ksienzyk, Bianka; Konstandin, Nikola P.; Schneider, Stephanie; Hopfner, Karl-Peter; Graf, Alexander; Krebs, Stefan; Blum, Helmut; Middeke, Jan Moritz; Stölzel, Friedrich; Thiede, Christian; Wolf, Stephan; Bohlander, Stefan K.; Preiss, Caroline; Chen-Wichmann, Linping; Wichmann, Christian; Sauerland, Maria Cristina; Büchner, Thomas; Berdel, Wolfgang E.; Wörmann, Bernhard J.; Braess, Jan; Hiddemann, Wolfgang; Spiekermann, Karsten; Greif, Philipp A.

    2016-01-01

    The t(8;21) translocation is one of the most frequent cytogenetic abnormalities in acute myeloid leukaemia (AML) and results in the RUNX1/RUNX1T1 rearrangement. Despite the causative role of the RUNX1/RUNX1T1 fusion gene in leukaemia initiation, additional genetic lesions are required for disease development. Here we identify recurring ZBTB7A mutations in 23% (13/56) of AML t(8;21) patients, including missense and truncating mutations resulting in alteration or loss of the C-terminal zinc-finger domain of ZBTB7A. The transcription factor ZBTB7A is important for haematopoietic lineage fate decisions and for regulation of glycolysis. On a functional level, we show that ZBTB7A mutations disrupt the transcriptional repressor potential and the anti-proliferative effect of ZBTB7A. The specific association of ZBTB7A mutations with t(8;21) rearranged AML points towards leukaemogenic cooperativity between mutant ZBTB7A and the RUNX1/RUNX1T1 fusion. PMID:27252013

  2. Central nervous system haemorrhage causing early death in acute promyelocytic leukaemia

    PubMed Central

    Borowska, Anna; Stelmaszczyk-Emmel, Anna

    2016-01-01

    Acute promyelocytic leukaemia (APL) is a rare type of paediatric leukaemia characterised by a specific genetic mutation and life-threatening coagulopathy. The discovery of all-trans retinoic acid (ATRA), which acts directly on promyelocytic locus-retinoic acid receptor α (PML-RARα) gene product, brought a revolution to the therapy of this disorder. Unfortunately, despite an improvement in the complete remission rate, the early death (ED) rate has not changed significantly, and the haemorrhages remain a major problem. The most common bleeding site, which accounts for about 65-80% of haemorrhages, is the central nervous system. Second in line are pulmonary haemorrhages (32%), while gastrointestinal bleedings are relatively rare. Haemorrhages result from thrombocytopaenia, disseminated intravascular coagulopathy (DIC), and systemic fibrinolysis. Herein we present a boy aged one year and nine months with APL. The patient was not eligible for ATRA administration due to poor clinical condition. He developed bleeding diathesis that presented as disseminated intravascular coagulation (DIC) and led to intracranial haemorrhage, which resulted in the patient's death. PMID:26862315

  3. TelEMA: a low-cost and user-friendly telephone assessment platform.

    PubMed

    Fernandez, Katya C; Johnson, Matthew R; Rodebaugh, Thomas L

    2013-12-01

    Ecological momentary assessment (EMA), or the repeated assessment of individuals' behaviors and experiences over time, is a methodologically advantageous approach to the study of psychological constructs. Recently, advances in computer technology have allowed for EMA research to be conducted in a more convenient, automated, and secure manner by administering surveys on participants' telephones and storing the results directly to a central server. The present article introduces TelEMA, an easy-to-use, low-cost telephone assessment platform for clinical and research applications. A single server running TelEMA can be shared among many experimenters, studies, and participants simultaneously. TelEMA routes telephone calls and text messages through a third-party service, so experimenters may conduct studies with no up-front cost or technical expertise. TelEMA provides a secure Web interface for experimenters or clinicians to design studies, enroll participants, monitor compliance, and collate response data from anywhere. Participants complete surveys using their own telephones. Surveys may contain keypress or voice recording questions, and the timing and content of each survey may be randomized and customized. A pilot study was conducted in which individuals used the TelEMA system to complete four randomly timed surveys per day for one week; the surveys assessed state affect and social anxiety. Results indicated that participants found TelEMA easy to use and secure, and compliance rates were on par with other EMA methods using mobile devices. Overall, TelEMA is a practical and robust system that enables fast and inexpensive deployment of EMAs. PMID:23239075

  4. Plasma fibronectin deficiency during chemotherapy of acute myeloid leukaemia.

    PubMed

    Brodin, B; Liedén, G; Malm, C; Vikrot, O

    1983-03-01

    Plasma fibronectin was determined using a laser nephelometric method in 10 patients with acute myeloid leukaemia undergoing chemotherapy. There was a continuous fall during the first 3 weeks to about 50% of the normal level. The decrease of fibronectin may contribute to the lowered resistance against infection characteristic of these patients. PMID:6574587

  5. Pulmonary function after treatment for acute lymphoblastic leukaemia in childhood.

    PubMed Central

    Nysom, K.; Holm, K.; Olsen, J. H.; Hertz, H.; Hesse, B.

    1998-01-01

    The aim of this study was to examine pulmonary function after acute lymphoblastic leukaemia in childhood and identify risk factors for reduced pulmonary function. We studied a population-based cohort of 94 survivors of acute lymphoblastic leukaemia in childhood who were in first remission after treatment without spinal irradiation or bone marrow transplantation. Pulmonary function test results were compared with reference values for our laboratory, based on 348 healthy subjects who had never smoked from a local population study. A median of 8 years after cessation of therapy (range 1-18 years) the participants had a slight, subclinical, restrictive ventilatory insufficiency and reduced transfer factor and transfer coefficient. The changes in lung function were related to younger age at treatment and to more dose-intensive treatment protocols that specified more use of cranial irradiation and higher cumulative doses of anthracyclines, cytosine arabinoside and intravenous cyclophosphamide than previous protocols. We conclude that, 8 years after treatment without bone marrow transplantation or spinal irradiation, survivors of childhood acute lymphoblastic leukaemia in first remission were without pulmonary symptoms but had signs of slight restrictive pulmonary disease including reduced transfer factor. The increased dose intensity of many recent protocols for childhood acute lymphoblastic leukaemia may lead to increased late pulmonary toxicity. PMID:9662245

  6. Immunological and ultrastructural studies in acute biphenotypic leukaemia.

    PubMed Central

    Shetty, V; Chitale, A; Matutes, E; Buccheri, V; Morilla, R; Catovsky, D

    1993-01-01

    AIMS--To compare the sensitivity of the ultrastructural method to detect myeloperoxidase (MPO) with light microscopy and immunocytochemistry using an anti-MPO antibody; to examine the expression of lymphoid antigens in relation to MPO activity in blast cells from cases of biphenotypic leukaemia. METHODS--Blast cells from 14 cases of biphenotypic acute leukaemia were analysed. Immunological markers were performed by single or double immunofluorescence staining on a flow cytometer. The presence of MPO was determined by light microscopy, electron microscopy on fixed and unfixed cells, and by immunoalkaline phosphatase with an anti-MPO antibody. The immunogold method was applied at the ultrastructural level to assess the expression of lymphoid and myeloid antigens at the same time as the MPO activity. RESULTS--Six of the 14 cases were initially classified as acute lymphoblastic leukaemia (ALL) and eight as acute myeloid leukaemia (AML). MPO activity was shown at the ultrastructural level in 4-99% blasts from all cases. Six of the 14 were MPO negative by light microscopy and three of these were negative with the antibody anti-MPO. Coexpression of lymphoid antigens (CD19, CD10, or CD2) and MPO was shown by the immunogold method in four out of 11 cases; in seven cases the blasts coexpressed myeloid antigens (CD13, CD33) and MPO. CONCLUSIONS--Electron microscopy is more sensitive for showing MPO than light microscopy and immunocytochemistry; the immunogold method combined with MPO used at the ultrastructural level can help to define the cell lineage involved in biphenotypic leukaemia by highlighting the myeloid component defined by MPO. Images PMID:8227405

  7. Time Trends and Geographical Distribution of Childhood Leukaemia in Basrah, Iraq, from 2004 to 2009

    PubMed Central

    Alrudainy, Laith A; Hassan, Jenan G; Salih, Hussam M; Abbas, Mohammed K; Majeed, Athar AS

    2011-01-01

    Objectives: This study aimed to assess the incidence and trend of childhood leukaemia in Basrah. Methods: This was a hospital-based cancer registry study carried out at the Pediatric Oncology Ward, Maternity & Children’s Hospital and other institutes in Basrah, Iraq. All children with leukaemia, aged 0 to 14 years diagnosed and registered in Basrah from January 2004 to December 2009 were included in the study. Their records were retrieved and studied. The pattern of childhood leukaemia by year of diagnosis, age at diagnosis, morphological subtypes, and geographical distribution was analysed. Rates of childhood leukaemia over time were calculated for six years using standard linear regression. Results: The total number of cases of childhood leukaemia was 181. The number of cases ranged from 21 in year 1, to 31 in the final year reaching a peak of 39 in 2006. Leukaemia rates did not change over the study period (test for trend was not significant, P = 0.81). The trend line shows a shift towards younger children (less than 5 years). The commonest types of leukaemia were acute lymphoblastic leukaemia (ALL), then acute myeloid leukaemia (AML) and finally chronic myeloid leukaemia (CML). Conclusion: Annual rates of childhood leukaemia in Basrah were similar to those in other countries with a trend towards younger children. This raises the question about the effect of environmental catastrophes in the alteration of some specific rates of childhood leukaemia, rather than the overall incidence rate. There is a need for further epidemiological studies to understand the aetiology of childhood leukaemia in Basrah. PMID:21969893

  8. Radiation measurement platform for balloon flights based on the TriTel silicon detector telescope

    NASA Astrophysics Data System (ADS)

    Zabori, Balazs; Hirn, Attila; Pazmandi, Tamas; Apathy, Istvan; Szanto, Peter; Deme, Sandor

    Several measurements have been performed on the cosmic radiation field from the surface of the Earth up to the maximum altitudes of research airplanes. However the cosmic radiation field is not well known between 15 km and 30 km. Our experiment idea based on to study the radiation environment in the stratosphere. The main technical goals of our experiment were to test at first time the TriTel 3D silicon detector telescope system for future ISS missons and to develop a balloon technology platform for advanced cosmic radiation and dosimetric measurements. The main scientific goals were to give an assessment of the cosmic radiation field at the altitude of the BEXUS balloons, to use the TriTel system to determine dosimetric and radiation quantities during the ballon flight and to intercompare the TriTel and Pille results to provide a correction factor definition method for the Pille ISS measurements. To fulfil the scientific and technological objectives several different dosimeter systems were included in the experiment: an advanced version of the TriTel silicon detector telescope, Geiger-Müller counters, Pille passive thermoluminescent dosimeters and Solid State Nuclear Track Detectors. The experiment was built by students from Hungarian universities and flew on board the BEXUS stratospheric balloon in Northern Sweden (from ESRANGE Space Center). The float altitude was approximately 28.6 km and the total flight time was about 4 hours. The active instruments measured in real time and the ground team received the collected data continuously during the mission. The main technical goals were received since the operation of the TriTel experienced no failures and the experiment worked as it expected. This paper presents the scientific goals and results. From the TriTel measurements the deposited energy spectra, the Linear Energy Transfer spectra, the average quality factor of the cosmic radiation as well as the absorbed dose and the dose equivalent were determined for the

  9. Managing pregnancy in chronic myeloid leukaemia.

    PubMed

    Palani, Renuka; Milojkovic, Dragana; Apperley, Jane F

    2015-04-01

    Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the

  10. Phase I/II study of vaccination with dendritic-like leukaemia cells for the immunotherapy of acute myeloid leukaemia.

    PubMed

    Roddie, H; Klammer, M; Thomas, C; Thomson, R; Atkinson, A; Sproul, A; Waterfall, M; Samuel, K; Yin, J; Johnson, P; Turner, M

    2006-04-01

    Twenty-two patients with acute myeloid leukaemia were recruited into a phase I/II clinical trial investigating the vaccination of patients in complete remission (CR) with autologous dendritic-like leukaemia cells (DLLC). At trial entry, leukaemia cells were harvested and tested for their ability to undergo cytokine-induced dendritic cell differentiation. Patients were then treated with intensive chemotherapy. Five patients achieved both CR and had leukaemia cells that successfully underwent differentiation and therefore proceeded to vaccination. Four escalating doses of DLLC were administered weekly by subcutaneous injection. Vaccination was generally well tolerated although one patient developed extensive eczema and an increased antinuclear factor titre possibly indicating induction of autoimmunity. Development of anti-leukaemic T-cell responses was assessed by enzyme-linked immunospot analysis of gamma-interferon secreting T lymphocytes and by human leucocyte antigen tetramer analysis for WT1-specific T cells. Increases in anti-leukaemic T-cell responses were demonstrated in four patients, but only two of the five remained in remission more than 12 months postvaccination. The study has demonstrated that generation of DLLC is feasible in only a subgroup of patients and is currently neither broadly applicable or clinically effective. PMID:16611305

  11. Tel2p, a regulator of yeast telomeric length in vivo, binds to single-stranded telomeric DNA in vitro.

    PubMed

    Kota, R S; Runge, K W

    1999-09-01

    The telomeres of the yeast Saccharomyces cerevisiae consist of a duplex region of TG(1-3) repeats that acquire a single-stranded 3' extension of the TG(1-3) strand at the end of S-phase. The length of these repeats is kept within a defined range by regulators such as the TEL2-encoded protein (Tel2p). Here we show that Tel2p can specifically bind to single-stranded TG(1-3). Tel2p binding produced several shifted bands; however, only the slowest migrating band contained Tel2p. Methylation protection and interference experiments as well as gel shift experiments using inosine-containing probes indicated that the faster migrating bands resulted from Tel2p-mediated formation of DNA secondary structures held together by G-G interactions. Tel2p bound to single-stranded substrates that were at least 19 bases in length and contained 14 bases of TG(1-3), and also to double-stranded/single-stranded hybrid substrates with a 3' TG(1-3) overhang. Tel2p binding to a hybrid substrate with a 24 base single-stranded TG(1-3) extension also produced a band characteristic of G-G-mediated secondary structures. These data suggest that Tel2p could regulate telomeric length by binding to the 3' single-stranded TG(1-3) extension present at yeast telomeres. PMID:10525964

  12. Amino-acid substitutions at codon 13 of the N-ras oncogene in human acute myeloid leukaemia

    NASA Astrophysics Data System (ADS)

    Bos, Johannes L.; Toksoz, Deniz; Marshall, Christopher J.; Verlaan-de Vries, Matty; Veeneman, Gerrit H.; van der Eb, Alex J.; van Boom, Jacques H.; Janssen, Johannes W. G.; Steenvoorden, Ada C. M.

    1985-06-01

    DNAs from four out of five patients with acute myeloid leukaemia (AML) tested by an in vivo selection assay in nude mice using transfected mouse NIH 3T3 cells were found to contain an activated N-ras oncogene. Using a set of synthetic oligonucleotide probes, we have detected a mutation at codon 13 in all four genes. The same codon is mutated in an additional AML DNA that is positive in the focus-formation assay on 3T3 cells. DNA from the peripheral blood of one patient in remission does not contain a codon 13 mutation.

  13. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    PubMed Central

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E.; Cowley, Mark J.; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R.; Alexandrov, Ludmil B.; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  14. Mutations affecting both the rearranged and the unrearranged PML alleles in refractory acute promyelocytic leukaemia.

    PubMed

    Iaccarino, Licia; Ottone, Tiziana; Divona, Mariadomenica; Cicconi, Laura; Cairoli, Roberto; Voso, Maria Teresa; Lo-Coco, Francesco

    2016-03-01

    Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance. PMID:26728337

  15. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents.

    PubMed

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; Itzykson, Raphael; de Botton, Stéphane; Quesnel, Bruno; Commes, Thérèse; Jourdan, Eric; Vainchenker, William; Bernard, Olivier; Pata-Merci, Noemie; Solier, Stéphanie; Gayevskiy, Velimir; Dinger, Marcel E; Cowley, Mark J; Selimoglu-Buet, Dorothée; Meyer, Vincent; Artiguenave, François; Deleuze, Jean-François; Preudhomme, Claude; Stratton, Michael R; Alexandrov, Ludmil B; Padron, Eric; Ogawa, Seishi; Koscielny, Serge; Figueroa, Maria; Solary, Eric

    2016-01-01

    The cytidine analogues azacytidine and 5-aza-2'-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14±5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents is associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect. PMID:26908133

  16. RNAi screen identifies Brd4 as a therapeutic target in acute myeloid leukaemia

    PubMed Central

    Zuber, Johannes; Shi, Junwei; Wang, Eric; Rappaport, Amy R.; Herrmann, Harald; Sison, Edward A.; Magoon, Daniel; Qi, Jun; Blatt, Katharina; Wunderlich, Mark; Taylor, Meredith J.; Johns, Christopher; Chicas, Agustin; Mulloy, James C.; Kogan, Scott C.; Brown, Patrick; Valent, Peter; Bradner, James E.; Lowe, Scott W.; Vakoc, Christopher R.

    2012-01-01

    Epigenetic pathways can regulate gene expression by controlling and interpreting chromatin modifications. Cancer cells are characterized by altered epigenetic landscapes, and commonly exploit the chromatin regulatory machinery to enforce oncogenic gene expression programs1. Although chromatin alterations are, in principle, reversible and often amenable to drug intervention, the promise of targeting such pathways therapeutically has been limited by an incomplete understanding of cancer-specific dependencies on epigenetic regulators. Here we describe a non-biased approach to probe epigenetic vulnerabilities in acute myeloid leukaemia (AML), an aggressive haematopoietic malignancy that is often associated with aberrant chromatin states2. By screening a custom library of small hairpin RNAs (shRNAs) targeting known chromatin regulators in a genetically defined AML mouse model, we identify the protein bromodomain-containing 4 (Brd4) as being critically required for disease maintenance. Suppression of Brd4 using shRNAs or the small-molecule inhibitor JQ1 led to robust antileukaemic effects in vitro and in vivo, accompanied by terminal myeloid differentiation and elimination of leukaemia stem cells. Similar sensitivities were observed in a variety of human AML cell lines and primary patient samples, revealing that JQ1 has broad activity in diverse AML subtypes. The effects of Brd4 suppression are, at least in part, due to its role in sustaining Myc expression to promote aberrant self-renewal, which implicates JQ1 as a pharmacological means to suppress MYC in cancer. Our results establish small-molecule inhibition of Brd4 as a promising therapeutic strategy in AML and, potentially, other cancers, and highlight the utility of RNA interference (RNAi) screening for revealing epigenetic vulnerabilities that can be exploited for direct pharmacological intervention. PMID:21814200

  17. Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia.

    PubMed

    Sive, J I; Basilico, S; Hannah, R; Kinston, S J; Calero-Nieto, F J; Göttgens, B

    2016-01-01

    Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction. PMID:26126967

  18. Genome-scale definition of the transcriptional programme associated with compromised PU.1 activity in acute myeloid leukaemia

    PubMed Central

    Sive, J I; Basilico, S; Hannah, R; Kinston, S J; Calero-Nieto, F J; Göttgens, B

    2016-01-01

    Transcriptional dysregulation is associated with haematological malignancy. Although mutations of the key haematopoietic transcription factor PU.1 are rare in human acute myeloid leukaemia (AML), they are common in murine models of radiation-induced AML, and PU.1 downregulation and/or dysfunction has been described in human AML patients carrying the fusion oncogenes RUNX1-ETO and PML-RARA. To study the transcriptional programmes associated with compromised PU.1 activity, we adapted a Pu.1-mutated murine AML cell line with an inducible wild-type PU.1. PU.1 induction caused transition from leukaemia phenotype to monocytic differentiation. Global binding maps for PU.1, CEBPA and the histone mark H3K27Ac with and without PU.1 induction showed that mutant PU.1 retains DNA-binding ability, but the induction of wild-type protein dramatically increases both the number and the height of PU.1-binding peaks. Correlating chromatin immunoprecipitation (ChIP) Seq with gene expression data, we found that PU.1 recruitment coupled with increased histone acetylation induces gene expression and activates a monocyte/macrophage transcriptional programme. PU.1 induction also caused the reorganisation of a subgroup of CEBPA binding peaks. Finally, we show that the PU.1 target gene set defined in our model allows the stratification of primary human AML samples, shedding light on both known and novel AML subtypes that may be driven by PU.1 dysfunction. PMID:26126967

  19. Childhood leukaemia and population movements in France, 1990–2003

    PubMed Central

    Bellec, S; Baccaïni, B; Goubin, A; Rudant, J; Ripert, M; Hémon, D; Clavel, J

    2007-01-01

    In a national study, we investigated the incidence of childhood leukaemia (CL) over a 14-year period in France in relation to several measures based on the proportion of individuals who changed address between the last two national censuses. A positive association was found with the proportion of migrants who came from a distant place. The further the migrants came, the higher was the incidence of leukaemia, particularly among children aged 0–4 years in ‘isolated' communes at the time of diagnosis (RR=1.4, 95% CI: 1.1,1.8 in the highest category of migration distance). Although the role of the population density was less obvious, a more marked association was found above a certain threshold. No association with the proportion of commuters was observed. PMID:18087281

  20. Cytogenetic abnormalities in acute leukaemia of ambiguous lineage: an overview.

    PubMed

    Manola, Kalliopi N

    2013-10-01

    Acute leukaemia of ambiguous lineage (ALAL) is a rare complex entity with heterogeneous clinical, immunophenotypic, cytogenetic and molecular genetic features and adverse outcome. According to World Health Organization 2008 classification, ALAL encompasses those leukaemias that show no clear evidence of differentiation along a single lineage. The rarity of ALAL and the lack of uniform diagnostic criteria have made it difficult to establish its cytogenetic features, although cytogenetic analysis reveals clonal chromosomal abnormalities in 59-91% of patients. This article focuses on the significance of cytogenetic analysis in ALAL supporting the importance of cytogenetic analysis in the pathogenesis, diagnosis, prognosis, follow up and treatment selection of ALAL. It reviews in detail the types of chromosomal aberrations, their molecular background, their correlation with immunophenotype and age distribution and their prognostic relevance. It also summarizes some novel chromosome aberrations that have been observed only once. Furthermore, it highlights the ongoing and future research on ALAL in the field of cytogenetics. PMID:23888868

  1. Neuropsychological and neurological outcome after relapse of lymphoblastic leukaemia.

    PubMed

    Christie, D; Battin, M; Leiper, A D; Chessells, J; Vargha-Khadem, F; Neville, B G

    1994-04-01

    Fourteen children who relapsed after initial remission of leukaemia were studied. Six received a second course of cranial radiotherapy, while the remaining eight children were given total body irradiation before bone marrow transplantation. The postirradiation somnolence syndrome was common after cranial radiotherapy. All children had mild/soft neurological signs, mostly of coordination. None had a major motor disability. All but the youngest child had cataracts; two children required an operation for these. All children were growth hormone deficient. Verbal IQ, attention, and concentration were selectively reduced (with respect to normative levels). The time between the two treatments, age at relapse, and higher doses of radiotherapy all correlated with cognitive outcome, with girls showing greater impairments than boys. Only two children were performing at age appropriate levels on measures of academic achievement. It is concluded that neurological and neuropsychological morbidity is significantly increased by the current treatments prescribed after the relapse of leukaemia. PMID:7514391

  2. Encephalopathy in Acute Leukaemia Associated with Methotrexate Therapy

    PubMed Central

    Kay, H. E. M.; Knapton, P. J.; O'Sullivan, J. P.; Wells, D. G.; Harris, Ruth F.; Innes, Elizabeth M.; Stuart, J.; Schwartz, F. C. M.; Thompson, Eileen N.

    1972-01-01

    Seven patients are described in whom dementia developed during treatment with methotrexate for meningeal leukaemia. The patients presented with confusion, tremor, ataxia, irritability, and somnolence. There were major epileptic fits in two cases and in one case there was progression to coma and death. Necropsy findings in the latter showed infarcted areas in the temporal and parietal lobes, with no evidence of active leukaemic disease or of viral encephalitis. The condition has not responded to radiotherapy and no positive evidence of viral encephalitis has been obtained. On the other hand, when treated with folinic and folic acid the deterioration has been arrested and there has been some improvement; thus the condition appears to be due to methotrexate. The occurrence of so many cases within the past year of a condition not previously described is probably attributable to the introduction of intensive cytotoxic therapy directed against meningeal leukaemia. ImagesFIG. 2.FIG. 3.FIG. 4FIG. 5 PMID:4504035

  3. The genetics and mechanisms of T cell acute lymphoblastic leukaemia.

    PubMed

    Belver, Laura; Ferrando, Adolfo

    2016-07-25

    T cell acute lymphoblastic leukaemia (T-ALL) is an aggressive haematological malignancy derived from early T cell progenitors. In recent years genomic and transcriptomic studies have uncovered major oncogenic and tumour suppressor pathways involved in T-ALL transformation and identified distinct biological groups associated with prognosis. An increased understanding of T-ALL biology has already translated into new prognostic biomarkers and improved animal models of leukaemia and has opened opportunities for the development of targeted therapies for the treatment of this disease. In this Review we examine our current understanding of the molecular mechanisms of T-ALL and recent developments in the translation of these results to the clinic. PMID:27451956

  4. Tel1 and Rif2 Regulate MRX Functions in End-Tethering and Repair of DNA Double-Strand Breaks

    PubMed Central

    Wang, Weibin; Niu, Hengyao; Clerici, Michela; Sung, Patrick; Longhese, Maria Pia

    2016-01-01

    The cellular response to DNA double-strand breaks (DSBs) is initiated by the MRX/MRN complex (Mre11-Rad50-Xrs2 in yeast; Mre11-Rad50-Nbs1 in mammals), which recruits the checkpoint kinase Tel1/ATM to DSBs. In Saccharomyces cerevisiae, the role of Tel1 at DSBs remains enigmatic, as tel1Δ cells do not show obvious hypersensitivity to DSB-inducing agents. By performing a synthetic phenotype screen, we isolated a rad50-V1269M allele that sensitizes tel1Δ cells to genotoxic agents. The MRV1269MX complex associates poorly to DNA ends, and its retention at DSBs is further reduced by the lack of Tel1. As a consequence, tel1Δ rad50-V1269M cells are severely defective both in keeping the DSB ends tethered to each other and in repairing a DSB by either homologous recombination (HR) or nonhomologous end joining (NHEJ). These data indicate that Tel1 promotes MRX retention to DSBs and this function is important to allow proper MRX-DNA binding that is needed for end-tethering and DSB repair. The role of Tel1 in promoting MRX accumulation to DSBs is counteracted by Rif2, which is recruited to DSBs. We also found that Rif2 enhances ATP hydrolysis by MRX and attenuates MRX function in end-tethering, suggesting that Rif2 can regulate MRX activity at DSBs by modulating ATP-dependent conformational changes of Rad50. PMID:26901759

  5. Expression of the TEL-Syk Fusion Protein in Hematopoietic Stem Cells Leads to Rapidly Fatal Myelofibrosis in Mice

    PubMed Central

    Graham, Michelle T.; Abram, Clare L.; Hu, Yongmei; Lowell, Clifford A.

    2013-01-01

    The TEL-Syk fusion protein was isolated from a patient with myelodysplasia with megakaryocyte blasts. Expression of TEL-Syk transforms interleukin-3 (IL-3)-dependent Ba/F3 cells in vitro by deregulating STAT5-mediated signal transduction pathways. In vivo, TEL-Syk expression in pre-B cells blocks B cell differentiation, leading to lymphoid leukemia. Here, we demonstrate that TEL-Syk introduced into fetal liver hematopoietic cells, which are then adoptively transferred into lethally irradiated recipients, leads to an aggressive myelodysplasia with myelofibrosis that is lethal in mice by 60–75 days. Expression of TEL-Syk induces a short-lived myeloexpansion that is rapidly followed by bone marrow failure and extreme splenic/hepatic fibrosis accompanied by extensive apoptosis. The disease is dependent on Syk kinase activity. Analysis of serum from TEL-Syk mice reveals an inflammatory cytokine signature reminiscent of that found in the sera from patients and mouse models of myeloproliferative neoplasms. TEL-Syk expressing cells showed constitutive STAT5 phosphorylation, which was resistant to JAK inhibition, consistent with deregulated cytokine signaling. These data indicate that expression of TEL-Syk in fetal liver hematopoietic cells results in JAK-independent STAT5 phosphorylation ultimately leading to a uniquely aggressive and lethal form of myelofibrosis. PMID:24116232

  6. Leukaemia clusters in childhood: geographical analysis in Britain.

    PubMed Central

    Knox, E G

    1994-01-01

    STUDY OBJECTIVE--To validate previously demonstrated spatial clustering of childhood leukaemias by showing relative proximities of selected map features to cluster locations, compared with control locations. If clusters are real, then they are likely to be close to a determining hazard. DESIGN--Cluster postcode loci and partially matched control postcodes were compared in terms of distances to railways, main roads, churches, surface water, woodland areas, and railside industrial installations. Further supporting comparisons between non-clustered cases and random postcode controls with those map features representable as single grid points were made. SETTING--England, Wales, and Scotland 1966-83. SUBJECTS--Grid referenced registrations of 9406 childhood leukaemias and non-Hodgkin's lymphomas, including 264 pairs (or more) separated by < 150 m, and grid references of random postcodes in equal numbers. MAIN RESULTS--The 264 clusters showed relative proximities (or the inverse) to several map features, of which the most powerful was an association with railways. The non-railway associations seemed to be statistically indirect. Some railside industrial installations, identified from a railway atlas, also showed relative proximities to leukaemia clusters, as well as to non-clustered cases, but did not "explain" the railway effect. These installations, with seemingly independent geographical associations, included oil refineries, petrochemical plants, oil storage and oil distribution depots, power stations, and steelworks. CONCLUSIONS--The previously shown childhood leukaemia clusters are confirmed to be non-random through their systematic associations with certain map features when compared with the control locations. The common patterns of close association of clustered and non-clustered cases imply a common aetiological component arising from a common environmental hazard--namely the use of fossil fuels, especially petroleum. PMID:7964336

  7. Feline leukaemia virus and its clinical effects in cats.

    PubMed

    Mackey, L

    1975-01-01

    Feline leukemia virus (FeLV) infection is common among cats where contact is high. The virus can be transmitted readily between cats. It causes a variety of haemopoietic and lymphoid neoplasms; the most common types are alimentary, multicentric and thymic lymphosarcoma and lymphatic leukaemia. The virus is involved in the aetiology of certain other diseases including anaemia, glomerulonephritis and an immunosuppressive syndrome which predisposes cats to intercurrent infections. Many infected cats mount an immune response and do not suffer from any of these. The immune status is shown by serum antibody levels to feline leukaemia virus associated cell membrane antigens. Cats with a titre of 32 or more are most unlikely to suffer any ill effects and may eliminate the virus infection. The outcome of infection in an individual cat depends on the immunological competence of the cat, the dose of virus received and its ability to induce immunosuppression. FeLV infection can be detected by examination of tissues by electron microscopy, and by culture of virus from plasma and other tissues. In the United States, a method is now in use for the detection of leukaemia virus antigen in peripheral blood leukocytes; this is carried out on ordinary blood films. Successful prototype vaccines have been developed against FeLV. This paper describes the natural history of the virus, the diseases in which it is implicated and discusses recently developed diagnostic methods. PMID:163515

  8. Informing TEL Strategy through Formal and Informal Channels: A Case Study

    ERIC Educational Resources Information Center

    Walker, David; Sloan, David; Boyle, Lynn; Walsh, Lorraine

    2011-01-01

    Purpose: The purpose of this paper is to outline and discuss a multifaceted approach to embedding change in academic practice, resulting in the integration of technology-enhanced learning (TEL) within the wider institutional strategic approach to learning and teaching. Design/methodology/approach: This approach is evidenced through a discussion of…

  9. Tel1 and Rad51 are involved in the maintenance of telomeres with capping deficiency

    PubMed Central

    Di Domenico, Enea Gino; Mattarocci, Stefano; Cimino-Reale, Graziella; Parisi, Paola; Cifani, Noemi; D’Ambrosio, Ettore; Zakian, Virginia A.; Ascenzioni, Fiorentina

    2013-01-01

    Vertebrate-like T2AG3 telomeres in tlc1-h yeast consist of short double-stranded regions and long single-stranded overhang (G-tails) and, although based on Tbf1-capping activity, they are capping deficient. Consistent with this idea, we observe Y’ amplification because of homologous recombination, even in the presence of an active telomerase. In these cells, Y’ amplification occurs by different pathways: in Tel1+ tlc1h cells, it is Rad51-dependent, whereas in the absence of Tel1, it depends on Rad50. Generation of telomeric G-tail, which is cell cycle regulated, depends on the MRX (Mre11-Rad50-Xrs2) complex in tlc1h cells or is MRX-independent in tlc1h tel1Δ mutants. Unexpectedly, we observe telomere elongation in tlc1h lacking Rad51 that seems to act as a telomerase competitor for binding to telomeric G-tails. Overall, our results show that Tel1 and Rad51 have multiple roles in the maintenance of vertebrate-like telomeres in yeast, supporting the idea that they may participate to evolutionary conserved telomere protection mechanism/s acting at uncapped telomeres. PMID:23677619

  10. The Development of the Teacher Emotional Labor Scale (TELS): Validity and Reliability

    ERIC Educational Resources Information Center

    Cukur, Cem Safak

    2009-01-01

    The current study had two main purposes. The first was to develop and validate an instrument to measure emotional labor among teachers (Teacher Emotional Labor Scale, TELS) with an emphasis on the emotion regulation strategies during critical work events. The second was to investigate whether emotional deviance could be considered as one of the…

  11. Vocational Education Approach: New TEL Settings--New Prospects for Teachers' Instructional Activities?

    ERIC Educational Resources Information Center

    Hämäläinen, Raija; De Wever, Bram

    2013-01-01

    This study focuses on vocational education teachers' instructional activities in a new technology-enhanced learning (TEL) setting. A content analysis is applied to investigate teachers' and students' interactions in a 3D game context. The findings illustrate that when teachers' and students' interactions are mediated by a…

  12. Implementation of Tel Aviv University MOOCs in Academic Curriculum: A Pilot Study

    ERIC Educational Resources Information Center

    Soffer, Tal; Cohen, Anat

    2015-01-01

    The study presented in this paper examines the feasibility of using MOOCs [Massive open online courses] as a learning environment in academic courses. This paper focuses on the students who participated in two MOOCs offered by Tel Aviv University (TAU) during the year 2013. The preliminary findings of this pilot study illustrate the scope of…

  13. A case of Mac Tel 2 with an unusual sub macular vitelliform lesion

    PubMed Central

    Lekha, T.; Sarwate, Nikit; Sarwate, Renuka

    2015-01-01

    Method: Observational case report describing the clinical, FFA, OCT and mfERG findings in an elderly female patient with atypical features of macular telangiectasia (Mac Tel 2) Results: A 71-year-old lady was detected to have characteristic features of Mac Tel 2 in the left eye (LE) and a yellowish sub macular vitelliform like lesion in the right eye (RE). FFA showed ill defined hyper fluorescence in the RE and telangiectasia and parafoveal leakage typical of Mac Tel 2 in the LE. On OCT RE had hyper reflective clump of echoes subfoveally with an intact RPE and LE had foveal thinning with hypo reflective intraretinal cavities. mfERG responses were normal in the RE and reduced in the LE. During the course of 3 years LE showed natural progression while RE remained unchanged. Conclusion: Structural and functional evaluation of an unusual sub macular vitelliform lesion seen in association with Mac Tel 2 and its course over a period of 3 years is described. The differentiating features of this lesion from adult onset foveomacular vitelliform dystrophy (AFMD) are discussed.

  14. Instructional Design or School Politics? A Discussion of "Orchestration" in TEL Research

    ERIC Educational Resources Information Center

    Perrotta, C.; Evans, M. A.

    2013-01-01

    This paper argues that the emphasis on orchestration as a metaphor for teaching in technology-enhanced learning (TEL) environments, featured in recent academic discussions, is an opportunity to broaden the scope of the inquiry into educational technology. Drawing on sociological literature and research that investigated the systemic factors that…

  15. A Delphi Study on Technology Enhanced Learning (TEL) Applied on Computer Science (CS) Skills

    ERIC Educational Resources Information Center

    Porta, Marcela; Mas-Machuca, Marta; Martinez-Costa, Carme; Maillet, Katherine

    2012-01-01

    Technology Enhanced Learning (TEL) is a new pedagogical domain aiming to study the usage of information and communication technologies to support teaching and learning. The following study investigated how this domain is used to increase technical skills in Computer Science (CS). A Delphi method was applied, using three-rounds of online survey…

  16. Renata Adler Memorial Research Center for Child Welfare and Protection, Tel-Aviv University

    ERIC Educational Resources Information Center

    Ronen, Tammie

    2011-01-01

    The Renata Adler Memorial Research Center for Child Welfare and Protection operates within the Bob Shapell School of Social Work at Tel-Aviv University in Israel. The main aims of this research center are to facilitate study and knowledge about the welfare of children experiencing abuse or neglect or children at risk and to link such knowledge to…

  17. Diffusion of Web Supported Instruction in Higher Education--The Case of Tel-Aviv University

    ERIC Educational Resources Information Center

    Soffer, Tal; Nachmias, Rafi; Ram, Judith

    2010-01-01

    This paper describes a study that focused on long-term web-supported learning diffusion among lecturers at Tel Aviv University (TAU), from an organizational point of view. The theoretical models we used to examine this process are Rogers' model for "Diffusion of Innovation" (1995) and Bass's "Diffusion Model" (1969). The study was conducted…

  18. The potential of clofarabine in MLL-rearranged infant acute lymphoblastic leukaemia.

    PubMed

    Stumpel, Dominique J P M; Schneider, Pauline; Pieters, Rob; Stam, Ronald W

    2015-09-01

    MLL-rearranged acute lymphoblastic leukaemia (ALL) in infants is the most difficult-to-treat type of childhood ALL, displaying a chemotherapy-resistant phenotype, and unique histone modifications, gene expression signatures and DNA methylation patterns. MLL-rearranged infant ALL responds remarkably well to nucleoside analogue drugs in vitro, such as cytarabine and cladribine, and to the demethylating agents decitabine and zebularine as measured by cytotoxicity assays. These observations led to the inclusion of cytarabine into the treatment regimens currently used for infants with ALL. However, survival chances for infants with MLL-rearranged ALL do still not exceed 30-40%. Here we explored the in vitro potential of the novel nucleoside analogue clofarabine for MLL-rearranged infant ALL. Therefore we used both cell line models as well as primary patient cells. Compared with other nucleoside analogues, clofarabine effectively targeted primary MLL-rearranged infant ALL cells at the lowest concentrations, with median LC50 values of ∼25 nM. Interestingly, clofarabine displayed synergistic cytotoxic effects in combination with cytarabine. Furthermore, at concentrations of 5-10nM clofarabine induced demethylation of the promoter region of the tumour suppressor gene FHIT (Fragile Histidine Triad), a gene typically hypermethylated in MLL-rearranged ALL. Demethylation of the FHIT promoter region was accompanied by subtle re-expression of this gene both at the mRNA and protein level. We conclude that clofarabine is an interesting candidate for further studies in MLL-rearranged ALL in infants. PMID:26188848

  19. Effects of pharmacological and genetic disruption of CXCR4 chemokine receptor function in B-cell acute lymphoblastic leukaemia.

    PubMed

    Randhawa, Shubhchintan; Cho, Byung S; Ghosh, Dipanjan; Sivina, Mariela; Koehrer, Stefan; Müschen, Markus; Peled, Amnon; Davis, Richard E; Konopleva, Marina; Burger, Jan A

    2016-08-01

    B cell acute lymphoblastic leukaemia (B-ALL) cells express high levels of CXCR4 chemokine receptors for homing and retention within the marrow microenvironment. Bone marrow stromal cells (BMSC) secrete CXCL12, the ligand for CXCR4, and protect B-ALL cells from cytotoxic drugs. Therefore, the therapeutic use of CXCR4 antagonists has been proposed to disrupt cross talk between B-ALL cells and the protective stroma. Because CXCR4 antagonists can have activating agonistic function, we compared the genetic and pharmacological deletion of CXCR4 in B-ALL cells, using CRISPR-Cas9 gene editing and CXCR4 antagonists that are in clinical use (plerixafor, BKT140). Both genetic and pharmacological CXCR4 inhibition significantly reduced B-ALL cell migration to CXCL12 gradients and beneath BMSC, and restored drug sensitivity to dexamethasone, vincristine and cyclophosphamide. NOD/SCID/IL-2rγnull mice injected with CXCR4 gene-deleted B-ALL cells had significant delay in disease progression and superior survival when compared to control mice injected with CXCR4 wild-type B-ALL cells. These findings indicate that anti-leukaemia activity of CXCR4 antagonists is primarily due to CXCR4 inhibition, rather than agonistic activity, and corroborate that CXCR4 is an important target to overcome stroma-mediated drug resistance in B-ALL. PMID:27071778

  20. Adenovirus detection in Guthrie cards from paediatric leukaemia cases and controls

    PubMed Central

    Vasconcelos, G M; Kang, M; Pombo-de-Oliveira, M S; Schiffman, J D; Lorey, F; Buffler, P; Wiemels, J L

    2008-01-01

    Archived neonatal blood cards (Guthrie cards) from children who later contracted leukaemia and matched normal controls were assayed for adenovirus (AdV) C DNA content using two highly sensitive methods. In contrast to a previous report, AdV DNA was not detected at a higher frequency among neonates who later developed leukaemia, when compared with controls. PMID:19002185

  1. Chronic lymphocytic leukaemia in pregnancy: a case report and literature review

    PubMed Central

    Maxwell, Cynthia; Grady, Rosheen; Crump, Michael

    2009-01-01

    Chronic lymphocytic leukaemia is a rare condition reported in pregnancy. We review a case of a woman presenting for pregnancy care with active disease and review the literature on this condition. This case raises several important issues with regard to managing complex medical diseases such as leukaemia in pregnant women, including the role of multidisciplinary care.

  2. Acute leukaemia after exposure to a weed killer, 2-methyl-4-chlorphenoxyacetic acid.

    PubMed

    Timonen, T T; Palva, I P

    1980-01-01

    Acute leukaemia is known to develop in many cases of benzene-induced pancytopenia [1]. This is a report of the development of acute leukaemia in a patient who had apparently recovered from pancytopenia after chronic exposure to a weed killer, 2-methyl-4-chlorphenoxyacetic acid. PMID:6769284

  3. Expression of interleukin 6 receptors and interleukin 6 mRNA by bovine leukaemia virus-induced tumour cells.

    PubMed

    Droogmans, L; Cludts, I; Cleuter, Y; Kerkhofs, P; Adam, E; Willems, L; Kettmann, R; Burny, A

    1994-11-01

    Bovine leukaemia virus (BLV) is the aetiologic agent of bovine leucosis. The virus induces malignancies of the B-cell lineage (leukaemia/lymphoma). The role played by interleukin 6 (IL-6) in the BLV-induced leukemogenesis process was evaluated. Six cell lines derived from BLV-induced tumours were tested for the expression of IL-6 receptors. Two cell lines (LB155 and YR2) display 250-300 receptor per cell (kd = 1.7 10(-10) M and 1.4 10(-10) M, respectively) whereas the other four (LB159, LB167, YR1 and M51) do not display detectable amounts of receptors. Very low (if any) expression of IL-6 receptors has been found in the case of the B lymphocytes of animals in persistent lymphocytosis (PL). Despite the presence of IL-6 receptors on the surface of LB155 and YR2 cells, no influence of exogenous IL-6 on their growth has been observed. Northern analyses indicated the presence of IL-6 transcripts only in the case of mRNA isolated from LB155 cells. Since this cell line also expresses receptors for the cytokine, an autocrine loop may exist in these cells. Experiments in which bovine and bovine epithelial cell lines were transfected with a plasmid containing the bovine IL-6 promoter controlling the expression of the reporter cat gene failed to indicate any influence of the viral transactivator p34tax on the activity of this promoter. We conclude that IL-6 receptors and IL-6 mRNA can be found in some BLV-induced tumours, but this does not correlate with viral expression in BLV-induced leukaemia/lymphoma. PMID:7893972

  4. The risk of childhood leukaemia following exposure to ionising radiation--a review.

    PubMed

    Wakeford, Richard

    2013-03-01

    Since the early years of follow-up of the Japanese atomic-bomb survivors, it has been apparent that childhood leukaemia has a particular sensitivity to induction by ionising radiation, the excess relative risk (ERR) being expressed as a temporal wave with time since exposure. This pattern has been generally confirmed by studies of children treated with radiotherapy. Case-control studies of childhood leukaemia and antenatal exposure to diagnostic x-rays, a recent large cohort study of leukaemia following CT examinations of young people, and a recent large case-control study of natural background γ-radiation and childhood leukaemia have found evidence of raised risks following low-level exposure. These findings indicate that an ERR/Sv for childhood leukaemia of ~50, which may be derived from risk models based upon the Japanese atomic-bomb survivors, is broadly applicable to low dose or low dose-rate exposure circumstances. PMID:23296257

  5. Epipodophyllotoxins, alkylating agents, and radiation and risk of secondary leukaemia after childhood cancer.

    PubMed Central

    Hawkins, M. M.; Wilson, L. M.; Stovall, M. A.; Marsden, H. B.; Potok, M. H.; Kingston, J. E.; Chessells, J. M.

    1992-01-01

    OBJECTIVE--To investigate the incidence and aetiology of secondary leukaemia after childhood cancer in Britain. DESIGN--Cohort study and a case-control study. SETTING--Britain and population based National Register of Childhood Tumours. SUBJECTS--Cohort of 16,422 one year survivors of childhood cancer diagnosed in Britain between 1962 and 1983, among whom 22 secondary leukaemias were observed. A case-control study of 26 secondary leukaemias observed among survivors of childhood cancer diagnosed in Britain between 1940 and 1983; 96 controls were selected matched for sex, type of first cancer, age at first cancer, and interval to diagnosis of secondary leukaemia. MAIN OUTCOME MEASURES--Dose of radiation averaged over patients' active bone marrow and total accumulated dose of epipodophyllotoxins, alkylating agents, vinca alkaloids, antimetabolites, and antibiotics (mg/m2) given for the original cancer. RESULTS--Cumulative risk of secondary leukaemia within the cohort did not exceed 0.5% over the initial five years beyond one year survival, except that after non-Hodgkin's lymphomas 1.4% of patients developed secondary leukaemia. Corresponding figure for patients treated for non-Hodgkin's lymphomas in the early 1980s was 4%. The relative risk of secondary leukaemia increased significantly with exposure to epipodophyllotoxins and dose of radiation averaged over patients' active bone marrow. Ten patients developed leukaemia after having an epipodophyllotoxin-teniposide in nine cases, etoposide in one. Chromosomal translocations involving 11q23 were observed relating to two secondary leukaemias from a total of six for which there were successful cytogenetic studies after administration of an epipodophyllotoxin. CONCLUSIONS--Epipodophyllotoxins acting alone or together with alkylating agents or radiation seem to be involved in secondary leukaemia after childhood cancer. PMID:1581717

  6. Uranium-235 and childhood leukaemia around Greenham Common airfield.

    PubMed

    Bithell, J F; Draper, G J

    1999-09-01

    There has been considerable publicity recently concerning the possible release of enriched uranium from the Greenham Common USAF base near Newbury in Berkshire. Evidence for the release relies on an internal report of the Atomic Weapons Research Establishment at Aldermaston, the authors of which postulated that it resulted from a fire in 1958 involving a B47 bomber standing on the runway. Their report contained a much publicised contour map of excess 235U levels estimated from the ratio of 235U to 238U in 26 evergreen leaf samples examined. The current concern of the inhabitants of Newbury centres mostly on the incidence of leukaemia, which was known beforehand to be slightly elevated in parts of West Berkshire, at least for young children. A number of cases have received considerable press publicity, with suggestions that their homes are located close to the base or the flight-path. The reports are, however, anecdotal and are not based on a complete register of cases. We have examined the evidence for this putative association by re-analysing the uranium data and determining the spatial relationship to the base of cases of childhood leukaemia diagnosed in the years 1966-87. We conclude that, although the excess uranium found has a non-random distribution, it does not support the pattern depicted by the contours and bears no relation to the incidence of childhood leukaemia for the period we examined. In any case, the increase in level of environmental radiation as a result of the putative release must be very small and is at variance with the reporting in some of the national press. PMID:10503703

  7. Acute leukaemias in adult Ethiopians in a teaching hospital.

    PubMed

    Shamebo, M

    1994-01-01

    Eighty-two consecutive cases of acute leukaemias in adult Ethiopians were admitted to the Tikur Anbessa (Black Lion) Hospital, a teaching and referral hospital in Addis Abeba, Ethiopia, from January 1982 to December 1992. These cases were studied to describe the clinical and haematological findings, response to therapy and prognosis. The age range was 13-78 (mean 29.6) years. The male to female ratio was 1.6:1. Acute myeloblastic (AML) and acute lymphoblastic (ALL) leukaemias occurred in 53.7% and 46.3%, respectively. The commonest symptoms were anaemia, fever and bleeding tendencies. The commonest signs were pallor, fever, sternal tenderness and purpura. Splenomegaly was more commonly seen in ALL patients. The haematological findings were anaemia (mean Hgb 6.35 g%), leucocytosis (mean WBC count 88,507/mm3) and thrombocytopenia (mean platelet count 31,700/mm3). Of the patients eligible for evaluation treated with chemotherapeutic agents, only 38.4% of ALL and 6.2% of AML achieved complete remission. Twenty-seven patients with ALL died from one day to 84 (median 1.0) months after diagnosis. Ten are lost to follow-up from two weeks to 36 (median 2.5) months, one is still alive 40 months after diagnosis. Thirty-nine of the AML patients died from one day to nine (median 0.3) months after diagnosis. Five are lost to follow-up from two weeks to two and a half (median 2.0) months. The causes of death were sepsis and bleeding, separately or in combination. Increasing numbers of acute leukaemia patients are being referred to this centre. Therefore, attempts should be made to equip it for the treatment of such cases. PMID:8187778

  8. miR-196b directly targets both HOXA9/MEIS1 oncogenes and FAS tumour suppressor in MLL-rearranged leukaemia

    PubMed Central

    Li, Zejuan; Huang, Hao; Chen, Ping; He, Miao; Li, Yuanyuan; Arnovitz, Stephen; Jiang, Xi; He, Chunjiang; Hyjek, Elizabeth; Zhang, Jun; Zhang, Zhiyu; Elkahloun, Abdel; Cao, Donglin; Shen, Chen; Wunderlich, Mark; Wang, Yungui; Neilly, Mary Beth; Jin, Jie; Wei, Minjie; Lu, Jun; Valk, Peter J.M.; Delwel, Ruud; Lowenberg, Bob; Le Beau, Michelle M.; Vardiman, James; Mulloy, James C.; Zeleznik-Le, Nancy J.; Liu, Paul P.; Zhang, Jiwang; Chen, Jianjun

    2012-01-01

    HOXA9, and MEIS1 have essential oncogenic roles in mixed lineage leukaemia (MLL)-rearranged leukaemia. Here we show that they are direct targets of miRNA-196b, a microRNA (miRNA) located adjacent to and co-expressed with HOXA9, in MLL-rearranged leukaemic cells. Forced expression of miR-196b significantly delays MLL-fusion-mediated leukemogenesis in primary bone marrow transplantation through suppressing Hoxa9/Meis1 expression. However, ectopic expression of miR-196b results in more aggressive leukaemic phenotypes and causes much faster leukemogenesis in secondary transplantation than MLL fusion alone, likely through the further repression of Fas expression, a proapoptotic gene downregulated in MLL-rearranged leukaemia. Overexpression of FAS significantly inhibits leukemogenesis and reverses miR-196b-mediated phenotypes. Targeting Hoxa9/Meis1 and Fas by miR-196b is probably also important for normal haematopoiesis. Thus, our results uncover a previously unappreciated miRNA-regulation mechanism by which a single miRNA may target both oncogenes and tumour suppressors, simultaneously, or, sequentially, in tumourigenesis and normal development per cell differentiation, indicating that miRNA regulation is much more complex than previously thought. PMID:22353710

  9. Knock-down of argonaute 2 (AGO2) induces apoptosis in myeloid leukaemia cells and inhibits siRNA-mediated silencing of transfected oncogenes in HEK-293 cells.

    PubMed

    Naoghare, Pravin K; Tak, Yu Kyung; Kim, Min Jung; Han, Eunyoung; Song, Joon Myong

    2011-10-01

    Understanding the role of oncomirs allows new insights into the development of modern therapeutic approaches for the repression of multiple oncomirs in cancer cells. At present, no suitable approach is available to repress the development of multiple oncomirs in cancer cells. Herein, we report that argonaute 2 (AGO2) could be a unique molecule to regulate the development of multiple oncomirs in cancer cells. Knock-down of AGO2 by custom-made AGO2 siRNA resulted in the induction of apoptosis in myeloid leukaemia cells (HL-60). Further investigations revealed that knock-down of AGO2 by custom-made AGO2 siRNA in HEK-293 cells resulted in silencing of the expression of target genes vascular endothelial growth factor A and histone deacetylase 2, which are known to be involved in the development of myeloid leukaemia. From these results, it can be predicted that AGO2 could regulate siRNA-mediated RNAi pathways in cancer cells. Furthermore, we investigated the possible implication of AGO2 in drug-induced apoptosis. Investigations revealed that treatment with the newly synthesized drug analogue SH-03[{(7S,7aR,13aS)-9,10-dimethoxy-3,3-dimethyl-7,7a,13,13atetrahydro-3H-chromeno[3,4-b]pyrano[2,3-h]chromen-7-ol}] could induce AGO2-mediated apoptosis in myeloid leukaemia cells via intrinsic apoptotic pathways independent of Dicer. PMID:21535412

  10. Bone marrow fibrosis in childhood acute lymphoblastic leukaemia.

    PubMed Central

    Wallis, J P; Reid, M M

    1989-01-01

    Bone marrow trephine biopsy specimens were obtained at diagnosis from 63 of 76 consecutively presenting children with acute lymphoblastic leukaemia (ALL). The association between marrow fibrosis and presenting features, including immunophenotype, was analysed. Reticulin was increased in 45 of 56 cases in which blasts expressed B lineage markers, but in only one of seven with T-ALL. A weak association was also found between marrow fibrosis and splenomegaly in those with common ALL. Marrow fibrosis is apparently associated with some examples of ALL of B cell lineage, but precisely which subtypes and whether the phenomenon is clinically important remain to be determined. PMID:2613918

  11. The Effects of Herbs and Fruits on Leukaemia

    PubMed Central

    Saedi, Tayebeh Azam; Md Noor, Sabariah; Ismail, Patimah; Othman, Fauziah

    2014-01-01

    In developing countries, herbal therapy is the first and basis form of treatment for most types of diseases. About 75–80% of the world's population prefers herbal therapy as a major treatment due to its better adequacy and satisfactoriness, which enhance human body's symmetry with minimal side effects. Fruits and plants have been presented from the past as promising tools in becoming a natural anticancer agents. Many of these plant extracts are currently used in cancer therapy and prevention. This review paper will particularly explore and emphasize on herbs and fruits used in the treatment of the leukaemia. PMID:25250054

  12. Illegitimate RAG-mediated recombination events are involved in IKZF1 Δ3-6 deletion in BCR-ABL1 lymphoblastic leukaemia.

    PubMed

    Dong, Y; Liu, F; Wu, C; Li, S; Zhao, X; Zhang, P; Jiao, J; Yu, X; Ji, Y; Zhang, M

    2016-09-01

    Breakpoint cluster region-Abelson murine leukaemia viral oncogene homologue 1 (BCR-ABL1), encoded by the Philadelphia (Ph) chromosome, is the characteristic of chronic myeloid leukaemia (CML) and a subset of acute lymphoblastic leukaemia (ALL). We demonstrated that expression of the Ik6 transcript, which lacked exons 3-6, was observed exclusively in BCR-ABL1(+) B ALL and lymphoid blast crisis CML (BC-CML) patients harbouring the IKZF1 Δ3-6 deletion. To confirm the hypothesis that illegitimate recombination activating gene protein (RAG)-mediated recombination events are involved in IKZF1 Δ3-6 deletion in BCR-ABL1 lymphoblastic leukaemia, we first demonstrated that the expression rates of RAG1 and RAG2, collectively called RAG, were higher in ALL and BC-CML (lymphoid). Notably, analysis of relationships among RAG, BCR-ABL1 and Ikaros 6 (Ik6) showed that Ik6 can be generated only if RAG and BCR-ABL1 are co-existing. The sequencing data showed that the deleted segments of introns 2 and 6 contained cryptic recombination signal sequences (cRSSs) and frequently had non-template nucleotides inserted between breakpoints. Furthermore, we used chromatin immunoprecipitation (ChIP) technology and demonstrated that the sequences directly flanking IKZF1 Δ3-6 deletion breakpoints have significantly higher levels of histone H3 lysine 4 trimethylation (H3K4me3) modifications. Overall, RAG expression, good-quality cRSS and a specific chromatin modification, H3K4me3, satisfy the conditions of RAG's off-target effects on IKZF1. Our work provides evidence for RAG-mediated IKZF1 Δ3-6 deletion. Our results raise the prospect that RAG is a valuable biomarker in disease surveillance. Dissecting the contribution of RAG should not only provide valuable mechanistic insights, but will also lead to a new therapeutic direction. PMID:27198500

  13. Telomerase and Tel1p Preferentially Associate with Short Telomeres in S. cerevisiae

    PubMed Central

    Sabourin, Michelle; Tuzon, Creighton T.; Zakian, Virginia A.

    2009-01-01

    SUMMARY In diverse organisms, telomerase preferentially elongates short telomeres. We generated a single short telomere in otherwise wild-type (WT) S. cerevisiae cells. The binding of the positive regulators Ku and Cdc13p was similar at short and WT-length telomeres. The negative regulators Rif1p and Rif2p were present at the short telomere, although Rif2p levels were reduced. Two telomerase holoenzyme components, Est1p and Est2p, were preferentially enriched at short telomeres in late S/G2 phase, the time of telomerase action. Tel1p, the yeast ATM-like checkpoint kinase, was highly enriched at short telomeres from early S through G2 phase and even into the next cell cycle. Nonetheless, induction of a single short telomere did not elicit a cell-cycle arrest. Tel1p binding was dependent on Xrs2p and required for preferential binding of telomerase to short telomeres. These data suggest that Tel1p targets telomerase to the DNA ends most in need of extension. PMID:17656141

  14. Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks.

    PubMed

    Rendeiro, André F; Schmidl, Christian; Strefford, Jonathan C; Walewska, Renata; Davis, Zadie; Farlik, Matthias; Oscier, David; Bock, Christoph

    2016-01-01

    Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status-which distinguishes the two major subtypes of CLL-was accurately predicted by the chromatin profiles and gene regulatory networks inferred for IGHV-mutated versus IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukaemia and demonstrated the feasibility of large-scale chromatin accessibility mapping in cancer cohorts and clinical research. PMID:27346425

  15. Traffic-related air pollution and risk for leukaemia of an adult population.

    PubMed

    Raaschou-Nielsen, Ole; Ketzel, Matthias; Harbo Poulsen, Aslak; Sørensen, Mette

    2016-03-01

    Air pollution causes lung cancer, but associations with other cancers have not been established. We investigated whether long-term exposure to traffic-related air pollution is associated with the risk of the general population for leukaemia. We identified 1,967 people in whom leukaemia was diagnosed in 1992-2010 from a nation-wide cancer registry and selected 3,381 control people at random, matched on sex and year of birth, from the entire Danish population. Residential addresses since 1971 were traced in a population registry, and outdoor concentrations of NOx and NO2 , as indicators of traffic-related air pollution, were calculated at each address in a dispersion model. We used conditional logistic regression to estimate the risk for leukaemia after adjustment for income, educational level, cohabitation status and co-morbidity. In linear analyses, we found odds ratios for acute myeloid leukaemia of 1.20 (95% confidence interval: 1.04-1.38) per 20 µg/m(3) increase in NOx and 1.31 (1.02-1.68) per 10 µg/m(3) increase in NO2 , calculated as time-weighted average exposure at all addresses since 1971. We found no association with chronic myeloid or lymphocytic leukaemia. This study indicates an association between long-term exposure to traffic-related air pollution and acute myeloid leukaemia in the general population, but not for other subtypes of leukaemia. PMID:26415047

  16. Evans syndrome secondary to chronic lymphocytic leukaemia: presentation, treatment, and outcome.

    PubMed

    Carli, Giuseppe; Visco, Carlo; Falisi, Erika; Perbellini, Omar; Novella, Elisabetta; Giaretta, Ilaria; Ferrarini, Isacco; Sandini, Alessandra; Alghisi, Alberta; Ambrosetti, Achille; Rodeghiero, Francesco

    2016-05-01

    Evans syndrome (ES) is defined by the combination (either simultaneous or sequential) of immune thrombocytopenia (ITP) and autoimmune haemolytic anaemia (AIHA). When related to secondary conditions, ES may arise in patients with chronic lymphocytic leukaemia (CLL), which is frequently associated to autoimmune cytopenias (AIC). We analysed 25 patients with ES secondary to CLL, which were identified from a large series of consecutive patients with CLL, diagnosed and followed up in two institutions. They represented 2.9 % of the whole series. Thirteen patients presented with concurrent ITP and AIHA (simultaneous ES), while others developed the two AIC sequentially. Occurrence of ES was associated with unfavourable biological prognostic factors like ZAP-70 expression, unmutated immunoglobulin heavy chain variable region gene status, 17-p13 deletion and TP53 gene mutations. Of note, the majority of patients with ES (66 %) had stereotyped B cell receptor configuration. Most patients had short-lasting remissions and required second-line treatments to control the autoimmune manifestations of ES. Patients with ES were associated with inferior survival compared to patients not developing AIC, especially when ES developed early in the course of CLL, although the reduced survival was not confirmed by multivariate analysis. In conclusion, ES secondary to CLL is a difficult-to-treat complication, characterised by adverse biological features and clinical outcome. PMID:27001309

  17. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line

    PubMed Central

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-01-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  18. Transcriptional and functional defects of dendritic cells derived from the MUTZ-3 leukaemia line.

    PubMed

    Rasaiyaah, Jane; Noursadeghi, Mahdad; Kellam, Paul; Chain, Benjamin

    2009-07-01

    Dendritic cells (DC) generated from MUTZ-3, an immortalized acute myeloid leukaemia-derived cell line, have potential application as a model for the study of human DC, and as a tool with which to stimulate immunotherapeutic responses to cancer. However, the relationship of MUTZ-3 DC to their non-transformed counterparts remains incompletely understood. Immunoselected CD14+ MUTZ-3 cells were used to generate a homogeneous population of DC (M3DC). These cells had a cell surface phentoype and morphology characteristic of conventional monocyte-derived DC (MDDC). Whole genome transcriptome comparison of M3DC and MDDC however, revealed extensive differences between these two cell types. Functional ontology-based data analysis revealed three enriched clusters of genes downregulated in M3DC, with functions in pathogen recognition, DC maturation and cytokine/chemokine signalling. Downregulation of protein expression was confirmed for several of these genes. The molecular differences were accompanied by a profoundly impaired phenotypic and functional response of M3DC to microbial stimulation. The immortalized phenotype of MUTZ-3 therefore reflects not only deregulated proliferative capacity, but substantial perturbation of normal antigen-presenting cell function. These results have important implications for studies using MUTZ-3 as a model of MDDC or for cancer immunotherapy. PMID:19538250

  19. Photoperiod Influences Growth and mll (Mixed-Lineage Leukaemia) Expression in Atlantic Cod

    PubMed Central

    Nagasawa, Kazue; Giannetto, Alessia; Fernandes, Jorge M. O.

    2012-01-01

    Photoperiod is associated to phenotypic plasticity of somatic growth in several teleost species. However, the molecular mechanisms underlying this phenomenon are currently unknown but it is likely that epigenetic regulation by methyltransferases is involved. The MLL (mixed-lineage leukaemia) family comprises histone methyltransferases that play a critical role in regulating gene expression during early development in mammals. So far, these genes have received scant attention in teleost fish. In the present study, the mean weight of Atlantic cod juveniles reared under continuous illumination was found to be 13% greater than those kept under natural photoperiod conditions for 120 days. We newly determined cDNA sequences of five mll (mll1, mll2, mll3a, mll4b and mll5) and two setd1 (setd1a and setd1ba) paralogues from Atlantic cod. Phylogenetic analysis revealed that the cod genes clustered within the appropriate mll clade and comparative mapping of mll paralogues showed that these genes lie within a region of conserved synteny among teleosts. All mll and setd1 genes were highly expressed in gonads and fast muscle of adult cod, albeit at different levels, and they were differentially regulated with photoperiod in muscle of juvenile fish. Following only one day of exposure to constant light, mll1, mll4b and setd1a were up to 57% lower in these fish compared to the natural photoperiod group. In addition, mRNA expression of myogenic regulatory factors (myog and myf-5) and pax7 in fast muscle was also affected by different photoperiod conditions. Notably, myog was significantly elevated in the continuous illumination group throughout the time course of the experiment. The absence of a day/night cycle is associated with a generalised decrease in mll expression concomitant with an increase in myog transcript levels in fast muscle of Atlantic cod, which may be involved in the observed epigenetic regulation of growth by photoperiod in this species. PMID:22590633

  20. Current standard treatment of adult acute promyelocytic leukaemia.

    PubMed

    Lo-Coco, Francesco; Cicconi, Laura; Breccia, Massimo

    2016-03-01

    The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease. PMID:26687281

  1. Immunophenotypic characterisation of acute leukaemia after polycythemia vera.

    PubMed Central

    Hernández, J M; Orfao, A; González, M; Cuesta, B; López-Berges, M C; Cañizo, M C; Ciudad, J; San Miguel, J F

    1993-01-01

    AIMS--To analyze the immunophenotype of blast cells in patients with acute leukaemia after polycythemia vera, together with the most relevant clinical and haematological disease characteristics. METHODS--The immunophenotype was analysed in nine patients by immunofluorescence flow cytometry using a panel of 15 monoclonal antibodies. The DNA content of blast cells was determined using Vindelov's technique. RESULTS--The most relevant clinical and haematological disease characteristics included: the presence of enlarged spleen and liver by 56% and 67%, respectively; a moderate degree of leucocytosis with thrombocytopenia while haemoglobin was normal in 50% of patients. All patients received alkylating agents or hydroxyurea, or both. Interestingly, the chronic phase in patients receiving this latter drug was shorter. All cases showed a myeloid phenotype, four of them reactive only to early myeloid antigens (CD13/33); in the remaining cases the blast cells displayed granulomonocytic (CD14+, CD15+), erythroid (CD71 ), or megakaryocytic (CD61+, CD41+) markers. Coexpression of lymphoid related antigens (CD7, TdT, or CD19) was also detected. The morphological assessment of blast cells agreed with the immunophenotyping in five out of the nine cases. Blast cells from all six patients analysed displayed a diploid DNA content and the proportion of S-phase cells ranged from 0.4% to 4%. CONCLUSIONS--These findings suggest a pluripotential stem cell with myeloid commitment as the target cell of acute leukaemia after polycythemia vera. PMID:8157758

  2. Antibody-based treatment of acute myeloid leukaemia.

    PubMed

    Mulford, Deborah A; Jurcic, Joseph G

    2004-01-01

    Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML. PMID:14680472

  3. The MRX Complex Ensures NHEJ Fidelity through Multiple Pathways Including Xrs2-FHA-Dependent Tel1 Activation.

    PubMed

    Iwasaki, Daichi; Hayashihara, Kayoko; Shima, Hiroki; Higashide, Mika; Terasawa, Masahiro; Gasser, Susan M; Shinohara, Miki

    2016-03-01

    Because DNA double-strand breaks (DSBs) are one of the most cytotoxic DNA lesions and often cause genomic instability, precise repair of DSBs is vital for the maintenance of genomic stability. Xrs2/Nbs1 is a multi-functional regulatory subunit of the Mre11-Rad50-Xrs2/Nbs1 (MRX/N) complex, and its function is critical for the primary step of DSB repair, whether by homologous recombination (HR) or non-homologous end joining. In human NBS1, mutations result truncation of the N-terminus region, which contains a forkhead-associated (FHA) domain, cause Nijmegen breakage syndrome. Here we show that the Xrs2 FHA domain of budding yeast is required both to suppress the imprecise repair of DSBs and to promote the robust activation of Tel1 in the DNA damage response pathway. The role of the Xrs2 FHA domain in Tel1 activation was independent of the Tel1-binding activity of the Xrs2 C terminus, which mediates Tel1 recruitment to DSB ends. Both the Xrs2 FHA domain and Tel1 were required for the timely removal of the Ku complex from DSB ends, which correlates with a reduced frequency of imprecise end-joining. Thus, the Xrs2 FHA domain and Tel1 kinase work in a coordinated manner to maintain DSB repair fidelity. PMID:26990569

  4. Analysis of candidate genes for macular telangiectasia type 2

    PubMed Central

    Parmalee, Nancy L.; Schubert, Carl; Merriam, Joanna E.; Allikmets, Kaija; Bird, Alan C.; Gillies, Mark C.; Peto, Tunde; Figueroa, Maria; Friedlander, Martin; Fruttiger, Marcus; Greenwood, John; Moss, Stephen E.; Smith, Lois E.H.; Toomes, Carmel; Inglehearn, Chris F.

    2010-01-01

    Purpose To find the gene(s) responsible for macular telangiectasia type 2 (MacTel) by a candidate-gene screening approach. Methods Candidate genes were selected based on the following criteria: those known to cause or be associated with diseases with phenotypes similar to MacTel, genes with known function in the retinal vasculature or macular pigment transport, genes that emerged from expression microarray data from mouse models designed to mimic MacTel phenotype characteristics, and genes expressed in the retina that are also related to diabetes or hypertension, which have increased prevalence in MacTel patients. Probands from eight families with at least two affected individuals were screened by direct sequencing of 27 candidate genes. Identified nonsynonymous variants were analyzed to determine whether they co-segregate with the disease in families. Allele frequencies were determined by TaqMan analysis of the large MacTel and control cohorts. Results We identified 23 nonsynonymous variants in 27 candidate genes in at least one proband. Of these, eight were known single nucleotide polymorphisms (SNPs) with allele frequencies of >0.05; these variants were excluded from further analyses. Three previously unidentified missense variants, three missense variants with reported disease association, and five rare variants were analyzed for segregation and/or allele frequencies. No variant fulfilled the criteria of being causal for MacTel. A missense mutation, p.Pro33Ser in frizzled homolog (Drosophila) 4 (FZD4), previously suggested as a disease-causing variant in familial exudative vitreoretinopathy, was determined to be a rare benign polymorphism. Conclusions We have ruled out the exons and flanking intronic regions in 27 candidate genes as harboring causal mutations for MacTel. PMID:21179236

  5. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia

    PubMed Central

    Lilljebjörn, Henrik; Henningsson, Rasmus; Hyrenius-Wittsten, Axel; Olsson, Linda; Orsmark-Pietras, Christina; von Palffy, Sofia; Askmyr, Maria; Rissler, Marianne; Schrappe, Martin; Cario, Gunnar; Castor, Anders; Pronk, Cornelis J. H.; Behrendtz, Mikael; Mitelman, Felix; Johansson, Bertil; Paulsson, Kajsa; Andersson, Anna K.; Fontes, Magnus; Fioretos, Thoas

    2016-01-01

    Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease. PMID:27265895

  6. Identification of ETV6-RUNX1-like and DUX4-rearranged subtypes in paediatric B-cell precursor acute lymphoblastic leukaemia.

    PubMed

    Lilljebjörn, Henrik; Henningsson, Rasmus; Hyrenius-Wittsten, Axel; Olsson, Linda; Orsmark-Pietras, Christina; von Palffy, Sofia; Askmyr, Maria; Rissler, Marianne; Schrappe, Martin; Cario, Gunnar; Castor, Anders; Pronk, Cornelis J H; Behrendtz, Mikael; Mitelman, Felix; Johansson, Bertil; Paulsson, Kajsa; Andersson, Anna K; Fontes, Magnus; Fioretos, Thoas

    2016-01-01

    Fusion genes are potent driver mutations in cancer. In this study, we delineate the fusion gene landscape in a consecutive series of 195 paediatric B-cell precursor acute lymphoblastic leukaemia (BCP ALL). Using RNA sequencing, we find in-frame fusion genes in 127 (65%) cases, including 27 novel fusions. We describe a subtype characterized by recurrent IGH-DUX4 or ERG-DUX4 fusions, representing 4% of cases, leading to overexpression of DUX4 and frequently co-occurring with intragenic ERG deletions. Furthermore, we identify a subtype characterized by an ETV6-RUNX1-like gene-expression profile and coexisting ETV6 and IKZF1 alterations. Thus, this study provides a detailed overview of fusion genes in paediatric BCP ALL and adds new pathogenetic insights, which may improve risk stratification and provide therapeutic options for this disease. PMID:27265895

  7. Life span, leukaemia and amyloid incidences of untreated and polycation-treated AKR mice.

    PubMed Central

    Ebbesen, P.

    1978-01-01

    AKR mice, which have a short mean survival time and usually die with leukaemia, were studied from one month of age for correlation between these two parameters. For untreated animals we found the same mean survival time whether or not leukaemia occurred. By treating sucklings with the polycations diethylaminoethyl-dextran or hexadimethrine bromide the leukaemia incidence was significantly reduced. However, the mean survival time was unchanged, and remained the same in leukaemic and non-leukaemic animals. It is therefore suggested that the early death of AKR mice results from an ageing process and does not require leukaemia for implementation. Our prophylactic polycation treatment was furthermore found to induce spleen amyloid in some but not all of the mice that remained non-leukaemic. PMID:619959

  8. Bone marrow and splenic histology in hairy cell leukaemia.

    PubMed

    Wotherspoon, Andrew; Attygalle, Ayoma; Mendes, Larissa Sena Teixeira

    2015-12-01

    Hairy cell leukaemia is a rare chronic neoplastic B-cell lymphoproliferation that characteristically involves blood, bone marrow and spleen with liver, lymph node and skin less commonly involved. Histologically, the cells have a characteristic appearance with pale/clear cytoplasm and round or reniform nuclei. In the spleen, the infiltrate involves the red pulp and is frequently associated with areas of haemorrhage (blood lakes). The cells stain for B-cell related antigens as well as with antibodies against tartrate-resistant acid phosphatase, DBA44 (CD72), CD11c, CD25, CD103, CD123, cyclin D1 and annexin A1. Mutation of BRAF -V600E is present and antibody to the mutant protein can be used as a specific marker. Bone marrow biopsy is essential in the initial assessment of disease as the bone marrow may be inaspirable or unrepresentative of degree of marrow infiltration as a result of the tumour associated fibrosis preventing aspiration of the tumour cell component. Bone marrow biopsy is important in the assessment of therapy response but in this context staining for CD11c and Annexin A1 is not helpful as they are also markers of myeloid lineage and identification of low level infiltration may be obscured. In this context staining for CD20 may be used in conjunction with morphological assessment and staining of serial sections for cyclin D1 and DBA44 to identify subtle residual infiltration. Staining for CD79a and CD19 is not recommended as these antibodies will identify plasma cells and can lead to over-estimation of disease. Staining for CD20 should not be used in patients following with anti-CD20 based treatments. Down regulation of cyclin D1 and CD25 has been reported in patients following BRAF inhibitor therapy and assessment of these antigens should not be used in this context. Histologically, hairy cell leukaemia needs to be distinguished from other B-cell lymphoproliferations associated with splenomegaly including splenic marginal zone lymphoma, splenic

  9. tax and rex Sequences of bovine leukaemia virus from globally diverse isolates: rex amino acid sequence more variable than tax.

    PubMed

    McGirr, K M; Buehring, G C

    2005-02-01

    Bovine leukaemia virus (BLV) is an important agricultural problem with high costs to the dairy industry. Here, we examine the variation of the tax and rex genes of BLV. The tax and rex genes share 420 bases and have overlapping reading frames. The tax gene encodes a protein that functions as a transactivator of the BLV promoter, is required for viral replication, acts on cellular promoters, and is responsible for oncogenesis. The rex facilitates the export of viral mRNAs from the nucleus and regulates transcription. We have sequenced five new isolates of the tax/rex gene. We examined the five new and three previously published tax/rex DNA and predicted amino acid sequences of BLV isolates from cattle in representative regions worldwide. The highest variation among nucleic acid sequences for tax and rex was 7% and 5%, respectively; among predicted amino acid sequences for Tax and Rex, 9% and 11%, respectively. Significantly more nucleotide changes resulted in predicted amino acid changes in the rex gene than in the tax gene (P < or = 0.0006). This variability is higher than previously reported for any region of the viral genome. This research may also have implications for the development of Tax-based vaccines. PMID:15702995

  10. Acute myeloid leukaemia as a cause of acute ischaemic heart disease

    PubMed Central

    van Haelst, P.L.; Schot, B.; Hoendermis, E.S.; van den Berg, M.P.

    2006-01-01

    Ischaemic heart disease is almost invariably the result of atherosclerotic degeneration of the coronary arteries. However, other causes of ischaemic heart disease should always be considered. Here we describe two patients with a classic presentation of ischaemic heart disease resulting from acute leukaemia. The pathophysiological mechanisms of acute leukaemia leading to ischaemic heart disease are discussed. ImagesFigure 1AFigure 1BFigure 2 PMID:25696595

  11. Pseudozyma aphidis fungaemia with invasive fungal pneumonia in a patient with acute myeloid leukaemia: case report and literature review.

    PubMed

    Joo, Hyonsoo; Choi, Yeon-Geun; Cho, Sung-Yeon; Choi, Jae-Ki; Lee, Dong-Gun; Kim, Hee-Je; Jo, Irene; Park, Yeon-Joon; Lee, Kyo-Young

    2016-01-01

    Pseudozyma species rarely cause invasive diseases in humans, which are usually isolated from plants. There have been anecdotal reports regarding Pseudozyma species infections in patients with underlying diseases or in neonates. However, clinical data and the pathogenicity in humans are still insufficient. We experienced a case of Pseudozyma aphidis fungaemia with invasive fungal pneumonia that developed during reinduction chemotherapy in a 51-year-old male with acute myeloid leukaemia (AML). P. aphidis was suspected based on the morphology of the yeast isolated from the blood and was confirmed via rDNA gene sequencing analysis. The patient successfully underwent stem cell transplantation with continuing antifungal treatment and finally completely recovered from both the AML and infectious complications. Here, we report a case of P. aphidis infection that developed during neutropenia in an AML patient and review the global literature. PMID:26608844

  12. Harnessing the immune system in acute myeloid leukaemia.

    PubMed

    Austin, Rebecca; Smyth, Mark J; Lane, Steven W

    2016-07-01

    Acute myeloid leukaemia (AML) is an aggressive blood cancer caused by the proliferation of immature myeloid cells. The genetic abnormalities underlying AML affect signal transduction pathways, transcription factors and epigenetic modifiers. In solid tumours, it is emerging that the genetic landscape of the tumour has a direct effect on the anti-tumour immune responses and response to immunotherapeutic treatment. However, there remains little information as to whether genetic abnormalities affect anti-leukemic immune responses. This review discusses current knowledge of AML antigens and immune responses to AML with a particular focus on the role of T cells and natural killer cells. Understanding immune responses to AML has implications for the development and use of immunotherapies to treat AML patients with distinct genetic abnormalities. PMID:27247119

  13. Orbital mass secondary to infantile acute lymphoblastic leukaemia.

    PubMed

    Hossain, Ibtesham Tausif; Moosajee, Mariya; Abou-Rayyah, Yassir; Pavasovic, Vesna

    2016-01-01

    An 8-month-old Asian infant girl was referred with a 1-week history of left periorbital swelling on a background of a narrowed left palpebral aperture over the preceding 8 weeks. There was no history of chronic illness, fever or other systemic features. Examination revealed a tender and fluctuant medial canthal swelling with associated periorbital haematoma. There were no other ophthalmic findings and neurological examination was normal. A MRI scan of the brain and orbit demonstrated abnormal soft tissue with features of an aggressive tumour in the left orbital region with no globe invasion. Peripheral blood smear revealed blast cells, confirmed by bone marrow aspirate. A diagnosis of infant acute lymphoblastic leukaemia was made. The patient was started on risk-stratified chemotherapy according to the Interfant-06 Protocol The periorbital swelling resolved by day eight following a course of prednisolone, the patient continues on chemotherapy and is currently in molecular remission. PMID:27143162

  14. Metabolic syndrome in the survivors of childhood acute lymphoblastic leukaemia.

    PubMed

    Abu-Ouf, Noran M; Jan, Mohammed M

    2015-01-01

    Metabolic syndrome is a common complication encountered in children surviving acute lymphoblastic leukaemia (ALL). Affected patients develop obesity, insulin resistance, hypertension, and hyperlipidemia. Metabolic syndrome is a consequence of multiple factors, particularly hormonal imbalance induced by various ALL treatments. This review aims to evaluate the risk factors and mechanisms leading to the development of metabolic syndrome. Further research is needed to improve our understanding of the mechanisms leading to insulin resistance and the associated endothelial and adipose tissue dysfunction. Future studies should also examine other possible contributing factors, such as environmental and genetic factors. Understanding these factors will help in guiding modifications of the current ALL treatment protocols in order to prevent the development of this syndrome and hence improve the quality of life of ALL survivors. Until this is achieved, clinicians should continue to identify patients at risk early and use a therapeutic approach that combines dietary restrictions and enhanced physical activity. PMID:25081809

  15. Skin nodules in a patient with acute lymphoblastic leukaemia

    PubMed Central

    Le Clech, Lenaïg; Hutin, Pascal; Le Gal, Solène; Guillerm, Gaëlle

    2014-01-01

    Opportunistic infections cause a significant morbidity and mortality in immunocompromised patients. We describe the case of a patient with skin fusariosis and a probable cerebral toxoplasmosis after UCB stem cell transplantation for B-cell acute lymphoblastic leukaemia. Fusarium species (spp) infections are difficult to treat. To date, there has been no consensus on the treatment of fusariosis and the management of its side effects. Given the negative pretransplant Toxoplasma serology in this case, identifying the origin of the Toxoplasma infection was challenging. All usual transmission routes were screened for and ruled out. The patient's positive outcome was not consistent with that of the literature reporting 60% mortality due to each infection. PMID:24408938

  16. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation.

    PubMed

    Xu, Shuang-Nian; Wang, Tian-Shi; Li, Xi; Wang, Yi-Ping

    2016-01-01

    Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations. PMID:27586085

  17. A case–control study of risk of leukaemia in relation to mobile phone use

    PubMed Central

    Cooke, R; Laing, S; Swerdlow, A J

    2010-01-01

    Background: Mobile phone use is now ubiquitous, and scientific reviews have recommended research into its relation to leukaemia risk, but no large studies have been conducted. Methods: In a case–control study in South East England to investigate the relation of acute and non-lymphocytic leukaemia risk to mobile phone use, 806 cases with leukaemia incident 2003–2009 at ages 18–59 years (50% of those identified as eligible) and 585 non-blood relatives as controls (provided by 392 cases) were interviewed about mobile phone use and other potentially aetiological variables. Results: No association was found between regular mobile phone use and risk of leukaemia (odds ratio (OR)=1.06, 95% confidence interval (CI)=0.76, 1.46). Analyses of risk in relation to years since first use, lifetime years of use, cumulative number of calls and cumulative hours of use produced no significantly raised risks, and there was no evidence of any trends. A non-significantly raised risk was found in people who first used a phone 15 or more years ago (OR=1.87, 95% CI=0.96, 3.63). Separate analyses of analogue and digital phone use and leukaemia subtype produced similar results to those overall. Conclusion: This study suggests that use of mobile phones does not increase leukaemia risk, although the possibility of an effect after long-term use, while biologically unlikely, remains open. PMID:20940717

  18. SIRT2 activates G6PD to enhance NADPH production and promote leukaemia cell proliferation

    PubMed Central

    Xu, Shuang-Nian; Wang, Tian-Shi; Li, Xi; Wang, Yi-Ping

    2016-01-01

    Like most other types of cancer cells, leukaemia cells undergo metabolic reprogramming to support rapid proliferation through enhancing biosynthetic processes. Pentose phosphate pathway (PPP) plays a pivotal role in meeting the anabolic demands for cancer cells. However, the molecular mechanism by which PPP contributes to leukaemia remains elusive. Here, we report that leukaemia cell proliferation is dependent on the oxidative branch of PPP, in particular the first and rate-limiting enzyme glucose-6-phosphate dehydrogenase (G6PD). Knockdown of G6PD reduces NADPH level in acute myeloid leukaemia (AML) cell lines. Exogenous lipid supplements partially restore the proliferation of G6PD-depleted cells. Deacetylase SIRT2 promotes NADPH production through deacetylating G6PD at lysine 403 (K403). Activation of G6PD by SIRT2 supports the proliferation and clonogenic activity of leukaemia cells. Chemical inhibitors against SIRT2 suppress G6PD activity, leading to reduced cell proliferation of leukaemia cells, but not normal hematopoietic stem and progenitor cells. Importantly, SIRT2 is overexpressed in clinical AML samples, while K403 acetylation is downregulated and G6PD catalytic activity is increased comparing to that of normal control. Together, our study reveals that acetylation regulation of G6PD is involved in the metabolic reprogramming of AML, and SIRT2 serves as a promising target for further therapeutic investigations. PMID:27586085

  19. Mutation allele burden remains unchanged in chronic myelomonocytic leukaemia responding to hypomethylating agents

    DOE PAGESBeta

    Merlevede, Jane; Droin, Nathalie; Qin, Tingting; Meldi, Kristen; Yoshida, Kenichi; Morabito, Margot; Chautard, Emilie; Auboeuf, Didier; Fenaux, Pierre; Braun, Thorsten; et al

    2016-02-24

    The cytidine analogues azacytidine and 5-aza-2’-deoxycytidine (decitabine) are commonly used to treat myelodysplastic syndromes, with or without a myeloproliferative component. It remains unclear whether the response to these hypomethylating agents results from a cytotoxic or an epigenetic effect. In this study, we address this question in chronic myelomonocytic leukaemia. We describe a comprehensive analysis of the mutational landscape of these tumours, combining whole-exome and whole-genome sequencing. We identify an average of 14 ± 5 somatic mutations in coding sequences of sorted monocyte DNA and the signatures of three mutational processes. Serial sequencing demonstrates that the response to hypomethylating agents ismore » associated with changes in DNA methylation and gene expression, without any decrease in the mutation allele burden, nor prevention of new genetic alteration occurence. Lastly, our findings indicate that cytosine analogues restore a balanced haematopoiesis without decreasing the size of the mutated clone, arguing for a predominantly epigenetic effect.« less

  20. Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity.

    PubMed

    Kutszegi, Nóra; Semsei, Ágnes F; Gézsi, András; Sági, Judit C; Nagy, Viktória; Csordás, Katalin; Jakab, Zsuzsanna; Lautner-Csorba, Orsolya; Gábor, Krisztina Míta; Kovács, Gábor T; Erdélyi, Dániel J; Szalai, Csaba

    2015-01-01

    L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin-Frankfurt-Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01-0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09-0.53); p = 8.48E-04 and OR = 3.02 (1.36-6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. PMID:26457809

  1. Economic impact of genomic diagnostics for intermediate-risk acute myeloid leukaemia.

    PubMed

    Cressman, Sonya; Karsan, Aly; Hogge, Donna E; McPherson, Emily; Bolbocean, Corneliu; Regier, Dean A; Peacock, Stuart J

    2016-08-01

    Acute Myeloid Leukaemia (AML) is a rare but serious group of diseases that require critical decision-making for curative treatment. Over the past decade, scientific discovery has revealed dozens of prognostic gene mutations for AML while sequencing costs have plummeted. In this study, we compared the cost-effectiveness of multigene integrative analysis (genomic analysis) with the standard molecular testing currently used for diagnosis of intermediate-risk AML. We used a decision analytic model with data for costs and outcomes from British Columbia, Canada, to assess the long-term (10-year) economic impacts. Our results suggest that genomic analysis would result in a 26% increase in the use of first-remission allogeneic stem cell transplantation. The resulting treatment decisions and downstream effects would come at an additional cost of $12 556 [2013 Canadian dollars (CAD)] per person and the incremental cost-effectiveness ratio would be $49 493 per quality-adjusted life-year gained. Cost-effectiveness was dependent on quality of life during the long-term (5-10) years of survival, relapse rates following first-remission chemotherapy and the upfront cost of transplantation. Non-relapse mortality rates, short-term quality of life and the cost of genomic sequencing had only minor impacts. Further research on post-remission outcomes can lead to improvements in the cost-effectiveness of curative treatments for AML. PMID:27098559

  2. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model.

    PubMed

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-08-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1(tg) mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  3. Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing.

    PubMed

    Ding, Li; Ley, Timothy J; Larson, David E; Miller, Christopher A; Koboldt, Daniel C; Welch, John S; Ritchey, Julie K; Young, Margaret A; Lamprecht, Tamara; McLellan, Michael D; McMichael, Joshua F; Wallis, John W; Lu, Charles; Shen, Dong; Harris, Christopher C; Dooling, David J; Fulton, Robert S; Fulton, Lucinda L; Chen, Ken; Schmidt, Heather; Kalicki-Veizer, Joelle; Magrini, Vincent J; Cook, Lisa; McGrath, Sean D; Vickery, Tammi L; Wendl, Michael C; Heath, Sharon; Watson, Mark A; Link, Daniel C; Tomasson, Michael H; Shannon, William D; Payton, Jacqueline E; Kulkarni, Shashikant; Westervelt, Peter; Walter, Matthew J; Graubert, Timothy A; Mardis, Elaine R; Wilson, Richard K; DiPersio, John F

    2012-01-26

    Most patients with acute myeloid leukaemia (AML) die from progressive disease after relapse, which is associated with clonal evolution at the cytogenetic level. To determine the mutational spectrum associated with relapse, we sequenced the primary tumour and relapse genomes from eight AML patients, and validated hundreds of somatic mutations using deep sequencing; this allowed us to define clonality and clonal evolution patterns precisely at relapse. In addition to discovering novel, recurrently mutated genes (for example, WAC, SMC3, DIS3, DDX41 and DAXX) in AML, we also found two major clonal evolution patterns during AML relapse: (1) the founding clone in the primary tumour gained mutations and evolved into the relapse clone, or (2) a subclone of the founding clone survived initial therapy, gained additional mutations and expanded at relapse. In all cases, chemotherapy failed to eradicate the founding clone. The comparison of relapse-specific versus primary tumour mutations in all eight cases revealed an increase in transversions, probably due to DNA damage caused by cytotoxic chemotherapy. These data demonstrate that AML relapse is associated with the addition of new mutations and clonal evolution, which is shaped, in part, by the chemotherapy that the patients receive to establish and maintain remissions. PMID:22237025

  4. Chronic lymphocytic leukaemia induces an exhausted T cell phenotype in the TCL1 transgenic mouse model

    PubMed Central

    Gassner, Franz J; Zaborsky, Nadja; Catakovic, Kemal; Rebhandl, Stefan; Huemer, Michael; Egle, Alexander; Hartmann, Tanja N; Greil, Richard; Geisberger, Roland

    2015-01-01

    Although chronic lymphocytic leukaemia (CLL) is a B cell malignancy, earlier studies have indicated a role of T cells in tumour growth and disease progression. In particular, the functional silencing of antigen-experienced T cells, called T cell exhaustion, has become implicated in immune evasion in CLL. In this study, we tested whether T cell exhaustion is recapitulated in the TCL1tg mouse model for CLL. We show that T cells express high levels of the inhibitory exhaustion markers programmed cell death 1 (PDCD1, also termed PD-1) and lymphocyte-activation gene 3 (LAG3), whereas CLL cells express high levels of CD274 (also termed PD-ligand 1). In addition, the fraction of exhausted T cells increases with CLL progression. Finally, we demonstrate that exhausted T cells are reinvigorated towards CLL cytotoxicity by inhibition of PDCD1/CD274 interaction in vivo. These results suggest that T cell exhaustion contributes to CLL pathogenesis and that interference with PDCD1/CD274 signalling holds high potential for therapeutic approaches. PMID:25940792

  5. Clinical relevance of molecular aberrations in paediatric acute myeloid leukaemia at first relapse.

    PubMed

    Bachas, Costa; Schuurhuis, Gerrit Jan; Reinhardt, Dirk; Creutzig, Ursula; Kwidama, Zinia J; Zwaan, C Michel; van den Heuvel-Eibrink, Marry M; De Bont, Evelina S J M; Elitzur, Sarah; Rizzari, Carmelo; de Haas, Valérie; Zimmermann, Martin; Cloos, Jacqueline; Kaspers, Gertjan J L

    2014-09-01

    Outcome for relapsed paediatric acute myeloid leukaemia (AML) remains poor. Strong prognostic factors at first relapse are lacking, which hampers optimization of therapy. We assessed the frequency of molecular aberrations (FLT3, NRAS, KRAS, KIT, WT1 and NPM1 genes) at first relapse in a large set (n = 198) of relapsed non-French-American-British M3, non-Down syndrome AML patients that received similar relapse treatment. We correlated molecular aberrations with clinical and biological factors and studied their prognostic relevance. Hotspot mutations in the analysed genes were detected in 92 out of 198 patients (46·5%). In 72 of these 92 patients (78%), molecular aberrations were mutually exclusive for the currently analysed genes. FLT3-internal tandem repeat (ITD) (18% of total group) mutations were most frequent, followed by NRAS (10·2%), KRAS (8%), WT1 (8%), KIT (8%), NPM1 (5%) and FLT3-tyrosine kinase domain (3%) mutations. Presence of a WT1 aberration was an independent risk factor for second relapse (Hazard Ratio [HR] = 2·74, P = 0·013). In patients who achieved second complete remission (70·2%), WT1 and FLT3-ITD aberrations were independent risk factors for poor overall survival (HR = 2·32, P = 0·038 and HR = 1·89, P = 0·045 respectively). These data show that molecular aberrations at first relapse are of prognostic relevance and potentially useful for risk group stratification of paediatric relapsed AML and for identification of patients eligible for personalized treatment. PMID:24962064

  6. A meta-analysis of leukaemia risk from protracted exposure to low-dose gamma radiation

    PubMed Central

    Schubauer-Berigan, M K

    2010-01-01

    Context More than 400 000 workers annually receive a measurable radiation dose and may be at increased risk of radiation-induced leukaemia. It is unclear whether leukaemia risk is elevated with protracted, low-dose exposure. Objective We conducted a meta-analysis examining the relationship between protracted low-dose ionising radiation exposure and leukaemia. Data sources Reviews by the National Academies and United Nations provided a summary of informative studies published before 2005. PubMed and Embase databases were searched for additional occupational and environmental studies published between 2005 and 2009. Study selection We selected 23 studies that: (1) examined the association between protracted exposures to ionising radiation and leukaemia excluding chronic lymphocytic subtype; (2) were a cohort or nested case–control design without major bias; (3) reported quantitative estimates of exposure; and (4) conducted exposure–response analyses using relative or excess RR per unit exposure. Methods Studies were further screened to reduce information overlap. Random effects models were developed to summarise between-study variance and obtain an aggregate estimate of the excess RR at 100 mGy. Publication bias was assessed by trim and fill and Rosenthal's file drawer methods. Results We found an ERR at 100 mGy of 0.19 (95% CI 0.07 to 0.32) by modelling results from 10 studies and adjusting for publication bias. Between-study variance was not evident (p=0.99). Conclusions Protracted exposure to low-dose gamma radiation is significantly associated with leukaemia. Our estimate agreed well with the leukaemia risk observed among exposed adults in the Life Span Study (LSS) of atomic bomb survivors, providing increased confidence in the current understanding of leukaemia risk from ionising radiation. However, unlike the estimates obtained from the LSS, our model provides a precise, quantitative summary of the direct estimates of excess risk from studies of

  7. Temporal trends in childhood leukaemia incidence following exposure to radioactive fallout from atmospheric nuclear weapons testing.

    PubMed

    Wakeford, Richard; Darby, Sarah C; Murphy, Michael F G

    2010-05-01

    Notably raised rates of childhood leukaemia incidence have been found near some nuclear installations, in particular Sellafield and Dounreay in the United Kingdom, but risk assessments have concluded that the radiation doses estimated to have been received by children or in utero as a result of operations at these installations are much too small to account for the reported increases in incidence. This has led to speculation that the risk of childhood leukaemia arising from internal exposure to radiation following the intake of radioactive material released from nuclear facilities has been substantially underestimated. The radionuclides discharged from many nuclear installations are similar to those released into the global environment by atmospheric nuclear weapons testing, which was at its height in the late-1950s and early-1960s. Measurements of anthropogenic radionuclides in members of the general public resident in the vicinity of Sellafield and Dounreay have found levels that do not differ greatly from those in persons living remote from nuclear installations that are due to ubiquitous exposure to the radioactive debris of nuclear weapons testing. Therefore, if the leukaemia risk to children resulting from deposition within the body of radioactive material discharged from nuclear facilities has been grossly underestimated, then a pronounced excess of childhood leukaemia would have been expected as a consequence of the short period of intense atmospheric weapons testing. We have examined childhood leukaemia incidence in 11 large-scale cancer registries in three continents for which data were available at least as early as 1962. We found no evidence of a wave of excess cases corresponding to the peak of radioactive fallout from atmospheric weapons testing. The absence of a discernible increase in the incidence of childhood leukaemia following the period of maximum exposure to the radioactive debris of this testing weighs heavily against the suggestion that

  8. Prognostic indices in chronic lymphocytic leukaemia: where do we stand how do we proceed?

    PubMed

    Baliakas, P; Mattsson, M; Stamatopoulos, K; Rosenquist, R

    2016-04-01

    The remarkable clinical heterogeneity in chronic lymphocytic leukaemia (CLL) has highlighted the need for prognostic and predictive algorithms that can be employed in clinical practice to assist patient management and therapy decisions. Over the last 20 years, this research field has been rewarding and many novel prognostic factors have been identified, especially at the molecular genetic level. Whilst detection of recurrent cytogenetic aberrations and determination of the immunoglobulin heavy variable gene somatic hypermutation status have an established role in outcome prediction, next-generation sequencing has recently revealed novel mutated genes with clinical relevance (e.g. NOTCH1, SF3B1 and BIRC3). Efforts have been made to combine variables into prognostic indices; however, none has been universally adopted. Although a unifying model for all groups of patients and in all situations is appealing, this may prove difficult to attain. Alternatively, focused efforts on patient subgroups in the same clinical context and at certain clinically relevant 'decision points', that is at diagnosis and at initiation of first-line or subsequent treatments, may provide a more accurate approach. In this review, we discuss the advantages and disadvantages as well as the clinical applicability of three recently proposed prognostic models, the MD Anderson nomogram, the integrated cytogenetic and mutational model and the CLL-international prognostic index. We also consider future directions taking into account novel aspects of the disease, such as the tumour microenvironment and the dynamics of (sub)clonal evolution. These aspects are particularly relevant in view of the increasing number of new targeted therapies that have recently emerged. PMID:26709197

  9. The prognostic impact of clinical and molecular features in hairy cell leukaemia variant and splenic marginal zone lymphoma.

    PubMed

    Hockley, Sarah L; Else, Monica; Morilla, Alison; Wotherspoon, Andrew; Dearden, Claire; Catovsky, Daniel; Gonzalez, David; Matutes, Estella

    2012-08-01

    Hairy cell leukaemia variant (HCL-variant) and splenic marginal zone lymphoma (SMZL) are disorders with overlapping features. We investigated the prognostic impact in these disorders of clinical and molecular features including IGH VDJ rearrangements, IGHV gene usage and TP 53 mutations. Clinical and laboratory data were collected before therapy from 35 HCL-variant and 68 SMZL cases. End-points were the need for treatment and overall survival. 97% of HCL-variant and 77% of SMZL cases required treatment (P = 0·009). Survival at 5 years was significantly worse in HCL-variant [57% (95% confidence interval 38-73%)] compared with SMZL [84% (71-91%); Hazard Ratio 2·25 (1·20-4·25), P = 0·01]. In HCL-variant, adverse prognostic factors for survival were older age (P = 0·04), anaemia (P = 0·01) and TP 53 mutations (P = 0·02). In SMZL, splenomegaly, anaemia and IGHV genes with >98% homology to the germline predicted the need for treatment; older age, anaemia and IGHV unmutated genes (100% homology) predicted shorter survival. IGHV gene usage had no impact on clinical outcome in either disease. The combination of unfavourable factors allowed patients to be stratified into risk groups with significant differences in survival. Although HCL-variant and SMZL share some features, they have different outcomes, influenced by clinical and biological factors. PMID:22594855

  10. Risk of childhood leukaemia in the vicinity of nuclear installations--findings and recent controversies.

    PubMed

    Laurier, Dominique; Grosche, Bernd; Hall, Per

    2002-01-01

    The identification of a local excess of cancer cases, possibly associated with ionizing radiation, always receives substantial media coverage and communication about clusters is difficult. We reviewed studies that examined the risk of leukaemia among young people near nuclear installations. An excess of leukaemia exists near some nuclear installations, at least for the reprocessing plants at Sellafield and Dounreay and the nuclear power plant Krümmel. Nonetheless, the results of multi-site studies invalidate the hypothesis of an increased risk of leukaemia related to nuclear discharge. Up until now, analytic studies have not found an explanation for the leukaemia clusters observed near certain nuclear installations. The hypothesis of an infectious aetiology associated with population mixing has been proposed, but needs to be investigated further. The review illustrates two recent examples in France (La Hague reprocessing plant) and in Germany (Krümmel power plant), where controversies developed after reports of increased leukaemia risks. These examples show the importance of recalling the current epidemiological knowledge and of using systematic recording of cases to replace the alleged excesses in a more general framework. Some elements should also be suggested from the recent French and German experiences to reinforce credibility in the results. PMID:11990512

  11. In-Q-Tel, the strategic investment firm for the U.S. Intelligence Community

    NASA Astrophysics Data System (ADS)

    Ulvick, S. J.; Tighe, D. W.

    2008-04-01

    In-Q-Tel is a strategic investment firm that works to identify, adapt, and deliver innovative technology solutions to support the missions of the Central Intelligence Agency and the broader U.S. Intelligence Community (IC). Launched by the CIA in 1999 as a private, independent, not-for-profit organization, IQT's mission is to identify and partner with companies developing cutting-edge technologies that serve the national security interests of the United States. Working from an evolving strategic blueprint defining the Intelligence Community's critical technology needs, IQT engages with entrepreneurs, growth companies, researchers, and venture capitalists to deliver technologies that provide superior capabilities for the CIA and the broader IC. To date, IQT has reviewed more than 6,300 business proposals, invested in more than 100 companies, and delivered more than 140 technology solutions to the U.S. Intelligence Community.

  12. Mapping air pollution by biological monitoring in the metropolitan Tel Aviv area.

    PubMed

    Lavi, Aya; Potchter, Oded; Omer, Itzhak; Fireman, Elizabeth

    2016-06-01

    Conventional environmental monitoring is not surrogate of personal exposure. In contrast, biomonitoring provides information on the presence of substances in the human body, making it highly relevant to the assessment of exposure to toxic substances. Induced sputum (IS) is a noninvasive technique for detecting inflammation and reflecting particulate matter content in the airways. In this study, we mapped particulate matter dispersion in metropolitan Tel Aviv by both biomonitoring techniques employing IS samples and by environmental monitoring. All adults referred to the Pulmonary Lab for respiratory symptom evaluation in 2007 and in 2009 were enrolled. Pulmonary function tests were performed by conventional methods. Particulate size distribution in IS was analyzed, and maps of air pollution were created. Biomonitoring was more informative and enabled mapping of wider areas. Integration of biomonitoring and environmental monitoring should be considered in forming public health policy on containment of airborne particles of toxic substances. PMID:26600473

  13. The infrared variability and nature of symbiotic stars. II - RR Tel

    NASA Astrophysics Data System (ADS)

    Feast, M. W.; Whitelock, P. A.; Catchpole, R. M.; Roberts, G.; Carter, B. S.

    1983-03-01

    The presence of a cool Mira-like component having a period of 387 days is established for the very slow nova symbiotic system RR Tel in the 1972-1981 period, using JHKL IR photometry. Single star models for the system are suggested to be unlikely in view of evidence for a similar periodicity in the photographic region prior to the 1944 outburst. These results are consistent with the presence of a constant period and mean luminosity Mira at all times. If the Mira component is normal, then the IR excess increases toward Mira minimum and may be interpreted as a partial heating of the dust by the blue component and/or ionized gas in the system. The evidence indicates that all slow novae contain cool giant or supergiant components, so that the systems must be of great physical size.

  14. Living with the Diagnosis and Treatment of Leukaemia in a Child with Down's Syndrome: A Mother's Reflection

    ERIC Educational Resources Information Center

    Self, Donna

    2008-01-01

    In this article I will discuss the impact of my 2-year-old son's diagnosis and treatment of leukaemia. I will outline the background to being told he had leukaemia before describing the family dynamics that emerged during this time for me, my husband and our other child. My story will focus on managing the practicalities of a long stay in hospital…

  15. Economic evaluation of treatment for acute lymphoblastic leukaemia in childhood.

    PubMed

    Rae, C; Furlong, W; Jankovic, M; Moghrabi, Albert; Naqvi, A; Sala, A; Samson, Y; DePauw, S; Feeny, D; Barr, R

    2014-11-01

    Berlin-Frankfurt-Munster (BFM) and Dana-Farber Cancer Institute (DFCI) consortia's treatment strategies for acute lymphoblastic leukaemia (ALL) in children are widely used. We compared the health effects and monetary costs of hospital treatments for these two strategies. Parents of children treated at seven centres in Canada, Italy and the USA completed health-related quality of life (HRQL) assessments during four active treatment phases and at 2 years after treatment. Mean HRQL scores were used to calculate quality-adjusted life years (QALYs) for a period of 5 years following diagnosis. Total costs of treatment were determined from variables in administrative databases in a universally accessible and publicly funded healthcare system. Valid HRQL assessments (n = 1200) were collected for 307 BFM and 317 DFCI patients, with costs measured for 66 BFM and 28 DFCI patients. QALYs per patient were <1.0% greater for BFM than DFCI. Median HRQL scores revealed no difference in QALYs. The difference in mean total costs for BFM (US$88 480) and DFCI (US$93 026) was not significant (P = 0.600). This study provides no evidence of superiority for one treatment strategy over the other. Current BFM or DFCI strategies should represent conventional management for the next economic evaluation of treatments for ALL in childhood. PMID:24393150

  16. Present and future of molecular monitoring in chronic myeloid leukaemia.

    PubMed

    Soverini, Simona; De Benedittis, Caterina; Mancini, Manuela; Martinelli, Giovanni

    2016-05-01

    Currently, physicians treating chronic myeloid leukaemia (CML) patients can rely on a wide spectrum of therapeutic options: the best use of such options is essential to achieve excellent clinical outcomes and, possibly, treatment-free remission (TFR). To accomplish this, proper integration of expert clinical and laboratory monitoring of CML patients is fundamental. Molecular response (MR) monitoring of patients at defined time points has emerged as an important success factor for optimal disease management and BCR-ABL1 kinase domain mutation screening is useful to guide therapeutic reassessment in patients who do not achieve optimal responses to tyrosine kinase inhibitor therapy. Deeper MRs might be associated with improved long-term survival outcomes. More importantly, they are considered a gateway to TFR. In molecular biology, novel procedures and technologies are continually being developed. More sophisticated molecular tools and automated analytical solutions are emerging as CML treatment endpoints and expectations become more and more ambitious. Here we provide a critical overview of current and novel methodologies, present their strengths and pitfalls and discuss what their present and future role might be. PMID:26947577

  17. Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia.

    PubMed

    Gaynon, Paul S; Sun, Weili

    2016-06-01

    New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure. PMID:27221005

  18. Personalization of dexamethasone therapy in childhood acute lymphoblastic leukaemia.

    PubMed

    Jackson, Rosanna K; Irving, Julie A E; Veal, Gareth J

    2016-04-01

    Dexamethasone is a key component in the treatment of childhood acute lymphoblastic leukaemia (ALL). Despite playing a key role in the improved survival of ALL over several decades, intensification of dexamethasone therapy has also contributed to the increased toxicity associated with treatment, which is now seen to be at unacceptable levels given the favourable disease prognosis. Therefore the focus for treatment is now shifting towards reducing toxicity whilst maintaining current survival rates. As approximately 50% of patients were successfully treated on less intensive protocols of the 1980s, it has been questioned whether therapy intensification is necessary in all patients. Furthermore, there remains a subset of children who are still not cured of their disease. New strategies are therefore needed to identify patients who could benefit from dose reduction or intensification. However, adjusting a potentially life threatening therapy is a challenging task, particularly given the heterogeneous nature of ALL. This review focuses on the potential for patient stratification based on our current knowledge of dexamethasone pharmacokinetics, pharmacogenetics and the action of dexamethasone at the cellular level. A carefully designed, combined approach is needed if we are to achieve the aim of improved personalization of dexamethasone therapy for future patients. PMID:26729065

  19. Use of natural killer cells as immunotherapy for leukaemia

    PubMed Central

    Grzywacz, Bartosz; Miller, Jeffrey S.; Verneris, Michael R.

    2008-01-01

    Natural killer (NK) cells potentially play a significant role in eradicating residual disease following allogeneic haematopoietic cell transplantation, and have been explored as tools for adoptive immunotherapy for chemotherapy-refractory patients. NK cell cytotoxicity is modulated by multiple activating and inhibitory receptors that maintain a balance between self-tolerance and providing surveillance against pathogens and malignant transformation. The functional characteristics of NK cells are dictated by the strength of inhibitory receptor signalling. Major histocompatibility complex (MHC)-specific inhibitory receptor acquisition occurs sequentially during NK cell development, and is determined by the nature of immunological reconstitution after allogeneic haematopoietic cell transplantation. Polymorphisms of inhibitory receptors [killer immunoglobulin-like receptors (KIRs)] and their ligands (MHC) contribute to interindividual variability. As a result, the functional NK cell repertoire of individual donors has variable potential for graft-vs-leukaemia reactions. Models predicting NK cell alloreactivity, including KIR ligand mismatch and missing KIR ligand strategies, are discussed as algorithms for optimal NK cell donor selection. Future modifications to improve NK cell adoptive immunotherapy by means of increasing target recognition and reducing inhibitory signalling are being explored. PMID:18790450

  20. Hairy cell leukaemia and occupational exposure to benzene.

    PubMed Central

    Clavel, J; Conso, F; Limasset, J C; Mandereau, L; Roche, P; Flandrin, G; Hémon, D

    1996-01-01

    OBJECTIVES: The role of occupational exposures in hairy cell leukaemia (HCL) was investigated through a multicentre, hospital based, case-control study. This paper analyses the role of exposure to benzene in HCL. METHODS: A population of 226 male cases of HCL and 425 matched controls were included in the study. Benzene exposure was evaluated by expert review of the detailed data on occupational exposures generated by case-control interviews. RESULTS: No association was found between HCL and employment in a job exposed to benzene (odds ratio (OR) 0.9 (95% confidence interval (95% CI) 0.6-1.3)). The sample included 125 subjects, 34 cases (15%), and 91 controls (21%) who had been exposed to benzene, as individually assessed by the experts, for at least one hour a month during one of their jobs. Benzene exposure was not associated with a risk of HCL (OR 0.8 (0.5-1.2)). No trend towards an increase in OR was detected for increasing exposures, the percentage of work time involving exposure to > 1 ppm, or the duration of exposure. No findings suggested a particular risk period, when the OR associated with the time since first or last exposure, or since the end of exposure, were examined. CONCLUSIONS: In conclusion, with the low exposures prevalent in the sample, the study did not show any association between benzene exposure and HCL. PMID:8983464

  1. Longitudinal language outcomes following intrathecal chemotherapy for acute lymphoblastic leukaemia.

    PubMed

    Lewis, Fiona M; Perry, Meghan L; Murdoch, Bruce E

    2013-04-01

    Intrathecal chemotherapy (ITC) is the treatment option for acute lymphoblastic leukaemia (ALL). Neurocognitive deficits have been described following ITC, but language status post-treatment is yet to be clarified. This study examined the language skills of nine children following ITC for ALL (mean age 7;8 years and 3;2 years post-diagnosis at baseline measurement) and nine age- and sex-matched controls, at baseline then 2 years later, using a battery of tests assessing general language skills. An assessment of cognitively-demanding high level language skills was undertaken on a sub-group of the children (n =12). Statistical analysis revealed no significant difference between children treated with ITC and controls when comparing change in performance scores from baseline measurement to 2 years post-baseline measurement. Descriptive analysis of three of the ALL participants in the Intermediate Stage survivorship at language re-assessment indicated no clinically-significant change in performance over 2 years for all measures except receptive language skills, which improved over the time for two of the children. As language skills continue to develop into late adolescence, the need for the monitoring of language abilities of children treated at a young age with ITC as they enter the Intermediate and Late Stages of survivorship is discussed. PMID:22663017

  2. Therapeutic drug monitoring of aminoglycosides in acute myeloid leukaemia patients.

    PubMed

    Mareville, Julie; Gay, Julie; Cliquennois, Emmanuel; Herbaux, Charles; Pasquier, Florence; Allorge, Delphine; Blondiaux, Nicolas; Berthon, Céline; Alfandari, Serge

    2012-05-01

    International guidelines limit the use of aminoglycosides in febrile neutropenia to severe situations. We retrospectively reviewed the use of aminoglycosides in adult acute myeloid leukaemia patients admitted in 2009. Our guidelines include precise indications (severe sepsis, shock, drug resistance), dosing regimens (once-daily 20 mg/kg/day amikacin, 5 mg/kg/day gentamicin), durations of treatment, drug monitoring timing, and target C(max) concentrations (40 mg/l amikacin, 20 mg/l gentamicin). Thirty-one patients received 46 aminoglycoside courses: 31 amikacin and 15 gentamicin. The mean prescribed dosage was 19 ± 2.8 mg/kg/day for amikacin and 4.7 ± 0.9 mg/kg/day for gentamicin. The mean duration of use was 2.9 days for both drugs. The mean C(max) for amikacin was 47 ± 13 mg/l and for gentamicin was 13.6 ± 7.5 mg/l. In compliant regimens, all amikacin patients and a third of gentamicin patients had adequate C(max). Among 23 isolated pathogens, 65.5% were susceptible to both drugs and 11.5% to amikacin only. This vindicates the 20 mg/kg/day amikacin dosage and suggests a need to increase the gentamicin dosage. PMID:22235869

  3. Azacitidine: A Review in Myelodysplastic Syndromes and Acute Myeloid Leukaemia.

    PubMed

    Scott, Lesley J

    2016-05-01

    Azacitidine (Vidaza(®)) is a pyrimidine nucleoside analogue of cytidine and is approved in the EU for use in patients with higher-risk myelodysplastic syndromes (MDS) and acute myeloid leukaemia (AML), including older patients (aged ≥65 years) with AML with >30 % bone marrow blasts (BMB) who are ineligible for haematopoietic stem cell transplant. This article reviews the clinical efficacy and tolerability of azacitidine in the treatment of these patient populations, as well as summarizing its pharmacological properties. In pivotal, international, phase 3 trials, subcutaneous azacitidine was an effective and well tolerated treatment in patients with higher-risk MDS or AML, including older patients with AML with >30 % BMB, with extensive evidence from the real-world setting confirming its efficacy and safety in these patient populations. Azacitidine is the only approved hypomethylating agent that has been shown to prolong overall survival compared with conventional care regimens and thus, it is recommended as the first-line hypomethylating agent for most patients with higher-risk MDS. Hence, azacitidine remains and important agent for use in the treatment of higher-risk MDS and AML, including in older patients with AML with >30 % BMB. PMID:27193945

  4. Non-coding recurrent mutations in chronic lymphocytic leukaemia.

    PubMed

    Puente, Xose S; Beà, Silvia; Valdés-Mas, Rafael; Villamor, Neus; Gutiérrez-Abril, Jesús; Martín-Subero, José I; Munar, Marta; Rubio-Pérez, Carlota; Jares, Pedro; Aymerich, Marta; Baumann, Tycho; Beekman, Renée; Belver, Laura; Carrio, Anna; Castellano, Giancarlo; Clot, Guillem; Colado, Enrique; Colomer, Dolors; Costa, Dolors; Delgado, Julio; Enjuanes, Anna; Estivill, Xavier; Ferrando, Adolfo A; Gelpí, Josep L; González, Blanca; González, Santiago; González, Marcos; Gut, Marta; Hernández-Rivas, Jesús M; López-Guerra, Mónica; Martín-García, David; Navarro, Alba; Nicolás, Pilar; Orozco, Modesto; Payer, Ángel R; Pinyol, Magda; Pisano, David G; Puente, Diana A; Queirós, Ana C; Quesada, Víctor; Romeo-Casabona, Carlos M; Royo, Cristina; Royo, Romina; Rozman, María; Russiñol, Nuria; Salaverría, Itziar; Stamatopoulos, Kostas; Stunnenberg, Hendrik G; Tamborero, David; Terol, María J; Valencia, Alfonso; López-Bigas, Nuria; Torrents, David; Gut, Ivo; López-Guillermo, Armando; López-Otín, Carlos; Campo, Elías

    2015-10-22

    Chronic lymphocytic leukaemia (CLL) is a frequent disease in which the genetic alterations determining the clinicobiological behaviour are not fully understood. Here we describe a comprehensive evaluation of the genomic landscape of 452 CLL cases and 54 patients with monoclonal B-lymphocytosis, a precursor disorder. We extend the number of CLL driver alterations, including changes in ZNF292, ZMYM3, ARID1A and PTPN11. We also identify novel recurrent mutations in non-coding regions, including the 3' region of NOTCH1, which cause aberrant splicing events, increase NOTCH1 activity and result in a more aggressive disease. In addition, mutations in an enhancer located on chromosome 9p13 result in reduced expression of the B-cell-specific transcription factor PAX5. The accumulative number of driver alterations (0 to ≥4) discriminated between patients with differences in clinical behaviour. This study provides an integrated portrait of the CLL genomic landscape, identifies new recurrent driver mutations of the disease, and suggests clinical interventions that may improve the management of this neoplasia. PMID:26200345

  5. The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization.

    PubMed

    Sawicka, Marta; Wanrooij, Paulina H; Darbari, Vidya C; Tannous, Elias; Hailemariam, Sarem; Bose, Daniel; Makarova, Alena V; Burgers, Peter M; Zhang, Xiaodong

    2016-06-24

    The phosphatidylinositol 3-kinase-related protein kinases are key regulators controlling a wide range of cellular events. The yeast Tel1 and Mec1·Ddc2 complex (ATM and ATR-ATRIP in humans) play pivotal roles in DNA replication, DNA damage signaling, and repair. Here, we present the first structural insight for dimers of Mec1·Ddc2 and Tel1 using single-particle electron microscopy. Both kinases reveal a head to head dimer with one major dimeric interface through the N-terminal HEAT (named after Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR1) repeat. Their dimeric interface is significantly distinct from the interface of mTOR complex 1 dimer, which oligomerizes through two spatially separate interfaces. We also observe different structural organizations of kinase domains of Mec1 and Tel1. The kinase domains in the Mec1·Ddc2 dimer are located in close proximity to each other. However, in the Tel1 dimer they are fully separated, providing potential access of substrates to this kinase, even in its dimeric form. PMID:27129217

  6. 76 FR 13438 - AccessTel, Inc., American Asset Management Corp., DME Interactive Holdings, Inc., DocuPort, Inc...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-03-11

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION AccessTel, Inc., American Asset Management Corp., DME Interactive Holdings, Inc., DocuPort, Inc... is a lack of current and accurate information concerning the securities of DME Interactive...

  7. Organizing the Library to Suit the Undergraduates' Information Gathering Behavior at the Tel-Hai Academic College in Israel

    ERIC Educational Resources Information Center

    Chai, Iris

    2007-01-01

    The study examined the factors influencing information gathering behavior of undergraduates at Tel-Hai Academic College, so that library services can cope effectively with this behavior. Related to the findings, we changed our circulation desk to become a "one stop shop" for directions to all library information.

  8. Sae2 Function at DNA Double-Strand Breaks Is Bypassed by Dampening Tel1 or Rad53 Activity

    PubMed Central

    Gnugnoli, Marco; Menin, Luca; Clerici, Michela; Longhese, Maria Pia

    2015-01-01

    The MRX complex together with Sae2 initiates resection of DNA double-strand breaks (DSBs) to generate single-stranded DNA (ssDNA) that triggers homologous recombination. The absence of Sae2 not only impairs DSB resection, but also causes prolonged MRX binding at the DSBs that leads to persistent Tel1- and Rad53-dependent DNA damage checkpoint activation and cell cycle arrest. Whether this enhanced checkpoint signaling contributes to the DNA damage sensitivity and/or the resection defect of sae2Δ cells is not known. By performing a genetic screen, we identify rad53 and tel1 mutant alleles that suppress both the DNA damage hypersensitivity and the resection defect of sae2Δ cells through an Sgs1-Dna2-dependent mechanism. These suppression events do not involve escaping the checkpoint-mediated cell cycle arrest. Rather, defective Rad53 or Tel1 signaling bypasses Sae2 function at DSBs by decreasing the amount of Rad9 bound at DSBs. As a consequence, reduced Rad9 association to DNA ends relieves inhibition of Sgs1-Dna2 activity, which can then compensate for the lack of Sae2 in DSB resection and DNA damage resistance. We propose that persistent Tel1 and Rad53 checkpoint signaling in cells lacking Sae2 increases the association of Rad9 at DSBs, which in turn inhibits DSB resection by limiting the activity of the Sgs1-Dna2 resection machinery. PMID:26584331

  9. The Dimeric Architecture of Checkpoint Kinases Mec1ATR and Tel1ATM Reveal a Common Structural Organization*

    PubMed Central

    Sawicka, Marta; Wanrooij, Paulina H.; Darbari, Vidya C.; Tannous, Elias; Hailemariam, Sarem; Bose, Daniel; Makarova, Alena V.; Burgers, Peter M.; Zhang, Xiaodong

    2016-01-01

    The phosphatidylinositol 3-kinase-related protein kinases are key regulators controlling a wide range of cellular events. The yeast Tel1 and Mec1·Ddc2 complex (ATM and ATR-ATRIP in humans) play pivotal roles in DNA replication, DNA damage signaling, and repair. Here, we present the first structural insight for dimers of Mec1·Ddc2 and Tel1 using single-particle electron microscopy. Both kinases reveal a head to head dimer with one major dimeric interface through the N-terminal HEAT (named after Huntingtin, elongation factor 3, protein phosphatase 2A, and yeast kinase TOR1) repeat. Their dimeric interface is significantly distinct from the interface of mTOR complex 1 dimer, which oligomerizes through two spatially separate interfaces. We also observe different structural organizations of kinase domains of Mec1 and Tel1. The kinase domains in the Mec1·Ddc2 dimer are located in close proximity to each other. However, in the Tel1 dimer they are fully separated, providing potential access of substrates to this kinase, even in its dimeric form. PMID:27129217

  10. 77 FR 39559 - In the Matter of AngelCiti Entertainment, Inc., BodyTel Scientific, Inc., Clearant, Inc...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-07-03

    ... From the Federal Register Online via the Government Publishing Office SECURITIES AND EXCHANGE COMMISSION In the Matter of AngelCiti Entertainment, Inc., BodyTel Scientific, Inc., Clearant, Inc., Data... accurate information concerning the securities of AngelCiti Entertainment, Inc. because it has not...

  11. [Pregnancy outcome in five women after autologous bone marrow transplantation for acute lymphoblastic leukaemia].

    PubMed

    Hołowiecka, Aleksandra; Zielińska, Monika; Rozmus, Wioletta; Krzemień, Sławomira; Hołowiecki, Jerzy

    2005-10-01

    There are reports of successful pregnancies in women with haematological malignancies after either autologous or allogeneic bone marrow transplantation (BMT). We report six cases of uncomplicated pregnancies in five women treated with high-dose chemotherapy, radiotherapy and autologous bone marrow transplantation (ABMT) for acute lymphoblastic leukaemia. One patient was diagnosed as having leukaemia during pregnancy. The pregnancy ended with medical termination. Each woman received conditioning regimens without total body irradiation (TBI). Of five women, who received AMBT, all resumed spontaneous cyclical menstruation post transplantation. All of them conceived naturally between 15-52 months following ABMT. We noted one miscarriage in our 29-year-old patient. Six pregnancies went to term and each resulted in the successful delivery of a full-term baby. We did not notice any case of relapse of leukaemia in pregnancy. PMID:16417095

  12. The cellular basis of immunosuppression caused by the radiation leukaemia virus

    PubMed Central

    Peled, A.; Haran-Ghera, N.

    1974-01-01

    Infection of adult C57B1/6 mice with the radiation leukaemia virus resulted in suppression of the ability of the animals to respond to an immunizing inoculum of sheep erythrocytes. Results of the transfer experiments indicated that the immunosuppressive effect was expressed at the immunocompetent cell level, and that the virus affected the thymus-derived population of immunocytes. The immunosuppressive effect of the virus on thymus cells, independent of any contribution by cells of bone marrow origin, was verified with thymus-independent immunogens, polyvinylpyrrolidone (PVP) or pneumococcal polysaccharide SIII (PPS). Mice inoculated with the radiation leukaemia virus produced nearly normal amounts of plaque-forming cells producing antibodies against PVP and PPS, thereby confirming that the immunosuppressive effect of the radiation leukaemia virus was on thymus-derived cells. PMID:4369273

  13. Chronic neutrophilic leukaemia and plasma cell-related neutrophilic leukaemoid reactions.

    PubMed

    Bain, Barbara J; Ahmad, Shahzaib

    2015-11-01

    Many cases reported as 'chronic neutrophilic leukaemia' have had an associated plasma cell neoplasm. Recent evidence suggests that the great majority of such cases represent a neutrophilic leukaemoid reaction to the underlying multiple myeloma or monoclonal gammopathy of undetermined significance. We have analysed all accessible reported cases to clarify the likely diagnosis and to ascertain whether toxic granulation, Döhle bodies and an increased neutrophil alkaline phosphatase score were useful in making a distinction between chronic neutrophilic leukaemia and a neutrophilic leukaemoid reaction. We established that all these changes occur in both conditions. Toxic granulation and Döhle bodies are more consistently present in leukaemoid reactions but also occur quite frequently in chronic neutrophilic leukaemia. The neutrophil alkaline phosphatase score is increased in both conditions and is of no value in making a distinction. PMID:26218186

  14. Mononeuritis multiplex in a patient with B-cell prolymphocytic leukaemia: a diagnostic challenge

    PubMed Central

    Le Clech, Lenaïg; Rizcallah, Marie Jeanne; Alavi, Zarrin; Hutin, Pascal

    2013-01-01

    B-cell prolymphocytic leukaemia (BPLL) is a haematological malignancy defined as lymphocytosis and splenomegaly with >55% circulating cells being clonal prolymphocytes of B-cell origin. The evolution of this disease is more aggressive than chronic lymphocytic leukaemia. We reported a case of a 62-year-old man with BPLL who, on treatment, attained cytological, immunophenotypic and complete cytogenetic remission. He subsequently developed an asymmetric sensorimotor neurological disorder, suggestive of lymphomatous infiltration (neurolymphocytosis). Repetition of the MRI and the electromyography was essential for diagnosis. Progressive mononeuritis multiplex in B-cell leukaemias/lymphomas is rare and may be the only presenting symptom of relapsed or progressive disease. Repeat imaging studies based on judicious evaluation of the clinical scenario for exclusion of other causes of neurological symptoms is necessary. This can be challenging in patients with long-standing malignancies who have received multiple courses of chemotherapy and/or radiotherapy. PMID:24000206

  15. HA14-1, a small molecule inhibitor of Bcl-2, bypasses chemoresistance in leukaemia cells.

    PubMed

    Oliver, Lisa; Mahé, Béatrice; Gréé, René; Vallette, François M; Juin, Philippe

    2007-06-01

    We analyzed the biological activity of HA14-1, a small organic compound inhibitor of Bcl-2, against established leukaemia cell lines and blasts from acute myeloid leukaemia (AML) patients. HA14-1 had a potent killing activity against the leukaemia cell line that expressed endogenous or ectopic Bcl-2. This activity was mostly caspase-independent and was not altered by the expression of a multidrug-resistant phenotype. Moreover, HA14-1 efficiently induced cell death in a broad spectrum of AML blasts but not in normal peripheral blood lymphocytes. Thus, single-agent regimens using Bcl-2 inhibitors such as HA14-1 may be advantageous in overcoming some forms of chemoresistance in AML. PMID:17224180

  16. Childhood leukaemia incidence around French nuclear installations using geographic zoning based on gaseous discharge dose estimates

    PubMed Central

    Evrard, A-S; Hémon, D; Morin, A; Laurier, D; Tirmarche, M; Backe, J-C; Chartier, M; Clavel, J

    2006-01-01

    The present study investigated for the first time the incidence of childhood leukaemia (1990–2001) around French nuclear installations using a geographic zoning based on estimated doses to the red bone marrow due to gaseous radioactive discharges. The observed number of cases of acute leukaemia (O=750) in 40 km2 centred on 23 French nuclear installations between 1990 and 2001 was lower than expected (E=795.01), although not significantly so (standardised incidence ratio SIR=0.94, 95% confidence interval=(0.88–1.01)). In none of the five zones defined on the basis of the estimated doses was the SIR significantly >1. There was no evidence of a trend in SIR with the estimated doses for all the children or for any of the three age groups studied. This study confirmed that there was no evidence of an increased incidence of childhood leukaemia around the 23 French nuclear sites. PMID:16622448

  17. Functional Dissection of Caenorhabditis elegans CLK-2/TEL2 Cell Cycle Defects during Embryogenesis and Germline Development

    PubMed Central

    Moser, Sandra C.; von Elsner, Sophie; Büssing, Ingo; Alpi, Arno; Schnabel, Ralf; Gartner, Anton

    2009-01-01

    CLK-2/TEL2 is essential for viability from yeasts to vertebrates, but its essential functions remain ill defined. CLK-2/TEL2 was initially implicated in telomere length regulation in budding yeast, but work in Caenorhabditis elegans has uncovered a function in DNA damage response signalling. Subsequently, DNA damage signalling defects associated with CLK-2/TEL2 have been confirmed in yeast and human cells. The CLK-2/TEL2 interaction with the ATM and ATR DNA damage sensor kinases and its requirement for their stability led to the proposal that CLK-2/TEL2 mutants might phenocopy ATM and/or ATR depletion. We use C. elegans to dissect developmental and cell cycle related roles of CLK-2. Temperature sensitive (ts) clk-2 mutants accumulate genomic instability and show a delay of embryonic cell cycle timing. This delay partially depends on the worm p53 homolog CEP-1 and is rescued by co-depletion of the DNA replication checkpoint proteins ATL-1 (C. elegans ATR) and CHK-1. In addition, clk-2 ts mutants show a spindle orientation defect in the eight cell stages that lead to major cell fate transitions. clk-2 deletion worms progress through embryogenesis and larval development by maternal rescue but become sterile and halt germ cell cycle progression. Unlike ATL-1 depleted germ cells, clk-2–null germ cells do not accumulate DNA double-strand breaks. Rather, clk-2 mutant germ cells arrest with duplicated centrosomes but without mitotic spindles in an early prophase like stage. This germ cell cycle arrest does not depend on cep-1, the DNA replication, or the spindle checkpoint. Our analysis shows that CLK-2 depletion does not phenocopy PIKK kinase depletion. Rather, we implicate CLK-2 in multiple developmental and cell cycle related processes and show that CLK-2 and ATR have antagonising functions during early C. elegans embryonic development. PMID:19360121

  18. Space-time clustering of childhood leukaemia in Greece: evidence supporting a viral aetiology.

    PubMed Central

    Petridou, E.; Revinthi, K.; Alexander, F. E.; Haidas, S.; Koliouskas, D.; Kosmidis, H.; Piperopoulou, F.; Tzortzatou, F.; Trichopoulos, D.

    1996-01-01

    The method introduced by Knox for evaluation of space-time clustering has been applied to 872 cases of childhood (0-14 year old) leukaemia diagnosed in Greece over the 10 year period 1980-89. Greek towns are characterised by substantial population mixing due to internal migration, whereas there is relative isolation in mountainous rural areas. Predetermined space (5 km) and time (1 year) limits were used on the basis of previous reports in order to define the clustering cell. There is highly significant evidence for clustering of childhood leukaemia in Greece as a whole, the observed number of pairs that are close in both spaces and time exceeding the expected number by 5.2% (P = 0.004). The excess is particularly evident for leukaemia cases in 0 to 4-year-old children, among whom the observed number of pairs that are close in both space and time exceeded the expected number by 9.4% (P = 0.004). There is no evidence of space-time clustering for leukaemia cases older than 5 years. The overall pattern is descriptively similar in urban and semiurban areas and is especially marked for acute lymphoblastic leukaemia at the childhood peak ages (2-4 years) with an excess of 19% (P = 0.0006). In the rural population there is evidence for clustering of cases belonging to older and broader age groups, a phenomenon compatible with a delay in the development of herd immunity against putative infectious aetiological agents. The findings of the present study provide support for the hypothesis that a substantial proportion of cases of childhood leukaemia may arise as a rare sequel to exposure to an agent or agents, most probably viral in nature. PMID:8630293

  19. Impact on learning of an e-learning module on leukaemia: a randomised controlled trial

    PubMed Central

    2012-01-01

    Background e-learning resources may be beneficial for complex or conceptually difficult topics. Leukaemia is one such topic, yet there are no reports on the efficacy of e-learning for leukaemia. This study compared the learning impact on senior medical students of a purpose-built e-learning module on leukaemia, compared with existing online resources. Methods A randomised controlled trial was performed utilising volunteer senior medical students. Participants were randomly allocated to Study and Control groups. Following a pre-test on leukaemia administered to both groups, the Study group was provided with access to the new e-learning module, while the Control group was directed to existing online resources. A post-test and an evaluation questionnaire were administered to both groups at the end of the trial period. Results Study and Control groups were equivalent in gender distribution, mean academic ability, pre-test performance and time studying leukaemia during the trial. The Study group performed significantly better than the Control group in the post-test, in which the group to which the students had been allocated was the only significant predictor of performance. The Study group’s evaluation of the module was overwhelmingly positive. Conclusions A targeted e-learning module on leukaemia had a significant effect on learning in this cohort, compared with existing online resources. We believe that the interactivity, dialogic feedback and integration with the curriculum offered by the e-learning module contributed to its impact. This has implications for e-learning design in medicine and other disciplines. PMID:22640463

  20. Long-term in vitro maintenance of clonal abundance and leukaemia-initiating potential in acute lymphoblastic leukaemia

    PubMed Central

    Pal, D; Blair, H J; Elder, A; Dormon, K; Rennie, K J; Coleman, D J L; Weiland, J; Rankin, K S; Filby, A; Heidenreich, O; Vormoor, J

    2016-01-01

    Lack of suitable in vitro culture conditions for primary acute lymphoblastic leukaemia (ALL) cells severely impairs their experimental accessibility and the testing of new drugs on cell material reflecting clonal heterogeneity in patients. We show that Nestin-positive human mesenchymal stem cells (MSCs) support expansion of a range of biologically and clinically distinct patient-derived ALL samples. Adherent ALL cells showed an increased accumulation in the S phase of the cell cycle and diminished apoptosis when compared with cells in the suspension fraction. Moreover, surface expression of adhesion molecules CD34, CDH2 and CD10 increased several fold. Approximately 20% of the ALL cells were in G0 phase of the cell cycle, suggesting that MSCs may support quiescent ALL cells. Cellular barcoding demonstrated long-term preservation of clonal abundance. Expansion of ALL cells for >3 months compromised neither feeder dependence nor cancer initiating ability as judged by their engraftment potential in immunocompromised mice. Finally, we demonstrate the suitability of this co-culture approach for the investigation of drug combinations with luciferase-expressing primograft ALL cells. Taken together, we have developed a preclinical platform with patient-derived material that will facilitate the development of clinically effective combination therapies for ALL. PMID:27109511

  1. Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia.

    PubMed

    Ridinger-Saison, M; Evanno, E; Gallais, I; Rimmelé, P; Selimoglu-Buet, D; Sapharikas, E; Moreau-Gachelin, F; Guillouf, C

    2013-09-01

    Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. PMID:23852375

  2. Subgroups of Paediatric Acute Lymphoblastic Leukaemia Might Differ Significantly in Genetic Predisposition to Asparaginase Hypersensitivity

    PubMed Central

    Kutszegi, Nóra; Semsei, Ágnes F.; Gézsi, András; Sági, Judit C.; Nagy, Viktória; Csordás, Katalin; Jakab, Zsuzsanna; Lautner-Csorba, Orsolya; Gábor, Krisztina Míta; Kovács, Gábor T.; Erdélyi, Dániel J.; Szalai, Csaba

    2015-01-01

    L-asparaginase (ASP) is a key element in the treatment of paediatric acute lymphoblastic leukaemia (ALL). However, hypersensitivity reactions (HSRs) to ASP are major challenges in paediatric patients. Our aim was to investigate genetic variants that may influence the risk to Escherichia coli-derived ASP hypersensitivity. Sample and clinical data collection was carried out from 576 paediatric ALL patients who were treated according to protocols from the Berlin—Frankfurt—Münster Study Group. A total of 20 single nucleotide polymorphisms (SNPs) in GRIA1 and GALNT10 genes were genotyped. Patients with GRIA1 rs4958351 AA/AG genotype showed significantly reduced risk to ASP hypersensitivity compared to patients with GG genotype in the T-cell ALL subgroup (OR = 0.05 (0.01–0.26); p = 4.70E-04), while no such association was found in pre-B-cell ALL. In the medium risk group two SNPs of GRIA1 (rs2055083 and rs707176) were associated significantly with the occurrence of ASP hypersensitivity (OR = 0.21 (0.09–0.53); p = 8.48E-04 and OR = 3.02 (1.36–6.73); p = 6.76E-03, respectively). Evaluating the genders separately, however, the association of rs707176 with ASP HSRs was confined only to females. Our results suggest that genetic variants of GRIA1 might influence the risk to ASP hypersensitivity, but subgroups of patients can differ significantly in this respect. PMID:26457809

  3. A four-point clinical criteria distinguishes immune thrombocytopenia from acute lymphoblastic leukaemia.

    PubMed

    Lum, S H; How, S J; Ariffin, H; Krishnan, S

    2016-02-01

    Immune thrombocytopenia is the most common diagnosis of isolated thrombocytopenia. The dilemma encountered by paediatricians is missing diagnosis of acute leukaemia in children with isolated thrombocytopenia. We demonstrated childhood ITP could be diagnosed using a four point clinical criteria without missing a diagnosis of acute leukaemia. Hence, bone marrow examination is not necessary in children with typical features compatible with ITP prior to steroid therapy. This can encourage paediatricians to choose steroid therapy, which is cheaper and non-blood product, as first line platelet elevating therapy in children with significant haemorrhage. PMID:27130741

  4. Cooperation between bovine leukaemia virus transactivator protein and Ha-ras oncogene product in cellular transformation.

    PubMed Central

    Willems, L; Heremans, H; Chen, G; Portetelle, D; Billiau, A; Burny, A; Kettmann, R

    1990-01-01

    Human T-lymphotropic viruses (HTLV-I and -II) and bovine leukaemia virus (BLV) express transactivator proteins able to increase long terminal repeat (LTR) directed viral expression. These transacting factors are though to be involved in the induction of leukaemia by these viruses. Transfection of BLV transactivator p34tax together with Ha-ras immortalizes and transforms rat embryo fibroblasts, in vitro. The transformed cell induce tumours in nude mice. These data emphasize the causal role exerted by p34tax in in vivo tumorigenesis. Images Fig. 1. Fig. 2. Fig. 3. PMID:2158445

  5. Leukaemia, lymphoma, and multiple myeloma in seamen on tankers

    PubMed Central

    Nilsson, R. I.; Nordlinder, R.; Horte, L. G.; Jarvholm, B.

    1998-01-01

    OBJECTIVES: To investigate the risk of lymphatic and haematopoietic malignancies in deck crew on tankers exposed to cargo vapours. METHODS: The study design was as a nested case-referent study in two cohorts of male Swedish seamen 20-64 years of age at the national census 1960 (n 13,449) and 1970 (n 11,290), respectively. Cases were detected by record linkage with the Swedish Cancer Register 1961-79 and 1971-87, respectively. For each case, three to five age matched referents from the population were selected. Exposure was assessed from data in the Swedish Registry of Seamen and from a register of Swedish ships. RESULTS: Seamen in the 1970 cohort, who had been exposed to cargo vapours for at least one month on chemical or product tankers, had an increased risk of lymphatic and haematopoietic malignancies (Mantel- Haenszel odds ratio (OR) 2.6, 95% confidence interval (95% CI) 1.1 to 5.9)) with a significant exposure-response relation (conditional logistic regression analysis, p = 0.04). The ORs were increased for both lymphoma (3.2), multiple myeloma (4.0), and leukaemia (1.6), but the increase was only significant for non-Hodgkin's lymphoma (OR 3.3, 95% CI 1.1 to 10.6). There were no significantly increased risks for the 1960 cohort or for seamen exposed only on crude oil tankers, but these groups had few exposed cases and low cumulative exposure to benzene and other light petroleum products. CONCLUSIONS: Seamen exposed to cargo vapours from gasoline and other light petroleum products on chemical or product tankers had an increased incidence of lymphatic and haematopoietic malignancies. One possible cause is exposure to benzene during loading, unloading, and tank cleaning operations.   PMID:9849537

  6. Targeting survival pathways in chronic myeloid leukaemia stem cells

    PubMed Central

    Sinclair, A; Latif, A L; Holyoake, T L

    2013-01-01

    Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a fusion oncogene BCR-ABL, which encodes a protein with constitutive TK activity. The implementation of tyrosine kinase inhibitors (TKIs) marked a major advance in CML therapy; however, there are problems with current treatment. For example, relapse occurs when these drugs are discontinued in the majority of patients who have achieved a complete molecular response on TKI and these agents are less effective in patients with mutations in the BCR-ABL kinase domain. Importantly, TKI can effectively target proliferating mature cells, but do not eradicate quiescent leukaemic stem cells (LSCs), therefore allowing disease persistence despite treatment. It is essential that alternative strategies are used to target the LSC population. BCR-ABL activation is responsible for the modulation of different signalling pathways, which allows the LSC fraction to evade cell death. Several pathways have been shown to be modulated by BCR-ABL, including PI3K/AKT/mTOR, JAK-STAT and autophagy signalling pathways. Targeting components of these survival pathways, alone or in combination with TKI, therefore represents an attractive potential therapeutic approach for targeting the LSC. However, many pathways are also active in normal stem cells. Therefore, potential targets must be validated to effectively eradicate CML stem cells while sparing normal counterparts. This review summarizes the main pathways modulated in CML stem cells, the recent developments and the use of novel drugs to target components in these pathways which may be used to target the LSC population. Linked Articles This article is part of a themed section on Emerging Therapeutic Aspects in Oncology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2013.169.issue-8 PMID:23517124

  7. Chronic myeloid leukaemia following repeated exposure to chest radiography and computed tomography in a patient with pneumothorax: A case report and literature review

    PubMed Central

    JU, FANG-HE; GONG, XU-BO; JIANG, LI-BIN; HONG, HUI-HUA; YANG, JUN-CHAO; XU, TING-ZHEN; CHEN, YU; WANG, ZHEN

    2016-01-01

    It is well known that radioactive rays may cause damage to the human body. Progress in modern medicine has led to an increased risk of therapeutic and diagnostic radiation exposure of patients. Although clear evidence of a radiation dose-dependent risk of chronic myeloid leukaemia, particularly for patients exposed to radiation at a young age, has been established, it is not known whether radiation exposure during diagnostic imaging also increases the risk of cancer. The present study reports the case of a patient who underwent several diagnostic imaging tests (including repeated chest radiography and computed tomography) for recurrent pneumothorax. At around one year subsequent to these tests, the patient was diagnosed with chronic myeloid leukaemia. The patient exhibited an increase in white blood cell count over time, and a bone marrow smear test showed a myeloid/erythroid ratio of 13.9:1. In addition, the qualitative breakpoint cluster region (BCR)/Abelson (ABL) gene test revealed positive results for BCR/ABL fusion (p210). Based on the data reported in the current case, research aimed at elucidating the potential risks associated with diagnostic radiation is urgently required. It is crucial that medical professionals consider the potential harmful side effects of diagnostic radiation when ordering radiation-based diagnostic imaging examinations. PMID:27073486

  8. Soil properties in urban parks and city population in Tel Aviv-Jaffa: Mutual effects

    NASA Astrophysics Data System (ADS)

    Oz, A.; Sarah, P.; Zhevelev, H.

    2012-04-01

    Urban parks are man-made open spaces, located in the city area and having two major functions: conservation of natural resources and optimization of the physical and social environment. This study aimed to investigate the relations between the soil properties and the socioeconomic profile of the populations in the parks in Tel Aviv. The city of Tel Aviv was divided into three geographical regions: South, Central and North. This division reflects the course of development of the city from south to north, and encompasses differing socio-economic levels of residents. In each geographical region 15 parks were randomly chosen, and were divided into three groups by size (2-10, 10-20 and 20-50 acres). In each park soil was sampled in two microenvironments (lawn and path), from three points and from three depth layers (0-2, 5-10 and 10-20 cm) in July-August 2011. Before the sampling, penetration depth was determined at all the points. Each of the soil samples was analyzed for organic matter content, pH, electrical conductivity, and sodium and chlorine contents. For each type of microenvironment, the results were analyzed with respect to three factors: size of park, region of city, and soil depth. It was found that the urban park soil properties varied widely: sodium and chlorine contents from 1.8 to 12 and from 1.9 to 7.8 meq/kg, respectively; and electrical conductivity from 0.40 to 1.47 dS/m. In the lawn microenvironment, electrical conductivity, chlorine and sodium increased in all depths with park size. This trend was significant only in the upper layer. In the path microenvironment no such trend was seen. In the center of the city lower values of soil properties than in the other regions were found at all depths. Soil properties decreased with depth in all three geographical regions, in all three sizes of park, and in both microenvironments. For all sizes of park, in all geographical regions, and in both microenvironments, penetration depths were found be similar. We

  9. Proposals for the classification of chronic (mature) B and T lymphoid leukaemias. French-American-British (FAB) Cooperative Group.

    PubMed Central

    Bennett, J M; Catovsky, D; Daniel, M T; Flandrin, G; Galton, D A; Gralnick, H R; Sultan, C

    1989-01-01

    Peripheral blood, bone marrow films, and bone marrow biopsy specimens from 110 patients, well characterised by clinical and laboratory studies, including electron microscopy, were reviewed, to determine proposals for the classification of chronic (mature) B and T cell leukaemias. On the basis of cytology and membrane phenotype the following disorders were defined: (i) B cell type: chronic lymphocytic leukaemia (CLL); CLL of mixed cell type, which includes cases with more than 10% and less than 55% prolymphocytes (CLL/PL), and a less well defined form with pleomorphic lymphocytes but less than 10% prolymphocytes; prolymphocytic leukaemia (PLL); hairy cell leukaemia (HCL); HCL variant; splenic lymphoma with circulating villous lymphocytes; leukaemic phase of non-Hodgkin's lymphoma (follicular lymphoma, intermediate, or mantle zone lymphoma and others); lymphoplasmacytic lymphoma with peripheral blood disease (mostly Waldenström's macroglobulinaemia); and plasma cell leukaemia. (ii) T cell type: T/CLL, which was differentiated from reactive T/lymphocytosis; T/PLL; adult T cell leukaemia/lymphoma; and Sézary's syndrome. The recognition of distinct entities within the B and T cell leukaemias seems to have clinical and epidemiological connotations. It is hoped that these proposals may serve as the basis for further work, discussion, and improved management of patients. Images Fig 1 Fig 1 Fig 1 Fig 2 Fig 3 Fig 3 Fig 4 Fig 5 Fig 6 PMID:2738163

  10. TriTel 3 dimensional space dosimetric telescope in the European Student Earth Orbiter project of ESA

    NASA Astrophysics Data System (ADS)

    Zábori, Balázs; Hirn, Attila

    2012-02-01

    The development of the European Student Earth Orbiter (ESEO) was announced in the year of 2008 by the European Space Agency for students interested in the space exploration. The Budapest University of Technology and Economics joined this international cooperation with three student groups among other participating European universities. One of them is the ESEO-TriTel team. The development of the TriTel 3D silicon detector telescope began in the KFKI Atomic Energy Research Institute several years ago in order to determine the average radiation quality factor of the space radiation field for dosimetric purposes. In the year 2011—before the start of the ESEO mission—it will be operated on board the European Columbus module of the International Space Station (ISS) and will be installed in the Russian segment of the ISS as well. The ESEO version of TriTel will fly higher than the ISS version, at an altitude of 520 km. At this altitude the Earth's geomagnetic field is much lower and the spectrum of the radiation field is also different. In the ESEO-TriTel experiment the anisotropies in the radiation field, the effects of the Earth shadow and the South Atlantic Anomaly (SAA) will be analysed and the results will be compared with the fluxes calculated with the standard AP-8 and AE-8 trapped proton and electron models. In the near future the frequency of manned space flights will probably increase, we can think of the continuous human presence in the near-Earth region (low Earth orbits) or the proposed human Mars expedition. That is why the cosmic radiation field is interesting not only in the near-Earth region but at higher altitudes or in the interplanetary field as well. The present paper addresses the optimal shielding of the dosimetric telescopes of TriTel in order to avoid the saturation of the electronics. The amount of optimal shielding is equivalent to the effective thickness of astronaut's space suit, which means that the same dose will be measured as what the

  11. Feedback mechanisms control coexistence in a stem cell model of acute myeloid leukaemia.

    PubMed

    Crowell, Helena L; MacLean, Adam L; Stumpf, Michael P H

    2016-07-21

    Haematopoietic stem cell dynamics regulate healthy blood cell production and are disrupted during leukaemia. Competition models of cellular species help to elucidate stem cell dynamics in the bone marrow microenvironment (or niche), and to determine how these dynamics impact leukaemia progression. Here we develop two models that target acute myeloid leukaemia with particular focus on the mechanisms that control proliferation via feedback signalling. It is within regions of parameter space permissive of coexistence that the effects of competition are most subtle and the clinical outcome least certain. Steady state and linear stability analyses identify parameter regions that allow for coexistence to occur, and allow us to characterise behaviour near critical points. Where analytical expressions are no longer informative, we proceed statistically and sample parameter space over a coexistence region. We find that the rates of proliferation and differentiation of healthy progenitors exert key control over coexistence. We also show that inclusion of a regulatory feedback onto progenitor cells promotes healthy haematopoiesis at the expense of leukaemia, and that - somewhat paradoxically - within the coexistence region feedback increases the sensitivity of the system to dominance by one lineage over another. PMID:27130539

  12. Massive retroperitoneal lymphadenopathy as a terminal event in hairy cell leukaemia.

    PubMed

    Mehta, A B; Catovsky, D; O'Brien, C J; Lott, M; Bowley, N; Hemmingway, A

    1983-01-01

    A case of hairy cell leukaemia complicated as a terminal event by massive retroperitoneal lymphadenopathy is described. The patient had recently been treated with lithium carbonate and had previously been demonstrated to suffer from a systemic vasculitis, either or both of which may have contributed to the development of this rare complication. PMID:6360496

  13. Dendritic cell-based immunotherapy in myeloid leukaemia: translating fundamental mechanisms into clinical applications.

    PubMed

    van de Loosdrecht, A A; van den Ancker, W; Houtenbos, I; Ossenkoppele, G J; Westers, T M

    2009-01-01

    Immunotherapy for leukaemia patients, aiming at the generation of anti-leukaemic T cell responses, could provide a new therapeutic approach to eliminate minimal residual disease (MRD) cells in acute myeloid leukaemia (AML). Leukaemic blasts harbour several ways to escape the immune system including deficient MHC class II expression, low levels of co-stimulatory molecules and suppressive cytokines. Therapeutic vaccination with dendritic cells (DC) is now recognized as an important investigational therapy. Due to their unique antigen presenting capacity, immunosuppressive features of the leukaemic blasts can be circumvented. DC can be successfully cultured from leukaemic blasts in 60-70% of patients and show functional potential in vivo. Alternatively, monocyte derived DC obtained at time of complete remission loaded with leukaemia-specific antigens can be used as vaccine. Several sources of leukaemia-associated antigen and different methods of loading antigen onto DC have been used in an attempt to optimize antitumour responses including apoptotic cells, necrotic cell lysates and tumour-associated pep-tides. Currently, the AML-derived cell line MUTZ-3, an immortalized equivalent of CD34(+) DC precursor cells, is under investigation for vaccination purposes. For effective DC vaccination the intrinsic tolerant state of the patient must be overcome. Therefore, the development of efficient and safe adjuvants in antigen specific immunotherapeutic programs should be encouraged. PMID:19031033

  14. Childhood leukaemia in North West England 1954-1977: epidemiology, incidence and survival.

    PubMed Central

    Birch, J. M.; Swindell, R.; Marsden, H. B.; Morris Jones, P. H.

    1981-01-01

    The annual incidence of leukaemia among children aged up to 14 years as estimated by the Manchester Children's Tumour Registry has been analysed for the 24 years 1954-1977. A significant increase in acute lymphoid leukaemia (ALL) was found, while the incidence of acute myeloid leukaemia (AML) remained constant. Other types of leukaemia were too rare to be analysed separately. The increase in ALL was concentrated among boys in the 1--5-year age group. Analysis with respect to initial white-cell count showed the increase to be more pronounced in children with initial white cell counts of 1-5 x 10(4)/microliters. The proportion of cases presenting in Lancashire compared with Greater Manchester did not change during the study period. The distribution of cases with respect to social class and socio-economic group of the parents also remained constant. Due to advances in the treatment of childhood ALL survival improved considerably during the study period and no increase in mortality was seen. PMID:6939448

  15. Fr-MLV infection induces erythroleukaemia instead of lymphoid leukaemia in mice given pituitary grafts.

    PubMed Central

    Fontanini, G.; Basolo, F.; Garzelli, C.; Squartini, F.; Toniolo, A.

    1990-01-01

    Here we report that the slow-transforming helper component of Friend murine leukaemia virus (Fr-MLV), which produces lymphoid leukaemias in normal mice, induces erythroleukaemia in mice given syngeneic pituitary grafts (SPG). Newborn mice were infected with Fr-MLV and, at one month of age, were transplanted with two pituitary glands under the kidney capsule. Sham-operated infected mice and uninfected transplanted mice served as controls. SPG selectively reduced the mean survival times of infected mice. Histopathology showed that, while most infected non-transplanted mice developed lymphoid leukaemias, virtually all Fr-MLF-infected mice given SPG developed erythroleukaemias. Experiments in vitro showed that Fr-MLV infection markedly depressed concanavalin A induced DNA synthesis in cells from spleen, thymus and lymph nodes. Addition of prolactin or growth hormone further suppressed lectin-induced mitogenesis of lymphoid cells from infected mice, but failed to influence the response of uninfected controls. These experiments indicate that, in mice, pituitary hormones modulate the development and the histological features of Fr-MLV induced leukaemias, and suggest that endocrine-immunological interactions play a role in retrovirus induced tumorigenesis. Images Figure 2 PMID:2372485

  16. X-ray detector calibration at CEA/Bruyères-le-Châtel

    NASA Astrophysics Data System (ADS)

    Beck, L.; Stemmler, P.; Ban, G.; Villette, B.; Frotté, V.; Bizeuil, C.; Boutin, J.-Y.; Nazet, C.

    1996-02-01

    At CEA/Bruyères-le-Châtel (Service CEM), there are facilities to calibrate X-ray detectors from 200 eV to 100 keV, with an accuracy of 4% at high energies ( E > 3 keV). The source is the direct radiation from the X-ray tubes [C Kα (277 eV) to Ti KαKβ (4.51/4.93 keV)] or fluorescence emission from secondary targets [Mg Kα (1.25 keV) to U Kα (98 keV)]. In addition, calibrations are carried out with the synchrotron radiation of the Super-ACO storage ring (LURE-Orsay), by selecting the monoenergetic beams with a double crystal monochromator which is tunable between 0.8 and 8 keV. The resolution is better than 1 eV. This last tool is very useful in the study of the absorption edges of the detector compounds (for example, Si K-edge and Ar K-edge). Some examples are presented of results obtained between 1 and 50 keV, with special reference to high flux detectors such as gold photocathodes and silicon avalanche photodiodes. Thick silicon photodiodes (for the high energy range) were also calibrated.

  17. The major vault protein is related to the toxic anion resistance protein (TelA) family.

    PubMed

    Suprenant, Kathy A; Bloom, Nathan; Fang, Jianwen; Lushington, Gerald

    2007-03-01

    Vaults are barrel-shaped ribonucleoprotein particles that are abundant in certain tumors and multidrug resistant cancer cells. Prokaryotic relatives of the major vault protein, MVP, have not been identified. We used sequence analysis and molecular modeling to show that MVP and the toxic anion resistance protein, TelA of Rhodobacter sphaeroides strain 2.4.1, share a novel fold that consists of a three-stranded antiparallel beta-sheet. Because of this strong structural correspondence, we examined whether mammalian cell vaults respond to tellurite treatment. In the presence of the oxyanion tellurite, large vault aggregates, or vaultosomes, appear at the cell periphery in 15 min or less. Vaultosome formation is temperature-dependent, reversible, and occurs in normal human umbilical vein endothelial cells as well as transformed HeLa cervical cancer cells. Vaultosome formation is not restricted to tellurite and occurs in the presence of other toxic oxyanions (selenate, selinite, arsenate, arsenite, vanadate). In addition, vaultosomes form independently from other stress-induced ribonucleoprotein complexes, stress granules and aggresomes. Vaultosome formation is therefore a unique cellular response to an environmental toxin. PMID:17337707

  18. Sapphirine and fluid inclusions in Tel Thanoun mantle xenoliths,Syria

    NASA Astrophysics Data System (ADS)

    Bilal, Ahmad

    2016-04-01

    Volcanoes along the Syrian rift, which extend a distance of about 1000 km, brought to the surface mantle xenoliths within erupted basalts, during multiples periods of volcanic activity. Xenoliths in early Cretaceous volcanoes originate in the garnet peridotite field of the subcontinental mantle, whereas those in recent Cenozoic volcanoes, the prime object of this study, are issued from shallower levels (spinel peridotite field). The recent discovery of sapphirine-bearing websterite in Tel Thanoun, a small volcanic diatreme inside the larger Quaternary volcanic field (Djebel Al Arab), allows us to estimate the P-T evolution and fluid-rock interaction at the volcanic source. Harzburgites and lherzolites are equilibrated at a temperature of about 1000 °C at a depth of 35-40 km. Sapphirine appears to have formed during cooling, at depth at a temperature of about 900 °C, at a time where spinel exsolution occurred in harzburgite and lherzolite pyroxenes. This occurred in the presence of a high-density pure CO2 fluid phase, still present in primary fluid inclusions. The highly-aluminous sapphirine-bearing protolith might be former garnet websterite (possibly uplifted during cretaceous magmatism), which resided and cooled in the spinel peridotite stability field, and was then dragged and brought to the surface by quaternary basalts.

  19. Levels of expression of CD19 and CD20 in chronic B cell leukaemias.

    PubMed Central

    Ginaldi, L; De Martinis, M; Matutes, E; Farahat, N; Morilla, R; Catovsky, D

    1998-01-01

    AIMS: To investigate whether the antigen levels of the B cell lineage markers CD19 and CD20 can distinguish between normal and neoplastic B cells or characterise distinct expression patterns among the chronic B cell leukaemias. METHODS: Peripheral blood cells from 70 patients with B cell disorders and 17 healthy donors were analysed by quantitative flow cytometry. Direct immunofluorescence staining was performed with phycoerythrin conjugated CD19 and CD20 monoclonal antibodies. Standard microbeads with different capacities to bind mouse immunoglobulins were used to convert the mean fluorescence intensity (MFI) values into number of antigen molecules/cell, expressed as antibody binding capacity (ABC). RESULTS: CD19 and CD20 ABC values in leukaemic B cells differed from those of normal blood B lymphocytes. The results identified distinct profiles of CD19 and CD20 expression in the various types of B cell leukaemias. In all leukaemias studied except hairy cell leukaemia (HCL), CD19 expression was significantly lower than the mean (SD) value in normal B cells (22 (7) x 10(3) molecules/cell), as follows: chronic lymphocytic leukaemia (CLL), 13 (7) x 10(3); B prolymphocytic leukaemia (B-PLL), 16 (9) x 10(3); splenic lymphoma with villous lymphocytes (SLVL), 15 (11) x 10(3); mantle cell lymphoma (MCL), 10 (7) x 10(3). In HCL there was strong CD19 expression (38 (16) x 10(3)). In contrast, the level of expression of membrane CD20 was higher than the mean (SD) value in normal B cells (94 (16) x 10(3) molecules/cell) in MCL (123 (51) x 10(3)); B-PLL (129 (47) x 10(3)); SLVL (167 (72) x 10(3)); and HCL (312 (110) x 10(3)); while it was significantly lower (65 (11) x 10(3)) in CLL compared with normal B cells and the other B cell leukaemias. CONCLUSIONS: Quantitative determination of CD19 and CD20 may provide useful diagnostic information for the study of B lymphoproliferative disorders. PMID:9708202

  20. Hypermethylation and down-regulation of DLEU2 in paediatric acute myeloid leukaemia independent of embedded tumour suppressor miR-15a/16-1

    PubMed Central

    2014-01-01

    Background Acute Myeloid Leukaemia (AML) is a highly heterogeneous disease. Studies in adult AML have identified epigenetic changes, specifically DNA methylation, associated with leukaemia subtype, age of onset and patient survival which highlights this heterogeneity. However, only limited DNA methylation studies have elucidated any associations in paediatric AML. Methods We interrogated DNA methylation on a cohort of paediatric AML FAB subtype M5 patients using the Illumina HumanMethylation450 (HM450) BeadChip, identifying a number of target genes with p <0.01 and Δβ >0.4 between leukaemic and matched remission (n = 20 primary leukaemic, n = 13 matched remission). Amongst those genes identified, we interrogate DLEU2 methylation using locus-specific SEQUENOM MassARRAY® EpiTYPER® and an increased validation cohort (n = 28 primary leukaemic, n = 14 matched remission, n = 17 additional non-leukaemic and cell lines). Following methylation analysis, expression studies were undertaken utilising the same patient samples for singleplex TaqMan gene and miRNA assays and relative expression comparisons. Results We identified differential DNA methylation at the DLEU2 locus, encompassing the tumour suppressor microRNA miR-15a/16-1 cluster. A number of HM450 probes spanning the DLEU2/Alt1 Transcriptional Start Site showed increased levels of methylation in leukaemia (average over all probes >60%) compared to disease-free haematopoietic cells and patient remission samples (<24%) (p < 0.001). Interestingly, DLEU2 mRNA down-regulation in leukaemic patients (p < 0.05) was independent of the embedded mature miR-15a/16-1 expression. To assess prognostic significance of DLEU2 DNA methylation, we stratified paediatric AML patients by their methylation status. A subset of patients recorded methylation values for DLEU2 akin to non-leukaemic specimens, specifically patients with sole trisomy 8 and/or chromosome 11 abnormalities. These patients also showed

  1. Consensus definitions of 14 severe acute toxic effects for childhood lymphoblastic leukaemia treatment: a Delphi consensus.

    PubMed

    Schmiegelow, Kjeld; Attarbaschi, Andishe; Barzilai, Shlomit; Escherich, Gabriele; Frandsen, Thomas Leth; Halsey, Christina; Hough, Rachael; Jeha, Sima; Kato, Motohiro; Liang, Der-Cherng; Mikkelsen, Torben Stamm; Möricke, Anja; Niinimäki, Riitta; Piette, Caroline; Putti, Maria Caterina; Raetz, Elizabeth; Silverman, Lewis B; Skinner, Roderick; Tuckuviene, Ruta; van der Sluis, Inge; Zapotocka, Ester

    2016-06-01

    Although there are high survival rates for children with acute lymphoblastic leukaemia, their outcome is often counterbalanced by the burden of toxic effects. This is because reported frequencies vary widely across studies, partly because of diverse definitions of toxic effects. Using the Delphi method, 15 international childhood acute lymphoblastic leukaemia study groups assessed acute lymphoblastic leukaemia protocols to address toxic effects that were to be considered by the Ponte di Legno working group. 14 acute toxic effects (hypersensitivity to asparaginase, hyperlipidaemia, osteonecrosis, asparaginase-associated pancreatitis, arterial hypertension, posterior reversible encephalopathy syndrome, seizures, depressed level of consciousness, methotrexate-related stroke-like syndrome, peripheral neuropathy, high-dose methotrexate-related nephrotoxicity, sinusoidal obstructive syndrome, thromboembolism, and Pneumocystis jirovecii pneumonia) that are serious but too rare to be addressed comprehensively within any single group, or are deemed to need consensus definitions for reliable incidence comparisons, were selected for assessment. Our results showed that none of the protocols addressed all 14 toxic effects, that no two protocols shared identical definitions of all toxic effects, and that no toxic effect definition was shared by all protocols. Using the Delphi method over three face-to-face plenary meetings, consensus definitions were obtained for all 14 toxic effects. In the overall assessment of outcome of acute lymphoblastic leukaemia treatment, these expert opinion-based definitions will allow reliable comparisons of frequencies and severities of acute toxic effects across treatment protocols, and facilitate international research on cause, guidelines for treatment adaptation, preventive strategies, and development of consensus algorithms for reporting on acute lymphoblastic leukaemia treatment. PMID:27299279

  2. Mec1/ATR regulates the generation of single-stranded DNA that attenuates Tel1/ATM signaling at DNA ends

    PubMed Central

    Clerici, Michela; Trovesi, Camilla; Galbiati, Alessandro; Lucchini, Giovanna; Longhese, Maria Pia

    2014-01-01

    Tel1/ATM and Mec1/ATR checkpoint kinases are activated by DNA double-strand breaks (DSBs). Mec1/ATR recruitment to DSBs requires the formation of RPA-coated single-stranded DNA (ssDNA), which arises from 5′–3′ nucleolytic degradation (resection) of DNA ends. Here, we show that Saccharomyces cerevisiae Mec1 regulates resection of the DSB ends. The lack of Mec1 accelerates resection and reduces the loading to DSBs of the checkpoint protein Rad9, which is known to inhibit ssDNA generation. Extensive resection is instead inhibited by the Mec1-ad mutant variant that increases the recruitment near the DSB of Rad9, which in turn blocks DSB resection by both Rad53-dependent and Rad53-independent mechanisms. The mec1-ad resection defect leads to prolonged persistence at DSBs of the MRX complex that causes unscheduled Tel1 activation, which in turn impairs checkpoint switch off. Thus, Mec1 regulates the generation of ssDNA at DSBs, and this control is important to coordinate Mec1 and Tel1 signaling activities at these breaks. PMID:24357557

  3. Splenic B cell lymphoma with circulating villous lymphocytes: differential diagnosis of B cell leukaemias with large spleens.

    PubMed Central

    Melo, J V; Hegde, U; Parreira, A; Thompson, I; Lampert, I A; Catovsky, D

    1987-01-01

    The clinical, haematological, morphological and histological features of a series of 22 patients presenting with splenic lymphoma with circulating villous lymphocytes were assessed and compared with those of patients with other forms of chronic B cell leukaemia in an attempt to differentiate this condition from hairy cell leukaemia, prolymphocytic leukaemia, and chronic lymphocytic leukaemia, with which this condition has many features in common. The disease was twice as common in men than in women, with a mean (SD) age at diagnosis of 72 (9) years, and the most consistent presenting feature was massive enlargement of the spleen, which showed white and red pulp disease with a plasmacytic component. Small monoclonal bands were found in 60% of cases. Images Fig 1 Fig 2 Fig 3 Fig 4 PMID:3497180

  4. Multi-disciplinary study for the exploration of deep low enthalpy geothermal reservoirs, Neuchâtel, Switzerland

    NASA Astrophysics Data System (ADS)

    Mauri, G.; Abdelfettah, Y.; Negro, F.; Schill, E.; Vuataz, F.

    2011-12-01

    The authorities of the canton of Neuchâtel, in the Western part of Switzerland, are willing to develop geothermal energy for district heating in the two main cities of the canton: Neuchâtel, located along the Lake of Neuchâtel, and La Chaux-de-Fonds situated in a high valley of the Jura Massif. The geology of both areas is linked to the Jura Range and present complex structures, where the landscape is composed of anticlines associated with overthrust faults, which are overcut by strike-slip fault and secondary faulting events. The rock formations go from the Trias, which forms the detachment layer, up to the Quaternary rock. Bedrocks are mainly composed of limestones and marls, which can reach a thickness of several hundreds meters. The three main deep aquifers investigated in this area, from the shallowest (≤ 400 m below surface) to deepest (< 2000 m), are the Malm, the Dogger and the Muschelkalk. The estimated temperatures, based on previous studies, should range between 20 to 65 oC, which are function of depth, elevation and groundwater velocity. The expected low temperature is mainly due to the presence of karstic systems, which drains the heat towards the low elevation of the basin. The present study is based on gravimetry surveys, 3D geological models and 3D gravimetry models to best characterize the underground structures and to find areas where the rock properties would be favourable to geothermal exploitation. This means targets where permeability and porosity are high in the potential aquifers, allowing a significant flow at the future production wells. The results indicate that gravity anomalies are associated with both shallow and deep geological structures in the two exploration sites and that high resolution of dense grid gravity measurements combined with realistic 3D models of the geological structures allow to characterize interesting features for deep geothermal exploration. Gravity corrections were carried out with a computing code using

  5. Trends in childhood leukaemia in the Nordic countries in relation to fallout from atmospheric nuclear weapons testing.

    PubMed Central

    Darby, S. C.; Olsen, J. H.; Doll, R.; Thakrar, B.; Brown, P. D.; Storm, H. H.; Barlow, L.; Langmark, F.; Teppo, L.; Tulinius, H.

    1992-01-01

    OBJECTIVE--To obtain further information about the risks of childhood leukaemia after exposure to ionising radiation at low doses and low dose rates before or after birth or to the father's testes shortly before conception. DESIGN--Observational study of trends in incidence of childhood leukaemia in relation to estimated radiation exposures due to fallout from atmospheric nuclear weapons testing during the 1950s and 1960s. SETTING--Nordic countries. SUBJECTS--Children aged under 15 years. MAIN OUTCOME MEASURES--Incidence rates of leukaemia by age at diagnosis, sex, country, and calendar year of diagnosis or year of birth; exposure category; relation between leukaemia and exposure for children aged 0-14 and 0-4 separately. RESULTS--During the high fallout period the average estimated dose equivalent to the fetal red bone marrow was around 140 mu Sv and the average annual testicular dose 140 mu Sv. There was little evidence of increased incidence of leukaemia among children born in these years. Doses to the red bone marrow of a child after birth were higher, and during the high exposure period children would have been subjected to an additional dose equivalent of around 1500 mu Sv, similar to doses received by children in several parts of central and eastern Europe owing to the Chernobyl accident and about 50% greater than the annual dose equivalent to the red bone marrow of a child from natural radiation. leukaemia incidence and red marrow dose was not related overall, but rates of leukaemia in the high exposure period were slightly higher than in the surrounding medium exposure period (relative risk for ages 0-14: 1.07, 95% confidence interval 1.00 to 1.14; for ages 0-4: 1.11, 1.00 to 1.24). CONCLUSIONS--Current predicted risks of childhood leukaemia after exposure to radiation are not greatly underestimated for low dose rate exposures. PMID:1586779

  6. Ionising radiation and risk of death from leukaemia and lymphoma in radiation-monitored workers (INWORKS): an international cohort study

    PubMed Central

    Leuraud, Klervi; Richardson, David B; Cardis, Elisabeth; Daniels, Robert D; Gillies, Michael; O'Hagan, Jacqueline A; Hamra, Ghassan B; Haylock, Richard; Laurier, Dominique; Moissonnier, Monika; Schubauer-Berigan, Mary K; Thierry-Chef, Isabelle; Kesminiene, Ausrele

    2015-01-01

    Summary Background There is much uncertainty about the risks of leukaemia and lymphoma after repeated or protracted low-dose radiation exposure typical of occupational, environmental, and diagnostic medical settings. We quantified associations between protracted low-dose radiation exposures and leukaemia, lymphoma, and multiple myeloma mortality among radiation-monitored adults employed in France, the UK, and the USA. Methods We assembled a cohort of 308 297 radiation-monitored workers employed for at least 1 year by the Atomic Energy Commission, AREVA Nuclear Cycle, or the National Electricity Company in France, the Departments of Energy and Defence in the USA, and nuclear industry employers included in the National Registry for Radiation Workers in the UK. The cohort was followed up for a total of 8·22 million person-years. We ascertained deaths caused by leukaemia, lymphoma, and multiple myeloma. We used Poisson regression to quantify associations between estimated red bone marrow absorbed dose and leukaemia and lymphoma mortality. Findings Doses were accrued at very low rates (mean 1·1 mGy per year, SD 2·6). The excess relative risk of leukaemia mortality (excluding chronic lymphocytic leukaemia) was 2·96 per Gy (90% CI 1·17–5·21; lagged 2 years), most notably because of an association between radiation dose and mortality from chronic myeloid leukaemia (excess relative risk per Gy 10·45, 90% CI 4·48–19·65). Interpretation This study provides strong evidence of positive associations between protracted low-dose radiation exposure and leukaemia. Funding Centers for Disease Control and Prevention, Ministry of Health, Labour and Welfare of Japan, Institut de Radioprotection et de Sûreté Nucléaire, AREVA, Electricité de France, National Institute for Occupational Safety and Health, US Department of Energy, US Department of Health and Human Services, University of North Carolina, Public Health England. PMID:26436129

  7. Leukaemia, brain tumours and exposure to extremely low frequency magnetic fields: cohort study of Swiss railway employees

    PubMed Central

    Röösli, Martin; Lörtscher, Manfred; Egger, Matthias; Pfluger, Dominik; Schreier, Nadja; Lörtscher, Emanuel; Locher, Peter; Spoerri, Adrian; Minder, Christoph

    2007-01-01

    Aims To investigate the relationship between extremely low frequency magnetic field (ELF‐MF) exposure and mortality from leukaemia and brain tumour in a cohort of Swiss railway workers. Methods 20 141 Swiss railway employees with 464 129 person‐years of follow‐up between 1972 and 2002 were studied. Mortality rates for leukaemia and brain tumour of highly exposed train drivers (21 μT average annual exposure) were compared with medium and low exposed occupational groups (i.e. station masters with an average exposure of 1 μT). In addition, individual cumulative exposure was calculated from on‐site measurements and modelling of past exposures. Results The hazard ratio (HR) for leukaemia mortality of train drivers was 1.43 (95% CI 0.74 to 2.77) compared with station masters. For myeloid leukaemia the HR of train drivers was 4.74 (95% CI 1.04 to 21.60) and for Hodgkin's disease 3.29 (95% CI 0.69 to 15.63). Lymphoid leukaemia, non‐Hodgkin's disease and brain tumour mortality were not associated with magnetic field exposure. Concordant results were obtained from analyses based on individual cumulative exposure. Conclusions Some evidence of an exposure–response association was found for myeloid leukaemia and Hodgkin's disease, but not for other haematopoietic and lymphatic malignancies and brain tumours. PMID:17525094

  8. PU.1 downregulation in murine radiation-induced acute myeloid leukaemia (AML): from molecular mechanism to human AML

    PubMed Central

    Verbiest, Tom; Bouffler, Simon; Nutt, Stephen L.; Badie, Christophe

    2015-01-01

    The transcription factor PU.1, encoded by the murine Sfpi1 gene (SPI1 in humans), is a member of the Ets transcription factor family and plays a vital role in commitment and maturation of the myeloid and lymphoid lineages. Murine studies directly link primary acute myeloid leukaemia (AML) and decreased PU.1 expression in specifically modified strains. Similarly, a radiation-induced chromosome 2 deletion and subsequent Sfpi1 point mutation in the remaining allele lead to murine radiation-induced AML. Consistent with murine data, heterozygous deletion of the SPI1 locus and mutation of the −14kb SPI1 upstream regulatory element were described previously in human primary AML, although they are rare events. Other mechanisms linked to PU.1 downregulation in human AML include TP53 deletion, FLT3-ITD mutation and the recurrent AML1-ETO [t(8;21)] and PML-RARA [t(15;17)] translocations. This review provides an up-to-date overview on our current understanding of the involvement of PU.1 in the initiation and development of radiation-induced AML, together with recommendations for future murine and human studies. PMID:25750172

  9. Multidrug resistance in chronic myeloid leukaemia: how much can we learn from MDR–CML cell lines?

    PubMed Central

    Rumjanek, Vivian M.; Vidal, Raphael S.; Maia, Raquel C.

    2013-01-01

    The hallmark of CML (chronic myeloid leukaemia) is the BCR (breakpoint cluster region)–ABL fusion gene. CML evolves through three phases, based on both clinical and pathological features: a chronic phase, an accelerated phase and blast crisis. TKI (tyrosine kinase inhibitors) are the treatment modality for patients with chronic phase CML. The therapeutic potential of the TKI imatinib is affected by BCR–ABL dependent an independent mechanisms. Development of MDR (multidrug resistance) contributes to the overall clinical resistance. MDR involves overexpression of ABC -transporters (ATP-binding-cassette transporter) among other features. MDR studies include the analysis of cancer cell lines selected for resistance. CML blast crisis is accompanied by increased resistance to apoptosis. This work reviews the role played by the influx transporter OCT1 (organic cation transporter 1), by efflux ABC transporters, molecules involved in the modulation of apoptosis (p53, Bcl-2 family, CD95, IAPs (inhibitors of apoptosis protein)], Hh and Wnt/β-catenin pathways, cytoskeleton abnormalities and other features described in leukaemic cells of clinical samples and CML cell lines. An MDR cell line, Lucena-1, generated from K562 by stepwise exposure to vincristine, was used as our model and some potential anticancer drugs effective against the MDR cell line and patients’ samples are presented. PMID:24070327

  10. Methotrexate consolidation treatment according to pharmacogenetics of MTHFR ameliorates event-free survival in childhood acute lymphoblastic leukaemia.

    PubMed

    Salazar, J; Altés, A; del Río, E; Estella, J; Rives, S; Tasso, M; Navajas, A; Molina, J; Villa, M; Vivanco, J L; Torrent, M; Baiget, M; Badell, I

    2012-10-01

    Recent advances in treatment for childhood acute lymphoblastic leukaemia (ALL) have significantly increased outcome. High-dose methotrexate (MTX) is the most commonly used regimen during the consolidation period, but the optimal dose remains to be defined. We investigated the usefulness of the MTHFR genotype to increase the MTX dosage in the consolidation phase in 141 childhood ALL patients enrolled in the ALL/SHOP-2005 protocol. We also investigated the pharmacogenetic role of polymorphisms in genes involved in MTX metabolism on therapy-related toxicity and survival. Patients with a favourable MTHFR genotype (normal enzymatic activity) treated with MTX doses of 5 g m⁻² had a significantly lower risk of suffering an event than patients with an unfavourable MTHFR genotype (reduced enzymatic activity) that were treated with the classical MTX dose of 3 g m⁻² (P=0.012). Our results indicate that analysis of the MTHFR genotype is a useful tool to optimise MTX therapy in childhood patients with ALL. PMID:21747412

  11. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution

    PubMed Central

    Kasar, S.; Kim, J.; Improgo, R.; Tiao, G.; Polak, P.; Haradhvala, N.; Lawrence, M. S.; Kiezun, A.; Fernandes, S. M.; Bahl, S.; Sougnez, C.; Gabriel, S.; Lander, E. S.; Kim, H. T.; Getz, G.; Brown, J. R.

    2015-01-01

    Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution. PMID:26638776

  12. Whole-genome sequencing reveals activation-induced cytidine deaminase signatures during indolent chronic lymphocytic leukaemia evolution.

    PubMed

    Kasar, S; Kim, J; Improgo, R; Tiao, G; Polak, P; Haradhvala, N; Lawrence, M S; Kiezun, A; Fernandes, S M; Bahl, S; Sougnez, C; Gabriel, S; Lander, E S; Kim, H T; Getz, G; Brown, J R

    2015-01-01

    Patients with chromosome 13q deletion or normal cytogenetics represent the majority of chronic lymphocytic leukaemia (CLL) cases, yet have relatively few driver mutations. To better understand their genomic landscape, here we perform whole-genome sequencing on a cohort of patients enriched with these cytogenetic characteristics. Mutations in known CLL drivers are seen in only 33% of this cohort, and associated with normal cytogenetics and unmutated IGHV. The most commonly mutated gene in our cohort, IGLL5, shows a mutational pattern suggestive of activation-induced cytidine deaminase (AID) activity. Unsupervised analysis of mutational signatures demonstrates the activities of canonical AID (c-AID), leading to clustered mutations near active transcriptional start sites; non-canonical AID (nc-AID), leading to genome-wide non-clustered mutations, and an ageing signature responsible for most mutations. Using mutation clonality to infer time of onset, we find that while ageing and c-AID activities are ongoing, nc-AID-associated mutations likely occur earlier in tumour evolution. PMID:26638776

  13. Fallout from Chernobyl and incidence of childhood leukaemia in Finland, 1976-92.

    PubMed Central

    Auvinen, A.; Hakama, M.; Arvela, H.; Hakulinen, T.; Rahola, T.; Suomela, M.; Söderman, B.; Rytömaa, T.

    1994-01-01

    OBJECTIVE--To assess effects of fallout from Chernobyl on incidence of childhood leukaemia in Finland. DESIGN--Nationwide cohort study. External exposure measured for 455 Finnish municipalities with instruments driven 19,000 km throughout the country. Values specific to municipalities corrected for shielding due to houses and fallout from A bomb testing. Internal exposure estimated from whole body measurements on a random sample of 81 children. Mean effective dose for two years after incident calculated from these measurements. Data on childhood leukaemia obtained from Finnish cancer registry and verified through hospitals treating childhood cancers. SETTING--Finland, one of the countries most heavily contaminated by the Chernobyl accident; the population was divided into fifths by exposure. SUBJECTS--Children aged 0-14 years in 1976-92. MAIN OUTCOME MEASURES--Standardised incidence ratio of childhood leukaemia and relative excess risk of childhood leukaemia per mSv. From incidence data of Finnish cancer registry for 1976-85, expected numbers specific to sex and age group (0-4, 5-9, and 10-14 years) were calculated for each municipality for three periods (1976-85, 1986-8, and 1989-92) and pooled as exposure fifths. Dose response was estimated as regression slope of standardised incidence ratios on mean doses for fifths for each period. RESULTS--Population weighted mean effective doses for first two years after the accident were 410 microSv for the whole country and 970 microSv for the population fifth with the highest dose. In all Finland the incidence of childhood leukaemia did not increase 1976-92. The relative excess risk 1989-92 was not significantly different from zero (7% per mSv; 95% confidence interval -27% to 41%). CONCLUSIONS--An important increase in childhood leukaemia can be excluded. Any effect is smaller than eight extra cases per million children per year in Finland. The results are consistent with the magnitude of effect expected. PMID:8044092

  14. Early stem cell transplantation for chronic lymphocytic leukaemia: a chance for cure?

    PubMed Central

    Dreger, P.; von Neuhoff, N.; Kuse, R.; Sonnen, R.; Glass, B.; Uharek, L.; Schoch, R.; Löffler, H.; Schmitz, N.

    1998-01-01

    B-cell chronic lymphocytic leukaemia (CLL) cannot be cured by conventional therapy. To improve the prognosis of patients with CLL, we have designed a sequential treatment strategy that comprises intensive chemotherapy for mobilization of peripheral blood progenitor cells (PBPCs) and induction of minimal disease, followed by high-dose radiochemotherapy with stem cell reinfusion and post-transplant molecular monitoring by polymerase chain reaction (PCR) amplification of the complementary determining region III (CDRIII) gene. In a prospective study, we have evaluated this protocol in 18 patients with CLL, also including early stages of the disease. The median age was 49 (29-61) years; Binet stages were A, six; B, nine; and C, three. Adverse prognostic factors [high lymphocyte count and/or diffuse bone marrow (BM) infiltration] were present in 16 out of 18 patients. All patients showed a clone-specific molecular marker as demonstrated by PCR amplification of CDRIII rearrangements. For stem cell mobilization and reduction of tumour load, one to two cycles of Dexa-BEAM chemotherapy were administered, resulting in minimal disease (circulating lymphoma cells <1 x 10(9) l(-1); BM infiltration <20%; lymphomas <2 cm) in 16 out of 18 patients, including four patients who already had minimal disease before Dexa-BEAM. Stem cell harvesting was successful in 14 patients. All grafts [three BM, 11 peripheral blood (PB)] were purged from leukaemic cells using immunomagnetic methods. Thirteen patients having achieved minimal disease were reinfused with purged autologous stem cells (ASC) after preparation with total body irradiation and cyclophosphamide. Engraftment was delayed in patients receiving BM (n = 3) but prompt [neutrophils >0.5 x 10(9) l(-1) after 10 (9-13) days, platelets >20 x 10(9) l(-1) after 11 (9-214) days] in patients restored with PBPCs (n = 10). Procedure-related deaths did not occur. Although the results of CDRIII PCR suggest persistence or recurrence of the

  15. Core binding factor acute myeloid leukaemia and c-KIT mutations.

    PubMed

    Riera, Ludovica; Marmont, Filippo; Toppino, Daniela; Frairia, Chiara; Sismondi, Francesca; Audisio, Ernesta; Di Bello, Cristiana; D'Ardia, Stefano; Di Celle, Paola Francia; Messa, Emanuela; Inghirami, Giorgio; Vitolo, Umberto; Pich, Achille

    2013-05-01

    Core binding factor (CBF) acute myeloid leukaemia (AML) represents 5-8% of all AMLs and has a relatively favourable prognosis. However, activating c-KIT mutations are reported to be associated with higher risk of relapse and shorter survival. To verify the incidence and prognostic value of c-KIT mutations in CBF AML, we retrospectively analysed bone marrow samples of 23 consecutive adult patients with de novo CBF AML [14 inv(16) and 9 t(8;21)] treated at a single institution from 2000 to 2011. All patients received standard induction chemotherapy with cytarabine, idarubicin and etoposide; 13 underwent allogeneic stem cell transplantation. c-KIT mutations in exons 8, 9, 10, 11, 13, 14 and 17 were assessed by PCR amplification in combination with direct sequencing. c-KIT mutations (3 in exon 10 and 4 in exon 17) were detected in 7/23 (30.4%) patients, 3 with t(8;21) and 4 with inv(16). No difference in c-KIT mutation status was observed between cases with inv(16) or t(8;21) alone and cases with additional cytogenetic abnormalities. No association between gender, age, white blood cell and platelet count, peripheral blood and bone marrow blast cells at diagnosis, achievement of complete remission, cytogenetic risk groups and Wilms tumour gene 1 (WT1) levels was found. On the contrary, lactate dehydrogenase (LDH) values were higher in mutated than in non-mutated patients (p=0.01). Overall survival (OS) rates were longer in CBF compared to the other types of AML and disease-free survival (DFS) was longer in inv(16) than in t(8;21) AML. OS and DFS were similar in mutated and non-mutated CBF AML patients. Our results confirm a better prognosis for CBF AML than all other AML categories, and for inv(16) than t(8;21) AML. However, no prognostic value for c-KIT mutational status was found in our series. The association between LDH levels and c-KIT mutation would indicate a more active proliferation for mutated CBF AML. PMID:23467883

  16. A Study of Haemostatic Parameters in Patients of Chronic Myeloid Leukaemia

    PubMed Central

    Gupta, Naresh; Singh, Tejinder; Agarwal, Sunita

    2016-01-01

    Introduction Chronic Myeloid Leukaemia (CML) is characterized by derangement of various components of the haemostatic system resulting in thrombo-haemorrhagic complications. Although less common than other myeloproliferative neoplasms, derangement of various components of the haemostatic system is observed in CML. Haemostatic abnormalities have been described in relation to hyperleucostasis and drugs used to treat CML. However, the correlation between haemostatic derangements and phase of CML is unclear in the literature. Aim The purpose of this cross-sectional study was to assay various haemostatic parameters in patients of CML receiving Imatinib and to determine any correlation between them and phases of disease as well as the status of remission. Materials and Methods The study included 30 patients with CML (17 males, 13 females, mean age of 35.53 ± 8.92 years) receiving imatinib mesylate. Haemostatic parameters including platelet counts, Prothrombin Time (PT), activated Partial Thromboplastin Time (APTT), fibrinogen, D-dimers and Factor VIII levels were assayed for all patients using standard methods. Bcr-abl gene product (quantitative) was determined on the peripheral blood by reverse transcriptase polymerase chain reaction (RT-PCR). Patients were grouped into phases of disease (chronic, accelerated and blast) and their response to imatinib was determined in the form of remission (clinical, haematological and molecular). Correlations were drawn between them using spearman’s coefficient. Results A significant positive correlation was found between PT (p=0.002), fibrinogen (p=0.011), D-dimers (p=0.050), Factor VIII levels (p=0.006) with the phase of CML and a significant negative correlation was observed between PT (p=0.003, 0.006), fibrinogen (p=0.010, 0.005), D-dimers (p=0.035, 0.017), Factor VIII levels (p=0.005, 0.001) and clinical and haematological remission respectively. No significant correlation of platelet counts and APTT was seen with the phase of

  17. miR-664 negatively regulates PLP2 and promotes cell proliferation and invasion in T-cell acute lymphoblastic leukaemia

    SciTech Connect

    Zhu, Hong; Miao, Mei-hua; Ji, Xue-qiang; Xue, Jun; Shao, Xue-jun

    2015-04-03

    MicroRNAs (miRNAs) play important roles in the pathogenesis of many types of cancers by negatively regulating gene expression at posttranscriptional level. However, the role of microRNAs in leukaemia, particularly T-cell acute lymphoblastic leukaemia (T-ALL), has remained elusive. Here, we identified miR-664 and its predicted target gene PLP2 were differentially expressed in T-ALL using bioinformatics methods. In T-ALL cell lines, CCK-8 proliferation assay indicated that the cell proliferation was promoted by miR-664, while miR-664 inhibitor could significantly inhibited the proliferation. Moreover, migration and invasion assay showed that overexpression of miR-664 could significantly promoted the migration and invasion of T-ALL cells, whereas miR-664 inhibitor could reduce cell migration and invasion. luciferase assays confirmed that miR-664 directly bound to the 3'untranslated region of PLP2, and western blotting showed that miR-664 suppressed the expression of PLP2 at the protein levels. This study indicated that miR-664 negatively regulates PLP2 and promotes proliferation and invasion of T-ALL cell lines. Thus, miR-664 may represent a potential therapeutic target for T-ALL intervention. - Highlights: • miR-664 mimics promote the proliferation and invasion of T-ALL cells. • miR-664 inhibitors inhibit the proliferation and invasion of T-ALL cells. • miR-664 targets 3′ UTR of PLP2 in T-ALL cells. • miR-664 negatively regulates PLP2 in T-ALL cells.

  18. A specialist leukaemia/lymphoma registry in the UK. Part 1: Incidence and geographical distribution of Hodgkin's disease. Leukaemia Research Fund Data Collection Study Group.

    PubMed Central

    McKinney, P. A.; Alexander, F. E.; Ricketts, T. J.; Williams, J.; Cartwright, R. A.

    1989-01-01

    This paper describes the epidemiology of Hodgkin's disease occurring in parts of the United Kingdom between 1984 and 1986. The cases were carefully diagnosed and the data rigorously cross-checked as part of the larger Leukaemia Research Fund Data Collection Survey of all lymphoid and haematogenous malignancies. The age-specific rates show the lack of an older adult second peak. Spatial variation is examined in some detail. At county and district levels there is little heterogeneity in the distribution of cases. However, at the electoral ward level there were real differences for the younger age group (0-34). PMID:2605103

  19. Neonatal acute lymphocytic leukaemia: an unusual presentation of a rare disease.

    PubMed

    Palman, Jason; Karam, Maria; Chee, Ying; Kandala, Vijay

    2015-01-01

    Infantile acute lymphocytic leukaemia (ALL) seldom presents within the first month of life. Most are diagnosed before birth. Postnatal diagnoses are easily recognisable when characteristic features are present, namely hepatosplenomegaly, leukaemia cutis or infiltrative disease of the extramedullar and central nervous system. However, some children present with vague and non-specific symptoms masquerading as other diseases. We report an unusual presentation of infantile ALL in a 19-day-old infant, who struggled with feeding after a diagnosis of gastro-oesophageal reflux disease since birth. To the best of our knowledge, this is the youngest case report of neonatal ALL, presenting with vomiting, lethargy and dehydration. The neonate presented to our paediatric assessment unit acutely due to progression of her symptoms. General physical examination was unremarkable apart from signs of lethargy and dehydration. Blood investigation revealed an incidental finding of high white cells, including 90% blast cells. Early diagnosis in this case meant early treatment and a good prognosis. PMID:26178003

  20. Mild axonal neuropathy of children during treatment for acute lymphoblastic leukaemia.

    PubMed

    Reinders-Messelink, H A; Van Weerden, T W; Fock, J M; Gidding, C E; Vingerhoets, H M; Schoemaker, M M; Göeken, L N; Bökkerink, J P; Kamps, W A

    2000-01-01

    Neurophysiological functioning was studied prospectively in children treated for acute lymphoblastic leukaemia with a low dose vincristine regime (8 x 1.5 mg/m2/dose), to obtain more insight into vincristine neuropathy. A WHO neurotoxicity score was estimated and vibration sense and electrophysiological measurements were taken at standardized times during vincristine treatment. The WHO neurotoxicity score showed decreased or disappearance of Achilles tendon reflexes, and mild sensory disturbances, but a grade 3-4 neurotoxicity was not demonstrated by any of the children. Vibration perception thresholds increased progressively during treatment and amplitudes of action potentials of peroneal and sensory ulnar and median nerves decreased, whereas nerve conduction velocities stayed unchanged. Both vibration perception thresholds and the electrophysiological findings hardly exceeded the limits of normality. We conclude that children treated for acute lymphoblastic leukaemia with a low dose vincristine regimen have mild axonal neuropathy which may be responsible for the motor problems in these children. PMID:11030069

  1. Femoral diaphyseal stress fracture as the initial presentation of acute leukaemia in an adolescent.

    PubMed

    Chase, Helen Emily; Pang, Joe Hwong; Sanghrajka, Anish Pradip

    2016-01-01

    A 14-year-old boy was referred to the orthopaedic clinic by his general practitioner, reporting of a 6-week history of left thigh pain. Clinical examination was unremarkable. Radiographs demonstrated a periosteal reaction at the proximal femur. MRI scans demonstrated a stress fracture of the femur, with no associated sinister features and no evidence of a pathological lesion. As the fracture healed and symptoms improved, the patient became unwell with weight loss, lethargy, chest and jaw pain and fevers. After multiple blood tests over a 25-day period, including five full blood counts and two normal blood films, a third blood film finally demonstrated blasts in keeping with acute leukaemia. We discuss a literature review of musculoskeletal manifestations of leukaemia and the often atypical presentations found. PMID:27353177

  2. Stage IV sporadic Burkitt's leukaemia with osteolysis in the maxillary sinuses

    PubMed Central

    Yoshioka, Yohsuke; Yamachika, Eiki; Matsubara, Masakazu; Iida, Seiji

    2016-01-01

    We present a case of paediatric Stage IV sporadic Burkitt's leukaemia presenting as cheek enlargement with osteolysis of the maxilla. An 8-year-old boy was referred to our department with diffuse swelling of both cheeks. Head and neck examination revealed bilateral diffuse nontender swelling, non-fluctuant but slightly compressible. Computed tomography imaging showed enhancing bilateral bulky lesions expanding the maxillary sinuses, with associated osteolysis in the posterior walls of both sinuses. Laboratory results included blast cells in the peripheral blood, suggesting a haematopoietic tumour. We referred the patient to the Department of Paediatric Haematology and Oncology. Additional examinations eventually led to the diagnosis of Stage IV sporadic Burkitt's leukaemia. PMID:26872961

  3. Angiogenic factors in chronic lymphocytic leukaemia (CLL): Where do we stand?

    PubMed

    Aguirre Palma, Luis Mario; Gehrke, Iris; Kreuzer, Karl-Anton

    2015-03-01

    The role of angiogenesis in haematological malignancies such as chronic lymphocytic leukaemia (CLL) is difficult to envision, because leukaemia cells are not dependent on a network of blood vessels to support basic physiological requirements. Regardless, CLL cells secrete high levels of major angiogenic factors, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and platelet derived growth factor (PDGF). Nonetheless, it remains unclear how most angiogenic factors regulate accumulation and delayed apoptosis of CLL cells. Angiogenic factors such as leptin, granulocyte colony-stimulating factor (G-CSF), follistatin, angiopoietin-1 (Ang1), angiogenin (ANG), midkine (MK), pleiotrophin (PTN), progranulin (PGRN), proliferin (PLF), placental growth factor (PIGF), and endothelial locus-1 (Del-1), represent novel therapeutic targets of future CLL research but have remained widely overlooked. This review aims to outline our current understanding of angiogenic growth factors and their relationship with CLL, a still uncured haematopoietic malignancy. PMID:25459668

  4. Chronic myelogenous leukaemia with persistent neutrophilia, eosinophilia and basophilia in a cat.

    PubMed

    Mochizuki, Hiroyuki; Seki, Takahiro; Nakahara, Yoshitaka; Tomita, Akitada; Takahashi, Masashi; Fujino, Yasuhito; Ohno, Koichi; Tsujimoto, Hajime

    2014-06-01

    Chronic myelogenous leukaemia was diagnosed in a 7-year-old male neutered domestic shorthair cat. Leukocytosis (74,900/µl)--mature neutrophilia, eosinophilia and basophilia--was observed. Bone marrow aspiration revealed hypercellularity with proliferation of cells of myeloid lineage. An underlying condition leading to leukocytosis was not identified. The severe leukocytosis did not respond to antibiotic therapy. Based on these findings, chronic myelogenous leukaemia was diagnosed. Because of the absence of clinical signs, the cat was monitored without treatment until 7 months after diagnosis, when it developed pruritic skin lesions. Pruritus was controlled with oral prednisolone. Forty-two months after diagnosis, the cat developed nasal lymphoma, which was treated with radiation therapy, resulting in complete remission. The cat was still in good physical condition 63 months after diagnosis, despite the persistence of marked neutrophilia, eosinophilia and basophilia. PMID:24108200

  5. Park size and disturbance: impact on soil heterogeneity - a case study Tel-Aviv- Jaffa.

    NASA Astrophysics Data System (ADS)

    Zhevelev, Helena; Sarah, Pariente; Oz, Atar

    2015-04-01

    Parks and gardens are poly-functional elements of great importance in urban areas, and can be used for optimization of physical and social components in these areas. This study aimed to investigate alteration of soil properties with land usages within urban park and with area size of park. Ten parks differed by size (2 - 50 acres) were chosen, in random, in Tel-Aviv- Jaffa city. Soil was sampled in four microenvironments ((lawn, path, picnic and peripheral area (unorganized area) of each the park)), in three points and three depth (0-2, 5-10 and 10-20 cm). Penetration depth was measured in all point of sampling. For each soil sample electrical conductivity and organic matter content were determined. Averages of penetration depth drastically increased from the most disturbed microenvironments (path and picnic) to the less disturbed ones (lawn and peripheral). The maximal heterogeneity (by variances and percentiles) of penetration depth was found in the peripheral area. In this area, penetration depth increased with increasing park size, i.e., from 2.6 cm to 3.7 cm in the small and large parks, respectively. Averages of organic matter content and electrical conductivity decreased with soil depth in all microenvironments and increased with decreasing disturbance of microenvironments. Maximal heterogeneity for both of these properties was found in the picnic area. Increase of park size was accompanied by increasing of organic matter content in the upper depth in the peripheral area, i.e., from 2.4% in the small parks to 4.5% in the large ones. In all microenvironments the increasing of averages of all studied soil properties was accompanied by increasing heterogeneity, i.e., variances and upper percentiles. The increase in the heterogeneity of the studied soil properties is attributed to improved ecological soil status in the peripheral area, on the one hand, and to the high anthropogenic pressure in the picnic area, on the other. This means that the urban park offers

  6. Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia

    PubMed Central

    Avcu, Gulhadiye; Karapinar, Deniz Yilmaz; Yazici, Pinar; Duyu, Muhterem; Polat, Suleyha Hilmioglu; Atabay, Berna; Doganavsargil, Basak; Karapinar, Bulent

    2016-01-01

    Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients. PMID:26937339

  7. Difficult diagnosis of invasive fungal infection predominantly involving the lower gastrointestinal tract in acute lymphoblastic leukaemia.

    PubMed

    Avcu, Gulhadiye; Karapinar, Deniz Yilmaz; Yazici, Pinar; Duyu, Muhterem; Polat, Suleyha Hilmioglu; Atabay, Berna; Doganavsargil, Basak; Karapinar, Bulent

    2016-03-01

    Invasive fungal infections are most commonly seen in immunocompromised patients and usually affect the respiratory system. Gastrointestinal system involvement of mucormycosis and invasive aspergillosis is rarely reported in childhood. Here we describe a 5 year old boy with acute lymphoblastic leukaemia who developed invasive fungal infection particularly affecting the lower gastrointestinal system to emphasise the difficulties in diagnosis and management of invasive fungal infections in immunocompromised patients. PMID:26937339

  8. How does HTLV-1 cause adult T-cell leukaemia/lymphoma (ATL)?

    PubMed Central

    Bangham, Charles RM; Ratner, Lee

    2016-01-01

    A typical person infected with the retrovirus human T-lymphotropic virus type 1 (HTLV-1) carries tens of thousands of clones of HTLV-1-infected T lymphocytes, each clone distinguished by a unique integration site of the provirus in the host genome. However, only 5% of infected people develop the malignant disease adult T cell leukaemia/lymphoma, usually more than 50 years after becoming infected. We review the host and viral factors that cause this aggressive disease. PMID:26414684

  9. Mobile health for early retention in HIV care: a qualitative study in Kenya (WelTel Retain).

    PubMed

    Smillie, Kirsten; Van Borek, Natasha; van der Kop, Mia L; Lukhwaro, Abigael; Li, Neville; Karanja, Sarah; Patel, Anik R; Ojakaa, David; Lester, Richard T

    2014-01-01

    Many people newly diagnosed with HIV are lost to follow-up before timely initiation of antiretroviral therapy (ART). A randomised controlled trial (RCT), WelTel Kenya1, demonstrated the effectiveness of the WelTel text messaging intervention to improve clinical outcomes among patients initiating ART. In preparation for WelTel Retain, an RCT that will evaluate the effect of the intervention to retain patients in care immediately following HIV diagnosis, we conducted an informative qualitative study with people living with HIV (n = 15) and healthcare providers (HCP) (n = 5) in October 2012. Study objectives included exploring the experiences of people living with HIV who have attempted to engage in HIV care, the use of cell phones in everyday life, and perceptions of communicating via text message with HCP. Participants were recruited through convenience sampling. Semi-structured, qualitative interviews were conducted and recorded, transcribed verbatim and analysed using NVivo software. Analysis was guided by the Theory of Reasoned Action and the Technology Acceptance Model. Results indicate that while individuals have many motivators for engaging in care after diagnosis, structural and individual barriers including poverty, depression and fear of stigma prevent them from doing so. All participants had access to a mobile phone, and most were comfortable communicating through text messages, or were willing to learn. Both people living with HIV and HCP felt that increased communication via the text messaging intervention has the potential to enable early identification of problems, leading to timely problem solving that may improve retention and engagement in care during the first year after diagnosis. PMID:25555099

  10. Mre11 ATLD17/18 mutation retains Tel1/ATM activity but blocks DNA double-strand break repair.

    PubMed

    Limbo, Oliver; Moiani, Davide; Kertokalio, Aryandi; Wyman, Claire; Tainer, John A; Russell, Paul

    2012-12-01

    The Mre11 complex (Mre11-Rad50-Nbs1 or MRN) binds double-strand breaks where it interacts with CtIP/Ctp1/Sae2 and ATM/Tel1 to preserve genome stability through its functions in homology-directed repair, checkpoint signaling and telomere maintenance. Here, we combine biochemical, structural and in vivo functional studies to uncover key properties of Mre11-W243R, a mutation identified in two pediatric cancer patients with enhanced ataxia telangiectasia-like disorder. Purified human Mre11-W243R retains nuclease and DNA binding activities in vitro. X-ray crystallography of Pyrococcus furiosus Mre11 indicates that an analogous mutation leaves the overall Mre11 three-dimensional structure and nuclease sites intact but disorders surface loops expected to regulate DNA and Rad50 interactions. The equivalent W248R allele in fission yeast allows Mre11 to form an MRN complex that efficiently binds double-strand breaks, activates Tel1/ATM and maintains telomeres; yet, it causes hypersensitivity to ionizing radiation and collapsed replication forks, increased Rad52 foci, defective Chk1 signaling and meiotic failure. W248R differs from other ataxia telangiectasia-like disorder analog alleles by the reduced stability of its interaction with Rad50 in cell lysates. Collective results suggest a separation-of-function mutation that disturbs interactions amongst the MRN subunits and Ctp1 required for DNA end processing in vivo but maintains interactions sufficient for Tel1/ATM checkpoint and telomere maintenance functions. PMID:23080121

  11. Demonstration of cytoplasmic and nuclear antigens in acute leukaemia using flow cytometry.

    PubMed Central

    Farahat, N; van der Plas, D; Praxedes, M; Morilla, R; Matutes, E; Catovsky, D

    1994-01-01

    AIMS--To detect cytoplasmic and nuclear antigens using flow cytometry in acute leukaemia and to use this technique for double marker combinations. METHODS--Cytoplasmic staining was carried out in samples from 40 cases of acute leukaemia with monoclonal antibodies against the myeloid antigen CD13, the lymphoid antigens CD3, CD22, mu chain and the enzymes terminal deoxynucleotidyl transferase (TdT) and myeloperoxidase (MPO). The cells were fixed with paraformaldehyde and permeabilised with Tween 20 and Becton Dickinson's FACS lysing solution. Flow cytometry results were compared in the same cases with immunocytochemistry results using the alkaline phosphatase anti-alkaline phosphatase method. RESULTS--The gentle permeabilisation induced by this method permitted preservation of the membrane antigens and the size and morphology of the cells. The results using flow cytometry were comparable with those obtained using immunocytochemistry, with nearly complete concordance in most cases. CONCLUSIONS--This technique is simple, rapid, sensitive and reproducible and it is suitable for double staining procedures, such as nuclear and cytoplasmic, nuclear and membrane, or cytoplasmic and membrane. It therefore provides a powerful tool for extending the use of immunophenotyping for the diagnosis and follow up of acute leukaemia. It could also be used for the investigation of minimal residual disease. PMID:7962655

  12. Inhibitors of cyclooxygenase-2 (COX-2) suppressed the proliferation and differentiation of human leukaemia cell lines.

    PubMed

    Nakanishi, Y; Kamijo, R; Takizawa, K; Hatori, M; Nagumo, M

    2001-08-01

    Prostaglandins (PG) are known to play important roles in the proliferation and differentiation of leukaemia cells. The effect of the inhibitors of cyclooxygenase-2 (COX-2), a rate-limiting enzyme for the synthesis of PG, on the proliferation and differentiation of leukaemia cell lines was investigated. COX-2 inhibitors, NS-398 and nabumetone, suppressed the proliferation of U-937 and ML-1 cells by inducing a G0/G1 cell-cycle arrest. Cell-cycle arrest induced by these COX-2 inhibitors was not associated with an upregulation of the cyclin-dependent kinase inhibitors. COX-2 inhibitors also inhibited the differentiation of these cells induced by interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and retinoic acid (RA). Treatment with NS-398 did not suppress the levels of PGs produced by these cells. Although COX-2 antisense oligonucleotide showed a similar inhibitory effect on these cells, its inhibitory effect was smaller than that of NS-398. These results suggest that COX-2 inhibitors may suppress the proliferation and differentiation of leukaemia cells both via COX-2-dependent and -independent pathways. PMID:11506967

  13. BRAF mutation detection in hairy cell leukaemia from archival haematolymphoid specimens.

    PubMed

    Thomas, Carla; Amanuel, Benhur; Finlayson, Jill; Grieu-Iacopetta, Fabienne; Spagnolo, Dominic V; Erber, Wendy N

    2015-06-01

    Hairy cell leukaemia (HCL) is a rare, indolent chronic B-cell leukaemia accounting for approximately 2% of all adult leukaemias. The recent association of the BRAF p.Val600Glu (V600E) mutation in HCL makes it a valuable molecular diagnostic marker. We compared the ability of Sanger sequencing, fluorescent single-strand conformational polymorphism (F-SSCP) and high resolution melting (HRM) analysis to detect BRAF mutations in 20 cases of HCL consisting of four archival Romanowsky stained air-dried peripheral blood and bone marrow aspirate smears, 12 mercury fixed decalcified bone marrow trephine biopsies, three formalin fixed, paraffin embedded (FFPE) splenectomy samples and one fresh peripheral blood sample. DNA was amplified and BRAF mutation status determined by the three methods above. V600E mutation was identified in 94%, 89% and 72% of HCL cases by F-SSCP, HRM and Sanger sequencing, respectively. In one case, in addition to the p.Val600Glu mutation, a p.Lys601Thr (K601T) mutation was identified. DNA from archival slide scrapings, mercury-fixed and FFPE tissue can be used to identify BRAF mutations with high sensitivity, especially using HRM/F-SSCP. The V600E mutation can be used as a supplementary molecular marker to aid in the diagnosis of HCL and the presence of the mutation may provide a target for therapy. PMID:25938346

  14. Value of monoclonal anti-myeloperoxidase (MPO7) for diagnosing acute leukaemia.

    PubMed Central

    Storr, J; Dolan, G; Coustan-Smith, E; Barnett, D; Reilly, J T

    1990-01-01

    The expression of myeloperoxidase (MPO) was studied in 100 cases of acute leukaemia (83 with acute myeloid leukaemia (AML) and 17 acute lymphoblastic leukaemia (ALL) by both a conventional cytochemical method and the immunocytochemical antiperoxidase (APAAP) technique using the monoclonal antibody MPO7. In each case the staining was evaluated by light microscopical examination (percentage of positive cells). Of the 83 cases of AML, 78 (93.9%) were positive for MPO7 compared with 70 (84.3%) by cytochemistry. Antibodies against the myeloid markers CD13 and CD33 were positive in 71 (85.5%) and 70 (84.3%) cases, respectively. Importantly, all cases of ALL were negative for both MPO7 and cytochemical MPO staining even when they were positive for CD13 and CD33. These results indicate that the anti-myeloperoxidase antibody MPO7 is the most sensitive and specific reagent for the diagnosis of AML and should therefore be included in routine immunophenotyping panels. Images PMID:1977771

  15. Multi-loci diagnosis of acute lymphoblastic leukaemia with high-throughput sequencing and bioinformatics analysis.

    PubMed

    Ferret, Yann; Caillault, Aurélie; Sebda, Shéhérazade; Duez, Marc; Grardel, Nathalie; Duployez, Nicolas; Villenet, Céline; Figeac, Martin; Preudhomme, Claude; Salson, Mikaël; Giraud, Mathieu

    2016-05-01

    High-throughput sequencing (HTS) is considered a technical revolution that has improved our knowledge of lymphoid and autoimmune diseases, changing our approach to leukaemia both at diagnosis and during follow-up. As part of an immunoglobulin/T cell receptor-based minimal residual disease (MRD) assessment of acute lymphoblastic leukaemia patients, we assessed the performance and feasibility of the replacement of the first steps of the approach based on DNA isolation and Sanger sequencing, using a HTS protocol combined with bioinformatics analysis and visualization using the Vidjil software. We prospectively analysed the diagnostic and relapse samples of 34 paediatric patients, thus identifying 125 leukaemic clones with recombinations on multiple loci (TRG, TRD, IGH and IGK), including Dd2/Dd3 and Intron/KDE rearrangements. Sequencing failures were halved (14% vs. 34%, P = 0.0007), enabling more patients to be monitored. Furthermore, more markers per patient could be monitored, reducing the probability of false negative MRD results. The whole analysis, from sample receipt to clinical validation, was shorter than our current diagnostic protocol, with equal resources. V(D)J recombination was successfully assigned by the software, even for unusual recombinations. This study emphasizes the progress that HTS with adapted bioinformatics tools can bring to the diagnosis of leukaemia patients. PMID:26898266

  16. Dendritic cells and myeloid leukaemias: plasticity and commitment in cell differentiation.

    PubMed

    Rasaiyaah, Jane; Yong, Kwee; Katz, David R; Kellam, Paul; Chain, Benjamin M

    2007-08-01

    Dendritic cells (DCs) are key antigen-presenting cells (APCs), which link innate and adaptive immunity, ultimately activating antigen-specific T cells. This review examines the relationship between the acute and chronic myeloid leukaemias and cells with DC properties. DCs are non-dividing terminally differentiated cells, and ex vivo leukaemic cells or cell lines show little similarity to DCs. However, many leukaemias differentiate further in response to defined stimuli, and retain a degree of lineage plasticity. Therefore, several studies have explored the response of leukaemic cells to the in vitro regimens used to differentiate ex vivo primary DCs. Recent data suggest that the most 'dendritic-like' cells can be derived from more undifferentiated myeloid leukaemias, such as the myelomonocytic Mutz-3 cell line. These findings have important implications for understanding the developmental origins of DCs, for harnessing the APC properties of this class of tumour to stimulate the therapeutic anti-tumour immunity, and for developing useful models for the study of human DC physiology and pathology. There is a strong rationale for further exploration of this class of tumour and its relationship to the normal DC. PMID:17614817

  17. Ibrutinib (Imbruvica). Relapsed chronic lymphocytic leukaemia and mantle cell lymphoma: uncertain impact on survival.

    PubMed

    January

    2016-04-01

    codynamic interactions are also likely in view of its adverse effect profile. There is no consensus on the treatment of patients with refractory or relapsed mantle cell lymphoma, or for patients with relapsed or possibly refractory chronic lymphocytic leukaemia. Ibrutinib inhibits an enzyme involved in regulating B lymphocyte activity. It has been authorised in the European Union for these conditions. Clinical evaluation of ibrutinib in mantle cell lymphoma is based on a single non-comparative trial in 111 patients, in which the median overall survival time was 22.5 months. Clinical evaluation of ibrutinib in chronic lymphocytic leukaemia is based on two randomised trials. One unblinded trial compared ibrutinib versus ofatumumab and involved 391 patients, most of whom were sufficiently fit to receive anticancer combination therapy. Ibrutinib was more effective than ofatumumab, but the choice of this comparator might not have been appropriate for most of the patients who received it. The other double-blind, placebo-controlled trial involved 578 patients with relapsed or refractory chronic lymphocytic leukaemia. Ibrutinib was added to the bendamustine + rituximab combination. No significant difference in mortality was observed between the two groups. The main adverse effects of ibrutinib were: gastrointestinal disorders such as diarrhoea; life-threatening infections and bleeding disorders; and cardiac disorders, including atrial fibrillation. Ibrutinib carries a risk of multiple pharmacokinetic interactions. Pharmacodynamic interactions are also likely in view of its adverse effect profile. PMID:27183765

  18. Active Immunotherapy Used Alone for Maintenance of Patients with Acute Myeloid Leukaemia

    PubMed Central

    Freeman, Charles B.; Harris, Rodney; Geary, Colin G.; Leyland, Michael J.; MaCiver, John E.; Delamore, Irvine W.

    1973-01-01

    A total of 32 patients suffering from acute myeloid leukaemia were initially treated with daunorubicin and cytosine arabinoside, and eight who achieved full remission were given a brief cytoreduction course of cyclophosphamide and thioguanine. Of these eight patients seven were then actively immunized with 10 irradiated allogeneic acute myeloid leukaemia cells and B.C.G. at weekly intervals. Six of these patients have survived in apparent good health for more than one year. Bone marrow changes suggestive of relapse were used as an indication for further short courses of chemotherapy, and except on single occasions in two different patients clinical relapse has been prevented. The average duration of first (bone marrow) remission appears to be comparable with the best achieved in trials using regular chemotherapy for maintenance, though criteria for determining relapse may be different. The rate of reinduction of remissions (bone marrow) in this series was high, with a subsequent increase in overall survival time. Possible explanations for the high rate of reinduction include, firstly, the effects of active immunization with specific leukaemia antigen; secondly, non-specific adjuvant effect; thirdly, avoidance of drug resistance; and, fourthly, early diagnosis of relapse by frequent bone marrow examinations. PMID:4519012

  19. THE GEMINI NICI PLANET-FINDING CAMPAIGN: DISCOVERY OF A CLOSE SUBSTELLAR COMPANION TO THE YOUNG DEBRIS DISK STAR PZ Tel

    SciTech Connect

    Biller, Beth A.; Liu, Michael C.; Wahhaj, Zahed; Dupuy, Trent J.; Ftaclas, Christ; Nielsen, Eric L.; Close, Laird M.; Males, Jared; Skemer, Andrew; Hayward, Thomas L.; Hartung, Markus; Chun, Mark; Clarke, Fraser; Tecza, Matthias; Thatte, Niranjan; Reid, I. Neill; Shkolnik, Evgenya L.; Alencar, Silvia H. P.; Artymowicz, Pawel

    2010-09-01

    We report the discovery of a tight substellar companion to the young solar analog PZ Tel, a member of the {beta} Pic moving group observed with high-contrast adaptive optics imaging as part of the Gemini Near-Infrared Coronagraphic Imager Planet-Finding Campaign. The companion was detected at a projected separation of 16.4 {+-} 1.0 AU (0.''33 {+-} 0.''01) in 2009 April. Second-epoch observations in 2010 May demonstrate that the companion is physically associated and shows significant orbital motion. Monte Carlo modeling constrains the orbit of PZ Tel B to eccentricities >0.6. The near-IR colors of PZ Tel B indicate a spectral type of M7 {+-} 2 and thus this object will be a new benchmark companion for studies of ultracool, low-gravity photospheres. Adopting an age of 12{sup +8} {sub -4} Myr for the system, we estimate a mass of 36 {+-} 6 M {sub Jup} based on the Lyon/DUSTY evolutionary models. PZ Tel B is one of the few young substellar companions directly imaged at orbital separations similar to those of giant planets in our own solar system. Additionally, the primary star PZ Tel A shows a 70 {mu}m emission excess, evidence for a significant quantity of circumstellar dust that has not been disrupted by the orbital motion of the companion.

  20. Spatial variability of soil and vegetation characteristics in an urban park in Tel-Aviv

    NASA Astrophysics Data System (ADS)

    Sarah, Pariente; Zhevelev, Helena M.; Oz, Atar

    2010-05-01

    Mosaic-like spatial patterns, consisting of divers soil microenvironments, characterize the landscapes of many urban parks. These microenvironments may differ in their pedological, hydrological and floral characteristics, and they play important roles in urban ecogeomorphic system functioning. In and around a park covering 50 ha in Tel Aviv, Israel, soil properties and herbaceous vegetation were measured in eight types of microenvironments. Six microenvironments were within the park: area under Ceratonia siliqua (Cs-U), area under Ficus sycomorus (Fi-U), a rest area under F. sycomorus (Re-U), an open area with bare soil (Oa-S), an open area with biological crusts (Oa-C), and an open area with herbaceous vegetation (Oa-V). Outside the park were two control microenvironments, located, respectively, on a flat area (Co-P) and an inclined open area (Co-S). The soil was sampled from two depths (0-2 and 5-10 cm), during the peak of the growing season (March). For each soil sample, moisture content, organic matter content, CaCO3 content, texture, pH, electrical conductivity, and soluble ions contents were determined in 1:1 water extraction. In addition, prior to the soil sampling, vegetation cover, number of species, and species diversity of herbaceous vegetation were measured. The barbecue fires and visitors in each of the microenvironments were counted. Whereas the soil organic matter and vegetation in Fi-U differed from those in the control(Co-P, Co-S), those in Oa-V were similar to those in the control. Fi-U was characterized by higher values of soil moisture, organic matter, penetration depth, and vegetation cover than Cs-U. Open microenvironments within the park (Oa-S, Oa-C, Oa-V) showed lower values of soil penetration than the control microenvironments. In Oa-V unique types of plants such as Capsella bursa-pastoris and Anagallis arvensis, which did not appear in the control microenvironments, were found. This was true also for Fi-U, in which species like Oxalis pes

  1. Indications of stellar prominence oscillations on fast rotating stars: the cases of HK Aqr and PZ Tel

    NASA Astrophysics Data System (ADS)

    Leitzinger, M.; Odert, P.; Zaqarashvili, T. V.; Greimel, R.; Hanslmeier, A.; Lammer, H.

    2016-08-01

    We present the analysis of six nights of spectroscopic monitoring of two young and fast rotating late-type stars, namely the dMe star HK Aqr and the dG/dK star PZ Tel. On both stars we detect absorption features reminiscent of signatures of co-rotating cool clouds or prominences visible in Hα. Several prominences on HK Aqr show periodic variability in the prominence tracks which follow a sinusoidal motion (indication of prominence oscillations). On PZ Tel we could not find any periodic variability in the prominence tracks. By fitting sinusoidal functions to the prominence tracks we derive amplitudes and periods which are similar to those of large amplitude oscillations seen in solar prominences. In one specific event we also derive a periodic variation of the prominence track in the Hβ spectral line which shows an anti-phase variation with the one derived for the Hα spectral line. Using these parameters and estimated mass density of a prominence on HK Aqr we derive a minimum magnetic field strength of ˜2 G. The relatively low strength of the magnetic field is explained by the large height of this stellar prominence (≥ 0.67 stellar radii above the surface).

  2. Rapidly progressing, fatal and acute promyelocytic leukaemia that initially manifested as a painful third molar: a case report

    PubMed Central

    2009-01-01

    Introduction Acute promyelocytic leukaemia, an uncommon and devastating subtype of leukaemia, is highly prevalent in Latin American populations. The disease may be detected by a dentist since oral signs are often the initial manifestation. However, despite several cases describing oral manifestations of acute promyelocytic leukaemia and genetic analysis, reports of acute promyelocytic leukaemia in Hispanic populations are scarce. The identification of third molar pain as an initial clinical manifestation is also uncommon. This is the first known case involving these particular features. Case presentation A 24-year-old Latin American man without relevant antecedents consulted a dentist for pain in his third molar. After two dental extractions, the patient experienced increased pain, poor healing, jaw enlargement and bleeding. A physical examination later revealed that the patient had pallor, jaw enlargement, ecchymoses and gingival haemorrhage. Laboratory findings showed pancytopaenia, delayed coagulation times, hypoalbuminaemia and elevated lactate dehydrogenase. Splenomegaly was detected on ultrasonography. Peripheral blood and bone marrow analyses revealed a hypercellular infiltrate of atypical promyelocytic cells. Cytogenetic analysis showing genetic translocation t(15;17) further confirmed acute promyelocytic leukaemia. Despite early chemotherapy, the patient died within one week due to intracranial bleeding secondary to disseminated intravascular coagulation. Conclusion The description of this unusual presentation of acute promyelocytic leukaemia, the diagnostic difficulties and the fatal outcome are particularly directed toward dental surgery practitioners to emphasise the importance of clinical assessment and preoperative evaluation as a minimal clinically-oriented routine. This case may also be of particular interest to haematologists, since the patient's cytogenetic analysis, clinical course and therapeutic response are well documented. PMID:19946580

  3. BoLA antigens are associated with increased frequency of persistent lymphocytosis in bovine leukaemia virus infected cattle and with increased incidence of antibodies to bovine leukaemia virus.

    PubMed

    Stear, M J; Dimmock, C K; Newman, M J; Nicholas, F W

    1988-01-01

    The association between bovine major histocompatibility system (BoLA) type and persistent lymphocytosis in cattle with antibodies to bovine leukaemia virus was examined by comparing antigen frequencies in cattle with persistent lymphocytosis to controls matched for age, sex, breed and presence of antibodies to BLV. The cattle came from nine dairy herds in south-east Queensland, Australia; six herds were Australian Illawarra Shorthorn (AIS), two herds were Jersey and one herd was Friesian. Antigen W6 and Eu28R were more common in cattle with persistent lymphocytosis than in controls. Antigen W8 was less common in AIS cattle with persistent lymphocytosis. A study of 24 offspring from one sire, heterozygous for W10 and Eu28R, showed that offspring inheriting Eu28R from the sire were significantly more likely to have antibodies to BLV than offspring inheriting the opposing W10 haplotype. PMID:2843067

  4. Ceramide and glutathione define two independently regulated pathways of cell death initiated by p53 in Molt-4 leukaemia cells.

    PubMed Central

    El-Assaad, Wissal; Kozhaya, Lina; Araysi, Sawsan; Panjarian, Shoghag; Bitar, Fadi F; Baz, Elizabeth; El-Sabban, Marwan E; Dbaibo, Ghassan S

    2003-01-01

    The tumour suppressor p53 induces cell death by launching several pathways that are either dependent on or independent of gene transcription. Accumulation of the sphingolipid ceramide and reactive oxygen species are among these pathways. Crossregulation of these two pathways is possible owing to the demonstrated inhibition of neutral sphingomyelinase by glutathione, the predominant cellular antioxidant, and has been observed in some cytokine-dependent cell-death models. In a model of irradiation-induced cell death of Molt-4 leukaemia cells, it was found that ceramide accumulation and glutathione depletion were dependent on p53 up-regulation. The loss of p53 owing to expression of the papilloma virus E6 protein inhibited both pathways after irradiation. However, in this model, these two pathways appeared to be independently regulated on the basis of the following observations: (1) glutathione supplementation or depletion did not alter irradiation-induced ceramide accumulation, (2) exogenous ceramide treatment did not induce glutathione depletion, (3) glutathione depletion was dependent on new protein synthesis, whereas ceramide accumulation was independent of it and (4) caspase activation was required for ceramide accumulation but not for glutathione depletion. Furthermore, caspase 9 activation, which is dependent on the release of mitochondrial cytochrome c, was not required for ceramide accumulation. This suggested that a caspase, other than caspase 9, was necessary for ceramide accumulation. Interestingly, Bcl-2 expression inhibited these pathways, indicating a possible role for mitochondria in regulating both pathways. These findings indicate that these two pathways exhibit cross-regulation in cytokine-dependent, but not in p53-dependent, cell-death models. PMID:12967322

  5. Survival of twenty-two months in a patient with primary plasma cell leukaemia treated with melphalan and prednisolone.

    PubMed Central

    Walker, J. D.; Kaczmarski, R. S.

    1988-01-01

    In the majority of cases plasma cell leukaemia is a rapidly fatal disease with a mean survival time of five months. There have been reports of increased survival using various regimens of chemotherapy although most cases eventually relapse. We describe a patient with primary plasma cell leukaemia who responded to a combination of oral melphalan and prednisolone with control of the disease in the bone marrow but relapsed with extramedullary disease in the central nervous system and testes, and died 22 months after diagnosis. Melphalan poorly penetrates the central nervous system and its testicular penetration is unknown. Images Figure 1 PMID:3174543

  6. T cell acute lymphoblastic leukaemia presenting with sudden onset right oculomotor nerve palsy with normal neuroradiography and cerebrospinal fluid studies

    PubMed Central

    Bhatt, Vijaya Raj; Naqi, Muniba; Bartaula, Rajiv; Murukutla, Srujitha; Misra, Sulagna; Popalzai, Muhammad; Paramanathan, Kavitha; Dai, Qun

    2012-01-01

    Leptomeningeal disease presenting with neurological dysfunction is not uncommon in leukaemia. However, it is often accompanied by abnormalities in cerebrospinal fluid (CSF) studies and/or neuroradiography. Here, the authors describe a case of a young patient presenting with sudden onset right oculomotor nerve palsy with normal neuroradiography and CSF studies, who was subsequently diagnosed to have T cell acute lymphoblastic leukaemia (T-ALL). This case highlights that neurological manifestations can be the initial presenting feature of T-ALL and can occur suddenly despite normal neuroradiography and initial CSF studies. PMID:22605802

  7. Report of the second international symposium on molecular epidemiology in childhood leukaemia and embryonal tumours, Rio de Janeiro, Brazil.

    PubMed

    Pombo de Oliveira, M S; Ferman, S; de Camargo, B

    2008-01-01

    The recent International Symposium on Molecular epidemiology in Embryonal Tumours and Paediatric Leukaemia was held on 4-6 March 2008 in Rio de Janeiro, Brazil. It proved a very productive meeting in which studies relating to genetics, therapeutical trials, identification of risk factors in acute leukaemia neuroblastoma and Wilms' tumours were presented. Over 120 participants gathered for three days of fruitful discussions, including representatives of paediatrics, haematology, laboratory, epidemiology and pathology. Debates were held about strategies of applications of important biomarkers for clinical trials. Highlights of each of the scientific presentations are summarized below. PMID:22275972

  8. Geranylated flavanone tomentodiplacone B inhibits proliferation of human monocytic leukaemia (THP-1) cells

    PubMed Central

    Kollár, Peter; Bárta, Tomáš; Závalová, Veronika; Šmejkal, Karel; Hampl, Aleš

    2011-01-01

    BACKGROUND AND PURPOSE Paulownia tomentosa is a rich source of geranylated flavanones, some of which we have previously shown to have cytotoxic activity. To identify members of this class of compounds with cytostatic effects, we assessed the effects of the geranylated flavanone tomentodiplacone B (TOM B) on cell cycle progression and cell cycle regulatory pathways of THP-1 human monocytic leukaemia cells. EXPERIMENTAL APPROACH Cell viability was measured by dye exclusion and proliferation by WST-1 assays; cell cycle was monitored by flow cytometry. Regulatory proteins were assessed by immunoprecipitation and kinase assays, and Western blotting. KEY RESULTS Tomentodiplacone B had no effect during the first 24 h of cell growth at concentrations between 1 and 2.5 µM, but inhibited cell growth in a dose-dependent manner at concentrations of 5 µM or higher. Growth inhibition during the first 24 h of exposure to TOM B was not accompanied by cytotoxicity as cells were accumulated in G1 phase dose-dependently. This G1 phase accumulation was associated with down-regulation of cyclin-dependent kinase 2 activity and also protein levels of cyclins E1 and A2. However, key stress-related molecules (γ-H2AX, p53 and p21) were not induced, suggesting that TOM B acts by directly inhibiting the cyclin-dependent kinase 2 signalling pathway rather than initiating DNA damage or cellular stress. CONCLUSIONS AND IMPLICATIONS Our study provides the first evidence that TOM B directly inhibits proliferation of human monocytic leukaemia cells, and thus is a potential anticancer agent, preventing leukaemia cells from progressing from G1 phase into DNA synthesis. PMID:21175584

  9. Residential exposure to electromagnetic fields and childhood leukaemia: a meta-analysis.

    PubMed Central

    Angelillo, I. F.; Villari, P.

    1999-01-01

    Although individual epidemiological investigations have suggested associations between residential exposure to electromagnetic fields (EMFs) and childhood leukaemia, overall the findings have been inconclusive. Several of these studies do, however, lend themselves to application of the meta-analysis technique. For this purpose we carried out searches using MEDLINE and other sources, and 14 case-control studies and one cohort study were identified and evaluated for epidemiological quality and included in the meta-analysis. Relative risk estimates were extracted from each of the studies and pooled. Separate meta-analyses were performed on the basis of the assessed EMF exposure (wiring configuration codes, distance to power distribution equipment, spot and 24-h measures of magnetic field strength (magnetic flux density) and calculated magnetic field). The meta-analysis based on wiring configuration codes yielded a pooled relative risk estimate of 1.46 (95% confidence interval (CI) = 1.05-2.04, P = 0.024) and for that for exposure to 24-h measurements of magnetic fields, 1.59 (95% CI = 1.14-2.22, P = 0.006), indicating a potential effect of residential EMF exposure on childhood leukaemia. In most cases, lower risk estimates were obtained by pooling high-quality studies than pooling low-quality studies. There appears to be a clear trend for more recent studies to be of higher quality. Enough evidence exists to conclude that dismissing concerns about residential EMFs and childhood leukaemia is unwarranted. Additional high-quality epidemiological studies incorporating comparable measures for both exposure and outcomes are, however, needed to confirm these findings and, should they prove to be true, the case options for minimizing exposure should be thoroughly investigated to provide definitive answers for policy-makers. PMID:10612886

  10. Distribution of childhood leukaemias and non-Hodgkin's lymphomas near nuclear installations in England and Wales.

    PubMed Central

    Bithell, J. F.; Dutton, S. J.; Draper, G. J.; Neary, N. M.

    1994-01-01

    OBJECTIVE--To examine the relation between the risk of childhood leukaemia and non-Hodgkin's lymphoma and proximity of residence to nuclear installations in England and Wales. DESIGN--Observed and expected numbers of cases were calculated and analysed by standard methods based on ratios of observed to expected counts and by a new statistical test, the linear risk score test, based on ranks and designed to be sensitive to excess incidence in close proximity to a putative source of risk. SETTING--Electoral wards within 25 km of 23 nuclear installations and six control sites that had been investigated for suitability for generating stations but never used. SUBJECTS--Children below age 15 in England and Wales, 1966-87. MAIN OUTCOME MEASURE--Registration of any leukaemia or non-Hodgkin's lymphoma. RESULTS--In none of the 25 km circles around the installations was the incidence ratio significantly greater than 1.0. The only significant results for the linear risk score test were for Sellafield (P = 0.00002) and Burghfield (P = 0.031). The circles for Aldermaston and Burghfield overlap; the incidence ratio was 1.10 in each. One of the control sites gave a significant linear risk score test result (P = 0.020). All the tests carried out were one sided with P values estimated by simulation. CONCLUSION--There is no evidence of a general increase of childhood leukaemia or non-Hodgkin's lymphoma around nuclear installations. Apart from Sellafield, the evidence for distance related risk is very weak. PMID:8086902

  11. Treatment-related deaths in second complete remission in childhood acute myeloid leukaemia.

    PubMed

    Molgaard-Hansen, Lene; Möttönen, Merja; Glosli, Heidi; Jónmundsson, Guðmundur K; Abrahamsson, Jonas; Hasle, Henrik

    2011-03-01

    The frequency and causes of treatment-related deaths (TRD) in second complete remission (CR2) in acute myeloid leukaemia (AML) were investigated in a historical, prospective cohort study of 429 children included in the Nordic Society of Paediatric Haematology and Oncology (NOPHO)-AML-88 and -93 trials. Relapse occurred in 158 children (39%). Seventeen (18%) of the 96 patients entering CR2 suffered TRD. The main causes were infection (59%) and complications from graft-versus-host disease (22%). Fourteen (82%) of 17 TRDs occurred in children undergoing haematopoietic stem cell transplantations (HSCT). Optimal supportive care after HSCT is essential, and studies on risk factors for TRD are needed. PMID:21241281

  12. The biology behind PI3K inhibition in chronic lymphocytic leukaemia

    PubMed Central

    Ortiz-Maldonado, Valentín; García-Morillo, Marcial

    2015-01-01

    Phosphoinositide 3′-kinase (PI3K) is a key component of both chronic active and tonic B-cell receptor-signalling pathways. As such, PI3K inhibitors have emerged as promising therapeutic agents for diverse lymphoid malignancies, particularly chronic lymphocytic leukaemia. Multiple in vitro experiments and clinical trials have shown efficacy of these agents across all prognostic subgroups with a favourable toxicity profile. Moreover, in vitro studies suggest that combinations with monoclonal antibodies and/or other immune strategies could enhance the effect of PI3K inhibition. PMID:25642313

  13. Richter's transformation presenting as splenic rupture after 6 years of complete remission of chronic lymphocytic leukaemia.

    PubMed

    Thyagarajan, Braghadheeswar; Alagusundaramoorthy, Sayee Sundar; Shah, Lopa; Agrawal, Abhinav

    2016-01-01

    Richter's transformation is a rare clinical condition occurring in about 5-10% of patients with chronic lymphocytic leukaemia (CLL). Patients usually present with lymphadenopathy, hepatosplenomegaly and elevated serum lactate dehydrogenase levels. These patients have a very poor prognosis with a median survival of about 10 months. We present a patient, with a history of CLL in complete remission, who presented with splenic rupture requiring splenectomy. She was eventually diagnosed with diffuse large B-cell lymphoma with Richter's transformation. PMID:27288204

  14. Cancer coverage: the public face of childhood leukaemia in 1960s Britain

    PubMed Central

    Barnes, Emm

    2008-01-01

    In the 1960s, stories of children fighting cancer, previously absent from the British news, started to feature ever more prominently in the national press. Conventional treatments could not keep children alive for many months, so the promise of a cure through the use of an alternative anti-cancer ‘serum’ was not easily dismissed as quackery. The Ministry of Health and cancer research organisations struggled to find a fair and honest way to inform the public and affected families about childhood leukaemia without raising or crushing hope. PMID:18316127

  15. Holoprosencephaly and Pure Red Cell Aplasia in a Feline Leukaemia Virus-Positive Kitten.

    PubMed

    Southard, T L; Rodriguez-Ramos Fernandez, J; Priest, H; Stokol, T

    2016-01-01

    A 9-month-old, female, domestic longhair cat with severe anaemia tested positive for feline leukaemia virus (FeLV) and was humanely destroyed and submitted for necropsy examination. Gross findings included a non-divided rostral telencephalon, consistent with semilobar holoprosencephaly. Histological examination of the bone marrow revealed an almost complete absence of erythroid precursor cells, consistent with pure red cell aplasia, and mild to moderate myelofibrosis. This case demonstrates a very unusual central nervous system defect, as well as an atypical presentation of pure red cell aplasia, in a FeLV-positive kitten. PMID:26897097

  16. The challenge of obesity in paediatric leukaemia treatment: it is not just size that matters.

    PubMed

    Tolbert, Jaszianne; Kearns, Gregory L

    2015-01-01

    In the last two decades, tremendous advances have been made in the treatment of acute lymphocytic leukaemia (ALL) in children with 5 year 'cure' rates in excess of 90%. The maintenance of remission is due, in part, to individualisation of therapy which must consider age, body size, genetic constitution and the impact of disease on drug disposition and action. This review, focused on treatment of ALL and one of the therapeutic mainstays, 6-mercaptopurine, illustrates the importance of obesity as a modulating factor in dose individualisation. PMID:25336436

  17. Spatio-temporal behavior of brightness temperature in Tel-Aviv and its application to air temperature monitoring.

    PubMed

    Pelta, Ran; Chudnovsky, A Alexandra; Schwartz, Joel

    2016-01-01

    This study applies remote sensing technology to assess and examine the spatial and temporal Brightness Temperature (BT) profile in the city of Tel-Aviv, Israel over the last 30 years using Landsat imagery. The location of warmest and coldest zones are constant over the studied period. Distinct diurnal and temporal BT behavior divide the city into four different segments. As an example of future application, we applied mixed regression models with daily random slopes to correlate Landsat BT data with monitored air temperature (Tair) measurements using 14 images for 1989-2014. Our preliminary results show a good model performance with R(2) = 0.81. Furthermore, based on the model's results, we analyzed the spatial profile of Tair within the study domain for representative days. PMID:26499933

  18. Expanding the Scope of Anatomical Sciences: The Case of "Human Evolution--The Fossil Evidence" Course at the Sackler School of Medicine, Tel-Aviv University

    ERIC Educational Resources Information Center

    Notzer, Netta; Abramovitz, Ruth

    2012-01-01

    The Anatomy Department at Tel-Aviv University Medical School offers its students an elective course of 26 didactic hours on human evolution. The course is open to students from all faculties, who must fulfill all academic requirements, without a prerequisite of a background in anatomy. Approximately 120 students attend annually, a third of them…

  19. The Dialectics of Assimilation and Multiculturalism: The Case of Children of Refugees and Migrant Workers in the Bialik-Rogozin School, Tel Aviv

    ERIC Educational Resources Information Center

    Dvir, Nurit; Aloni, Nimrod; Harari, Dor

    2015-01-01

    This paper focuses on children of refugees and migrant workers from 48 countries who study together in one multicultural school in the city of Tel Aviv, Israel. The context of our study is the current ethos of globalisation and within it the phenomenon of vast migrations and creation of intercultural social realities. The aims of the study were to…

  20. Glocalized New Age Spirituality: A Mental Map of the New Central Bus Station in Tel Aviv, Deciphered through Its Visual Codes and Based on Ethno-Visual Research

    ERIC Educational Resources Information Center

    Ben-Peshat, Malka; Sitton, Shoshana

    2011-01-01

    We present here the findings of an ethno-visual research study involving the creation of a mental map of images, artifacts and practices in Tel Aviv's New Central Bus Station. This huge and complex building, part bus station, part shopping mall, has become a stage for multicultural encounters and interactions among diverse communities of users.…

  1. Slower early response to treatment and distinct expression profile of childhood high hyperdiploid acute lymphoblastic leukaemia with DNA index < 1.16.

    PubMed

    Zaliova, Marketa; Hovorkova, Lenka; Vaskova, Martina; Hrusak, Ondrej; Stary, Jan; Zuna, Jan

    2016-09-01

    Acute lymphoblastic leukaemias (ALL) with 51-67 chromosomes are defined as high hyperdiploid (HHD) and are generally associated with good prognosis. However, several studies show heterogeneity in HHD ALL and suggest that the favourable prognosis is associated rather with higher ploidy defined by DNA index (DNAi) ≥ 1.16 or with a presence of specific single or combined trisomies. HHD ALL with DNAi < 1.16 are only rarely studied separately. Using single nucleotide polymorphism array, we analysed 89 childhood HHD ALL patients divided into groups with lower (<1.16; n = 34) and higher (≥1.16; n = 55) DNAi. We assessed treatment response, presence of secondary aberrations, mutations in RAS pathway genes and CREBBP and also gene expression profile (GEP) to reveal differences between the two subgroups. Cases with 51-54 chromosomes had DNAi 1.1-1.16 and cases with 55-67 chromosomes had DNAi ≥ 1.16. The groups with lower and higher DNAi had distinct response to early treatment and distinct GEP. The better response of the group with higher DNAi was associated with specific trisomies (trisomy of chromosome 10 or combined with trisomies 4 and/or 17). Our results suggest that cytogenetically defined HHD ALL can in fact be divided into two biologically distinguishable subgroups and that DNAi 1.16 is a relevant value to separate between the two. © 2016 Wiley Periodicals, Inc. PMID:27163296

  2. Insulin growth factor 1 receptor expression is associated with NOTCH1 mutation, trisomy 12 and aggressive clinical course in chronic lymphocytic leukaemia.

    PubMed

    Maura, Francesco; Mosca, Laura; Fabris, Sonia; Cutrona, Giovanna; Matis, Serena; Lionetti, Marta; Agnelli, Luca; Barbieri, Marzia; D'Anca, Marianna; Manzoni, Martina; Colombo, Monica; Massucco, Carlotta; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Ilariucci, Fiorella; Musolino, Caterina; Di Raimondo, Francesco; Cortelezzi, Agostino; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID:25786252

  3. Insulin Growth Factor 1 Receptor Expression Is Associated with NOTCH1 Mutation, Trisomy 12 and Aggressive Clinical Course in Chronic Lymphocytic Leukaemia

    PubMed Central

    Maura, Francesco; Mosca, Laura; Fabris, Sonia; Cutrona, Giovanna; Matis, Serena; Lionetti, Marta; Agnelli, Luca; Barbieri, Marzia; D’Anca, Marianna; Manzoni, Martina; Colombo, Monica; Massucco, Carlotta; Reverberi, Daniele; Gentile, Massimo; Recchia, Anna Grazia; Bossio, Sabrina; Ilariucci, Fiorella; Musolino, Caterina; Di Raimondo, Francesco; Cortelezzi, Agostino; Morabito, Fortunato; Ferrarini, Manlio; Neri, Antonino

    2015-01-01

    IGF1R is emerging as an important gene in the pathogenesis of many solid and haematological cancers and its over-expression has been reported as frequently associated with aggressive disease and chemotherapy resistance. In this study we performed an investigation of the role of IGF1R expression in a large and representative prospective series of 217 chronic lymphocytic leukaemia (CLL) patients enrolled in the multicentre O-CLL1 protocol (clinicaltrial.gov #NCT00917540). High IGF1R gene expression was significantly associated with IGHV unmutated (IGHV-UM) status (p<0.0001), high CD38 expression (p<0.0001), trisomy 12 (p<0.0001), and del(11)(q23) (p=0.014). Interestingly, higher IGF1R expression (p=0.002) characterized patients with NOTCH1 mutation (c.7541_7542delCT), identified in 15.5% of cases of our series by next generation sequencing and ARMS-PCR. Furthermore, IGF1R expression has been proven as an independent prognostic factor associated with time to first treatment in our CLL prospective cohort. These data suggest that IGF1R may play an important role in CLL biology, in particular in aggressive CLL clones characterized by IGHV-UM, trisomy 12 and NOTCH1 mutation. PMID:25786252

  4. Chronic prolymphocytoid leukaemia with an unusual immature immunophenotype.

    PubMed Central

    Lima, M; Coutinho, J; Orfão, A; Macedo, A L; San Miguel, J F; Justiça, B

    1994-01-01

    A case of a 58 year old woman with a chronic lymphoproliferative disorder of unusual clinical presentation, disease course, and immunophenotype is presented. At diagnosis she had severe anaemia, moderate lymphocytosis with some cells having prolymphocytoid features and a normal platelet count. A clinical examination yielded negative results. Only anaemia related symptoms were found and the patient became blood transfusion dependent. Both the lymphocytosis and the proportion of prolymphocytoid cells rose insidiously and thrombocytopenia developed later during the course of the disease. Three years later, the patient had a white cell count of 269 x 10(9)/l almost exclusively of prolymphocytoid cells and the bone marrow was diffusely infiltrated. She was refractory to chemotherapy and the anaemia did not improve after treatment with cyclosporine. Lymphoid cells were positive for cytoplasmatic CD3, HLA-Dr, CD34, CD38, CD7, CD56, CD13, CD33 and CD65. Membrane alpha beta and gamma delta T cell receptors (TCRs) were not expressed and the beta chain TCR gene was in germline configuration. Other membrane T, B, natural killer, and myelomonocytic markers were negative. Karyotype analysis was tried several times but metaphases were not obtained, even after stimulation with T cell mitogens. Images PMID:8027401

  5. The Gemini NICI Planet-finding Campaign: Discovery of a Close Substellar Companion to the Young Debris Disk Star PZ Tel

    NASA Astrophysics Data System (ADS)

    Biller, Beth A.; Liu, Michael C.; Wahhaj, Zahed; Nielsen, Eric L.; Close, Laird M.; Dupuy, Trent J.; Hayward, Thomas L.; Burrows, Adam; Chun, Mark; Ftaclas, Christ; Clarke, Fraser; Hartung, Markus; Males, Jared; Reid, I. Neill; Shkolnik, Evgenya L.; Skemer, Andrew; Tecza, Matthias; Thatte, Niranjan; Alencar, Silvia H. P.; Artymowicz, Pawel; Boss, Alan; de Gouveia Dal Pino, Elisabete; Gregorio-Hetem, Jane; Ida, Shigeru; Kuchner, Marc J.; Lin, Douglas; Toomey, Douglas

    2010-09-01

    We report the discovery of a tight substellar companion to the young solar analog PZ Tel, a member of the β Pic moving group observed with high-contrast adaptive optics imaging as part of the Gemini Near-Infrared Coronagraphic Imager Planet-Finding Campaign. The companion was detected at a projected separation of 16.4 ± 1.0 AU (0farcs33 ± 0farcs01) in 2009 April. Second-epoch observations in 2010 May demonstrate that the companion is physically associated and shows significant orbital motion. Monte Carlo modeling constrains the orbit of PZ Tel B to eccentricities >0.6. The near-IR colors of PZ Tel B indicate a spectral type of M7 ± 2 and thus this object will be a new benchmark companion for studies of ultracool, low-gravity photospheres. Adopting an age of 12+8 -4 Myr for the system, we estimate a mass of 36 ± 6 M Jup based on the Lyon/DUSTY evolutionary models. PZ Tel B is one of the few young substellar companions directly imaged at orbital separations similar to those of giant planets in our own solar system. Additionally, the primary star PZ Tel A shows a 70 μm emission excess, evidence for a significant quantity of circumstellar dust that has not been disrupted by the orbital motion of the companion. Based on observations obtained at the Gemini Observatory, which is operated by the Association of Universities for Research in Astronomy, Inc., under a cooperative agreement with the NSF on behalf of the Gemini partnership: the National Science Foundation (United States), the Science and Technology Facilities Council (United Kingdom), the National Research Council (Canada), CONICYT (Chile), the Australian Research Council (Australia), Ministério da Ciência e Tecnologia (Brazil), and Ministerio de Ciencia, Tecnología e Innovación Productiva (Argentina).

  6. Pre-clinical antitumour evaluation of Biphosphinic Palladacycle Complex in human leukaemia cells.

    PubMed

    Oliveira, Carlos R; Barbosa, Christiano M V; Nascimento, Fábio D; Lanetzki, Camilla S; Meneghin, Marília B; Pereira, Flávia E G; Paredes-Gamero, Edgar J; Ferreira, Alice T; Rodrigues, Tiago; Queiroz, Mary L S; Caires, Antonio C F; Tersariol, Ivarne L S; Bincoletto, Claudia

    2009-02-12

    Previous studies reported by our group have introduced a new antitumoural drug called Biphosphinic Palladacycle Complex (BPC). In this paper we show that BPC causes apoptosis in leukaemia cells (HL60 and Jurkat), but not in normal human lymphocytes. IC(50) values obtained for both cell lines using the MTT and trypan blue exclusion assays 5h after BPC treatment were lower than 8.0 microM. Using metachromatic fluorophore, acridine orange, we observed that BPC elicited lysosomal rupture of leukaemic cells. Furthermore, BPC triggered caspase-3 and caspase-6 activation and apoptosis in cell lines, inducing chromatin condensation, apoptotic bodies, and DNA fragmentation. Interestingly, the lysosomal cathepsin B inhibitor CA074 markedly decreased BPC-induced caspase-3 and caspase-6 activation as well as cell death. Lysosomal BPC-induced membrane destabilisation was not dependent on reactive oxygen species generation, which was consistent with the absence of cellular HL60 and Jurkat membrane lipid peroxidation. We conclude that, following BPC treatment, lysosomal membrane rupture precedes cell death and the apoptotic signalling pathway is initiated by the release of cathepsin B in the cytoplasm of leukaemia cells. As no toxic effects for human lymphocytes were observed, we suggest that BPC is more selective for transformed cells, mainly due to their exacerbated lysosome expression. PMID:19026616

  7. Efficacy of multi-functional liposomes containing daunorubicin and emetine for treatment of acute myeloid leukaemia.

    PubMed

    Myhren, Lene; Nilssen, Ida Mostrøm; Nicolas, Valérie; Døskeland, Stein Ove; Barratt, Gillian; Herfindal, Lars

    2014-09-01

    Despite recent advances in chemotherapy against acute myeloid leukaemia (AML), the disease still has high mortality, particularly for patients who tolerate extensive chemotherapy poorly. Nano-formulations have potential to minimise the adverse effects of chemotherapy. We present here a liposomal formulation encapsulating both the anthracycline daunorubicin (DNR) and emetine (Eme) for enhanced cytotoxic effect against AML cells. Eme could be loaded into the PEGylated liposomes together with DNR by the acid precipitation principle, with a loading efficiency of Eme at about 50% of that of DNR. The liposome surface was modified with folate to enhance drug loading into cells, giving higher cytotoxic activity. Both intracellular drug loading and cytotoxic activity could be further increased by anti-folate treatment of AML cells with methotrexate (MTX). The combination of DNR and Eme also increased drug loading in MTX-treated cells compared to DNR alone. Liposomes with both DNR and Eme were particularly efficient against AMLs with deficient p53. In conclusion, we have produced a multi-functional liposomal anti-leukaemic drug formulation designed to overcome some of the problems in anthracycline chemotherapy: (1) Combination of DNR and Eme to diminish drug resistance. (2) Using PEGylated stealth liposomes to minimise adverse side-effects. (3) Molecules on the liposomal surface target proteins on AML-cells ensure selectivity, which was enhanced by priming the leukaemia cells with MTX. PMID:24747809

  8. Versatility and nuances of the architecture of haematopoiesis - Implications for the nature of leukaemia.

    PubMed

    Brown, Geoffrey; Hughes, Philip J; Ceredig, Rhodri; Michell, Robert H

    2012-01-01

    For many years there was a widely accepted picture of how a haematopoietic stem cell (HSC) gives rise to the multiple types of blood and immune cells. This described the general nature of stem and progenitor cells and the pathways of cell development. Recent years have seen many attempts to re-draw the map of haematopoiesis. These have become increasingly complex, and they often envisage multiples routes to some cell types. The 'established' view that self-renewal in haematopoiesis only occurs in HSCs has been challenged by the recognition of self-renewing HSC-derived progenitor cells that display at least some fate restriction. This evolution of how normal haematopoiesis is viewed has inevitable implications for understanding the origins, disease progression and classification of the leukaemias. In essence, some progenitor cells are now seen as possessing a larger repertoire of routes to end-fates than was previously thought. This leads one to ask whether leukaemia stem cells are equally or less versatile than their normal counterparts? PMID:22071138

  9. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia.

    PubMed

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-01-01

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner. PMID:27534895

  10. Tracer‐Based Metabolic NMR‐Based Flux Analysis in a Leukaemia Cell Line

    PubMed Central

    Carrigan, John B.; Reed, Michelle A. C.; Ludwig, Christian; Khanim, Farhat L.; Bunce, Christopher M.

    2016-01-01

    Abstract High levels of reactive oxygen species (ROS) have a profound impact on acute myeloid leukaemia cells and can be used to specifically target these cells with novel therapies. We have previously shown how the combination of two redeployed drugs, the contraceptive steroid medroxyprogesterone and the lipid‐regulating drug bezafibrate exert anti‐leukaemic effects by producing ROS. Here we report a 13C‐tracer‐based NMR metabolic study to understand how these drugs work in K562 leukaemia cells. Our study shows that [1,2‐13C]glucose is incorporated into ribose sugars, indicating activity in oxidative and non‐oxidative pentose phosphate pathways alongside lactate production. There is little label incorporation into the tricarboxylic acid cycle from glucose, but much greater incorporation arises from the use of [3‐13C]glutamine. The combined medroxyprogesterone and bezafibrate treatment decreases label incorporation from both glucose and glutamine into α‐ketoglutarate and increased that for succinate, which is consistent with ROS‐mediated conversion of α‐ketoglutarate to succinate. Most interestingly, this combined treatment drastically reduced the production of several pyrimidine synthesis intermediates. PMID:27347458

  11. Plastic embedded core biopsy: a complementary approach to bone marrow aspiration for diagnosing acute myeloid leukaemia.

    PubMed Central

    Islam, A; Frisch, B; Henderson, E S

    1989-01-01

    Bone marrow aspirates and biopsy specimens were taken at diagnosis from 51 patients with acute myeloid leukaemia (AML). The diagnosis was based on morphological and cytochemical analyses, and the leukaemias were classified by FAB criteria. A considerable difference was observed between the results of bone marrow aspirates and the findings of plastic-embedded bone marrow biopsy specimens, particularly in marrow cellularity, extent of blast cell infiltration, and cell type involved in the leukaemic process. The myelomonocytic cell type seemed to predominate in the sections. In four cases there was considerable marrow infiltration with maturing, but dysplastic, granulocytic cells in the sections, but not in the aspirate smears. Features of potential prognostic importance, such as bone marrow infiltration with inflammatory cells, were easily recognised and quantified in the sections. These results indicate that plastic embedded bone marrow biopsy sections complement the findings of bone marrow aspiration in the diagnosis of AML and may also provide information of independent prognostic importance that cannot be obtained by other means. Images Fig 2 Fig 5 Fig 6 Fig 7 Fig 8 PMID:2649520

  12. Hydroxyurea synergizes with valproic acid in wild-type p53 acute myeloid leukaemia

    PubMed Central

    Leitch, Calum; Osdal, Tereza; Andresen, Vibeke; Molland, Maren; Kristiansen, Silje; Nguyen, Xuan Nhi; Bruserud, Øystein; Gjertsen, Bjørn Tore; McCormack, Emmet

    2016-01-01

    Palliative care in acute myeloid leukaemia (AML) is inadequate. For elderly patients, unfit for intensive chemotherapy, median survival is 2–3 months. As such, there is urgent demand for low-toxic palliative alternatives. We have repositioned two commonly administered anti-leukaemia drugs, valproic acid (VPA) and hydroxyurea (HU), as a combination therapy in AML. The anti-leukemic effect of VPA and HU was assessed in multiple AML cell lines confirming the superior anti-leukemic effect of combination therapy. Mechanistic studies revealed that VPA amplified the ability of HU to slow S-phase progression and this correlated with significantly increased DNA damage. VPA was also shown to reduce expression of the DNA repair protein, Rad51. Interestingly, the tumour suppressor protein p53 was revealed to mitigate cell cycle recovery following combination induced arrest. The efficacy of combination therapy was validated in vivo. Combination treatment increased survival in OCI-AML3 and patient-derived xenograft mouse models of AML. Therapy response was confirmed by optical imaging with multiplexed near-infrared labelled antibodies. The combination of HU and VPA indicates significant potential in preclinical models of AML. Both compounds are widely available and well tolerated. We believe that repositioning this combination could significantly enhance the palliative care of patients unsuited to intensive chemotherapy. PMID:26812881

  13. Cohort Profile: The French Childhood Cancer Survivor Study For Leukaemia (LEA Cohort)

    PubMed Central

    Berbis, Julie; Michel, Gérard; Baruchel, André; Bertrand, Yves; Chastagner, Pascal; Demeocq, François; Kanold, Justyna; Leverger, Guy; Plantaz, Dominique; Poirée, Marilyne; Stephan, Jean-Louis; Auquier, Pascal; Contet, Audrey; Dalle, Jean-Hugues; Ducassou, Stéphane; Gandemer, Virginie; Lutz, Patrick; Sirvent, Nicolas; Tabone, Marie-Dominique; Thouvenin-Doulet, Sandrine

    2015-01-01

    The main aim of the Leucémies de l’Enfant et l’Adolescent (LEA) project (Childhood and Adolescent Leukaemia) is to study the determinants (medical, socioeconomic, behavioural and environmental) of medium- and long-term outcomes of patients treated for childhood acute leukaemia (AL). The LEA study began in 2004 and is based on a French multicentric prospective cohort. Included are children treated for AL since January 1980 (incident and prevalent cases), surviving at month 24 for myeloblastic AL and lymphoblastic AL grafted in first complete remission or at month 48 for lymphoblastic AL not grafted in first complete remission. Information is collected during specific medical visits and notably includes the following data: socioeconomic data, AL history, physical late effects (such as fertility, cardiac function and metabolic syndrome) and quality of life. Data are collected every 2 years until the patient is 20 years old and has had a 10-year follow-up duration from diagnosis or last relapse. Thereafter, assessments are planned every 4 years. In active centres in 2013, eligible patients number more than 3000. The cohort has already included 2385 survivors, with rate of exhaustiveness of almost 80%. Data access can be requested from principal coordinators and must be approved by the steering committee. PMID:24639445

  14. Some immunological properties of lymphoid cells from patients with acute lymphatic leukaemia (ALL)

    PubMed Central

    Melief, C. J. M.; Schweitzer, Marjan; Zeylemaker, W. P.; Verhagen, E. H.; Eijsvoogel, V. P.

    1973-01-01

    The in vitro responses of lymphoid cells from the blood of children with acute lymphatic leukaemia to stimulation with phytohaemagglutinin, pokeweed mitogen, allogeneic lymphocytes and a cocktail of five different antigens were studied. In addition the stimulatory capacity in mixed lymphocyte culture was investigated as well as the formation of rosettes with sheep erythrocytes which were either uncoated or coated with antibody and complement. Whereas lymphocytes from acute lymphatic leukaemia patients in remission responded well to all stimuli tested, lymphoid cells from all seven patients in leukaemic stages with at least 80% lymphatic cells in the differential leucocyte count uniformly displayed strongly reduced or even absent responses. The phytohaemagglutinin response of cells from leukaemic stages was not only reduced but also delayed and the stimulatory capacity in mixed lymphocyte culture was always stronger than the responding capacity. These data indicate that the responses of cells from leukaemic stages are due to the presence of a small proportion of residual normal lymphocytes whereas the leukaemic cells themselves are unable to respond. The stimulatory capacity in mixed lymphocyte culture was reduced in four cases. The cells from two patients, however, displayed increased stimulatory capacity. The cells from different patients varied strongly with respect to the presence of surface markers as tested by rosette formation with sheep erythrocytes either uncoated or coated with antibody and complement. PMID:4520119

  15. Medical neglect death due to acute lymphoblastic leukaemia: an autopsy case report.

    PubMed

    Usumoto, Yosuke; Sameshima, Naomi; Tsuji, Akiko; Kudo, Keiko; Nishida, Naoki; Ikeda, Noriaki

    2014-12-01

    We report the case of 2-year-old girl who died of precursor B-cell acute lymphoblastic leukaemia (ALL), the most common cancer in children. She had no remarkable medical history. She was transferred to a hospital because of respiratory distress and died 4 hours after arrival. Two weeks before death, she had a fever of 39 degrees C, which subsided after the administration of a naturopathic herbal remedy. She developed jaundice 1 week before death, and her condition worsened on the day of death. Laboratory test results on admission showed a markedly elevated white blood cell count. Accordingly, the cause of death was suspected to be acute leukaemia. Forensic autopsy revealed the cause of death to be precursor B-cell ALL. With advancements in medical technology, the 5-year survival rate of children with ALL is nearly 90%. However, in this case, the deceased's parents preferred complementary and alternative medicine (i.e., naturopathy) to evidence-based medicine and had not taken her to a hospital for a medical check-up or immunisation since she was an infant. Thus, if she had received routine medical care, she would have a more than 60% chance of being alive 5 years after diagnosis. Therefore, we conclude that the parents should be accused of medical neglect regardless of their motives. PMID:25895240

  16. Genetic hierarchy and temporal variegation in the clonal history of acute myeloid leukaemia

    PubMed Central

    Hirsch, Pierre; Zhang, Yanyan; Tang, Ruoping; Joulin, Virginie; Boutroux, Hélène; Pronier, Elodie; Moatti, Hannah; Flandrin, Pascale; Marzac, Christophe; Bories, Dominique; Fava, Fanny; Mokrani, Hayat; Betems, Aline; Lorre, Florence; Favier, Rémi; Féger, Frédéric; Mohty, Mohamad; Douay, Luc; Legrand, Ollivier; Bilhou-Nabera, Chrystèle; Louache, Fawzia; Delhommeau, François

    2016-01-01

    In acute myeloid leukaemia (AML) initiating pre-leukaemic lesions can be identified through three major hallmarks: their early occurrence in the clone, their persistence at relapse and their ability to initiate multilineage haematopoietic repopulation and leukaemia in vivo. Here we analyse the clonal composition of a series of AML through these characteristics. We find that not only DNMT3A mutations, but also TET2, ASXL1 mutations, core-binding factor and MLL translocations, as well as del(20q) mostly fulfil these criteria. When not eradicated by AML treatments, pre-leukaemic cells with these lesions can re-initiate the leukaemic process at various stages until relapse, with a time-dependent increase in clonal variegation. Based on the nature, order and association of lesions, we delineate recurrent genetic hierarchies of AML. Our data indicate that first lesions, variegation and treatment selection pressure govern the expansion and adaptive behaviour of the malignant clone, shaping AML in a time-dependent manner. PMID:27534895

  17. Breastfeeding and early infection in the aetiology of childhood leukaemia in Down syndrome

    PubMed Central

    Flores-Lujano, J; Perez-Saldivar, M L; Fuentes-Pananá, E M; Gorodezky, C; Bernaldez-Rios, R; Del Campo-Martinez, M A; Martinez-Avalos, A; Medina-Sanson, A; Paredes-Aguilera, R; De Diego-Flores Chapa, J; Bolea-Murga, V; Rodriguez-Zepeda, M C; Rivera-Luna, R; Palomo-Colli, M A; Romero-Guzman, L; Perez-Vera, P; Alvarado-Ibarra, M; Salamanca-Gómez, F; Fajardo-Gutierrez, A; Mejía-Aranguré, J M

    2009-01-01

    Background: For a child to develop acute leukaemia (AL), environmental exposure may not be sufficient: interaction with a susceptibility factor to the disease, such as Down syndrome (DS), may also be necessary. We assessed whether breastfeeding and early infection were associated with the risk of developing AL in children with DS. Methods: Children with DS in Mexico City, and either with or without AL, were the cases (N=57) and controls (N=218), respectively. Population was divided in children with AL and with acute lymphoblastic leukaemia (ALL) and also in children ⩽6 and >6 years old. Results: Breastfeeding and early infections showed moderate (but not significant) association for AL, whereas hospitalisation by infection during the first year of life increased the risk: odds ratios (confidence interval 95%) were 0.84 (0.43–1.61), 1.70 (0.82–3.52); and 3.57 (1.59–8.05), respectively. A similar result was obtained when only ALL was analysed. Conclusion: We found that breastfeeding was a protective factor for developing AL and ALL, and during the first year of life, infections requiring hospitalisation were related to a risk for developing the disease in those children with DS >6 years of age. These data do not support the Greaves's hypothesis of early infection being protective for developing ALL. PMID:19707206

  18. Transplantation of CD3/CD19 depleted allografts from haploidentical family donors in paediatric leukaemia.

    PubMed

    Lang, Peter; Teltschik, Heiko-Manuel; Feuchtinger, Tobias; Müller, Ingo; Pfeiffer, Matthias; Schumm, Michael; Ebinger, Martin; Schwarze, Carl P; Gruhn, Bernd; Schrauder, Andre; Albert, Michael H; Greil, Johann; Urban, Christian; Handgretinger, Rupert

    2014-06-01

    Transplantation of T- and B-cell depleted allografts from haploidentical family donors was evaluated within a prospective phase II trial in children with acute lymphoblastic leukaemia, acute myeloid leukaemia and advanced myelodysplastic syndrome (n = 46). 20 patients had active disease; 19 patients received a second or third stem cell transplantation (SCT). Toxicity-reduced conditioning regimens consisted of fludarabine or clofarabine (in active disease only), thiotepa, melphalan and serotherapy. Graft manipulation was carried out with immunomagnetic microbeads. Primary engraftment occurred in 88%, with a median time to reach >1·0 × 10⁹/l leucocytes, >20 × 10⁹/l platelets and >0·1 × 10⁹/l T-cells of 10, 11 and 50 days, respectively. After retransplantation, engraftment occurred in 100%. Acute graft-versus-host disease (GvHD) grade II and III-IV occurred in 20% and 7%, chronic GvHD occurred in 21%. Both conditioning regimens had comparable toxicity. Transplant-related mortality (TRM) was 8% at one year and 20% at 5 years. Event-free survival at 3 years was: 25% (whole group), 46% (first, second or third complete remission [CR], first SCT) vs. 8% (active disease, first SCT) and 20% (second or third SCT, any disease status). This approach allows first or subsequent haploidentical SCTs to be performed with low TRM. Patients in CR may benefit from SCT, whereas the results in patients with active disease were poor. PMID:24588540

  19. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    SciTech Connect

    Cowan-Jacob, Sandra W. Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    A case study showing how the determination of multiple cocrystal structures of the protein tyrosine kinase c-Abl was used to support drug discovery, resulting in a compound effective in the treatment of chronic myelogenous leukaemia. Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery.

  20. Frequency of adult T-cell leukaemia/lymphoma and HTLV-I in Ibadan, Nigeria.

    PubMed Central

    Williams, C. K.; Alexander, S. S.; Bodner, A.; Levine, A.; Saxinger, C.; Gallo, R. C.; Blattner, W. A.

    1993-01-01

    Sera from a small sample of adult blood donors, healthy school children and patients with lymphoma, leukaemia, non-haematologic cancer, congenital and inflammatory disorders from Ibadan, Nigeria were screened for HTLV-I antibody by an enzyme-linked immunoabsorbent assay and confirmed by investigational Western blot. Seventy-nine of 236 positively screened samples could not be tested for confirmation. Seropositive reactivity was observed in nine of 123 blood donors, and 3 of 46 healthy school children but banding patterns on Western blot were often sparse. Among non-Burkitt's non Hodgkin's lymphoma patients six of 30 were HTLV-I positive including four of four with clinical features of adult T-cell leukaemia (ATL). Other clinical conditions had a frequency of positivity indistinguishable from healthy donors. Western blot patterns ranged from strong with multiple bands, which were uncommon, to those with only p24 and p21 envelope positive which were frequent. Given the relative paucity of clinical ATL and the unusual Western blot patterns the true rate of HTLV-I infection may be lower than estimated. It is possible that a cross-reactive HTLV-I-like virus accounts for this pattern. PMID:8471436

  1. Rise and fall of subclones from diagnosis to relapse in pediatric B-acute lymphoblastic leukaemia | Office of Cancer Genomics

    Cancer.gov

    There is incomplete understanding of genetic heterogeneity and clonal evolution during cancer progression. Here we use deep whole-exome sequencing to describe the clonal architecture and evolution of 20 pediatric B-acute lymphoblastic leukaemias from diagnosis to relapse. We show that clonal diversity is comparable at diagnosis and relapse and clonal survival from diagnosis to relapse is not associated with mutation burden.

  2. The proportion of childhood leukaemia incidence in Great Britain that may be caused by natural background ionizing radiation.

    PubMed

    Wakeford, R; Kendall, G M; Little, M P

    2009-04-01

    The aetiology of childhood leukaemia remains generally unknown, although exposure to moderate and high levels of ionizing radiation, such as those experienced during the atomic bombings of Japan or from radiotherapy, is an established cause. Risk models based primarily on studies of the Japanese atomic bomb survivors imply that low-level exposure to ionizing radiation, including ubiquitous natural background radiation, also raises the risk of childhood leukaemia. Using two sets of recently published leukaemia risk models and estimates of natural background radiation red-bone-marrow doses received by children, about 20% of the cases of childhood leukaemia in Great Britain are predicted to be attributable to this source. However, for one of these sets of risk models this attributable fraction is materially dependent on how the radiation-induced risk is assumed to be transferred between the Japanese atomic bomb survivors and Western children. Over a range of annual doses representing the range (0.5-2.5 mSv/year) experienced by most populations, the attributable proportion for the preferred risk-transfer model varies between 8 and 30%, with small deviations from a linear relationship that are largely due to the saturation of the model, although again this range of attributable fractions depends on the assumed transfer of risk between populations. PMID:19151785

  3. Adult myeloid leukaemia, geology, and domestic exposure to radon and gamma radiation: a case control study in central Italy

    PubMed Central

    Forastiere, F.; Sperati, A.; Cherubini, G.; Miceli, M.; Biggeri, A.; Axelson, O.

    1998-01-01

    OBJECTIVES: To investigate whether indoor randon or gamma radiation might play a part in myeloid leukaemia as suggested by studies based on crude geographical or geological data for exposure assessment. METHODS: For six months randon and gamma radiation was measured with solid state nuclear track detectors and thermoluminescent dosimeters in dwellings of 44 adult male cases of acute myeloid leukaemia and 211 controls (all subjects deceased). Conditional logistic regression ORs (ORs) and 95% confidence intervals (95% CIs) were estimated for quartiles of radon and gamma radiation and for municipality and dwelling characteristics. RESULTS: The risk of leukaemia was associated with an increasing urbanisation index (p value for trend = 0.008). An increased OR was found among those living in more modern houses (OR 3.0, 95% CI 1.4 to 6.6). Confirming the findings of a previous study in the same area, geological features bore a positive association with myeloid leukemia, even by adjusting for level of urbanisation. Contrary to expectations from the previous study, however, no association appeared between myeloid leukaemia and radon and gamma radiation; for the highest quartiles of exposure, ORs were 0.56 (95% CI 0.2 to 1.4) and 0.52 (95% CI 0.2 to 1.4), respectively. Considering only subjects who had lived > or = 20 years in the monitored home and adjusting for urbanisation, there was still no effect of exposure to radiation. CONCLUSIONS: In view of the limited numbers, the results do not in general refute a possible risk of myeloid leukaemia from exposure to indoor radon or gamma radiation, but decrease the credibility of such a relation in the area studied and also of other studies suggesting an effect without monitoring indoor radiation. Some other fairly strong determinants have appeared--that is, level of urbanisation and living in modern houses-- that might need further consideration.   PMID:9614394

  4. Risk analysis of leukaemia incidence among people living along the Techa River: a nested case-control study.

    PubMed

    Ostroumova, E; Gagnière, B; Laurier, D; Gudkova, N; Krestinina, L; Verger, P; Hubert, P; Bard, D; Akleyev, A; Tirmarche, M; Kossenko, M

    2006-03-01

    Large quantities of radioactive materials released over time from the Mayak nuclear weapons facility caused significant internal and external exposure for people living along the banks of the Techa River (Southern Urals, Russia). We conducted a nested case-control study in the Extended Techa River Cohort to determine whether the risk of leukaemia incidence increased with protracted exposure to ionising radiation or with other non-radiation risk factors. The study included 83 cases identified over 47 years of follow-up and 415 controls matched for sex, age at diagnosis, age (within a 5 year age group), and date of initial residence in the riverside area. External and internal doses have been calculated using the Techa River Dosimetry System 1996 (TRDS96). Conditional logistic regression was used to calculate odds ratios per Gray (OR/Gy) and 95% confidence intervals (95% CI). After excluding cases of chronic lymphoid leukaemia, the OR/Gy of total, external, and internal doses were 4.6 (95% CI: 1.7-12.3), 7.2 (95%CI: 1.7-30.0) and 5.4 (95%CI: 1.1-27.2), respectively. A history of solid tumour, either malignant or benign, before the leukaemia diagnosis was associated with a 2.5-fold increase in the leukaemia risk (95% CI: 1.1-5.9). Even though the analysis of confounders was less useful than expected because of missing data, multivariate analyses that took the exposure dose into account confirmed the association between leukaemia incidence and tumour history. PMID:16522942

  5. TelCoVis: Visual Exploration of Co-occurrence in Urban Human Mobility Based on Telco Data.

    PubMed

    Wu, Wenchao; Xu, Jiayi; Zeng, Haipeng; Zheng, Yixian; Qu, Huamin; Ni, Bing; Yuan, Mingxuan; Ni, Lionel M

    2016-01-01

    Understanding co-occurrence in urban human mobility (i.e. people from two regions visit an urban place during the same time span) is of great value in a variety of applications, such as urban planning, business intelligence, social behavior analysis, as well as containing contagious diseases. In recent years, the widespread use of mobile phones brings an unprecedented opportunity to capture large-scale and fine-grained data to study co-occurrence in human mobility. However, due to the lack of systematic and efficient methods, it is challenging for analysts to carry out in-depth analyses and extract valuable information. In this paper, we present TelCoVis, an interactive visual analytics system, which helps analysts leverage their domain knowledge to gain insight into the co-occurrence in urban human mobility based on telco data. Our system integrates visualization techniques with new designs and combines them in a novel way to enhance analysts' perception for a comprehensive exploration. In addition, we propose to study the correlations in co-occurrence (i.e. people from multiple regions visit different places during the same time span) by means of biclustering techniques that allow analysts to better explore coordinated relationships among different regions and identify interesting patterns. The case studies based on a real-world dataset and interviews with domain experts have demonstrated the effectiveness of our system in gaining insights into co-occurrence and facilitating various analytical tasks. PMID:26469282

  6. Successful pregnancy after total body irradiation and bone marrow transplantation for acute leukaemia.

    PubMed

    Giri, N; Vowels, M R; Barr, A L; Mameghan, H

    1992-07-01

    We report successful pregnancies in two young women (aged 24 and 20 years) following allogeneic bone marrow transplantation (BMT) for acute non-lymphoblastic leukaemia. Conditioning therapy consisted of cyclophosphamide (120 mg/kg) and total body irradiation (TBI, 12 Gy) in 2 Gy fractions once daily for 6 days or twice daily for 3 days. Graft-versus-host disease prophylaxis was with methotrexate alone. Both women were amenorrhoeic after BMT and gonadal testing indicated hypergonadotrophic hypogonadism. Both women had normal pregnancies (2 years and 5 years after BMT) resulting in normal healthy infants. Previously successful pregnancy has been reported after TBI in three women in whom the TBI dose was less than 8 Gy. Our cases illustrate that normal outcome of pregnancy is possible at even higher doses of TBI. PMID:1515886

  7. MicroRNA control of myelopoiesis and the differentiation block in acute myeloid leukaemia

    PubMed Central

    Palma, Catalina A; Tonna, Elise J; Ma, David F; Lutherborrow, Mark A

    2012-01-01

    Abstract In the relatively short period of time since their discovery, microRNAs have been shown to control many important cellular functions such as cell differentiation, growth, proliferation and apoptosis. In addition, microRNAs have been demonstrated as key drivers of many malignancies and can function as either tumour suppressors or oncogenes. The haematopoietic system is not outside the realm of microRNA control with microRNAs controlling aspects of stem cell and progenitor self-renewal and differentiation, with many, if not all, haematological disorders associated with aberrant microRNA expression and function. In this review, we focus on the current understanding of microRNA control of haematopoiesis and detail the evidence for the contribution and clinical relevance of aberrant microRNA function to the characteristic block of differentiation in acute myeloid leukaemia. PMID:22225649

  8. Mycobacterium genavense infection in a patient with long-standing chronic lymphocytic leukaemia.

    PubMed

    Krebs, T; Zimmerli, S; Bodmer, T; Lämmle, B

    2000-10-01

    We describe the first case of disseminated infection with Mycobacterium genavense in an HIV-seronegative patient with a chronic haematological disorder. Our patient, an 80-year-old woman, had been under long-term treatment with chlorambucil (partially in combination with prednisone) for B-cell chronic lymphocytic leukaemia (B-CLL). When she developed general fatigue and progressive anaemia, as well as progressive lymphadenopathy and splenomegaly, bone marrow biopsy revealed granulomas with acid-fast bacilli, and cultures of both bone marrow and blood grew M. genavense. The patient's CD4+ cell count was approximately 100 microL(-1). Treatment with clarithromycin, ethambutol and rifabutin resulted in improvement of anaemia and general health as well as in regression of lymphadenopathy and splenomegaly. PMID:11086646

  9. Childhood-onset eosinophilic granulomatosis with polyangiitis: a rare childhood vasculitis mimicking anthrax and eosinophilic leukaemia.

    PubMed

    Sahin, Sezgin; Adrovic, Amra; Barut, Kenan; Kasapcopur, Ozgur

    2016-01-01

    A 14-year-old boy previously misdiagnosed as having cutaneous anthrax was referred with a 2-month history of multiple wide and deep ulceronecrotic lesions in the lower extremities, which occurred after contact with animals. Skin biopsy was compatible with vasculitis. Further examination at our hospital elicited eosinophilia and a history of asthma. On the second day of hospitalisation, he developed deep vein thrombosis. A diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA) was established and intravenous methylprednisolone was administered. The patient showed remarkable improvement of the cutaneous lesions. Diagnosis of EGPA is challenging in the vasculitic phase and necessitates a detailed history that specifically questions the patient for an asthma background. This case illustrates a severe cutaneous presentation of EGPA and emphasises the difficulty of diagnosis as a result of overlapped signs and symptoms with cutaneous anthrax and leukaemia. EGPA should be kept in mind in the differential diagnosis of cutaneous lesions associated with eosinophilia. PMID:26887883

  10. Chronic Myeloid Leukaemia Presenting as Bilateral Retinal Haemorrhages with Multiple Retinal Infiltrates

    PubMed Central

    Barot, Rakesh K.; Gohel, Devadatta Jayantilal; Bhagat, Nupur

    2016-01-01

    Chronic Myeloid Leukaemia (CML) causes retinopathy manifesting as venous dilation and tortuosity, perivascular sheathing, retinal haemorrhages, microaneurysms, cotton-wool spots and optic nerve infiltration. Retina is the most commonly involved intraocular structure in CML. However, retinal involvement is a rare form of presentation of CML and few cases have been reported. We report a case of CML presenting as unilateral sudden visual loss. Fundus showed multiple white centered retinal haemorrhages in both eyes with unilateral macular oedema. Blood work-up showed raised WBC count, high platelet count and low Haemoglobin. Cytological analysis of bone marrow biopsy confirmed Philadelphia chromosome. After a course of Imatinib, visual acuity improved and haemorrhages resolved with normalization of macular thickness. In our case, patient presented early, leading to early detection producing better visual prognosis. This highlights the importance of detailed hematological work up in patients with retinal involvement to rule out leukaemic retinopathy.

  11. Initial presentation of CNS-restricted acute lymphoblastic B cell leukaemia as peripheral polyneuropathy.

    PubMed

    Piovezani Ramos, Guilherme; Villasboas Bisneto, Jose C; Chen, Dong; Pardanani, Animesh

    2016-01-01

    We report a case of a 58-year-old woman who presented with a 1-month course of progressive lower and upper extremity weakness in addition to binocular diplopia. Diagnostic lumbar puncture revealed atypical lymphoid cells with 28% blasts. Immunophenotype was consistent with B cell acute lymphoblastic leukaemia (B-ALL). Further work up showed no systemic involvement but extensive thoracolumbar-sacral leptomeningeal disease. The patient was treated with several courses of intrathecal and systemic chemotherapy followed by craniospinal irradiation for consolidation. There was initial steady improvement in neurological symptoms and leptomeningeal disease, the latter being ascertained through radiological studies and cerebrospinal fluid examination. After 10 months of response, the patient relapsed with central nervous system (CNS) and systemic disease. B-ALL is a rare precursor lymphoid neoplasm that generally presents with systemic disease. While CNS involvement is not uncommon, isolated involvement of this compartment without systemic disease is exceedingly rare. PMID:27095809

  12. Notch signalling in T cell lymphoblastic leukaemia/lymphoma and other haematological malignancies

    PubMed Central

    Aster, Jon C.; Blacklow, Stephen C.; Pear, Warren S.

    2010-01-01

    Notch receptors participate in a highly conserved signalling pathway that regulates normal development and tissue homeostasis in a context- and dose-dependent manner. Deregulated Notch signalling has been implicated in many diseases, but the clearest example of a pathogenic role is found in T cell lymphoblastic leukaemia/lymphoma (T-LL), in which the majority of human and murine tumours have acquired mutations that lead to aberrant increases in Notch1 signalling. Remarkably, it appears that the selective pressure for Notch mutations is virtually unique among cancers to T-LL, presumably reflecting a special context-dependent role for Notch in normal T cell progenitors. Nevertheless, there are some recent reports suggesting that Notch signalling has subtle yet important roles in other forms of hematologic malignancy as well. Here, we review the role of Notch signalling in various blood cancers, focusing on T-LL with an eye toward targeted therapeutics. PMID:20967796

  13. Monitoring minimal residual disease in acute myeloid leukaemia: a review of the current evolving strategies

    PubMed Central

    Ommen, Hans Beier

    2016-01-01

    Several disease-monitoring techniques are available for the physician treating acute myeloid leukaemia (AML). Besides immunohistochemistry assisted light microscopy, the past 20 years have seen the development and preclinical perfection of a number of techniques, most notably quantitative polymerase chain reaction (PCR) and multicolor flow cytometry. Late additions to the group of applicable assays include next generation sequencing and digital PCR. In this review the principles of use of these modalities at three different time points during the AML disease course are discussed, namely at the time of treatment evaluation, pretransplantation and postconsolidation. The drawbacks and pitfalls of each different technique are delineated. The evidence or lack of evidence for minimal residual disease guided treatment decisions is discussed. Lastly, future strategies in the MRD field are suggested and commented upon. PMID:26834951

  14. Non-tumour bone marrow lymphocytes correlate with improved overall survival in childhood acute lymphoblastic leukaemia.

    PubMed

    Edwin, Claire; Dean, Joanne; Bonnett, Laura; Phillips, Kate; Keenan, Russell

    2016-10-01

    Composition of tumour immune cell infiltrates correlates with response to treatment and overall survival (OS) in several cancer settings. We retrospectively examined immune cells present in diagnostic bone marrow aspirates from paediatric patients with B-cell acute lymphoblastic leukaemia. Our analysis identified a sub-group (∼30% of patients) with >2.37% CD20 and >6.05% CD7 expression, which had 100% OS, and a sub-group (∼30% of patients) with ≤2.37% CD20 and ≤6.05% CD7 expression at increased risk of treatment failure (66.7% OS, P < 0.05). Immune cell infiltrate at diagnosis may predict treatment response and could provide a means to enhance immediate treatment risk stratification. PMID:27348401

  15. Second-generation tyrosine kinase inhibitors in first-line treatment of chronic myeloid leukaemia (CML).

    PubMed

    Abruzzese, Elisabetta; Breccia, Massimo; Latagliata, Roberto

    2014-02-01

    Tyrosine kinase inhibitors (TKIs) have contributed to marked improvements in survival in patients with chronic myeloid leukaemia (CML). This article discusses the place of the second-generation TKIs dasatinib and nilotinib in the first-line treatment of CML and is based on published literature. The new agents are more potent and effective than imatinib. Data from pivotal clinical trials indicate that response to dasatinib and nilotinib is greater and more rapid than that to imatinib, resulting in a higher probability of patients achieving an optimal response to treatment. Differences between the newer agents with respect to patient groups for whom caution is advised, drug interaction potential, haematological toxicity, pulmonary toxicity, changes in the immune system and effects on laboratory parameters are discussed. With similar levels of efficacy, the choice of second-generation agents should be guided by the characteristics of the individual patient and the most suitable dosing regimen. PMID:24043361

  16. First reported association of chronic lymphocytic leukaemia and interstitial granulomatous dermatitis.

    PubMed

    Riaz, Irbaz Bin; Kamal, Muhammad Umar; Segal, Robert J; Anwer, Faiz

    2016-01-01

    Interstitial granulomatous dermatitis (IGD), a rare disease, is well known to be associated with connective tissue disorders, malignancies and several drugs. We describe this first case of IGD in association with chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL). A 66-year-old woman with a 6-year history of untreated CLL/SLL, presented with a 2-month history of progressively worsening eruption of the left thigh, along with fatigue, lymphadenopathy and night sweats. Skin biopsy showed findings consistent with IGD and infiltration of CLL. The eruption was non-responsive to treatment with antibiotics and local steroids. There was a significant improvement in the rash after an initial cycle of chemotherapy (combination therapy with bendamustine and rituximab) and complete resolution by the third cycle, for the treatment of her CLL. We suggest that the possibility of an underlying haematological malignancy should be investigated in patients with a skin rash non-responsive to conventional therapy. PMID:27194675

  17. Pharmacological targeting of PI3K isoforms as a therapeutic strategy in chronic lymphocytic leukaemia

    PubMed Central

    Blunt, Matthew D.; Steele, Andrew J.

    2015-01-01

    PI3Kδ inhibitors such as idelalisib are providing improved therapeutic options for the treatment of chronic lymphocytic leukaemia (CLL). However under certain conditions, inhibition of a single PI3K isoform can be compensated by the other PI3K isoforms, therefore PI3K inhibitors which target multiple PI3K isoforms may provide greater efficacy. The development of compounds targeting multiple PI3K isoforms (α, β, δ, and γ) in CLL cells, in vitro, resulted in sustained inhibition of BCR signalling but with enhanced cytotoxicity and the potential for improve clinical responses. This review summarises the progress of PI3K inhibitor development and describes the rationale and potential for targeting multiple PI3K isoforms. PMID:26500849

  18. Pharmacotherapeutic Management of Chronic Lymphocytic Leukaemia in Patients with Comorbidities: New Agents, New Hope.

    PubMed

    Goede, Valentin; Hallek, Michael

    2015-11-01

    Chronic lymphocytic leukaemia (CLL) is mostly considered a disease of the elderly. As such, many patients present with comorbidities. Several scores allow for a qualitative and quantitative assessment of comorbidity in patients with CLL. Although our knowledge about the impact of comorbidity on outcomes in patients with CLL is still incomplete, it is becoming increasingly apparent that comorbidities could negatively interfere with CLL treatment. Recently, a number of new agents have been approved for use in patients with previously untreated CLL and comorbidities (i.e. obinutuzumab, ofatumumab), as well as in patients with previously treated or high-risk CLL (i.e. idelalisib, ibrutinib). This review discusses the role of comorbidity in patients with CLL, together with the changing treatment landscape for CLL in this patient population. PMID:26446155

  19. Successful treatment of disseminated mucormycosis in a neutropenic patient with T-cell acute lymphoblastic leukaemia

    PubMed Central

    Guymer, Chelsea; Khurana, Sanjeev; Suppiah, Ram; Hennessey, Iain; Cooper, Celia

    2013-01-01

    Mucormycosis is a rare angioinvasive fungal infection, more commonly seen in immunosuppressed patients, with reported mortality rates of 95% in disseminated disease. We present a case report of a patient with T-cell acute lymphoblastic leukaemia who developed disseminated infection with mucormycosis (involving the pancreas, left occipital lobe, right lower lobe of lung, appendix and right kidney) after having completed induction and consolidation chemotherapy. Growth of Lichtheimia corymbifera was initially isolated following a right pleural tap with fungal elements identified repeatedly on subsequent pathology specimens. Following radical surgical debridement and concurrent treatment with combination antifungal therapy, the patient survived. This case demonstrates that aggressive multisite surgical de-bulking of disseminated fungal foci, in conjunction with combination antifungal therapy and reversal of immunosuppression, can result in survival despite the grave prognosis associated with disseminated mucormycosis. PMID:23904418

  20. A case of mandibular osteomyelitis in a patient with chronic myelomonocytic leukaemia.

    PubMed

    Kojima, Yuki; Ishigami, Takashi; Akiba, Masakazu

    2016-01-01

    We report a case of chronic myelomonocytic leukaemia (CMMoL) in a 68-year-old man who developed osteomyelitis of the mandible. At the initial visit, he reported uncontrolled gingival bleeding, despite self-administered haemostasis. He complained of severe pain in the socket, despite potent opioid analgesia. After consultation with the internal medicine specialists, we undertook a surgical anti-inflammatory approach that included sequestrectomy with massive blood transfusion. His physical condition was ameliorated after the surgical procedure, and he was discharged from the hospital. However, 3 months later, he died because of cardiac arrest after haemorrhagic shock and cardiovascular failure because his CMMoL had developed to an acute blastic crisis. This experience demonstrates that the most important goal in such cases is to alleviate a patient's discomfort by applying minimally invasive actions to eliminate infection and improve the quality of life without causing deterioration in the CMMoL status. PMID:27572681

  1. A case of mandibular osteomyelitis in a patient with chronic myelomonocytic leukaemia

    PubMed Central

    Kojima, Yuki; Ishigami, Takashi; Akiba, Masakazu

    2016-01-01

    We report a case of chronic myelomonocytic leukaemia (CMMoL) in a 68-year-old man who developed osteomyelitis of the mandible. At the initial visit, he reported uncontrolled gingival bleeding, despite self-administered haemostasis. He complained of severe pain in the socket, despite potent opioid analgesia. After consultation with the internal medicine specialists, we undertook a surgical anti-inflammatory approach that included sequestrectomy with massive blood transfusion. His physical condition was ameliorated after the surgical procedure, and he was discharged from the hospital. However, 3 months later, he died because of cardiac arrest after haemorrhagic shock and cardiovascular failure because his CMMoL had developed to an acute blastic crisis. This experience demonstrates that the most important goal in such cases is to alleviate a patient's discomfort by applying minimally invasive actions to eliminate infection and improve the quality of life without causing deterioration in the CMMoL status. PMID:27572681

  2. Anti-leukaemia activity as a bystander effect of graft-versus-host reactions.

    PubMed Central

    Johnson, P. R.; Hersey, P.

    1976-01-01

    The production of graft-versus-host (GVH) reactions in (PVGc X Wistar) F1 hybrids by the transfer of PVGc spleen cells resulted in significant resistance of these recipients to a subsequent challenge with the PVGc leukaemia. Protection was markedly dependent on dose and timing of allogeneic cell transfer and was abrogated by irradiation of the cells prior to transfer. GVH activity was shown to be a prerequisite for induction of the protective effect but was equally effective when produced by the transfer of Wistar spleen cells in place of PVGc cells. These points, plus the fact that invitro investigations of possible immune mechanisms failed to demonstrate cytotoxic immunity in treated rats, suggested a nonspecific "bystander" effect as the mechanism of protection. The implications of such a mechanism are discussed. PMID:5100

  3. Infectious proxies and childhood leukaemia: findings from the United Kingdom Childhood Cancer Study (UKCCS).

    PubMed

    Roman, Eve; Simpson, Jill; Ansell, Pat; Lightfoot, Tracy; Smith, Alex

    2009-01-01

    The United Kingdom Childhood Cancer Study (UKCCS) was specifically designed to investigate the potential etiological role of infections as one of its objectives and information on a number of markers of infectious exposure from multiple sources was collected (www.ukccs.org). This study found that a mother's recollections of past minor illness episodes in her children were unreliable, producing systematic case-control differences. From birth onwards children diagnosed with ALL between 2-5 years were found to have had more clinically diagnosed infectious illness episodes (not fewer) than unaffected children, with those with two or more neonatal infections being diagnosed with leukaemia around 7 months earlier than those with only one or none. The findings from these analyses and their implications for future research are reviewed and discussed in this paper. PMID:19091606

  4. Fatal disseminated fusarium infection in acute lymphoblastic leukaemia in complete remission

    PubMed Central

    Austen, B; McCarthy, H; Wilkins, B; Smith, A; Duncombe, A

    2001-01-01

    Fusarium species are increasingly recognised as serious pathogens in the immunocompromised. The outcome in the context of persistent severe neutropenia has been almost universally fatal. However, there have been several case reports of successful treatment if neutrophil recovery can be achieved. This report presents the case of a fatality that occurred despite neutrophil recovery. A 67 year old man developed disseminated fusariosis during the neutropenic phase of induction chemotherapy for acute lymphoblastic leukaemia. Fusarium dimerum was isolated from blood cultures. This species is highly unusual and very few case reports exist in the literature. An initial response to amphotericin treatment coincided with neutrophil recovery but a subsequent relapse occurred, despite adequate neutrophil counts, which proved fatal. It is postulated that reseeding of the blood from an occult site, namely the right vitreum in this case, led to this secondary relapse despite achieving complete leukaemic remission. Key Words: fusarium • disseminated • neutropenia • remission PMID:11376027

  5. Septic shock during platelet transfusion in a patient with acute myeloid leukaemia.

    PubMed

    Haesebaert, Julie; Bénet, Thomas; Michallet, Mauricette; Vanhems, Philippe

    2013-01-01

    Although rare, transfusion-associated bacterial contamination (TABC) is nowadays the main risk associated with platelet concentrate (PC) transfusion. Consequences vary from spontaneously resolving symptoms to severe sepsis and death. In this report we have summarised a case of bacterial contamination and sepsis during PC transfusion in a patient with acute myeloid leukaemia. Fifteen minutes after the PC transfusion began, she developed chills and rapidly worsened to septic shock. The episode was managed appropriately. The patient's blood cultures and PC unit cultures grew Escherichia coli. The microbiological susceptibilities of isolates from the patient and platelet bag were identical. No other source of E coli was found. Donor and blood products issued from the same donation investigations were negative. The causality between sepsis and PC transfusion might be difficult to confirm. As no method is available in daily practice to eliminate TABC risk, physicians should always consider TABC by immediately stopping the transfusion and conducting appropriate investigations. PMID:24172770

  6. Elevated serum levels of IGFBP-2 found in children suffering from acute leukaemia is accompanied by the occurrence of IGFBP-2 mRNA in the tumour clone.

    PubMed Central

    Wex, H.; Vorwerk, P.; Mohnike, K.; Bretschneider, D.; Kluba, U.; Aumann, V.; Blum, W. F.; Mittler, U.

    1998-01-01

    Insulin-like growth factor-binding proteins (IGFBPs) are important modulators of IGF action. In 50 children suffering from acute lymphoblastic leukaemia (ALL), we studied the serum levels of IGFBP-1,-2 and-3. The mean standard deviation score (SDS) values were estimated to be 0.7, 3.1 and -1.7 for the IGFBP-1,-2 and-3, respectively, compared with the normal range defined by a SDS from -2 to +2. IGFBP-1 and-3 were normal, but for IGFBP-2 we found a significantly elevated serum level compared with control groups (P < 0.05). However, during chemotherapy this increased serum IGFBP-2 normalized. In addition, we found a correlation between higher serum levels and the detection rate of the IGFBP-2 transcript in corresponding cells. In patients with ALL, the detection rates of IGFBP-2 mRNA were estimated to be 72% and 35% at the time of diagnosis and at day 33 of chemotherapy respectively; in the control groups (healthy children and children at their initial presentation of diabetes mellitus), the values were 28% and 33% respectively. Based on the correlation between IGFBP-2 serum levels and the corresponding gene expression as well as the normalization of IGFBP-2 levels during chemotherapy, we concluded that the increased serum level mainly originated from the tumour clone itself. Furthermore, possible functional consequences of elevated IGFBP-2 were outlined. Images Figure 2 Figure 3 PMID:9716037

  7. Breast Imaging Utilizing Dedicated Gamma Camera and (99m)Tc-MIBI: Experience at the Tel Aviv Medical Center and Review of the Literature Breast Imaging.

    PubMed

    Even-Sapir, Einat; Golan, Orit; Menes, Tehillah; Weinstein, Yuliana; Lerman, Hedva

    2016-07-01

    The scope of the current article is the clinical role of gamma cameras dedicated for breast imaging and (99m)Tc-MIBI tumor-seeking tracer, as both a screening modality among a healthy population and as a diagnostic modality in patients with breast cancer. Such cameras are now commercially available. The technology utilizing a camera composed of a NaI (Tl) detector is termed breast-specific gamma imaging. The technology of dual-headed camera composed of semiconductor cadmium zinc telluride detectors that directly converts gamma-ray energy into electronic signals is termed molecular breast imaging. Molecular breast imaging system has been installed at the Department of Nuclear medicine at the Tel Aviv Sourasky Medical Center, Tel Aviv in 2009. The article reviews the literature well as our own experience. PMID:27237439

  8. TESTIN Induces Rapid Death and Suppresses Proliferation in Childhood B Acute Lymphoblastic Leukaemia Cells

    PubMed Central

    Weeks, Robert J.; Ludgate, Jackie L.; LeMée, Gwenn; Morison, Ian M.

    2016-01-01

    Background Childhood acute lymphoblastic leukaemia (ALL) is the most common malignancy in children. Despite high cure rates, side effects and late consequences of the intensive treatments are common. Unquestionably, the identification of new therapeutic targets will lead to safer, more effective treatments. We identified TES promoter methylation and transcriptional silencing as a very common molecular abnormality in childhood ALL, irrespective of molecular subtype. The aims of the present study were to demonstrate that TES promoter methylation is aberrant, to determine the effects of TES re-expression in ALL, and to determine if those effects are mediated via TP53 activity. Methods Normal fetal and adult tissue DNA was isolated and TES promoter methylation determined by Sequenom MassARRAY. Quantitative RT-PCR and immunoblot were used to confirm re-expression of TES in ALL cell lines after 5’-aza-2’-deoxycytidine (decitabine) exposure or transfection with TES expression plasmids. The effects of TES re-expression on ALL cells were investigated using standard cell proliferation, cell death and cell cycle assays. Results In this study, we confirm that the TES promoter is unmethylated in normal adult and fetal tissues. We report that decitabine treatment of ALL cell lines results in demethylation of the TES promoter and attendant expression of TES mRNA. Re-expression of TESTIN protein in ALL cells using expression plasmid transfection results in rapid cell death or cell cycle arrest independent of TP53 activity. Conclusions These results suggest that TES is aberrantly methylated in ALL and that re-expression of TESTIN has anti-leukaemia effects which point to novel therapeutic opportunities for childhood ALL. PMID:26985820

  9. The risk profile of childhood leukaemia in Greece: a nationwide case-control study.

    PubMed

    Petridou, E; Trichopoulos, D; Kalapothaki, V; Pourtsidis, A; Kogevinas, M; Kalmanti, M; Koliouskas, D; Kosmidis, H; Panagiotou, J P; Piperopoulou, F; Tzortzatou, F

    1997-01-01

    The risk profile of childhood leukaemia in Greece was studied through a case-control investigation that included all 153 incident cases of the disease, ascertained throughout the country during 1993 and 1994, and two hospital controls for every case matched for gender, age and place of residence. The data were analysed using conditional logistic regression and the associations are expressed in terms of adjusted odds ratios (OR) and their 95% confidence intervals. Cases were born to mothers of a higher standard education, the OR for an increment of four schooling years being 1.48 (1.17-1.87) and had higher birth weight, the OR for an increment of 500g being 1.36 (1.04-1.77). Pet ownership and birth after a pregnancy with anaemia were associated with increased risk, the ORs being 2.18 (1.14-4.16) and 2.60 (1.39-4.86) respectively. From the frequency analyses, indicative inverse associations were found with birth order, household crowding and previous hospitalization with allergic diseases, whereas indicative positive associations were found with diabetes mellitus during pregnancy and with neonatal jaundice. Substantial or significant elevations were not found with respect to maternal smoking and coffee drinking during pregnancy, diagnostic radiography and ultrasonographic examinations or blood transfusions. A significant inverse association with maternal consumption of alcohol could be due to multiple comparisons, but a detrimental effect can probably be excluded. A non-significant positive association with total shots of viral vaccinations and a weak non-significant inverse association with breast feeding were also found. We interpret the findings of this study as being compatible with acute childhood leukaemia being linked with delayed development of herd immunity to fairly common infectious agents, in conjunction with accelerated perinatal and early post-natal growth. PMID:9365177

  10. Cerebrospinal fluid asparagine depletion during pegylated asparaginase therapy in children with acute lymphoblastic leukaemia.

    PubMed

    Henriksen, Louise T; Nersting, Jacob; Raja, Raheel A; Frandsen, Thomas L; Rosthøj, Steen; Schrøder, Henrik; Albertsen, Birgitte K

    2014-07-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Cerebrospinal fluid (CSF) asparagine depletion is considered a marker of asparaginase effect in the central nervous system (CNS) and may play a role in CNS-directed anti-leukaemia therapy. The objective of this study was to describe CSF asparagine depletion during 30 weeks of pegylated asparaginase therapy, 1000 iu/m(2) i.m. every second week, and to correlate CSF asparagine concentration with serum L-asparaginase enzyme activity. Danish children (1-17 years) with ALL, treated according to the Nordic Society of Paediatric Haematology and Oncology ALL2008 protocol, standard and intermediate risk, were included. CSF samples were obtained throughout L-asparaginase treatment at every scheduled lumbar puncture. A total of 128 samples from 31 patients were available for analysis. Median CSF asparagine concentration decreased from a pre-treatment level of 5·3 μmol/l to median levels ≤1·5 μmol/l. However, only 4/31 patients (five samples) had CSF asparagine concentrations below the limit of detection (0·1 μmol/l). In 11 patients, 24 paired same day serum and CSF samples were obtained. A decrease in CSF asparagine corresponded to serum enzyme activities above 50 iu/l. Higher serum enzyme activities were not followed by more extensive depletion. In conclusion, pegylated asparaginase 1000 iu/m(2) i.m. every second week effectively reduced CSF asparagine levels. PMID:24702187

  11. Allergy and acute leukaemia in children with Down syndrome: a population study. Report from the Mexican inter-institutional group for the identification of the causes of childhood leukaemia

    PubMed Central

    Núñez-Enríquez, J C; Fajardo-Gutiérrez, A; Buchán-Durán, E P; Bernáldez-Ríos, R; Medina-Sansón, A; Jiménez-Hernández, E; Amador-Sanchez, R; Peñaloza-Gonzalez, J G; Paredes-Aguilera, R; Alvarez-Rodriguez, F J; Bolea-Murga, V; de Diego Flores-Chapa, J; Flores-Lujano, J; Bekker-Mendez, V C; Rivera-Luna, R; del Carmen Rodriguez-Zepeda, M; Rangel-López, A; Dorantes-Acosta, E M; Núñez-Villegas, N; Velazquez-Aviña, M M; Torres-Nava, J R; Reyes-Zepeda, N C; Cárdenas-Cardos, R; Flores-Villegas, L V; Martinez-Avalos, A; Salamanca-Gómez, F; Gorodezky, C; Arellano-Galindo, J; Mejía-Aranguré, J M

    2013-01-01

    Background: Allergies have been described as protective factors against the development of childhood acute leukaemia (AL). Our objective was to investigate the associations between allergy history and the development of AL and acute lymphoblastic leukaemia (ALL) in children with Down syndrome (DS). Methods: A case–control study was performed in Mexico City. The cases (n=97) were diagnosed at nine public hospitals, and the controls (n=222) were recruited at institutions for children with DS. Odds ratios (OR) were calculated. Results: Asthma was positively associated with AL development (OR=4.18; 95% confidence interval (CI): 1.47–11.87), whereas skin allergies were negatively associated (OR=0.42; 95% CI: 0.20–0.91). Conclusion: Our findings suggest that allergies and AL in children with DS share biological and immune mechanisms. To our knowledge, this is the first study reporting associations between allergies and AL in children with DS. PMID:23695017

  12. Rearrangements of c-myc and c-abl genes in tumour cells in Burkitt's lymphoma.

    PubMed Central

    Casares, S; Rodríguez, J M; Martin, A; Parrado, A

    1993-01-01

    Rearrangements of oncogenes c-myc and c-abl were detected by non-radioactive hybridisation in a case of Burkitt's lymphoma/leukaemia. The surface phenotype of Burkitt's cells were positive for CD19, CD20, HLA-DR, CD14, CD33 and surface immunoglobulin markers. Although cytogenetic analysis was not performed, the c-myc and heavy immunoglobulin genes had the same 14.2 kilobase EcoRI molecular size fragment, suggesting a possible t(8;14) translocation which is a common marker of this malignancy. The c-abl oncogene was also rearranged in DNA digested BamHI and EcoRI. The physiopathological implications of the rearranged c-abl gene are unknown, this being the first case, as for as is known, of Burkitt's lymphoma/leukaemia with a rearranged c-abl gene. Images PMID:8408711

  13. Study of 30 patients with unexplained developmental delay and dysmorphic features or congenital abnormalities using conventional cytogenetics and multiplex FISH telomere (M-TEL) integrity assay.

    PubMed

    Popp, Susanne; Schulze, Birgit; Granzow, Martin; Keller, Monika; Holtgreve-Grez, Heidi; Schoell, Brigitte; Brough, Michaela; Hager, Hans-Dieter; Tariverdian, Gholamali; Brown, Jill; Kearney, Lyndal; Jauch, Anna

    2002-07-01

    Cryptic subtelomeric chromosome rearrangements are a major cause of mild to severe mental retardation pointing out the necessity of sensitive screening techniques to detect such aberrations among affected patients. In this prospective study a group of 30 patients with unexplained developmental retardation and dysmorphic features or congenital abnormalities were analysed using the recently published multiplex FISH telomere (M-TEL) integrity assay in combination with conventional G-banding analysis. The patients were selected by one or more of the following criteria defined by de Vries et al.: (a) family history with two or more affected individuals, (b) prenatal onset growth retardation, (c) postnatal growth abnormalities, (d) facial dysmorphic features, (e) non-facial dysmorphism and congenital abnormalities. In addition, we included two patients who met these criteria and revealed questionable chromosome regions requiring further clarification. In four patients (13.3%) cryptic chromosome aberrations were successfully determined by the M-TEL integrity assay and in two patients with abnormal chromosome regions intrachromosomal aberrations were characterized by targetted FISH experiments. Our results accentuate the requirement of strict selection criteria prior to patient testing with the M-TEL integrity assay. Another essential precondition is high-quality banding analysis to identify structural abnormal chromosomes. The detection of familial balanced translocation carriers in 50% of the cases emphasizes the significance of such an integrated approach for genetic counselling and prenatal diagnosis. PMID:12136233

  14. Identification of TEL-AML1 (ETV6-RUNX1) associated DNA and its impact on mRNA and protein output using ChIP, mRNA expression arrays and SILAC

    PubMed Central

    Linka, Yvonne; Ginzel, Sebastian; Borkhardt, Arndt; Landgraf, Pablo

    2014-01-01

    The contribution of the most common reciprocal translocation in childhood B-cell precursor leukemia t(12;21)(p13;q22) to leukemia development is still under debate. Direct as well as secondary indirect effects of the TEL-AML1 fusion protein are commonly recorded by using cell lines and patient samples, often bearing the TEL-AML1 fusion protein for decades. To identify direct targets of the fusion protein a short-term induction of TEL-AML1 is needed. We here describe in detail the experimental procedure, quality controls and contents of the ChIP, mRNA expression and SILAC datasets associated with the study published by Linka and colleagues in the Blood Cancer Journal [1] utilizing a short term induction of TEL-AML1 in an inducible precursor B-cell line model. PMID:26484077

  15. Immunohistochemical distinction of haematogones from B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL) on bone marrow trephine biopsies: a study on 62 patients.

    PubMed

    Al-Shieban, Saeed; Byrne, Elizabeth; Trivedi, Pritesh; Morilla, Ricardo; Matutes, Estella; Naresh, Kikkeri N

    2011-08-01

    Haematogones are normal, maturing B-cell precursors. They can be confused with neoplastic immature lymphoid cells of B lymphoblastic leukaemia/lymphoma or B-cell acute lymphoblastic leukaemia (B-ALL). Though multi-colour flow-cytometry strategies for distinguishing haematogones from cells of B-ALL are well-described, similar strategies have not been determined for bone marrow trephine biopsies (BMTB). We revisited the morphological and immunohistochemical features (CD20, CD34, TdT and PAX5 expression) in 69 BMTB from 62 patients - 27 with excess haematogones; seven with residual B-ALL after therapy; 18 with no reported excess of haematogones or residual acute leukaemia on BMTB; and 17 diagnostic samples of B-ALL. The distinctive immunophenotypic pattern of BMTB with excess haematogones was of CD34, TdT, CD20 and PAX5 accounting for increasing proportions of cells in the order mentioned, whereas among B-ALL, the immunohistochemical pattern was of CD20, PAX5 and TdT accounting for an equal proportion of cells. Furthermore, among haematogones, the intensity of CD20 expression was extremely heterogeneous as compared to the neoplastic cells in CD20-positive B-ALL. The TdT-positive haematogones were generally small and uniform, while a certain degree of heterogeneity was noticed among neoplastic B-ALL cells. This study provides a practical strategy to distinguish haematogones from B-ALL cells in BMTB. PMID:21722099

  16. A Fatal Case of Acute Myeloid Leukaemia-Methotrexate Related or Primary Autoimmune Disease Related: A Rare Case Report.

    PubMed

    Agarwal, Saurabh; Kaeley, Nidhi; Gupta, Priyanka; Gupta, Vibha; Bhatia, Rohan

    2016-03-01

    Methotrexate is being used for many years in the treatment of chronic medical disorders e.g. rheumatoid arthritis since 1951. It has been associated with various systemic toxicities and complications including bone marrow suppression and lymphomas. The development of leukaemia in a patient of chronic rheumatoid arthritis is either related with the primary disease or due to the drugs which are used in the treatment like cyclophosphamide. In our present case, a 70-year-old female who was a known case of Rheumatoid Arthritis (RA) and was on methotrexate once a week orally for the past 20 years presented with complaints of loss of appetite, loss of weight and anaemia since 2 months. After thorough examination and investigation, she was diagnosed with acute myeloid leukaemia (AML-M4) with bilateral chest consolidation. PMID:27134915

  17. Radiation exposure from CT scans in childhood and subsequent risk of leukaemia and brain tumours: a retrospective cohort study

    PubMed Central

    Pearce, Mark S; Salotti, Jane A; Little, Mark P; McHugh, Kieran; Lee, Choonsik; Kim, Kwang Pyo; Howe, Nicola L; Ronckers, Cecile M; Rajaraman, Preetha; Craft, Alan W; Parker, Louise; de González, Amy Berrington

    2012-01-01

    Summary Background Although CT scans are very useful clinically, potential cancer risks exist from associated ionising radiation, in particular for children who are more radiosensitive than adults. We aimed to assess the excess risk of leukaemia and brain tumours after CT scans in a cohort of children and young adults. Methods In our retrospective cohort study, we included patients without previous cancer diagnoses who were first examined with CT in National Health Service (NHS) centres in England, Wales, or Scotland (Great Britain) between 1985 and 2002, when they were younger than 22 years of age. We obtained data for cancer incidence, mortality, and loss to follow-up from the NHS Central Registry from Jan 1, 1985, to Dec 31, 2008. We estimated absorbed brain and red bone marrow doses per CT scan in mGy and assessed excess incidence of leukaemia and brain tumours cancer with Poisson relative risk models. To avoid inclusion of CT scans related to cancer diagnosis, follow-up for leukaemia began 2 years after the first CT and for brain tumours 5 years after the first CT. Findings During follow-up, 74 of 178 604 patients were diagnosed with leukaemia and 135 of 176 587 patients were diagnosed with brain tumours. We noted a positive association between radiation dose from CT scans and leukaemia (excess relative risk [ERR] per mGy 0·036, 95% CI 0·005–0·120; p=0·0097) and brain tumours (0·023, 0·010–0·049; p<0·0001). Compared with patients who received a dose of less than 5 mGy, the relative risk of leukaemia for patients who received a cumulative dose of at least 30 mGy (mean dose 51·13 mGy) was 3·18 (95% CI 1·46–6·94) and the relative risk of brain cancer for patients who received a cumulative dose of 50–74 mGy (mean dose 60·42 mGy) was 2·82 (1·33–6·03). Interpretation Use of CT scans in children to deliver cumulative doses of about 50 mGy might almost triple the risk of leukaemia and doses of about 60 mGy might triple the risk of brain

  18. Heterogeneity in the therapeutic approach to relapsed elderly patients with acute myeloid leukaemia: a survey from the Gruppo Italiano Malattie Ematologiche dell' Adulto (GIMEMA) Acute Leukaemia Working Party.

    PubMed

    Ferrara, Felicetto; Fazi, Paola; Venditti, Adriano; Pagano, Livio; Amadori, Sergio; Mandelli, Franco

    2008-06-01

    The percentage of long-term survivors in acute myeloid leukaemia (AML) in the elderly does not exceed 10-15% of patients enrolled into clinical trials because of lower complete remission (CR) rates and higher incidence of relapse. However, few data are available as the treatment of elderly patients with relapsed disease is concerned. The aim of this study was of collecting data on criteria adopted for the treatment of these patients. A questionnaire was e-mailed to 32 haematologic institutions involved in the Gruppo Italiano per le Malattie Ematologiche dell'Adulto (GIMEMA) group. Questions to be addressed regarded: (1) per cent of relapsed elderly patients treated with aggressive salvage chemotherapy; (2) the selection criteria adopted for inclusion into intensive reinduction; (3) the specific treatment adopted; (4) the treatment given to patients not eligible for intensive salvage. Per cent of patients enrolled into aggressive salvage regimens varied from 10 to 80% (median 50%). The most frequent factor influencing the therapeutic choice was performance status (97%). Additional factors were age >70 years (44%) and duration of first CR (53%). Fludarabine including regimens were most frequently used as aggressive salvage therapy (59%), while gemtuzumab ozogamicin was adopted in various combinations at 11 out of 32 institutions (34%). For patients not eligible to aggressive therapy, the most frequent approach included hydroxyurea (59%). Low dose ARA-C (LDARA-C) was adopted at five centres: as single agent (n = 1), with 6-thioguanine (n = 1), with vitamin D3 and all-trans retinoic acid (ATRA) (n = 2), or with ATRA alone (n = 1). The FLT3 inhibitor CEP-701 was used at one centre. We conclude that the treatment of AML in elderly relapsed patients is extremely heterogeneous. A marked selection is operated as to inclusion into aggressive salvage regimens and only a small minority of patients are offered experimental approaches. PMID:18271064

  19. Inhibition of proliferation by agricultural plant extracts in seven human adult T-cell leukaemia (ATL)-related cell lines.

    PubMed

    Kai, Hisahiro; Akamatsu, Ena; Torii, Eri; Kodama, Hiroko; Yukizaki, Chizuko; Sakakibara, Yoichi; Suiko, Masahito; Morishita, Kazuhiro; Kataoka, Hiroaki; Matsuno, Koji

    2011-07-01

    Adult T-cell leukaemia (ATL) is caused by human T-cell leukaemia virus type I (HTLV-I) infection and is resistant to conventional chemotherapy. We evaluated the inhibitory effects of agricultural plants on the proliferation of seven ATL-related human leukaemia cells, using three ATL cell lines (ED, Su9T01 and S1T), two human T-cell lines transformed by HTLV-I infection (HUT-102 and MT-2) and two HTLV-I-negative human T-cell acute lymphoblastic leukaemia cell lines (Jurkat and MOLT-4). A total of 52 samples of 80% ethanol extracts obtained from 30 types of agricultural plants were examined. On the basis of IC(50) values, we selected samples with greater activity than genistein, which was used as a positive control. The highest inhibitory effect was observed with extracts from leaves of Vaccinium virgatum Aiton (blueberry) on four cell lines (ED, Su9T01, HUT-102 and Jurkat); seeds of Momordica charantia L. (bitter gourd) exhibited the second highest activity. The bitter gourd seeds suppressed the proliferation of three cell lines (Su9T01, HUT-102 and Jurkat). The extracts from edible parts of Ipomea batatas LAM. (sweet potato), edible parts of Colocasia esculenta (L.) Schott (taro), skin of taro and seeds of Prunus mume Sieb. et Zucc. (mume) showed markedly greater inhibitory effects on Su9T01 than genistein. These findings suggest that ATL-preventative bioactive compounds may exist in these agricultural plants, which are considered to be functional foods. PMID:21293936

  20. Chemical sensitization and regulation of TRAIL-induced apoptosis in a panel of B-lymphocytic leukaemia cell lines.

    PubMed

    Kang, Jian; Kisenge, Rodrick R; Toyoda, Hidemi; Tanaka, Shigeki; Bu, Jun; Azuma, Eiichi; Komada, Yoshihiro

    2003-12-01

    Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) effectively kills tumour cells but not normal cells. We investigated TRAIL sensitivity and the TRAIL-induced apoptosis signalling pathway in a panel of B-lymphocytic leukaemia cell lines. Depending upon TRAIL sensitivity, leukaemia cells could be divided into three groups: highly sensitive, moderately sensitive and resistant. TRAIL receptor-2 (DR5) plays an important role in transducing apoptosis signals. DR5 was internalized into the cytoplasm where it recruited FAS-associated death domain protein (FADD) under TRAIL stimulation in both sensitive and resistant cells. However, the active form of caspase-8 was recruited to FADD and only sensitive cells showed increased caspase-8 activity upon TRAIL stimulation. The caspase-8 specific inhibitor, Z-IETD, impaired caspase-8 activation and completely abrogated TRAIL-induced apoptosis. These results suggest that TRAIL resistance in B-lymphocytic leukaemia cells is due to negative regulation at the level of caspase-8 activation and that caspase-8 activation is an indispensable process in TRAIL-induced apoptosis. However, FADD-like interleukin-1 beta-converting enzyme inhibitory protein (c-FLIPL) was similarly expressed and down-regulated after TRAIL stimulation in both sensitive and resistant cells. Interestingly, in some cell lines, TRAIL sensitivity and caspase-8 activity was enhanced or restored with the treatment of cycloheximide (CHX). In addition, X-linked inhibitor of apoptosis (XIAP) levels decreased significantly and rapidly following treatment with CHX. Down-regulation of XIAP may be responsible for enhancement or restoration of TRAIL sensitivity after CHX treatment in B-lymphocytic leukaemia cells. PMID:14632785

  1. [Results of the treatment of myelodysplastic syndrome (MDS)obtained by the Polish Paediatric Leukaemia /Lymphoma Study Group].

    PubMed

    Chybicka, A; Wójcik, D; Pietras, W; Bogusławska-Jaworska, J; Kolecki, P; Balcerska, A; Balwierz, W; Bubała, H; Eliasinska, A; Kowalczyk, J; Jackowska, T; Klus, K; Krenke, K; Kurylak, A; Malinowska, I; Matysiak, M; Stefańska, K; Stefaniak, M J; Rokicka-Milewska, R; Wiśniewska-Slusarz, H; Sońta-Jakimczyk, D; Wysocki, M

    2000-01-01

    Sixty children with MDS treated in six centres of the Polish Paediatric Leukaemia/Lymphoma Study Group in the period 1975-1999 were included in the study. In 20 children RAEB-T, in 13 RA, in 21 RAEB and in 6 CMML were diagnosed. Our own and literature data showed that BMT is the best therapy for children with MDS. We need a new comprehensive protocol for the diagnosis and treatment of children with MDS in Poland. PMID:12021466

  2. Induction of apoptosis and bcl-2 expression in acute lymphoblastic leukaemia and non-Hodgkin's lymphoma in children.

    PubMed

    Pituch-Noworolska, A; Hajto, B; Balwierz, W; Klus, K

    2001-01-01

    bcl-2 expression is associated with the expression of the multidrug resistance molecule (p-gp) and the resistance of leukaemia cells to the induction of apoptosis. The activity of p-gp is the main mechanism of resistance of leukaemia cells to chemotherapy. This study assessed the induction of apoptosis of acute lymphoblastic leukaemia (ALL) and non-Hodgkin's lymphoma (NHL) blastic cells following in vitro treatment with dexamethasone (DXM), vincristine (VCR), and tumour necrosis factor (TNF) in relation to the expression of bcl-2 and p-gp. Common ALL (cALL; n = 24 patients), common ALL with co-expression of myeloid antigens (cALL + My; n = 9), ALL-T (n = 9), and NHL [n = 6 (T type, n = 2; B type, n = 4)] were included. The expression of bcl-2 and p-gp and apoptosis were assayed by flow cytometry. Spontaneous apoptosis was low (< 5%) in cALL and ALL-T and higher (> 8%) in NHL and cALL + My. A high frequency of bcl-2 expression was noted in cALL and cALL + My. A high frequency of p-gp expression was observed in cALL + My, ALL-T, and NHL. There was a reverse association between bcl-2 expression and spontaneous apoptosis. DXM-induced apoptosis was observed in 52.63%, TNF-induced in 42.85%, VCR-induced in 36.36%, and GM-CSF-induced in 33.3% of leukaemia and lymphoma cases. DXM and GM-CSF-driven apoptosis was reversibly associated with bcl-2-expression (bcl-2-dependent mechanism). VCR and TNF-driven apoptosis was not associated with bcl-2 expression, suggesting a different, bcl-2-independent, mechanism(s) of its induction. The in vitro induction of apoptosis was not associated with expression of p-gp. PMID:11855781

  3. Bruyères-le-Châtel Neutron Evaluations of Actinides with the TALYS Code: The Fission Channel

    NASA Astrophysics Data System (ADS)

    Romain, P.; Morillon, B.; Duarte, H.

    2016-01-01

    For several years, various neutron evaluations of plutonium and uranium isotopes have been performed at Bruyères-le-Châtel (BRC), from 1 keV up to 30 MeV. Since only nuclear reaction models have been used to produce these evaluations, our approach was named the "Full Model" approach. Total, shape elastic and direct inelastic cross sections were obtained from the coupled channels model using a dispersive optical potential developed for actinides, with a large enough coupling scheme including the lowest octupolar band. All other cross sections were calculated using the Hauser-Feshbach theory (TALYS code) with a pre-equilibrium component above 8-10 MeV. In this paper, we focus our attention on the fission channel. More precisely, we will present the BRC contribution to fission modeling and the philosophy adopted in our "Full Model" approach. Performing evaluations with the "Full Model" approach implies the optimization of a large number of model parameters. With increasing neutron incident energy, many residual nuclei produced by nucleon emission also lead to fission. All available experimental data assigned to various fission mechanisms of the same nucleus were used to determine fission barrier parameters. For uranium isotopes, triple-humped fission barriers were required in order to reproduce accurately variations of the experimental fission cross sections. Our BRC fission modeling has shown that the effects of the class II or class III states located in the wells of the fission barrier sometimes provide an anti-resonant transmission rather than a resonant one. Consistent evaluations were produced for a large series of U and Pu isotopes. Resulting files were tested against integral data.

  4. A Study of the CryoTel® DS 1.5 Cryocooler for Higher Cooling Capacity

    NASA Astrophysics Data System (ADS)

    Kim, Yongsu; Wade, Jimmy; Wilson, Kyle

    2015-12-01

    The CryoTel® DS 1.5 is a split type Stirling cryocooler which was developed by Sunpower for systems requiring compact size, high efficiency, and high reliability. The DS 1.5 has a nominal lift of 1.5 watts at 77 K with 30 watts of input power. The cooler design includes gas bearings on the pistons and displacer for non-contact operation, and achieves low vibration by using dual-opposed pistons inside the wave generator, and a passive balancer on the cold head to offset the displacer motion. The efficiency of the DS 1.5 is ranked highly compared to other cryocoolers at 14.2% Carnot efficiency, but there are many customers who want more lift with the same size and reliability. Therefore, Sunpower performed a study on the feasibility of maximizing the lift of the DS 1.5 without increasing its size. This paper describes the analysis and test results of increasing the cooler power density by using a higher operating frequency and charge pressure. Prototype testing showed good agreement with the model. Testing performed at various frequencies and charge pressures with a few internal component changes resulted in a maximum lift of 2.1 watts with an input power of 43 watts, achieving 13.9% of Carnot. The prototype high-capacity DS 1.5 achieved 0.6 watts more lift with only a slight decrease in efficiency, and with less than 0.2% cooler mass increase. The impact on the cooldown time on a thermal mass system was tested and the cool-down time was 37% faster while consuming less input energy during that time. Sunpower plans to build more units to gain a broader range of performance data and will then decide whether to proceed with a commercial product.

  5. The Anti-cancer Activity of Vernonia divaricata Sw against Leukaemia, Breast and Prostate Cancers In Vitro

    PubMed Central

    Lowe, HIC; Daley-Beckford, D; Toyang, NJ; Watson, C; Hartley, S; Bryant, J

    2014-01-01

    Background: Vernonia divaricata is one of five endemic Vernonia species of Jamaica. The ethnomedicinal uses of other species have been established, however, scientific validation of this species has not yet been done and as such this paper is aimed at identifying the anti-cancer activity of V divaricata against leukaemia, breast and prostate cancer cell lines. Methods: Leaves and stems of V divaricata were dried and milled into powder. The crude hexane and methanol extracts of the leaves and stems were obtained and bio-assayed using WST-1 cell proliferation assay against leukaemia, breast and prostate cancer cell lines. Results: The crude hexane and methanol extracts of V divaricata were able to significantly retard the growth of the MCF-7 (breast), HL-60 (leukaemia) and the PC-3 (prostate) cancer cell lines. The crude methanol extract of the stem was the strongest, exhibiting anti-proliferation activity with IC50 values of 10.14, 12.63 and 9.894 μg/ml for the HL-60, MCF-7 and PC-3 cancer cell lines, respectively, with the most potent toward prostate cancer. Conclusion: The medicinal use of V divaricata as an anti-cancer agent was corroborated as the crude hexane and methanol extracts demonstrated potent anti-proliferation activity and as such hold potential for further research and development into a drug to prevent or treat various cancers. PMID:25429469

  6. Management of adult and paediatric acute lymphoblastic leukaemia in Asia: resource-stratified guidelines from the Asian Oncology Summit 2013

    PubMed Central

    Yeoh, Allen EJ; Tan, Daryl; Li, Chi-Kong; Hori, Hiroki; Tse, Eric; Pui, Ching-Hon

    2014-01-01

    The survival rates for both adult and children with acute lymphoblastic leukaemia have improved substantially in recent years with wider use of improved risk-directed therapy and supportive care. In nearly all developed countries, clinical practice guidelines have been formulated by multidisciplinary panels of leukaemia experts, with the goal of providing recommendations on standard treatment approaches based on current evidence. However, those guidelines do not take into account resource limitations in low-income countries, including financial and technical challenges. In Asia, there are huge disparities in economy and infrastructure among the countries, and even among different regions in some large countries. This review summarizes the recommendations developed for Asian countries by a panel of adult and paediatric leukaemia therapists, based on the availability of financial, skill and logistical resources, at a consensus session held as part of the 2013 Asian Oncology Summit in Bangkok, Thailand. The management strategies described here are stratified by a four-tier system (basic, limited, enhanced and maximum) based on the resources available to a particular country or region. PMID:24176570

  7. miR-22 has a potent anti-tumour role with therapeutic potential in acute myeloid leukaemia.

    PubMed

    Jiang, Xi; Hu, Chao; Arnovitz, Stephen; Bugno, Jason; Yu, Miao; Zuo, Zhixiang; Chen, Ping; Huang, Hao; Ulrich, Bryan; Gurbuxani, Sandeep; Weng, Hengyou; Strong, Jennifer; Wang, Yungui; Li, Yuanyuan; Salat, Justin; Li, Shenglai; Elkahloun, Abdel G; Yang, Yang; Neilly, Mary Beth; Larson, Richard A; Le Beau, Michelle M; Herold, Tobias; Bohlander, Stefan K; Liu, Paul P; Zhang, Jiwang; Li, Zejuan; He, Chuan; Jin, Jie; Hong, Seungpyo; Chen, Jianjun

    2016-01-01

    MicroRNAs are subject to precise regulation and have key roles in tumorigenesis. In contrast to the oncogenic role of miR-22 reported in myelodysplastic syndrome (MDS) and breast cancer, here we show that miR-22 is an essential anti-tumour gatekeeper in de novo acute myeloid leukaemia (AML) where it is significantly downregulated. Forced expression of miR-22 significantly suppresses leukaemic cell viability and growth in vitro, and substantially inhibits leukaemia development and maintenance in vivo. Mechanistically, miR-22 targets multiple oncogenes, including CRTC1, FLT3 and MYCBP, and thus represses the CREB and MYC pathways. The downregulation of miR-22 in AML is caused by TET1/GFI1/EZH2/SIN3A-mediated epigenetic repression and/or DNA copy-number loss. Furthermore, nanoparticles carrying miR-22 oligos significantly inhibit leukaemia progression in vivo. Together, our study uncovers a TET1/GFI1/EZH2/SIN3A/miR-22/CREB-MYC signalling circuit and thereby provides insights into epigenetic/genetic mechanisms underlying the pathogenesis of AML, and also highlights the clinical potential of miR-22-based AML therapy. PMID:27116251

  8. A Case Report on the Progression of Myeloid Sarcoma to Form Multiple Metastatic Deposits without Developing Acute Myeloid Leukaemia.

    PubMed

    Kohli, Sunita; Lee, Mark; Marshall, Scott

    2015-01-01

    Introduction. Myeloid sarcomas (MS) are rare tumours occurring at extramedullary sites. They are usually associated with other haematology disorders such as acute myeloid leukaemia, myelodysplastic syndrome, and chronic myeloproliferative neoplasms. They frequently occur with a diagnosis of acute myeloid leukaemia (AML) or with relapse of preexisting disease. Patients with myeloid sarcomas without history or evidence of myeloid leukaemia typically progress to form AML. Case Presentation. A case report of a patient diagnosed with an isolated myeloid sarcoma that rarely did not transform to AML but instead spread to form multiple myeloid sarcomas throughout the body. Discussion. This case identifies the risk of metastatic spread of these tumours rather than the development of AML which is poorly documented in the literature, due to the rarity of cases, and may be significant in the investigation and management of isolated myeloid sarcomas. This case highlights the need for clinicians to consider repeat cross-sectional imaging to investigate unexplained clinical decline or symptoms, when there is no sign of AML progression and to consider radiotherapy treatment early. PMID:26491577

  9. Dietary Phenolic Acids Act as Effective Antioxidants in Membrane Models and in Cultured Cells, Exhibiting Proapoptotic Effects in Leukaemia Cells

    PubMed Central

    Zambonin, Laura; Caliceti, Cristiana; Vieceli Dalla Sega, Francesco; Fiorentini, Diana; Hrelia, Silvana; Landi, Laura; Prata, Cecilia

    2012-01-01

    Caffeic, syringic, and protocatechuic acids are phenolic acids derived directly from food intake or come from the gut metabolism of polyphenols. In this study, the antioxidant activity of these compounds was at first evaluated in membrane models, where caffeic acid behaved as a very effective chain-breaking antioxidant, whereas syringic and protocatechuic acids were only retardants of lipid peroxidation. However, all three compounds acted as good scavengers of reactive species in cultured cells subjected to exogenous oxidative stress produced by low level of H2O2. Many tumour cells are characterised by increased ROS levels compared with their noncancerous counterparts. Therefore, we investigated whether phenolic acids, at low concentrations, comparable to those present in human plasma, were able to decrease basal reactive species. Results show that phenolic acids reduced ROS in a leukaemia cell line (HEL), whereas no effect was observed in normal cells, such as HUVEC. The compounds exhibited no toxicity to normal cells while they decreased proliferation in leukaemia cells, inducing apoptosis. In the debate on optimal ROS-manipulating strategies in cancer therapy, our work in leukaemia cells supports the antioxidant ROS-depleting approach. PMID:22792417

  10. A derivative of epigallocatechin-3-gallate induces apoptosis via SHP-1-mediated suppression of BCR-ABL and STAT3 signalling in chronic myelogenous leukaemia

    PubMed Central

    Jung, Ji Hoon; Yun, Miyong; Choo, Eun-Jeong; Kim, Sun-Hee; Jeong, Myoung-Seok; Jung, Deok-Beom; Lee, Hyemin; Kim, Eun-Ok; Kato, Nobuo; Kim, Bonglee; Srivastava, Sanjay K; Kaihatsu, Kunihiro; Kim, Sung-Hoon

    2015-01-01

    Background and Purpose Epigallocatechin-3-gallate (EGCG) is a component of green tea known to have chemo-preventative effects on several cancers. However, EGCG has limited clinical application, which necessitates the development of a more effective EGCG prodrug as an anticancer agent. Experimental Approach Derivatives of EGCG were evaluated for their stability and anti-tumour activity in human chronic myeloid leukaemia (CML) K562 and KBM5 cells. Key Results EGCG-mono-palmitate (EGCG-MP) showed most prolonged stability compared with other EGCG derivatives. EGCG-MP exerted greater cytotoxicity and apoptosis in K562 and KBM5 cells than the other EGCG derivatives. EGCG-MP induced Src-homology 2 domain-containing tyrosine phosphatase 1 (SHP-1) leading decreased oncogenic protein BCR-ABL and STAT3 phosphorylation in CML cells, compared with treatment with EGCG. Furthermore, EGCG-MP reduced phosphorylation of STAT3 and survival genes in K562 cells, compared with EGCG. Conversely, depletion of SHP-1 or application of the tyrosine phosphatase inhibitor pervanadate blocked the ability of EGCG-MP to suppress phosphorylation of BCR-ABL and STAT3, and the expression of survival genes downstream of STAT3. In addition, EGCG-MP treatment more effectively suppressed tumour growth in BALB/c athymic nude mice compared with untreated controls or EGCG treatment. Immunohistochemistry revealed increased caspase 3 and SHP-1 activity and decreased phosphorylation of BCR-ABL in the EGCG-MP-treated group relative to that in the EGCG-treated group. Conclusions and Implications EGCG-MP induced SHP-1-mediated inhibition of BCR-ABL and STAT3 signalling in vitro and in vivo more effectively than EGCG. This derivative may be a potent chemotherapeutic agent for CML treatment. PMID:25825203

  11. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War

    PubMed Central

    Kinlen, L

    2006-01-01

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1–14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1–4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural–urban population

  12. Childhood leukaemia and ordnance factories in west Cumbria during the Second World War.

    PubMed

    Kinlen, L

    2006-07-01

    Much evidence has accumulated that childhood leukaemia (CL) is a rare response to a common, but unidentified, infection and in particular that situations involving the unusual mixing of urban and rural groups (approximating to, respectively, groups infected with, and susceptible to, the relevant microorganism) can produce localised epidemics with consequent increases of the infrequent leukaemic complication. During the Second World War, explosives production factories were built and operated at Drigg and Sellafield, and a shell filling factory at Bootle, in west Cumbria, England, requiring substantial numbers of construction workers to be brought into this remote and isolated area. Following the design of an earlier study of CL near large (post-war) rural construction sites, mortality from this disease was investigated with the help of the Office of National Statistics, in the area around these Cumbrian factories where local workers largely lived, during the construction period and with particular reference to the overlapping construction and operational phase when the mixing of local and migrant workers would have been greatest. An excess of leukaemia deaths at ages 1-14 was found during the construction period (observed 3; observed/expected (O/E) 2.2, 95% confidence interval (CI): 0.6, 6.0), which was more marked and statistically significant during the overlap with operations (O 3; O/E 4.5, 95% CI: 1.1, 12.2), especially at ages 1-4 (O 2; O/E 7.1, CI: 1.2, 23.6). A previous investigation did not detect this excess because it considered only a small part of west Cumbria that omitted the communities where most of the workforce lived, having incorrectly attributed the post-war expansion of the village of Seascale (situated between Drigg and Sellafield) to the wartime ordnance factories. The present findings are consistent with the results of the earlier study of rural construction projects and with the general evidence that marked rural-urban population mixing

  13. Effectiveness of HB2 (anti-CD7)--saporin immunotoxin in an in vivo model of human T-cell leukaemia developed in severe combined immunodeficient mice.

    PubMed Central

    Morland, B. J.; Barley, J.; Boehm, D.; Flavell, S. U.; Ghaleb, N.; Kohler, J. A.; Okayama, K.; Wilkins, B.; Flavell, D. J.

    1994-01-01

    The transplantation of the human T-cell acute lymphoblastic leukaemia (T-ALL) cell line HSB-2 into severe combined immunodeficient (SCID) mice was found to produce a disseminated pattern of leukaemia similar to that seen in man. The intravenous injection of 10(7) HSB-2 cells was associated with a universally fatal leukaemia. Histopathological examination of animals revealed the spread of leukaemia initially from bone marrow to involve all major organs including the meninges. An immunotoxin (HB2-Sap) was constructed by conjugating the anti-CD7 MAb HB2 to the ribosome-inactivating protein saporin. An in vitro protein synthesis inhibition assay revealed specific delivery of HB2-Sap immunotoxin (IT) to CD7+ HSB-2 target cells with an IC50 of 4.5 pM. When SCID mice were injected with 10(6) HSB-2 cells and then treated 8 days later with a single intravenous dose of 10 micrograms of immunotoxin there was a significant therapeutic effect evidenced by the numbers of animals surviving in the therapy group compared with untreated controls (chi 2 = 5.348, P = 0.021). These results demonstrate the useful application of human leukaemia xenografts in SCID mice and the potential therapeutic effect of an anti-CD7 immunotoxin in human T-ALL. Images Figure 1 PMID:7507691

  14. Efficient resist edgebead removal for thick I-line resist coating application on TEL Mark 7 track sytem

    NASA Astrophysics Data System (ADS)

    Tran, Quang

    2000-08-01

    Photoresist coating process for IC device manufacturing requires correct target thickness, good uniformity and low defect density. For thick resist films used for Ion Implant, Top Metal layer and/or Pad masks, resist beads built up around the side edges and on top of wafer within 0-3 mm approximately from edges will need to be removed to eliminate defects during ion implantation and etch operations. The conventional method o f using solvent dispenses and optical exposure for edgebead removal does not necessarily solve this problem for resist thickness greater than 1.5 micron. For solvent EBR application, most resist track systems have both top and bottom dispenses nozzles for wafer edge cleaning. However, due to the high risk of unwanted EBR solvent splashes with top EBR nozzle onto wafer surface, which will destroy resist pattern resulting in yield loss, opt EBR solvent application is usually not used. Optical exposure system for wafer edges on the track equipment does not have enough power to completely expose thick photoresist film within a reasonable time for throughput requirement. Hence, the use of optical and backside EBRs only will result in incomplete resist edgebead removal. In this paper, we will describe a new top rinse nozzle design and a combined process of top and bottom EBRs to provide adequate and efficient resist removal around wafer edges for thick photoresist films. A low cost and easy modification to the existing standard to rinse nozzle fora TEL Mark 7 track system was done to provide efficient to solvent EBR application and to avoid solvent splash defects. The low angle to top rinse nozzle below 20 degrees was found to be important in reducing solvent droplet defects. The low angle of top rinse nozzle below 20 degrees was found to be important in reducing solvent droplet defects. Finally, a defect comparison study using KLS2132 will show a lower defect level for the modified top rinse nozzle than the standard one. Qualitative images of wafer

  15. Ancient settlements are significant sources of nutrients in Eastern Mediterranean ecosystems - the case of Tel Burna, Israel

    NASA Astrophysics Data System (ADS)

    Smejda, Ladislav; Hejcman, Michal; Shai, Itzhaq

    2016-04-01

    Past human settlement activities have caused changes in soil chemical properties that may persist in the cultural soil archive for a very long time and some of them are practically irreversible. We are studying the question if the large-scale mapping of elemental composition based on the surface layer of contemporary soil can reveal spatial patterns corresponding to areas of settlements, which were abandoned even millennia ago. Our case-study is focused on the archaeological site of Tel Burna, located in the Shephelah region, Israel, and its immediate surroundings, making a survey area of 68 ha. The site is known as the town flourishing mainly in the Late Bronze Age and Iron Age (13th-7th centuries BCE). The heyday of the town was during the 10th - 8th centuries BCE, when its summit was enclosed by a massive limestone wall. Later on the significance of the settlement declined, and the architecture vanished. The place has gradually turned to an uninhabited area, used in the recent period as a pasture. We have measured the chemical composition of 350 samples from the surface soil at and around the site by a portable XRF device as part of an on-going interdisciplinary research project studying this site. The results were analysed by standard statistical methods and also in geographical information systems, which were used for calculating models of elemental distribution patterns across the surveyed area. In this paper we discuss the observation that the anthropogenic impact on the chemical composition of soils became quite significant already in times of ancient societies. This human-induced signature was of such magnitude that it can still be detected today, not only in the sub-surface archaeological deposits, but also on the very surface of the present-day landscape. We are able to demonstrate that the nutrients accumulated within the precincts of ancient settlements through the intensive deposition of organic and inorganic waste have been slowly released into local

  16. The contribution of cat owners' attitudes and behaviours to the free-roaming cat overpopulation in Tel Aviv, Israel.

    PubMed

    Finkler, Hilit; Terkel, Joseph

    2012-04-01

    The attitudes and behaviours of cat owners in regard to treatment of cats may have a cumulative effect on the food availability, reproduction, density and welfare of the free-roaming cat population and thus also on the extent of cat overpopulation. Understanding this is thus a vital step in the a priori planning of cat management programs on any scale, as well as in developing public education programs on this issue. Although recent years have seen an accumulation of knowledge in regard to cat owners' attitudes and behaviours, the findings vary among countries and locations and in Israel this has never been investigated systematically. Using a questionnaire provided to cat owners in veterinary clinics, this study aimed at identifying those attitudes and behaviours that may be contributing to cat overpopulation in Tel Aviv, Israel, and at exploring the socio-economic factors that influence this problem. The findings show that the influential factors can be predicted from the cat owners' socio-economic status, mainly education and income, as well as gender and age. A consistency in those cat owner behaviours that contribute to cat overpopulation was also uncovered, revealing a sub-population of individuals who persist in the undesirable behaviours. Finally, a strong relationship between attitude and consequent behaviour was demonstrated, indicating the importance of education and targeted publicity as a means to influence attitudes and thereby change behaviours in this respect. We propose several measures by which to reduce the current extent of cat owners' contribution to the cat overpopulation: discouraging unwanted owner behaviours such as abandonment of their cats and allowing them to breed; promoting awareness of the neutering option among cat caretakers; and increasing pre-adoption neutering rates in shelters. Regional and national laws promoting responsible pet ownership need to be enacted. By improving the current level of knowledge and awareness among cat

  17. Fractional model for pharmacokinetics of high dose methotrexate in children with acute lymphoblastic leukaemia

    NASA Astrophysics Data System (ADS)

    Popović, Jovan K.; Spasić, Dragan T.; Tošić, Jela; Kolarović, Jovanka L.; Malti, Rachid; Mitić, Igor M.; Pilipović, Stevan; Atanacković, Teodor M.

    2015-05-01

    The aim of this study is to promote a model based on the fractional differential calculus related to the pharmacokinetic individualization of high dose methotrexate treatment in children with acute lymphoblastic leukaemia, especially in high risk patients. We applied two-compartment fractional model on 8 selected cases with the largest number (4-19) of measured concentrations, among 43 pediatric patients received 24-h methotrexate 2-5 g/m2 infusions. The plasma concentrations were determined by fluorescence polarization immunoassay. Our mathematical procedure, designed by combining Post's and Newton's method, was coded in Mathematica 8.0 and performed on Fujicu Celsius M470-2 PC. Experimental data show that most of the measured values of methotrexate were in decreasing order. However, in certain treatments local maximums were detected. On the other hand, integer order compartmental models do not give values which fit well with the observed data. By the use of our model, we obtained better results, since it gives more accurate behavior of the transmission, as well as the local maximums which were recognized in methotrexate monitoring. It follows from our method that an additional test with a small methotrexate dose can be suggested for the fractional system parameter identification and the prediction of a possible pattern with a full dose in the case of high risk patients. A special feature of the fractional model is that it can also recognize and better fit an observed non-monotonic behavior. A new parameter determination procedure can be successfully used.

  18. Authenticity and drug resistance in a panel of acute lymphoblastic leukaemia cell lines

    PubMed Central

    Beesley, A H; Palmer, M-L; Ford, J; Weller, R E; Cummings, A J; Freitas, J R; Firth, M J; Perera, K U; de Klerk, N H; Kees, U R

    2006-01-01

    Cell lines are important models for drug resistance in acute lymphoblastic leukaemia (ALL), but are often criticised as being unrepresentative of primary disease. There are also doubts regarding the authenticity of many lines. We have characterised a panel of ALL cell lines for growth and drug resistance and compared data with that published for primary patient specimens. In contrast to the convention that cell lines are highly proliferative, those established in our laboratory grow at rates similar to estimates of leukaemic cells in vivo (doubling time 53–442 h). Authenticity was confirmed by genetic fingerprinting, which also demonstrated the potential stability of long-term cultures. In vitro glucocorticoid resistance correlated well with that measured ex vivo, but all lines were significantly more sensitive to vincristine than primary specimens. Sensitivity to methotrexate was inversely correlated to that of glucocorticoids and L-asparaginase, indicating possible reciprocity in resistance mechanisms. A cell line identified as highly methotrexate resistant (IC50 >8000-fold higher than other lines) was derived from a patient receiving escalating doses of the drug, indicating in vivo selection of resistance as a cause of relapse. Many of these lines are suitable as models to study naturally occurring resistance phenotypes in paediatric ALL. PMID:17117183

  19. Biphosphinic palladacycle complex mediates lysosomal-membrane permeabilization and cell death in K562 leukaemia cells.

    PubMed

    Barbosa, Christiano M V; Oliveira, Carlos R; Nascimento, Fábio D; Smith, Mickaela C M; Fausto, Daniela M; Soufen, Marco Antonio; Sena, Eliana; Araújo, Ronaldo C; Tersariol, Ivarne L S; Bincoletto, Claudia; Caires, Antonio C F

    2006-08-01

    The cell death mechanism of cytotoxicity induced by the Biphosphinic Palladacycle Complex (BPC) was studied using a K562 leukaemia cell line. The IC50 values obtained for K562 cells post-72 h of BPC were less than 5.0 microM by using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and trypan blue assays. Using the Acridine Orange vital staining combining fluorescence microscopy it was observed that the complex triggers apoptosis in K562 cells, inducing DNA fragmentation, as analysed through electrophoresis. Lysosomal-membrane permeabilization was also observed in K562 cells post-5 h of BPC, which suggests intralysosomal accumulation by proton-trapping, since its pKa value ranged from 5.1 to 6.5. Caspase-3, and -6 activity induced by BPC in K562 cells was prevented by the cathepsin-B inhibitor [N-(L-3-trans-propylcarbamoyl-oxirane-2-carbonyl)-L-isoleucyl-L-proline] (CA074). These events occurred in the presence of endogenous bcl-2 and bax expression. Acute toxicological studies demonstrated that BPC produces no lesions for liver and kidney fourteen-days after drug administration (100 mg/kg--i.p.). White and red blood cells of BPC-treated mice presented normal morphological characteristics. Taken together, these data suggest a novel lysosomal pathway for BPC-induced apoptosis, in which lysosomes are the primary target and cathepsin B acts as death mediator. PMID:16831419

  20. Primary attachment of murine leukaemia virus vector mediated by particle-associated heparan sulfate proteoglycan

    PubMed Central

    Kureishy, Nina; Faruque, Daisy; Porter, Colin D.

    2006-01-01

    Target cell entry of murine leukaemia virus vectors proceeds via primary attachment, independent of the viral envelope protein and subsequent envelope–receptor interaction. Although much attention has been paid to modifying the latter for target cell specificity, the initial binding interaction has been overlooked, despite its opposing involvement both in providing the virus available for receptor binding and in depleting free virus. As a first step towards modifying primary attachment, both to provide specificity and to enhance vector availability, we sought to determine the nature of this interaction. Following an initial screen of GAGs (glycosaminoglycans) for their ability to inhibit virus binding and transduction, we have shown that production of virus from cells in which GAG sulfation is inhibited, or treatment of virus with heparinase III, reduces both particle attachment and infection. Detection in purified virus preparations of a neo-epitope generated by heparinase III confirmed the presence of virus-associated HSPG [HS (heparan sulfate) proteoglycan], acquired from the producer cell. We propose that host-acquired cell-surface HSPG (potentially including syndecan-2) provides a means of virus attachment to target cells that precedes specific receptor interaction and membrane fusion. Inhibition of HS biosynthesis may provide a sufficiently reduced background of primary binding such that novel mechanisms of attachment, ideally with appropriate target cell specificity, can be introduced. PMID:16895523

  1. Different reactivity of monoclonal antibodies against common acute lymphoblastic leukaemia antigen (CD10).

    PubMed Central

    Haralambidou, S; Melo, J V; Catovsky, D

    1987-01-01

    The reactivity of five monoclonal antibodies J5, OKB-cALLA, Nu-N1, Nu-N2 and VIL-A1 against the common acute lymphoblastic leukaemia (common-ALL) antigen (glycoprotein 100, CD10); was investigated by indirect immunofluorescence in cell suspensions, and by immunoperoxidase in cytocentrifuge slides of ALL, chronic B cell lymphoproliferative disorders, and plasma cell dyscrasias. The five monoclonal antibodies gave similar positive results with both techniques only in samples of ALL. J5 was positive in variable degrees by immunofluorescence in the majority of B cell disorders examined but this was not confirmed by immunoperoxidase. OKB-cALLA reacted in a similar way to J5 in both techniques, although with a lower percentage of cells by immunofluorescence. Nu-N1, Nu-N2, and VIL-A1 were mainly negative when tested by both immunofluorescence and immunoperoxidase in B cell disorders other than ALL and therefore seemed to be more specific for the diagnosis of common-ALL. PMID:2953763

  2. Identification of Arsenic Direct-Binding Proteins in Acute Promyelocytic Leukaemia Cells

    PubMed Central

    Zhang, Tao; Lu, Haojie; Li, Weijun; Hu, Ronggui; Chen, Zi

    2015-01-01

    The identification of arsenic direct-binding proteins is essential for determining the mechanism by which arsenic trioxide achieves its chemotherapeutic effects. At least two cysteines close together in the amino acid sequence are crucial to the binding of arsenic and essential to the identification of arsenic-binding proteins. In the present study, arsenic binding proteins were pulled down with streptavidin and identified using a liquid chromatograph-mass spectrometer (LC-MS/MS). More than 40 arsenic-binding proteins were separated, and redox-related proteins, glutathione S-transferase P1 (GSTP1), heat shock 70 kDa protein 9 (HSPA9) and pyruvate kinase M2 (PKM2), were further studied using binding assays in vitro. Notably, PKM2 has a high affinity for arsenic. In contrast to PKM2, GSTP1and HSPA9 did not combine with arsenic directly in vitro. These observations suggest that arsenic-mediated acute promyelocytic leukaemia (APL) suppressive effects involve PKM2. In summary, we identified several arsenic binding proteins in APL cells and investigated the therapeutic mechanisms of arsenic trioxide for APL. Further investigation into specific signal pathways by which PKM2 mediates APL developments may lead to a better understanding of arsenic effects on APL. PMID:26569224

  3. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    PubMed

    García-Muñoz, Ricardo; Llorente, Luis

    2014-08-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as 'dangerous cells'. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR's own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote 'reversible anergy' and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  4. Structural biology contributions to the discovery of drugs to treat chronic myelogenous leukaemia

    PubMed Central

    Cowan-Jacob, Sandra W.; Fendrich, Gabriele; Floersheimer, Andreas; Furet, Pascal; Liebetanz, Janis; Rummel, Gabriele; Rheinberger, Paul; Centeleghe, Mario; Fabbro, Doriano; Manley, Paul W.

    2007-01-01

    Chronic myelogenous leukaemia (CML) results from the Bcr-Abl oncoprotein, which has a constitutively activated Abl tyrosine kinase domain. Although most chronic phase CML patients treated with imatinib as first-line therapy maintain excellent durable responses, patients who have progressed to advanced-stage CML frequently fail to respond or lose their response to therapy owing to the emergence of drug-resistant mutants of the protein. More than 40 such point mutations have been observed in imatinib-resistant patients. The crystal structures of wild-type and mutant Abl kinase in complex with imatinib and other small-molecule Abl inhibitors were determined, with the aim of understanding the molecular basis of resistance and to aid in the design and optimization of inhibitors active against the resistance mutants. These results are presented in a way which illustrates the approaches used to generate multiple structures, the type of information that can be gained and the way that this information is used to support drug discovery. PMID:17164530

  5. Targeting survivin with YM155 (Sepantronium Bromide): a novel therapeutic strategy for paediatric acute myeloid leukaemia.

    PubMed

    Smith, Amanda M; Little, Erica B; Zivanovic, Andjelija; Hong, Priscilla; Liu, Alfred K S; Burow, Rachel; Stinson, Caedyn; Hallahan, Andrew R; Moore, Andrew S

    2015-04-01

    Despite aggressive chemotherapy, approximately one-third of children with acute myeloid leukaemia (AML) relapse. More effective treatments are urgently needed. Survivin is an inhibitor-of-apoptosis protein with key roles in regulating cell division, proliferation and apoptosis. Furthermore, high expression of Survivin has been associated with poor clinical outcome in AML. The survivin suppressant YM155 (Sepantronium Bromide) has pre-clinical activity against a range of solid cancers and leukemias, although data in AML is limited. Therefore, we undertook a comprehensive pre-clinical evaluation of YM155 in paediatric AML. YM155 potently inhibited cell viability in a diverse panel of AML cell lines. All paediatric cell lines were particularly sensitive, with a median IC50 of 0.038 μM. Cell cycle analyses demonstrated concentration-dependent increases in a sub-G1 population with YM155 treatment, suggestive of apoptosis that was subsequently confirmed by an increase in annexin-V positivity. YM155-mediated apoptosis was confirmed across a panel of 8 diagnostic bone marrow samples from children with AML. Consistent with the proposed mechanism of action, YM155 treatment was associated with down-regulation of survivin mRNA and protein expression and induction of DNA damage. These data suggest that YM155-mediated inhibition of survivin is a potentially beneficial therapeutic strategy for AML, particularly paediatric disease, and warrants further evaluation. PMID:25659731

  6. Tyrosine kinase inhibitors in Ph+ acute lymphoblastic leukaemia: facts and perspectives.

    PubMed

    Malagola, Michele; Papayannidis, Cristina; Baccarani, Michele

    2016-04-01

    Two tyrosine kinase inhibitors (TKIs), imatinib and dasatinib, are registered for the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukaemia (ALL) in adults. Other two TKIs (nilotinib and ponatinib) have been tested in the second-line, can offer an alternative in the patients who fail the first-line, and can acquire a role also in the first-line. Here, we provide a summary of the reports of TKIs, used alone, and in combination with chemotherapy. TKIs are very effective alone and with corticosteroids and are likely to improve substantially the outcome when they are combined with standard or dose-adapted chemotherapy. While the complete haematologic remission rate is always very high, close to 100 %, the cytogenetic and molecular remission rates are lower, so that TKIs are still considered as a complement to chemotherapy and as a bridge to allogeneic stem cell transplantation (allo-SCT). However, many patients relapse before transplant, and many patients still relapse, even if they have been submitted to allo-SCT. A proper use of TKIs, the introduction of ponatinib, and of "new generation" TKIs should improve further on the outcome of Ph+ ALL. PMID:26891878

  7. A multi-state model approach for prediction in chronic myeloid leukaemia.

    PubMed

    Lauseker, Michael; Hasford, Joerg; Hoffmann, Verena S; Müller, Martin C; Hehlmann, Rüdiger; Pfirrmann, Markus

    2015-06-01

    Multi-state models support prediction in medicine. With different states of disease, chronic myeloid leukaemia (CML) is particularly suited for the application of multi-state models. In this article, we tried to find a model for CML that allows predicting the prevalence of three different states (initial state of disease, remission and progression) in dependence on treatment, adjusted for age, sex and risk score. Based on the German CML Study IV, one of the largest randomised studies in CML, the model was able to represent the known effects of age and risk score on the probabilities of remission and progression. Patients achieving a major molecular remission had a better chance of surviving without progression, but this effect was not significant. Comparing treatments, patient of the high-dose arm had the greatest chance to be in the state "remission" at 5 years but did not seem to have an advantage considering "progression". The proposed illness-death model can be useful for predicting the course of CML based on the patient's individual covariates (trial registration: this is an explorative analysis of ClinicalTrials.gov Identifier: NCT00055874). PMID:25465231

  8. Dasatinib improves insulin sensitivity and affects lipid metabolism in a patient with chronic myeloid leukaemia.

    PubMed

    Iizuka, Katsumi; Niwa, Hiroyuki; Kato, Takehiro; Takeda, Jun

    2016-01-01

    A 65-year-old woman had been visiting our department for the treatment of type-2 diabetes mellitus since December 2012. Her glycated haemoglobin levels were well controlled (≈5.8% (40 mmol/mol)) by metformin (500 mg). In July 2014, her white cell count increased suddenly to 33 530 cells/μL and she was diagnosed with Ph+ chronic myeloid leukaemia. She was started on dasatinib (100 mg), which immediately normalised plasma levels of WCC. Dasatinib improved the glycaemic index to <6.0% and also improved plasma levels of triglycerides (TGs) and high-density lipoprotein-cholesterol (HDL-c). Levels of low-density lipoprotein-cholesterol were increased but remained within the normal range. The TG:HDL-c ratio and Quantitative Insulin Sensitivity Check Index rapidly improved. Followed by an improvement in insulin sensitivity, plasma levels of adiponectin and leptin were increased. This case study suggests that dasatinib might have positive as well as negative effects on the metabolism of glucose and lipids. PMID:26873919

  9. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition.

    PubMed

    Burger, Jan A; Landau, Dan A; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R; Abruzzo, Lynne V; Carter, Scott L; Keating, Michael J; Davids, Matthew S; Wierda, William G; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Dal Cin, Paola; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A; Nowak, Martin A; Getz, Gad; Wu, Catherine J

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  10. Multiple cotton wool spots following bone marrow transplantation for treatment of acute lymphatic leukaemia.

    PubMed Central

    Gloor, B; Gratwohl, A; Hahn, H; Kretzschmar, S; Robert, Y; Speck, B; Daicker, B

    1985-01-01

    Three patients with acute lymphatic leukaemia developed visual impairment due to occlusion of small retinal vessels with multiple cotton wool spots after treatment which included whole body and skull irradiation followed by bone marrow transplantation and cyclosporin A. Withdrawal of cyclosporin A and treatment with corticosteroids was followed by recovery of visual acuity. This retinopathy and the retinal changes seen in the immunodeficiency syndrome are thought to be closely related. The possible role of cyclosporin A is discussed, though cotton wool spots and retinal haemorrhages have never been described in renal transplant patients during treatment with this drug. Withdrawal of cyclosporin A, which is highly effective in preventing graft-versus-host disease, can be fatal. Irradiation of the skull prior to bone marrow transplantation and intrathecal administration of methotrexate may be the most important factors causing the retinal ischaemic signs described here. The inclusion of an ophthalmologist in the team monitoring transplant patients would lead to increased documentation and a better understanding of this disease. Images PMID:3888252

  11. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units

    PubMed Central

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  12. Mechanisms of tumour cell escape encountered in treating lymphocytic leukaemia with anti-idiotypic antibody.

    PubMed Central

    Gordon, J.; Abdul-Ahad, A. K.; Hamblin, T. J.; Stevenson, F. K.; Stevenson, G. T.

    1984-01-01

    Four patients with chronic lymphocytic leukaemia were treated by one or more infusions of polyclonal antibody specific for the immunoglobulin idiotype expressed on their leukaemic cells. The antibody was in the form of IgG from sheep antiserum. Three of the 4 cases showed a significant fall in blood lymphocyte count. On one occasion most of the residual circulating lymphocytes were apparently dead. However on all occasions the cell counts rebounded to near pre-infusion levels within one week. Viable lymphocytes recovered from the blood after infusion always showed evidence of antigenic modulation: a diminished level of surface idiotype in a patched distribution, with an accompanying refractoriness to lysis by anti-idiotype plus complement. When cultured in vitro blood lymphocytes from three of the four patients revealed an appreciable export of idiotypic Ig. These 3 patients showed plasma levels of idiotypic Ig up to 400 micrograms ml-1, reduced by plasma exchange prior to infusion. The fourth patient had a level of less than 4 micrograms ml-1, and was the only one in whom free antibody could be found in the plasma after infusion. These cases demonstrate two major factors which thwart antibody attack on leukaemic cells--extracellular antigen and antigenic modulation--as well as problems relating to sparseness of surface antigen, recruitment of effectors, and exhaustion of effectors. PMID:6722005

  13. Thiopurine methyltransferase and treatment outcome in the UK acute lymphoblastic leukaemia trial ALL2003

    PubMed Central

    Lennard, Lynne; Cartwright, Cher S; Wade, Rachel; Vora, Ajay

    2015-01-01

    The influence of thiopurine methyltransferase (TPMT) genotype on treatment outcome was investigated in the United Kingdom childhood acute lymphoblastic leukaemia trial ALL2003, a trial in which treatment intensity was adjusted based on minimal residual disease (MRD). TPMT genotype was measured in 2387 patients (76% of trial entrants): 2190 were homozygous wild-type, 189 were heterozygous for low activity TPMT alleles (166 TPMT*1/*3A, 19 TPMT*1/*3C, 3 TPMT*1/*2 and 1 TPMT*1/*9) and 8 were TPMT deficient. In contrast to the preceding trial ALL97, there was no difference in event-free survival (EFS) between the TPMT genotypes. The 5-year EFS for heterozygous TPMT*1/*3A patients was the same in both trials (88%), but for the homozygous wild-type TPMT*1/*1 patients, EFS improved from 80% in ALL97% to 88% in ALL2003. Importantly, the unexplained worse outcome for heterozygous TPMT*1/*3C patients observed in ALL97 (5-year EFS 53%) was not seen in ALL2003 (5-year EFS 94%). In a multivariate Cox regression analysis the only significant factor affecting EFS was MRD status (hazard ratio for high-risk MRD patients 4·22, 95% confidence interval 2·97–5·99, P < 0·0001). In conclusion, refinements in risk stratification and treatment have reduced the influence of TPMT genotype on treatment outcome in a contemporary protocol. PMID:25940902

  14. Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment.

    PubMed

    Russo, D; Malagola, M; Skert, C; Cancelli, V; Turri, D; Pregno, P; Bergamaschi, M; Fogli, M; Testoni, N; De Vivo, A; Castagnetti, F; Pungolino, E; Stagno, F; Breccia, M; Martino, B; Intermesoli, T; Cambrin, G R; Nicolini, G; Abruzzese, E; Tiribelli, M; Bigazzi, C; Usala, E; Russo, S; Russo-Rossi, A; Lunghi, M; Bocchia, M; D'Emilio, A; Santini, V; Girasoli, M; Lorenzo, R Di; Bernardi, S; Palma, A Di; Cesana, B M; Soverini, S; Martinelli, G; Rosti, G; Baccarani, M

    2015-01-01

    The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35-59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response. PMID:26383820

  15. Managing chronic myeloid leukaemia in the elderly with intermittent imatinib treatment

    PubMed Central

    Russo, D; Malagola, M; Skert, C; Cancelli, V; Turri, D; Pregno, P; Bergamaschi, M; Fogli, M; Testoni, N; De Vivo, A; Castagnetti, F; Pungolino, E; Stagno, F; Breccia, M; Martino, B; Intermesoli, T; Cambrin, G R; Nicolini, G; Abruzzese, E; Tiribelli, M; Bigazzi, C; Usala, E; Russo, S; Russo-Rossi, A; Lunghi, M; Bocchia, M; D'Emilio, A; Santini, V; Girasoli, M; Lorenzo, R Di; Bernardi, S; Palma, A Di; Cesana, B M; Soverini, S; Martinelli, G; Rosti, G; Baccarani, M

    2015-01-01

    The aim of this study was to investigate the effects of a non-standard, intermittent imatinib treatment in elderly patients with Philadelphia-positive chronic myeloid leukaemia and to answer the question on which dose should be used once a stable optimal response has been achieved. Seventy-six patients aged ⩾65 years in optimal and stable response with ⩾2 years of standard imatinib treatment were enrolled in a study testing a regimen of intermittent imatinib (INTERIM; 1-month on and 1-month off). With a minimum follow-up of 6 years, 16/76 patients (21%) have lost complete cytogenetic response (CCyR) and major molecular response (MMR), and 16 patients (21%) have lost MMR only. All these patients were given imatinib again, the same dose, on the standard schedule and achieved again CCyR and MMR or an even deeper molecular response. The probability of remaining on INTERIM at 6 years was 48% (95% confidence interval 35–59%). Nine patients died in remission. No progressions were recorded. Side effects of continuous treatment were reduced by 50%. In optimal and stable responders, a policy of intermittent imatinib treatment is feasible, is successful in about 50% of patients and is safe, as all the patients who relapsed could be brought back to optimal response. PMID:26383820

  16. Natural killer cell function and lymphoid subpopulations in acute non-lymphoblastic leukaemia in complete remission.

    PubMed Central

    Pizzolo, G.; Trentin, L.; Vinante, F.; Agostini, C.; Zambello, R.; Masciarelli, M.; Feruglio, C.; Dazzi, F.; Todeschini, G.; Chilosi, M.

    1988-01-01

    A long term follow-up study has been undertaken in 33 patients with acute non-lymphoblastic leukaemia (ANLL) in order to establish whether a correlation exists between the clinical course and the immunologic pattern of lymphoid subpopulations. Peripheral blood lymphoid cells have been investigated longitudinally (each 1 to 4 months) during complete remission (CR), by morphologic, phenotypic and functional analyses. Particular attention has been paid to the evaluation of the natural killer (NK) cell compartment, by the detection of cells expressing an NK-related phenotype and by NK in vitro assay. Among the patients so far evaluable, 20 relapsed (R) and 10 are long survivors in CR 'off therapy' (LS). The most relevant finding was represented by statistically higher values of NK activity observed in LS vs. R patients (P less than 0.01). The removal of adherent cells before the NK assay, performed to investigate the possible inhibitory effect on NK function played by the macrophage component, abolished this difference, due to a selective increase of NK function in the R group. The longitudinal study revealed that NK activity tended to decrease in individual patients who subsequently relapsed. These data suggest a possible role of NK cells in the relapse control of ANLL, although it cannot be excluded that the low level of NK activity observed in the R group is the result of impending relapse rather than its cause. PMID:3179190

  17. Clonal evolution in patients with chronic lymphocytic leukaemia developing resistance to BTK inhibition

    PubMed Central

    Burger, Jan A.; Landau, Dan A.; Taylor-Weiner, Amaro; Bozic, Ivana; Zhang, Huidan; Sarosiek, Kristopher; Wang, Lili; Stewart, Chip; Fan, Jean; Hoellenriegel, Julia; Sivina, Mariela; Dubuc, Adrian M.; Fraser, Cameron; Han, Yulong; Li, Shuqiang; Livak, Kenneth J.; Zou, Lihua; Wan, Youzhong; Konoplev, Sergej; Sougnez, Carrie; Brown, Jennifer R.; Abruzzo, Lynne V.; Carter, Scott L.; Keating, Michael J.; Davids, Matthew S.; Wierda, William G.; Cibulskis, Kristian; Zenz, Thorsten; Werner, Lillian; Cin, Paola Dal; Kharchencko, Peter; Neuberg, Donna; Kantarjian, Hagop; Lander, Eric; Gabriel, Stacey; O'Brien, Susan; Letai, Anthony; Weitz, David A.; Nowak, Martin A.; Getz, Gad; Wu, Catherine J.

    2016-01-01

    Resistance to the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has been attributed solely to mutations in BTK and related pathway molecules. Using whole-exome and deep-targeted sequencing, we dissect evolution of ibrutinib resistance in serial samples from five chronic lymphocytic leukaemia patients. In two patients, we detect BTK-C481S mutation or multiple PLCG2 mutations. The other three patients exhibit an expansion of clones harbouring del(8p) with additional driver mutations (EP300, MLL2 and EIF2A), with one patient developing trans-differentiation into CD19-negative histiocytic sarcoma. Using droplet-microfluidic technology and growth kinetic analyses, we demonstrate the presence of ibrutinib-resistant subclones and estimate subclone size before treatment initiation. Haploinsufficiency of TRAIL-R, a consequence of del(8p), results in TRAIL insensitivity, which may contribute to ibrutinib resistance. These findings demonstrate that the ibrutinib therapy favours selection and expansion of rare subclones already present before ibrutinib treatment, and provide insight into the heterogeneity of genetic changes associated with ibrutinib resistance. PMID:27199251

  18. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images

    NASA Astrophysics Data System (ADS)

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-10-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method.

  19. Suppressed spontaneous secretion of growth hormone in girls after treatment for acute lymphoblastic leukaemia.

    PubMed Central

    Moëll, C; Garwicz, S; Westgren, U; Wiebe, T; Albertsson-Wikland, K

    1989-01-01

    The spontaneous secretion of growth hormone during a 24 hour period and the response of growth hormone to growth hormone releasing hormone was studied in 13 girls who had received treatment for acute lymphoblastic leukemia that included cranial irradiation with 20-24 Gy in 12-14 fractions. At the time of investigation the girls were at varying stages of puberty and had normal concentrations of thyroid hormones. The mean interval between the end of treatment and investigation was 4.6 years. The mean age at onset of the disease was 3.2 years and at investigation 10.7 years. The average attained height equalled -0.3 SD at onset, and -1.0 SD at the time of investigation. Secretion of growth hormone was substantially reduced compared with controls and did not increase during puberty. A prompt rise in growth hormone secretion was seen after injection of growth hormone releasing hormone, but the mean maximum growth hormone concentration was, however, only 25 mU/l. There was no correlation between the 24 hour secretion and growth hormone response to growth hormone releasing hormone, or the time since irradiation. These results confirm earlier work that suggested that girls who had received treatment for acute lymphoblastic leukaemia, that included cranial irradiation, have a comparative growth hormone insufficiency characterised by normal prepubertal growth and slow growth during puberty because of an inability to respond to the increased demands for growth hormone at that time. PMID:2494952

  20. Site- and allele-specific polycomb dysregulation in T-cell leukaemia.

    PubMed

    Navarro, Jean-Marc; Touzart, Aurore; Pradel, Lydie C; Loosveld, Marie; Koubi, Myriam; Fenouil, Romain; Le Noir, Sandrine; Maqbool, Muhammad Ahmad; Morgado, Ester; Gregoire, Claude; Jaeger, Sebastien; Mamessier, Emilie; Pignon, Charles; Hacein-Bey-Abina, Salima; Malissen, Bernard; Gut, Marta; Gut, Ivo G; Dombret, Hervé; Macintyre, Elizabeth A; Howe, Steven J; Gaspar, H Bobby; Thrasher, Adrian J; Ifrah, Norbert; Payet-Bornet, Dominique; Duprez, Estelle; Andrau, Jean-Christophe; Asnafi, Vahid; Nadel, Bertrand

    2015-01-01

    T-cell acute lymphoblastic leukaemias (T-ALL) are aggressive malignant proliferations characterized by high relapse rates and great genetic heterogeneity. TAL1 is amongst the most frequently deregulated oncogenes. Yet, over half of the TAL1(+) cases lack TAL1 lesions, suggesting unrecognized (epi)genetic deregulation mechanisms. Here we show that TAL1 is normally silenced in the T-cell lineage, and that the polycomb H3K27me3-repressive mark is focally diminished in TAL1(+) T-ALLs. Sequencing reveals that >20% of monoallelic TAL1(+) patients without previously known alterations display microinsertions or RAG1/2-mediated episomal reintegration in a single site 5' to TAL1. Using 'allelic-ChIP' and CrispR assays, we demonstrate that such insertions induce a selective switch from H3K27me3 to H3K27ac at the inserted but not the germline allele. We also show that, despite a considerable mechanistic diversity, the mode of oncogenic TAL1 activation, rather than expression levels, impact on clinical outcome. Altogether, these studies establish site-specific epigenetic desilencing as a mechanism of oncogenic activation. PMID:25615415

  1. Herd-level determinants of bovine leukaemia virus prevalence in dairy farms.

    PubMed

    Erskine, Ronald J; Bartlett, Paul C; Byrem, Todd M; Render, Chelsea L; Febvay, Catherine; Houseman, Jessica T

    2012-11-01

    The prevalence of bovine leukaemia virus (BLV) was determined in 113 Michigan dairy herds by ELISA testing for anti-BLV antibodies in milk. Additionally, an interview regarding management practices with cooperating herd managers identified farm-level variables thought to be associated with prevalence of BLV. Twenty-three risk factors (P ≤ 0·1) were identified on one-way ANOVA or simple linear regression. Multivariate analysis identified several management practices whose predictive value for increased prevalence of BLV may relate to transmission among herd mates, e.g. reuse of hypodermic needles, lack of fly control, gouge dehorning and increased use of injections in dry cows. Additionally, exclusive breeding of heifers with artificial insemination was associated with decreased BLV prevalence, as compared with at least some use of natural service by a bull. Although intervention studies are needed before causal relationships can be concluded, and unaccounted variables related to transmission exist among dairy herds, these findings suggest management practices that may help dairy producers reduce the transmission of BLV within their herds. PMID:22963749

  2. Chronic lymphocytic leukaemia: could immunological tolerance mechanisms be the origin of lymphoid neoplasms?

    PubMed Central

    García-Muñoz, Ricardo; Llorente, Luis

    2014-01-01

    Immunological tolerance theory in chronic lymphocytic leukaemia (CLL): we suggest that B cells that express B-cell receptors (BCR) that recognize their own BCR epitopes are viewed by immune system as ‘dangerous cells’. BCR autonomous signalling may induce constant receptor editing and mistakes in allelic exclusion. The fact that whole BCR recognizes a self-antigen or foreing antigen may be irrelevant in early B cell development. In early B cells, autonomous signalling induced by recognition of the BCR’s own epitopes simulates an antigen-antibody engagement. In the bone marrow this interaction is viewed as recognition of self-molecules and induces receptor editing. In mature B cells autonomous signalling by the BCR may promote ‘reversible anergy’ and also may correct self-reactivity induced by the somatic hypermutation mechanisms in mutated CLL B cells. However, in unmutated CLL B cells, BCR autonomous signalling in addition to self-antigen recognition augments B cell activation, proliferation and genomic instability. We suggest that CLL originates from a coordinated normal immunologic tolerance mechanism to destroy self-reactive B cells. Additional genetic damage induced by tolerance mechanisms may immortalize self-reactive B cells and transform them into a leukemia. PMID:24645778

  3. Childhood acute lymphoblastic leukaemia and indicators of early immune stimulation: the Estelle study (SFCE)

    PubMed Central

    Ajrouche, R; Rudant, J; Orsi, L; Petit, A; Baruchel, A; Lambilliotte, A; Gambart, M; Michel, G; Bertrand, Y; Ducassou, S; Gandemer, V; Paillard, C; Saumet, L; Blin, N; Hémon, D; Clavel, J

    2015-01-01

    Background: Factors related to early stimulation of the immune system (breastfeeding, proxies for exposure to infectious agents, normal delivery, and exposure to animals in early life) have been suggested to decrease the risk of childhood acute lymphoblastic leukaemia (ALL). Methods: The national registry-based case–control study, ESTELLE, was carried out in France in 2010–2011. Population controls were frequency matched with cases on age and gender. The participation rates were 93% for cases and 86% for controls. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (OR) were estimated using unconditional regression models adjusted for age, gender, and potential confounders. Results: In all, 617 ALL and 1225 controls aged ⩾1 year were included. Inverse associations between ALL and early common infections (OR=0.8, 95% confidence interval (CI): 0.6, 1.0), non-first born (⩾3 vs 1; OR=0.7, 95% CI: 0.5, 1.0), attendance of a day-care centre before age 1 year (OR=0.7, 95% CI: 0.5, 1.0), breastfeeding (OR=0.8, 95% CI: 0.7, 1.0), and regular contact with pets (OR=0.8, 95% CI: 0.7, 1.0) in infancy were observed. Conclusions: The results support the hypothesis that conditions promoting the maturation of the immune system in infancy have a protective role with respect to ALL. PMID:25675150

  4. A high rate of telomeric sister chromatid exchange occurs in chronic lymphocytic leukaemia B-cells.

    PubMed

    Medves, Sandrine; Auchter, Morgan; Chambeau, Laetitia; Gazzo, Sophie; Poncet, Delphine; Grangier, Blandine; Verney, Aurélie; Moussay, Etienne; Ammerlaan, Wim; Brisou, Gabriel; Morjani, Hamid; Géli, Vincent; Palissot, Valérie; Berchem, Guy; Salles, Gilles; Wenner, Thomas

    2016-07-01

    Cancer cells protect their telomere ends from erosion through reactivation of telomerase or by using the Alternative Lengthening of Telomere (ALT) mechanism that depends on homologous recombination. Chronic lymphocytic leukaemia (CLL) B cells are characterized by almost no telomerase activity, shelterin deregulation and telomere fusions. To characterize telomeric maintenance mechanisms in B-CLL patients, we measured their telomere length, telomerase expression and the main hallmarks of the ALT activity i.e. C-circle concentration, an extra-chromosomal telomere repeat (ECTR), and the level of telomeric sister chromatid exchange (T-SCE) rate. Patients showed relative homogenous telomere length although almost no TERT transcript and nearly no C-circle were evidenced. Nevertheless, compared with normal B cells, B-CLL cells showed an increase in T-SCE rate that was correlated with a strong down-regulation of the topoisomerase III alpha (TOP3A) expression, involved in the dissolution of Holliday Junctions (HJ), together with an increased expression of SLX1A, SLX4, MUS81 and GEN1, involved in the resolution of HJ. Altogether, our results suggest that the telomere maintenance mechanism of B-CLL cells do not preferentially use telomerase or ALT. Rather, the rupture of the dissolvasome/resolvasome balance may increase telomere shuffling that could homogenize telomere length, slowing telomere erosion in this disease. PMID:26970083

  5. An Intelligent Decision Support System for Leukaemia Diagnosis using Microscopic Blood Images.

    PubMed

    Chin Neoh, Siew; Srisukkham, Worawut; Zhang, Li; Todryk, Stephen; Greystoke, Brigit; Peng Lim, Chee; Alamgir Hossain, Mohammed; Aslam, Nauman

    2015-01-01

    This research proposes an intelligent decision support system for acute lymphoblastic leukaemia diagnosis from microscopic blood images. A novel clustering algorithm with stimulating discriminant measures (SDM) of both within- and between-cluster scatter variances is proposed to produce robust segmentation of nucleus and cytoplasm of lymphocytes/lymphoblasts. Specifically, the proposed between-cluster evaluation is formulated based on the trade-off of several between-cluster measures of well-known feature extraction methods. The SDM measures are used in conjuction with Genetic Algorithm for clustering nucleus, cytoplasm, and background regions. Subsequently, a total of eighty features consisting of shape, texture, and colour information of the nucleus and cytoplasm sub-images are extracted. A number of classifiers (multi-layer perceptron, Support Vector Machine (SVM) and Dempster-Shafer ensemble) are employed for lymphocyte/lymphoblast classification. Evaluated with the ALL-IDB2 database, the proposed SDM-based clustering overcomes the shortcomings of Fuzzy C-means which focuses purely on within-cluster scatter variance. It also outperforms Linear Discriminant Analysis and Fuzzy Compactness and Separation for nucleus-cytoplasm separation. The overall system achieves superior recognition rates of 96.72% and 96.67% accuracies using bootstrapping and 10-fold cross validation with Dempster-Shafer and SVM, respectively. The results also compare favourably with those reported in the literature, indicating the usefulness of the proposed SDM-based clustering method. PMID:26450665

  6. Childhood leukaemia close to high-voltage power lines – the Geocap study, 2002–2007

    PubMed Central

    Sermage-Faure, C; Demoury, C; Rudant, J; Goujon-Bellec, S; Guyot-Goubin, A; Deschamps, F; Hemon, D; Clavel, J

    2013-01-01

    Background: High-voltage overhead power lines (HVOLs) are a source of extremely low-frequency magnetic fields (ELF-MFs), which are classified as possible risk factors for childhood acute leukaemia (AL). The study was carried out to test the hypothesis of an increased AL incidence in children living close to HVOL of 225–400 kV (VHV-HVOL) and 63–150 kV (HV-HVOL). Methods: The nationwide Geocap study included all the 2779 cases of childhood AL diagnosed in France over 2002–2007 and 30 000 contemporaneous population controls. The addresses at the time of inclusion were geocoded and precisely located around the whole HVOL network. Results: Increased odds ratios (ORs) were observed for AL occurrence and living within 50 m of a VHV-HVOL (OR=1.7 (0.9–3.6)). In contrast, there was no association with living beyond that distance from a VHV-HVOL or within 50 m of a HV-HVOL. Conclusion: The present study, free from any participation bias, supports the previous international findings of an increase in AL incidence close to VHV-HVOL. In order to investigate for a potential role of ELF-MF in the results, ELF-MF at the residences close to HVOL are to be estimated, using models based on the annual current loads and local characteristics of the lines. PMID:23558899

  7. Production and related variables in bovine leukaemia virus-infected cows.

    PubMed

    Jacobs, R M; Heeney, J L; Godkin, M A; Leslie, K E; Taylor, J A; Davies, C; Valli, V E

    1991-01-01

    A newly developed milk dot blot test was used to detect anti-bovine leukaemia virus (BLV) antibody in milk samples from 2079 lactating adult cows from among 61 herds. The milk dot blot test was highly repeatable; the concordance rate, compared with the agar gel immunodiffusion test performed on serum, was 83.5%. All herds contained BLV-positive cows; the prevalence rate was 36%. BLV-positive cows tended to come from larger herds and were older and more often later in lactation. Fourteen production and related variables (herd size, age, days open, days in milk, milk somatic cell count, milk, fat, and protein produced in the current lactation, projected production of milk, fat, and protein, and breed class average deviations for milk, fat, and protein) were compared between BLV-positive and BLV-negative cows. Although somatic cell count, milk produced, and projected production of milk and protein were related significantly to BLV status using simple tests of association, once the variables herd size, age and days in milk were controlled, these differences were removed. Further analyses using logistic (outcome: individual cow BLV status) and least-squares regression (outcome: herd proportion of BLV-positive cows) failed to show an association between any of the measured production or related variables and BLV-positivity. We concluded that the effect of BLV on production and related variables in dairy cows was below the sensitivity of our analytical techniques or was non-existent. PMID:1666473

  8. Chronic Lymphocytic Leukaemia: Census of Patients Treated in Italian Haematology Units.

    PubMed

    Salvi, Gianfranco; Innocenti, Idanna; Autore, Francesco; Laurenti, Luca

    2015-01-01

    This study was conducted by contacting the population of the Italian haematology units and collecting from 68% of them data concerning the number of patients with chronic lymphocytic leukaemia visited over the previous 12 months, with the aim of obtaining an overview of the treatment of this disease and comparing the results with the prevalence estimates found in literature. The projection obtained (about 17,000 patients visited in the previous 12 months) is probably overestimated because of double-counting of patients who may have been treated at two different facilities during the year, although it is also underestimated since the internal medicine units were not involved. The balance of these two opposite factors is not known. It is important to bear in mind the approximation with which the count was performed in facilities for which no official data were available. Albeit with these limits, the results obtained are in line with some existing prevalence data and make it possible to determine the portion of patients at different Binet stages and in the various age ranges, identifying the corresponding therapeutic treatments. Use of the CIRS scale to classify patients as FIT and UNFIT was seen to be still somewhat limited. PMID:26543525

  9. A survey of feline leukaemia virus infection of domestic cats from selected areas in Harare, Zimbabwe.

    PubMed

    Muchaamba, Francis; Mutiringindi, Takudzwa H; Tivapasi, Musavenga T; Dhliwayo, Solomon; Matope, Gift

    2014-01-01

    A cross-sectional study was conducted to detect the feline leukaemia virus (FeLV) p27 antigen and to determine risk factors and the haematological changes associated with infection in domestic cats in Zimbabwe. Sera were collected for detection of the p27 antigen, urea, creatinine, alanine aminotransferase and gamma-glutamyl transferase levels, whilst whole blood was collected for haematology. FeLV p27 antigen was detected using a rapid enzyme-linked immunosorbent assay (ELISA) test kit. Data on risk factors were analysed using a logistic regression model. Of the 100 cats tested, 41% (95% CI: 31.19% - 50.81%) (41/100) were positive for the FeLV p27 antigen. Sex and health status of cats were not significantly (p > 0.05) associated with infection. Intact cats (OR = 9.73), those living in multicat housing (OR = 5.23) and cats that had access to outdoor life (OR = 35.5) were found to have higher odds of infection compared with neutered cats, those living in single-cat housing, and without access to outdoor life, respectively. Biochemistry and haematology revealed no specific changes. The results showed that FeLV infection was high in sampled cats, providing evidence of active infection. Thus, it would be prudent to introduce specific control measures for FeLV infection in Zimbabwe. PMID:25686080

  10. A neutron study of the feline leukaemia virus fusion peptide: Implications for biological fusion?

    NASA Astrophysics Data System (ADS)

    Davies, Sarah M. A.; Darkes, Malcolm J. M.; Bradshaw, Jeremy P.

    Neutron diffraction studies were performed on stacked phospholipid bilayers to determine the effects of the feline leukaemia virus (FeLV) fusion peptide on membrane structure. Bilayers were composed of dioleoylphosphatidylcholine with 50% (mol) dioleoylphosphatidylglycerol. Neutron scattering profiles with peptide present showed an increase in scattering density in the lipid-tails region, whilst scattering by the lipid headgroup region was decreased. This is interpreted as a lowering of the packing density of the lipid headgroups and an increase in the packing density of the lipid tails. Modelling studies and experimental evidence have suggested that fusion peptides catalyse fusion by increasing the negative curvature of the target membrane's outer monolayer. Our results presented here add support to this hypothesis for the fusion mechanism. The 2H 2O scattering profile was also slightly perturbed in the lipid headgroup region with 1% (mol)FeLV fusion peptide present. The FeLV peptide had no significant effect on the organisation of bilayers containing only dioleoylphosphatidylcholine.

  11. Developing "Care Assistant": A smartphone application to support caregivers of children with acute lymphoblastic leukaemia.

    PubMed

    Wang, Jingting; Yao, Nengliang; Wang, Yuanyuan; Zhou, Fen; Liu, Yanyan; Geng, Zhaohui; Yuan, Changrong

    2016-04-01

    Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy. Caring for children with ALL is an uncommon experience for parents without medical training. They urgently need professional assistance when their children are recovering at home. This paper documents the process of developing an Android application (app) "Care Assistant" for family caregivers of children with ALL. Key informant interviews and focus group studies were used before programming the app. The key informants and focus group members included: caregivers of children with ALL, cancer care physicians and nurses, and software engineers. We found several major challenges faced by caregivers: limited access to evidence-based clinic information, lack of financial and social assistance, deficient communications with doctors or nurses, lack of disease-related knowledge, and inconvenience of tracking treatments and testing results. This feedback was used to develop "Care Assistant". This app has eight modules: personal information, treatment tracking, family care, financial and social assistance, knowledge centre, self-assessment questionnaires, interactive platform, and reminders. We have also developed a web-based administration portal to manage the app. The usability and effectiveness of "Care Assistant" will be evaluated in future studies. PMID:26271029

  12. Asparaginase-associated pancreatitis in children with acute lymphoblastic leukaemia in the NOPHO ALL2008 protocol.

    PubMed

    Raja, Raheel A; Schmiegelow, Kjeld; Albertsen, Birgitte K; Prunsild, Kaie; Zeller, Bernward; Vaitkeviciene, Goda; Abrahamsson, Jonas; Heyman, Mats; Taskinen, Mervi; Harila-Saari, Arja; Kanerva, Jukka; Frandsen, Thomas L

    2014-04-01

    L-asparaginase is an important drug in the treatment of childhood acute lymphoblastic leukaemia (ALL). Treatment is associated with several toxicities, including acute pancreatitis. Clinical course, presentation, re-exposure to L-asparginase after pancreatitis and risk of recurrent pancreatitis within an asparaginase-intensive protocol has been poorly reported. Children (1-17 years) on the ongoing Nordic Society of Paediatric Haematology and Oncology (NOPHO) ALL2008 protocol with asparaginase-associated pancreatitis (AAP) diagnosed between 2008 and 2012 were identified through the online NOPHO ALL toxicity registry. NOPHO ALL2008 includes eight or 15 doses of intramuscular pegylated L-asparginase (PEG-asparaginase) 1000 iu/m(2) /dose at 2-6 weeks intervals, with a total of 30 weeks of exposure to PEG-asparaginase (clinicaltrials.gov no: NCT00819351). Of 786 children, 45 were diagnosed with AAP with a cumulative risk of AAP of 5·9%. AAP occurred after a median of five doses (range 1-13), and 11 d (median) from the latest administration of PEG-Asparaginase. Thirteen patients developed pseudocysts (30%) and 11 patients developed necrosis (25%). One patient died from pancreatitis. Twelve AAP patients were re-exposed to L-asparginase, two of whom developed mild AAP once more, after four and six doses respectively. In conclusion, re-exposure to PEG-asparaginase in ALL patients with mild AAP seems safe. PMID:24428625

  13. Awareness of acute myeloid leukaemia risk induced by diagnosis of a myelodysplastic syndrome.

    PubMed

    Ousseine, Youssoufa M; Butow, Phyllis N; Julian-Reynier, Claire; Dring, Rebecca; Festy, Patrick; Fenaux, Pierre; Vey, Norbert; Mancini, Julien

    2016-07-01

    Myelodysplastic syndromes (MDS) can evolve to acute myeloid leukaemia (AML) in approximately 30% of cases. Knowing their AML risk is important for patients because it might impact adherence to care and psychological health. The aim of this study was to evaluate the awareness of AML risk among MDS patients and to study the factors associated with this awareness. A self-administered questionnaire was mailed to all members of French and Australian patients' national MDS associations. Data of 301 patients were analysed. Patients were satisfied with the information they had received, but 33.2% did not know that they had an increased risk of developing AML. Younger age, higher-risk MDS treatment, preferences for health-related information and satisfaction with information provided about treatment were the factors independently associated with awareness of AML risk. Compared to unaware patients, patients knowing their risk were more likely to participate in a hypothetical clinical trial (83.0% vs 72.4%, p=0.043). More efforts are needed to provide more systematic information about AML risk to patients wishing to know it. More research is needed to study if increasing awareness can lead to more active engagement of MDS patients in their care and can increase the rate of clinical trial participation. PMID:27173089

  14. Risk of leukaemia and residential exposure to air pollution in an industrial area in Northern Italy: a case-control study.

    PubMed

    Parodi, Stefano; Santi, Irene; Casella, Claudia; Puppo, Antonella; Montanaro, Fabio; Fontana, Vincenzo; Pescetto, Massimiliano; Stagnaro, Emanuele

    2015-01-01

    Leukaemia risk in adult populations exposed to environmental air pollution is poorly investigated. We have carried out a population-based case-control study in an area that included a fossil fuel power plant, a coke oven and two big chemical industries. Information on residential history and several risk factors for leukaemia was obtained from 164 cases, diagnosed between 2002 and 2005, and 279 controls. A higher risk for subjects residing in polluted areas was observed, but statistical significance was not reached (adjusted OR = 1.11 and 1.56 for subjects living in moderately and in heavily polluted zones, respectively, p = 0.190). Results suggest a possible aetiological role of residential air pollution from industrial sites on the risk of developing leukaemia in adult populations. However, the proportion of eligible subjects excluded from the study and the lack of any measure of air pollution prevent definitive conclusions from being drawn. PMID:25245102

  15. Marrow matrix metalloproteinases (MMPs) and tissue inhibitors of MMP in acute leukaemia: potential role of MMP-9 as a surrogate marker to monitor leukaemic status in patients with acute myelogenous leukaemia.

    PubMed

    Lin, Liang-In; Lin, Dong-Tsamn; Chang, Chi-Jen; Lee, Cheng-Yeh; Tang, Jih-Luh; Tien, Hwei-Fang

    2002-06-01

    Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) were demonstrated to have important implications in the progression and invasiveness of many malignant disorders. In contrast, the biological significance of these molecules in human leukaemias is not clear. We determined the levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 in the bone marrow of 37 patients with acute myelogenous leukaemia (AML) and 18 patients with acute lymphoblastic leukaemia (ALL) before chemotherapy. Nineteen bone marrow donors served as normal controls. After chemotherapy, sequential measurements were done during the course in 19 AML patients. The levels of TIMP-1 and TIMP-2 were significantly higher and MMP-9 levels were significantly lower in the AML and ALL patients than in the normal controls. MMP-2 levels were higher in ALL, but not AML patients, compared with controls. Moreover, the levels of marrow MMP-2 and MMP-9 did not parallel the numbers of leukaemic blasts in the peripheral blood. MMP-9 levels were significantly lower in the AML patients who achieved a complete remission (CR) than in those who did not (8.71 +/- 8.15 ng/ml vs 26.13 +/- 27.75 ng/ml, P < 0.05). The AML patients with lower MMP-9 levels (< or = 4.4 ng/ml) tended to have longer survival time than those with higher levels (> 12 months vs 4 months, P = 0.12). In addition, MMP-9 levels in the AML patients at CR rose to the same range as the controls, but dropped again at relapse, demonstrating a close relationship of marrow MMP-9 with disease status of AML. Therefore, we conclude that the level of marrow MMP-9 may be a useful surrogate marker for monitoring disease status in AML and propose it as a potential prognostic factor. PMID:12060118

  16. Altered neuronal responses and regulation of neurotrophic proteins in the medial septum following fimbria-fornix transection in CNTF- and leukaemia inhibitory factor-deficient mice.

    PubMed

    Naumann, Thomas; Steup, Andreas; Schnell, Oliver; Schubert, Klaus Oliver; Zhi, Qixia; Guijarro, Christian; Kirsch, Matthias; Hofmann, Hans-Dieter

    2006-10-01

    Degeneration of axotomized GABAergic septohippocampal neurones has been shown to be enhanced in ciliary neurotrophic factor (CNTF)-deficient mice following fimbria-fornix transection (FFT), indicating a neuroprotective function of endogenous CNTF. Paradoxically, however, the cholinergic population of septohippocampal neurones was more resistant to axotomy in these mutants. As leukaemia inhibitory factor (LIF) has been identified as a potential neuroprotective factor for the cholinergic medial septum (MS) neurones, FFT-induced responses were compared in CNTF(-/-), LIF(-/-) and CNTF/LIF double knockout mice. In CNTF(-/-) mice, FFT-induced cholinergic degeneration was confirmed to be attenuated as compared with wildtype mice. The expression of both LIF and LIF receptor beta was increased in the MS providing a possible explanation for the enhanced neuronal resistance to FFT in these animals. However, ablation of the LIF gene also produced paradoxical effects; following FFT in LIF(-/-) mice no loss of GABAergic or cholinergic MS neurones was detectable during the first postlesional week, suggesting that other efficient neuroprotective mechanisms are activated in these animals. In fact, enhanced activation of astrocytes, a source of neurotrophic proteins, was indicated by increased up-regulation of glial fibrillary acidic protein and vimentin expression. In addition, mRNA levels for neurotrophin signalling components (e.g. nerve growth factor, p75(NTR)) were differentially regulated. The positive effect on axotomized cholinergic neurones seen in CNTF(-/-) and LIF(-/-) mice as well as the increased up-regulation of astrogliose markers was abolished in CNTF/LIF double knockout animals. Our results indicate that endogenous CNTF and LIF are involved in the regulation of neuronal survival following central nervous system lesion and are integrated into a network of neurotrophic signals that mutually influence their expression and function. PMID:17074046

  17. CD33 monoclonal antibody conjugated Au cluster nano-bioprobe for targeted flow-cytometric detection of acute myeloid leukaemia

    NASA Astrophysics Data System (ADS)

    Retnakumari, Archana; Jayasimhan, Jasusri; Chandran, Parwathy; Menon, Deepthy; Nair, Shantikumar; Mony, Ullas; Koyakutty, Manzoor

    2011-07-01

    Protein stabilized gold nanoclusters (Au-NCs) are biocompatible, near-infrared (NIR) emitting nanosystems having a wide range of biomedical applications. Here, we report the development of a Au-NC based targeted fluorescent nano-bioprobe for the flow-cytometric detection of acute myeloid leukaemia (AML) cells. Au-NCs with ~ 25-28 atoms showing bright red-NIR fluorescence (600-750 nm) and average size of ~ 0.8 nm were prepared by bovine serum albumin assisted reduction-cum-stabilization in aqueous phase. The protein protected clusters were conjugated with monoclonal antibody against CD33 myeloid antigen, which is overexpressed in ~ 99.2% of the primitive population of AML cells, as confirmed by immunophenotyping using flow cytometry. Au-NC-CD33 conjugates having average size of ~ 12 nm retained bright fluorescence over an extended duration of ~ a year, as the albumin protein protects Au-NCs against degradation. Nanotoxicity studies revealed excellent biocompatibility of Au-NC conjugates, as they showed no adverse effect on the cell viability and inflammatory response. Target specificity of the conjugates for detecting CD33 expressing AML cells (KG1a) in flow cytometry showed specific staining of ~ 95.4% of leukaemia cells within 1-2 h compared to a non-specific uptake of ~ 8.2% in human peripheral blood cells (PBMCs) which are CD33low. The confocal imaging also demonstrated the targeted uptake of CD33 conjugated Au-NCs by leukaemia cells, thus confirming the flow cytometry results. This study demonstrates that novel nano-bioprobes can be developed using protein protected fluorescent nanoclusters of Au for the molecular receptor targeted flow cytometry based detection and imaging of cancer cells.

  18. Case-control study of leukaemia among young people near La Hague nuclear reprocessing plant: the environmental hypothesis revisited.

    PubMed Central

    Pobel, D.; Viel, J. F.

    1997-01-01

    OBJECTIVE: To investigate the association between childhood leukaemia and established risk factors or other factors related to La Hague nuclear waste reprocessing plant. DESIGN: Case-control study. SETTING: Area within a 35 km radius of La Hague, Normandy, France. SUBJECTS: Twenty seven cases of leukaemia diagnosed during the period 1978-93 in people aged under 25 years and 192 controls matched for sex, age, place of birth, and residence at time of diagnosis. MAIN OUTCOME MEASURES: Antenatal and postnatal exposure to x rays and viral infections, occupational exposure of parents (particularly ionising radiation), living conditions, lifestyle of parents and children. RESULTS: Increased trends were found for use of local beaches by mothers and children (P < or = 0.01); relative risks 2.87 (95% confidence intervals 1.05 to 8.72) and 4.49 (1.52 to 15.23) when categories were aggregated in two levels (more or less than once a month). Consumption of local fish and shellfish also showed an increased trend (P 0.01); relative risk 2.66 (0.91 to 9.51) when categories were grouped in two levels (more or less than once a week). A relative risk of 1.18 a year (1.03 to 1.42) was observed for length of residence in a granite-built house or in a granitic area. No association was shown with occupational radiation exposure in parents. CONCLUSIONS: There is some convincing evidence in childhood leukaemia of a causal role for environmental radiation exposure from recreational activities on beaches. New methods for identifying the environmental pathways, focusing on marine ecosystems, are warranted. PMID:9006467

  19. Evolution of procalcitonin, C-reactive protein and fibrinogen levels in neutropenic leukaemia patients with invasive pulmonary aspergillosis or mucormycosis.

    PubMed

    Roques, Marjorie; Chretien, Marie Lorraine; Favennec, Camille; Lafon, Ingrid; Ferrant, Emmanuelle; Legouge, Caroline; Plocque, Alexia; Golfier, Camille; Duvillard, Laurence; Amoureux, Lucie; Bastie, Jean Noel; Maurin-Bernier, Lory; Dalle, Frederic; Caillot, Denis

    2016-06-01

    Unlike bacterial infections, the value of procalcitonin (PCT) in detecting fungal infections in leukaemia patients is not clear. To determine whether the monitoring of PCT coupled with C-reactive protein (CRP) and fibrinogen (Fib) could be helpful in the management of pulmonary aspergillosis (IPA) or mucormycosis (PM), we retrospectively analysed the evolution of PCT, CRP and Fib levels in 94 leukaemia patients with proven/probable IPA (n = 77) or PM (n = 17) from D-12 to D12 relative to IFI onset defined as D0. Overall, 2140 assays were performed. From D-12 to D0, 12%, 5% and 1.4% of patients had PCT >0.5, 1 and 1.5 μg l(-1) , respectively, while CRP was >50, 75 and 100 mg l(-1) in 84%, 70% and 57% and Fib was >4, 5 and 6 g l(-1) in 96%, 80% and 61% of cases respectively (P < 10(-7) ). The same trends were observed from D1 to D12. Overall, between D-12 and D12, only 6.4% of patients had PCT >1.5 μg l(-1) , while CRP >100 mg l(-1) and Fib >6 g l(-1) were observed in 80% and 75% of cases respectively (P < 10(-7) ). In leukaemia patients, IPA or PM was accompanied by a significant increase in CRP and Fib while PCT remained low. PMID:26931315

  20. Plasma High Sensitivity Troponin T Levels in Adult Survivors of Childhood Leukaemias: Determinants and Associations with Cardiac Function

    PubMed Central

    Cheung, Yiu-fai; Yu, Wei; Cheuk, Daniel Ka-leung; Cheng, Frankie Wai-tsoi; Yang, Janet Yee-kwan; Yau, Jeffrey Ping-wa; Ho, Karin Ka-huen; Li, Chi-kong; Li, Rever Chak-ho; Yuen, Hui-leung; Ling, Alvin Siu-cheung; Li, Vivian Wing-yi; Wong, Wai-keung; Tsang, Kwong-cheong; Chan, Godfrey Chi-fung

    2013-01-01

    Background We sought to quantify plasma high sensitivity cardiac troponin (hs-cTnT) levels, their determinants, and their associations with left ventricular (LV) myocardial deformation in adult survivors of childhood acute leukaemias. Methods and Results One hundred adult survivors (57 males) of childhood acute leukaemias, aged 24.1±4.2 years, and 42 age-matched controls (26 males) were studied. Plasma cTnT was determined using a highly sensitive assay. Genotyping of NAD(P)H oxidase and multidrug resistance protein polymorphisms was performed. Left ventricular function was assessed by conventional, three-dimensional, and speckle tracking echocardiography. The medians (interquartile range) of hs-cTnT in male and female survivors were 4.9 (4.2 to 7.2) ng/L and 1.0 (1.0 to 3.5) ng/L, respectively. Nineteen survivors (13 males, 6 females) (19%) had elevated hs-cTnT (>95th centile of controls). Compared to those without elevated hs-TnT levels, these subjects had received larger cumulative anthracycline dose and were more likely to have leukaemic relapse, stem cell transplant, and cardiac irradiation. Their LV systolic and early diastolic myocardial velocities, isovolumic acceleration, and systolic longitudinal strain rate were significantly lower. Survivors having CT/TT at CYBA rs4673 had higher hs-cTnT levels than those with CC genotype. Functionally, increased hs-cTnT levels were associated with worse LV longitudinal systolic strain and systolic and diastolic strain rates. Conclusions Increased hs-cTnT levels occur in a significant proportion of adult survivors of childhood acute leukaemias and are associated with larger cumulative anthracycline dose received, history of leukaemic relapse, stem cell transplant, and cardiac irradiation, genetic variants in free radical metabolism, and worse LV myocardial deformation. PMID:24204736

  1. Health care providers' perspectives on a weekly text-messaging intervention to engage HIV-positive persons in care (WelTel BC1).

    PubMed

    Murray, Melanie C M; O'Shaughnessy, Sara; Smillie, Kirsten; Van Borek, Natasha; Graham, Rebecca; Maan, Evelyn J; van der Kop, Mia L; Friesen, Karen; Albert, Arianne; Levine, Sarah; Pick, Neora; Ogilvie, Gina; Money, Deborah; Lester, Richard

    2015-10-01

    Though evidence shows that Mobile health (mHealth) interventions can improve adherence and viral load in HIV-positive persons, few have studied the health care providers' (HCP) perspective. We conducted a prospective mixed methods pilot study using the WelTel intervention wherein HIV-positive participants (n = 25) received weekly interactive text messages for 6 months. Text message response rate and topic data were collected to illustrate the HCP experience. The aim of this study is to explore intervention acceptability and feasibility from the HCP perspective through a baseline focus group and end of study interviews with HCP impacted by the intervention. Interview data were thematically coded using the Technology Acceptance Model. HCPs identified that the WelTel intervention engaged patients in building relationships, while organizing and streamlining existing mHealth efforts and dealing with privacy issues. HCPs recognized that although workload would augment initially, intervention benefits were many, and went beyond simply improving HIV viral load. PMID:26297567

  2. Development of chronic lymphocytic leukaemia in a case of Sjögren's syndrome with systemic lupus erythematosus.

    PubMed

    Ho, C H; Chiang, Y M; Chong, L L; Lin, H Y; Hwang, T S

    1985-08-01

    Persistent lymphocytosis and intermittent fever were found in a 68-yr-old Chinese woman 5 yr after the diagnosis of Sjögren's syndrome with systemic lupus erythematosus (SLE). A series of examinations--including virology, bone marrow aspiration and surface markers of lymphocytes--was made to evaluate the nature of the lymphocytosis which had not been found previously. All of the results were consistent with the diagnosis of B-cell chronic lymphocytic leukaemia (CLL). Development of CLL in Sjögren's syndrome has seldom been described before and may be added to other malignancies associated with Sjögren's syndrome. PMID:3876599

  3. An unusual indication for splenectomy in hairy cell leukaemia: a report of three cases with persistent splenomegaly after chemoimmunotherapy.

    PubMed

    Sarid, Nadav; Ahmad, Humayun N; Wotherspoon, Andrew; Dearden, Claire E; Else, Monica; Catovsky, Daniel

    2015-12-01

    We describe three cases of relapsed hairy cell leukaemia (HCL) treated with pentostatin plus rituximab. All three achieved bone marrow complete remission but had persistent splenomegaly and hypersplenism. Because of the clinical uncertainty of its significance, they were all splenectomized. The spleen histology showed no evidence of HCL, but a five-fold thickening of the splenic capsule and areas of fibrosis in the red pulp. This process may have contributed to the lack of elasticity and caused the persistent splenomegaly. We discuss the clinical implications for future patient management. The three patients remain in remission at 1 + , 5 + and 9 + years. PMID:26403440

  4. PHA-induced soluble factor(s) can activate B-cells from patients with chronic lymphatic leukaemia.

    PubMed Central

    Robert, K H

    1979-01-01

    Blood lymphocytes from eight patients with chronic lymphatic leukaemia (CLL) were stimulated by phytohaemagglutinin (PHA). The effect was defined as a pronounced increase of 3H-thymidine incorporation, and a concomitant blast transformation of a large portion of surface Ig-positive, E-rosette-forming (E-RFC) negative cells. E-RFC depletion reduced these effects to nearly background levels, and the pooled data strongly suggest that malignant B-lymphocytes in CLL are capable of responding to a PHA-induced T cell factor. A possible use for this factor in characterizing different subpopulations of CLL cells is discussed. PMID:315847

  5. Early UK experience in the use of clofarabine in the treatment of relapsed and refractory paediatric acute lymphoblastic leukaemia.

    PubMed

    O'Connor, David; Sibson, Keith; Caswell, Mark; Connor, Philip; Cummins, Michelle; Mitchell, Chris; Motwani, Jayashree; Taj, Mary; Vora, Ajay; Wynn, Robert; Kearns, Pamela R

    2011-08-01

    Clofarabine is a second-generation purine nucleoside analogue, which has shown promising activity in relapsed and refractory paediatric acute lymphoblastic leukaemia (ALL). This report summarizes the early United Kingdom experience of clofarabine for the treatment of paediatric ALL in 23 patients, outside of the context of a clinical trial. Our results demonstrated that clofarabine-based chemotherapy regimes were effective and well-tolerated in this heavily pre-treated group, with an overall response rate of 67% when used in combination regimes. Responses were seen in both B and T cell disease and in patients with adverse cytogenetics. PMID:21689087

  6. Identification of novel kinase fusion transcripts in paediatric B cell precursor acute lymphoblastic leukaemia with IKZF1 deletion.

    PubMed

    Yano, Mio; Imamura, Toshihiko; Asai, Daisuke; Kiyokawa, Nobutaka; Nakabayashi, Kazuhiko; Matsumoto, Kenji; Deguchi, Takao; Hashii, Yoshiko; Honda, Yu-ko; Hasegawa, Daiichiro; Sasahara, Yoji; Ishii, Mutsuo; Kosaka, Yoshiyuki; Kato, Koji; Shima, Midori; Hori, Hiroki; Yumura-Yagi, Keiko; Hara, Junichi; Oda, Megumi; Horibe, Keizo; Ichikawa, Hitoshi; Sato, Atsushi

    2015-12-01

    Activating tyrosine kinase mutations or cytokine receptor signalling alterations have attracted attention as therapeutic targets for high-risk paediatric acute lymphoblastic leukaemia (ALL). We identified two novel kinase fusions, OFD1-JAK2 and NCOR1-LYN, in paediatric ALL patients with IKZF1 deletion, by mRNA sequencing. The patient with CSF2RA-CRLF2 also harboured IGH-EPOR. All these patients had high-risk features, such as high initial white blood cell counts and initial poor response to prednisolone. The functional analysis of these novel fusions is on-going to determine whether these genetic alterations can be targeted by drugs. PMID:26404892

  7. A 14-year paraneoplastic rash: urticarial vasculitis and dermal binding bullous pemphigoid secondary to chronic lymphocytic leukaemia.

    PubMed

    Kassim, J M; Igali, L; Levell, N J

    2015-06-01

    A 72-year-old woman with a 14-year history of urticarial vasculitis (UV) and a 13-year history of bullous pemphigoid (BP) presented with associated progressive chronic lymphocytic leukaemia (CLL). Both skin conditions responded poorly to treatment, until chemotherapy for CLL was commenced. The skin features showed a clear paraneoplastic course, resolving with chemotherapy and recurring when the CLL relapsed and the lymphocyte count rose above 5 × 10(9)/L. No case of UV secondary to CLL, and very few cases of BP related to CLL have been reported, and no paraneoplastic rash of any type lasting 14 years has been reported previously. PMID:25524180

  8. Effect of interleukins on the proliferation and survival of B cell chronic lymphocytic leukaemia cells.

    PubMed Central

    Mainou-Fowler, T; Copplestone, J A; Prentice, A G

    1995-01-01

    AIMS--To investigate the effects of interleukin (IL) 1, 2, 4, and 5 on the proliferation and survival of peripheral blood B cells from patients with B chronic lymphocytic leukaemia (B-CLL) and compare them with the effects on normal peripheral blood B cells. METHODS--The proliferation and survival of pokeweed mitogen (PWM) activated B cells from B-CLL (n = 12) and normal peripheral blood (n = 5) were studied in vitro in response to IL-1, IL-2 IL-4, and IL-5. Survival of cells in cultures with or without added interleukins was studied by microscopic examination of cells and DNA agarose gel electrophoresis. RESULTS--Proliferation was observed in both B-CLL and normal peripheral blood cells on culture with IL-2 alone and also in some, but not all, B-CLL and normal peripheral blood cells with IL-1 and IL-4. However, there was greater variability in B-CLL cell responses than in normal peripheral blood cells. Il-5 did not affect normal peripheral blood cell proliferation but it increased proliferation in two B-CLL cases. Synergistic effects of these cytokines were not detected. IL-4 inhibited normal peripheral blood and B-CLL cell proliferation after the addition of IL-2. Inhibition of B-CLL cell responses to IL-2 was also observed with IL-5 and Il-1. Survival of B-CLL cells in cultures was enhanced with IL-4 not by an increase in proliferation but by reduced apoptosis. No such effect was seen in normal peripheral blood cells. IL-2 had a less noticeable antiapoptotic effect; IL-5 enhanced apoptosis in B-CLL cells. CONCLUSIONS--B-CLL and normal peripheral blood cells proliferated equally well in response to IL-2. IL-4 had a much lower effect on B-CLL cell proliferation, but had noticeable antiapoptotic activity. IL-5 enhanced cell death by apoptosis. Images PMID:7629299

  9. Signalling thresholds and negative B-cell selection in acute lymphoblastic leukaemia.

    PubMed

    Chen, Zhengshan; Shojaee, Seyedmehdi; Buchner, Maike; Geng, Huimin; Lee, Jae Woong; Klemm, Lars; Titz, Björn; Graeber, Thomas G; Park, Eugene; Tan, Ying Xim; Satterthwaite, Anne; Paietta, Elisabeth; Hunger, Stephen P; Willman, Cheryl L; Melnick, Ari; Loh, Mignon L; Jung, Jae U; Coligan, John E; Bolland, Silvia; Mak, Tak W; Limnander, Andre; Jumaa, Hassan; Reth, Michael; Weiss, Arthur; Lowell, Clifford A; Müschen, Markus

    2015-05-21

    B cells are selected for an intermediate level of B-cell antigen receptor (BCR) signalling strength: attenuation below minimum (for example, non-functional BCR) or hyperactivation above maximum (for example, self-reactive BCR) thresholds of signalling strength causes negative selection. In ∼25% of cases, acute lymphoblastic leukaemia (ALL) cells carry the oncogenic BCR-ABL1 tyrosine kinase (Philadelphia chromosome positive), which mimics constitutively active pre-BCR signalling. Current therapeutic approaches are largely focused on the development of more potent tyrosine kinase inhibitors to suppress oncogenic signalling below a minimum threshold for survival. We tested the hypothesis that targeted hyperactivation--above a maximum threshold--will engage a deletional checkpoint for removal of self-reactive B cells and selectively kill ALL cells. Here we find, by testing various components of proximal pre-BCR signalling in mouse BCR-ABL1 cells, that an incremental increase of Syk tyrosine kinase activity was required and sufficient to induce cell death. Hyperactive Syk was functionally equivalent to acute activation of a self-reactive BCR on ALL cells. Despite oncogenic transformation, this basic mechanism of negative selection was still functional in ALL cells. Unlike normal pre-B cells, patient-derived ALL cells express the inhibitory receptors PECAM1, CD300A and LAIR1 at high levels. Genetic studies revealed that Pecam1, Cd300a and Lair1 are critical to calibrate oncogenic signalling strength through recruitment of the inhibitory phosphatases Ptpn6 (ref. 7) and Inpp5d (ref. 8). Using a novel small-molecule inhibitor of INPP5D (also known as SHIP1), we demonstrated that pharmacological hyperactivation of SYK and engagement of negative B-cell selection represents a promising new strategy to overcome drug resistance in human ALL. PMID:25799995

  10. Phenotypically Dormant and Immature Leukaemia Cells Display Increased Ribosomal Protein S6 Phosphorylation

    PubMed Central

    Pallis, Monica; Harvey, Tamsin; Russell, Nigel

    2016-01-01

    Mechanistic/mammalian target of rapamycin (mTOR) activity drives a number of key metabolic processes including growth and protein synthesis. Inhibition of the mTOR pathway promotes cellular dormancy. Since cells from patients with acute myeloid leukaemia (AML) can be phenotypically dormant (quiescent), we examined biomarkers of their mTOR pathway activity concurrently with Ki-67 and CD71 (indicators of cycling cells) by quantitative flow cytometry. Using antibodies to phosphorylated epitopes of mTOR (S2448) and its downstream targets ribosomal protein S6 (rpS6, S235/236) and 4E-BP1 (T36/45), we documented that these phosphorylations were negligible in lymphocytes, but evident in dormant as well as proliferating subsets of both mobilised normal stem cell harvest CD34+ cells and AML blasts. Although mTOR phosphorylation in AML blasts was lower than that of the normal CD34+ cells, p-4E-BP1 was 2.6-fold higher and p-rpS6 was 22-fold higher. Moreover, in contrast to 4E-BP1, rpS6 phosphorylation was higher in dormant than proliferating AML blasts, and was also higher in the immature CD34+CD38- blast subset. Data from the Cancer Genome Atlas show that rpS6 expression is associated with that of respiratory chain enzymes in AML. We conclude that phenotypic quiescence markers do not necessarily predict metabolic dormancy and that elevated rpS6 ser235/236 phosphorylation is characteristic of AML. PMID:26985829

  11. Chronic myelocytic leukaemia: HLA association and decreased erythrocyte C3b receptor expression.

    PubMed Central

    Ruuska, P; Silvennoinen-Kassinen, S; Timonen, T; Tiilikainen, A

    1985-01-01

    A series of 27 adult patients with chronic myelocytic leukaemia (CML) were examined for erythrocyte C3b receptor (EC3bR) expression. Twenty-five patients were successfully HLA typed and there was a positive association of CML with HLA-B40 (P less than 0.01). Only 10 (37%) of the patients were EC3bR positive (P less than 0.00001) compared to 223 healthy controls of whom 198 (89%) were EC3bR positive. The positivity of EC3bR and HLA-B40 occurred simultaneously in six patients (P less than 0.05). HLA-B40 positivity and EC3bR expression were correlated with the following variables: age at the time of CML diagnoses, duration of CML (until death or the end of follow-up period 1 July 1983), the stage of CML and simultaneous medication. EC3bR positive patients were significantly more often in remission (P less than 0.05) and also had shorter duration of the disease (P less than 0.005) then did EC3bR negative ones. No significant correlation existed between EC3bR status and the other parameters. The presence of HLA-B40 did not associate with any of the listed variables. These findings may indicate the loss of the receptor in the course of CML with increasing immaturity of cells released from bone marrow. PMID:3156701

  12. Targeting etoposide to acute myelogenous leukaemia cells using nanostructured lipid carriers coated with transferrin

    NASA Astrophysics Data System (ADS)

    Khajavinia, Amir; Varshosaz, Jaleh; Jafarian Dehkordi, Abbas

    2012-10-01

    The aim of the present study was to evaluate the diverse properties of transferrin (Tf)-conjugated nanostructured lipid carriers (NLCs) prepared using three different fatty amines, including stearylamine (SA), dodecylamine (DA) and spermine (SP), and two different methods for Tf coupling. Etoposide-loaded NLCs were prepared by an emulsion-solvent evaporation method followed by probe sonication. Chemical coupling of NLCs with Tf was mediated by an amide linkage between the surface-exposed amino group of the fatty amine and the carboxyl group of the protein. The physical coating was performed in a Ringer-Hepes buffer medium. NLCs were characterized by their particle size, zeta potential, polydispersity index, drug entrapment percentage, drug release profiles and Tf-coupling efficiency. The cytotoxicity of NLCs on K562 acute myelogenous leukaemia cells was studied by MTT assay, and their cellular uptake was studied by a flow cytometry method. SA-containing NLCs showed the lowest particle size, the highest zeta potential and the largest coupling efficiency values. The drug entrapment percentage and the zeta potential decreased after Tf coupling, but the average particle size increased. SP-containing formulations released their drug contents comparatively slower than SA- or DA-containing NLCs. Unconjugated NLCs released moderately more drug than Tf-NLCs. Flow cytometry studies revealed enhanced cellular uptake of Tf-NLCs compared to unconjugated ones. Blocking Tf receptors resulted in a significantly higher cell survival rate for Tf-NLCs. The highest cytotoxic activity was observed in the chemically coupled SA-containing nanoparticles, with an IC50 value of 15-fold lower than free etoposide.

  13. In vitro toxicity assay of cisplatin on mouse acute lymphoblastic leukaemia and spermatogonial stem cells.

    PubMed

    Shabani, R; Ashtari, K; Behnam, B; Izadyar, F; Asgari, H; Asghari Jafarabadi, M; Ashjari, M; Asadi, E; Koruji, M

    2016-06-01

    Testicular cancer is the most common cancer affecting men in reproductive age, and cisplatin is one of the major helpful chemotherapeutic agents for treatment of this cancer. In addition, exposure of testes cancer cells to cisplatin could potentially eliminate tumour cells from germ cells in patients. The aim of this study was to evaluate the effect of cisplatin on viability of mouse acute lymphoblastic leukaemia cell line (EL-4) and neonatal mouse spermatogonial cells in vitro. In this study, the isolated spermatogonial stem cells (SSC) and EL-4 were divided into six groups including control (received medium), sham (received DMSO in medium) and experimental groups which received different doses of cisplatin (0.5, 5, 10 and 15 μg ml(-1) ). Cells viability was evaluated with MTT assay. The identity of the cultured cells was confirmed by the expression of specific markers. Our finding showed that viability of both SSC and EL-4 cells was reduced with the dose of 15 μg/ml when compared to the control group (P ≤ 0.05). Also, the differences between the IC50 in doses 10 and 15 μg/ml at different time were significant (P ≤ 0.05). The number of TUNEL-positive cells was increased, and the BAX and caspase-3 expressions were upregulated in EL4 cells for group that received an effective dose of cisplatin). In conclusion, despite the dramatic effects of cisplatin on both cells, spermatogonial stem cells could form colony in culture. PMID:26428408

  14. Screened selection design for randomised phase II oncology trials: an example in chronic lymphocytic leukaemia

    PubMed Central

    2013-01-01

    Background As there are limited patients for chronic lymphocytic leukaemia trials, it is important that statistical methodologies in Phase II efficiently select regimens for subsequent evaluation in larger-scale Phase III trials. Methods We propose the screened selection design (SSD), which is a practical multi-stage, randomised Phase II design for two experimental arms. Activity is first evaluated by applying Simon’s two-stage design (1989) on each arm. If both are active, the play-the-winner selection strategy proposed by Simon, Wittes and Ellenberg (SWE) (1985) is applied to select the superior arm. A variant of the design, Modified SSD, also allows the arm with the higher response rates to be recommended only if its activity rate is greater by a clinically-relevant value. The operating characteristics are explored via a simulation study and compared to a Bayesian Selection approach. Results Simulations showed that with the proposed SSD, it is possible to retain the sample size as required in SWE and obtain similar probabilities of selecting the correct superior arm of at least 90%; with the additional attractive benefit of reducing the probability of selecting ineffective arms. This approach is comparable to a Bayesian Selection Strategy. The Modified SSD performs substantially better than the other designs in selecting neither arm if the underlying rates for both arms are desirable but equivalent, allowing for other factors to be considered in the decision making process. Though its probability of correctly selecting a superior arm might be reduced, it still performs reasonably well. It also reduces the probability of selecting an inferior arm. Conclusions SSD provides an easy to implement randomised Phase II design that selects the most promising treatment that has shown sufficient evidence of activity, with available R codes to evaluate its operating characteristics. PMID:23819695

  15. Phenotypically Dormant and Immature Leukaemia Cells Display Increased Ribosomal Protein S6 Phosphorylation.

    PubMed

    Pallis, Monica; Harvey, Tamsin; Russell, Nigel

    2016-01-01

    Mechanistic/mammalian target of rapamycin (mTOR) activity drives a number of key metabolic processes including growth and protein synthesis. Inhibition of the mTOR pathway promotes cellular dormancy. Since cells from patients with acute myeloid leukaemia (AML) can be phenotypically dormant (quiescent), we examined biomarkers of their mTOR pathway activity concurrently with Ki-67 and CD71 (indicators of cycling cells) by quantitative flow cytometry. Using antibodies to phosphorylated epitopes of mTOR (S2448) and its downstream targets ribosomal protein S6 (rpS6, S235/236) and 4E-BP1 (T36/45), we documented that these phosphorylations were negligible in lymphocytes, but evident in dormant as well as proliferating subsets of both mobilised normal stem cell harvest CD34+ cells and AML blasts. Although mTOR phosphorylation in AML blasts was lower than that of the normal CD34+ cells, p-4E-BP1 was 2.6-fold higher and p-rpS6 was 22-fold higher. Moreover, in contrast to 4E-BP1, rpS6 phosphorylation was higher in dormant than proliferating AML blasts, and was also higher in the immature CD34+CD38- blast subset. Data from the Cancer Genome Atlas show that rpS6 expression is associated with that of respiratory chain enzymes in AML. We conclude that phenotypic quiescence markers do not necessarily predict metabolic dormancy and that elevated rpS6 ser235/236 phosphorylation is characteristic of AML. PMID:26985829

  16. Extreme hyperferritinemia in the setting of acute myeloid leukaemia: a case report of hemophagocytic lymphohistiocytosis

    PubMed Central

    Denimal, Damien; Ménégaut, Louise; Rossi, Cédric; Duvillard, Laurence; Masson, David

    2016-01-01

    Introduction Major hyperferritinemia is a rare feature in clinical laboratories associated with a wide variety of disorders, including hemophagocytic lymphohistiocytosis (HLH). The diagnosis of HLH is based on clinical and biological criteria, such as those proposed by the Histiocyte Society. However, several of these criteria are not relevant in the specific setting of hematologic malignancies. Materials and methods A 69-year-old male was treated for an acute myeloid leukaemia. On day 15 after the start of chemotherapy, he developed severe sepsis with high fever, low blood pressure and hepatosplenomegaly. Results Blood tests were marked by extreme hyperferritinemia (191,000 µg/L, reference range: 26-388 µg/L) with increased C-reactive protein (87.0 mg/L) and procalcitonin (1.94 µg/L) and aspartate aminotransferase (499 U/L 37 °C) in the setting of chemotherapy-induced aplasia. This unusual extreme ferritinemia led to suspect HLH triggered by an invasive infection. Under intensive treatment, the clinical status improved and ferritin levels significantly decreased. Conclusions The diagnosis of HLH is usually based on clinical and biological criteria, mainly fever, splenomegaly, cytopenias, hypertriglyceridemia, hypofibrinogenemia, hemophagocytosis and hyperferritinemia. In this patient, the diagnosis of HLH was challenging because several criteria, such as hypertriglyceridemia, hemophagocytosis and hypofibrinogenemia, were absent. In addition, some criteria of HLH are not relevant in the setting of hematologic malignancy, in which fever, splenomegaly, cytopenias and elevated lactate dehydrogenase are commonly observed independently of HLH. This unusual case of extremely high ferritinemia emphasizes the important weight of the ferritin level for the diagnosis of HLH in adult patients in the setting of hematologic malignancies. PMID:27346972

  17. High event-free survival rate with minimum-dose-anthracycline treatment in childhood acute promyelocytic leukaemia: a nationwide prospective study by the Japanese Paediatric Leukaemia/Lymphoma Study Group.

    PubMed

    Takahashi, Hiroyuki; Watanabe, Tomoyuki; Kinoshita, Akitoshi; Yuza, Yuki; Moritake, Hiroshi; Terui, Kiminori; Iwamoto, Shotaro; Nakayama, Hideki; Shimada, Akira; Kudo, Kazuko; Taki, Tomohiko; Yabe, Miharu; Matsushita, Hiromichi; Yamashita, Yuka; Koike, Kazutoshi; Ogawa, Atsushi; Kosaka, Yoshiyuki; Tomizawa, Daisuke; Taga, Takashi; Saito, Akiko M; Horibe, Keizo; Nakahata, Tatsutoshi; Miyachi, Hayato; Tawa, Akio; Adachi, Souichi

    2016-08-01

    We evaluated the efficacy of treatment using reduced cumulative doses of anthracyclines in children with acute promyelocytic leukaemia (APL) in the Japanese Paediatric Leukaemia/Lymphoma Study Group AML-P05 study. All patients received two and three subsequent courses of induction and consolidation chemotherapy respectively, consisting of all-trans retinoic acid (ATRA), cytarabine and anthracyclines, followed by maintenance therapy with ATRA. Notably, a single administration of anthracyclines was introduced in the second induction and all consolidation therapies to minimize total doses of anthracycline. The 3-year event-free (EFS) and overall survival rates for 43 eligible children were 83·6% [95% confidence interval (CI): 68·6-91·8%] and 90·7% (95% CI: 77·1-96·4%), respectively. Although two patients died of intracranial haemorrhage or infection during induction phases, no cardiac adverse events or treatment-related deaths were observed during subsequent phases. Patients not displaying M1 marrow after the first induction therapy, or those under 5 years of age at diagnosis, showed inferior outcomes (3-year EFS rate; 33·3% (95% CI: 19·3-67·6%) and 54·6% (95% CI: 22·9-78·0%), respectively). In conclusion, a single administration of anthracycline during each consolidation phase was sufficient for treating childhood APL. In younger children, however, conventional ATRA and chemotherapy may be insufficient so that alternative therapies should be considered. PMID:27029412

  18. [High risk acute lymphoblastic leukaemia in children. Preliminary report after introducing a new version of New York (1997) protocol adjusted to the age of the patients. Report of the Polish Paediatric Leukaemia/Lymphoma Study Group].

    PubMed

    Skoczen, S; Klus, K; Armata, J; Kowalczyk, J; Wisniewska-Slusarz, H; Kolecki, P; Derwich, K; Matysiak, M; Krauze, A; Rokicka-Milewska, R; Pawelec, K; Boguslawska-Jaworska, J; Juszczak, K; Pisarek, J; Sońta-Jakimczyk, D; Tomaszewska, R; Łuszczynska, A; Wysocki, M; Styczyński, J

    2000-01-01

    The paper presents the experience of the Polish Paediatric Leukaemia/Lymphoma Study Group in the treatment of high-risk acute lymphoblastic leukaemia in children using a new version of the New York (1997-1999). Protocol with treatment intensity adjusted according to the age of the patients. From April 1997 to December 1999 a group of 49 children with leukocytosis ranging from 50 900/mm3 to 580 000/mm3 (median 122 000/mm3) and 6 children with leukocytosis below 50 000/mm3 and poor response to steroids were treated with this protocol. Children below 10 years (43 patients) were treated according to the previous protocol, children above 10 years (12 patients) were treated with intensified protocol (high doses of ARA-C in consolidation and intermediate doses of Mtx in maintenance). Induction was identical for all patients. Complete remission was achieved in 92.6% patients. There were 2 relapses. Six children died - 3 without remission, 2 due to a relapse, 1 due to treatment complications. The current opinions concerning classification of HRG-ALL and treatment possibilities in this group of children are discussed. PMID:12021459

  19. Tel Aviv-Heidelberg three-generation offspring study: Genetic determinants of apolipoprotein A1 and apolipoprotein B

    SciTech Connect

    Livshits, G.; Graff, E.; Brunner, D.

    1995-07-03

    The contribution of major gene and multifactorial effects on variation of plasma apolipoproteins A1 and B has been tested in a large sample of population-based Israeli pedigrees. Our most parsimonious and best fitting model for both apolipoproteins is consistent with Mendelian transmissibility, with significant contribution of major genes (with 2 alleles recessive and dominant within each locus) and polygenes, but neglects effects of common sib environment as well as related intergeneration differences in polygenic effects. Total genetic effects explain 71 and 58% of phenotypic variance of APO-A1 and APO-B levels. The major genes account for about 44 and 32% of the variance in APO-A1 and APO-B, respectively, and the frequency of the recessive alleles determining the high level of apolipoproteins under the study in the Israeli population is in the vicinity of 40% at each locus. 27 refs, 1 fig., 4 tabs.

  20. Survival of Mexican Children with Acute Myeloid Leukaemia Who Received Early Intensification Chemotherapy and an Autologous Transplant

    PubMed Central

    Jiménez-Hernández, Elva; Dueñas-González, María Teresa; Arellano-Galindo, José; Medrano-Ortíz-De-Zárate, María Elena; Bekker-Méndez, Vilma Carolina; Berges-García, Adolfina; Solís-Labastida, Karina; Sánchez-Jara, Berenice; Tiznado-García, Héctor Manuel; Jaimes-Reyes, Ethel Zulie; García-Jiménez, Xochiketzalli; Espinoza-Hernández, Laura; Núñez-Villegas, Nora Nancy; Franco-Ornelas, Sergio; Pérez-Casillas, Ruy Xavier; Martínez Villegas, Octavio; Palomares, Teresa Marin; Mejía-Aranguré, Juan Manuel

    2015-01-01

    Background. In Mexico and other developing countries, few reports of the survival of children with acute leukaemia exist. Objective. We aimed at comparing the disease-free survival of children with acute myeloid leukaemia who, in addition to being treated with the Latin American protocol of chemotherapy and an autologous transplant, either underwent early intensified chemotherapy or did not undergo such treatment. Procedure. This was a cohort study with a historical control group, forty patients, less than 16 years old. Group A (20 patients), diagnosed in the period 2005–2007, was treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy: high doses of cytarabine and mitoxantrone. Group B (20 patients), diagnosed in the period 1999–2004, was treated as Group A, but without the early intensified chemotherapy. Results. Relapse-free survival for Group A was 90% whereas that for Group B it was 60% (P = 0.041). Overall survival for Group A (18, 90%) was higher than that for Group B (60%). Complete remission continued for two years of follow-up. Conclusions. Relapse-free survival for paediatric patients treated with the Latin American protocol of chemotherapy with an autologous transplant plus early intensified chemotherapy was higher than that for those who did not receive early intensified chemotherapy. PMID:25821830

  1. Population-mixing at the place of residence at the time of birth and incidence of childhood leukaemia in France.

    PubMed

    Rudant, J; Baccaïni, B; Ripert, M; Goubin, A; Bellec, S; Hémon, D; Clavel, J

    2006-05-01

    The association between the risk of childhood leukaemia before age 7 years and population-mixing at the place of residence at birth was investigated by retrospectively considering all the children born in mainland French communes between 1st January 1990 and 31st December 1998. An increased risk of acute lymphoblastic leukaemia was found with higher levels of migration for children residing at birth in isolated communes with a population density > or =50 people per km2 (SIRR = 2.59, 95% CI: 1.48-4.49). No association was observed with lower population densities. For children residing in non-isolated communes at birth, the results were similar but less marked. The risk tended to increase only for population densities > or =5000 people per km2 (SIRR = 1.57, 95% CI: 0.99-2.52). The findings are consistent with epidemic models and support the hypothesis of an infectious aetiology relating to population-mixing. Population density may be seen as an indicator of the opportunity of contacts between inhabitants and should therefore be taken into account when investigating an infectious hypothesis. This is the first systematic study of population-mixing at the place of residence at the time of birth to be conducted on a national scale. PMID:16530405

  2. Violacein Induces Death of Resistant Leukaemia Cells via Kinome Reprogramming, Endoplasmic Reticulum Stress and Golgi Apparatus Collapse

    PubMed Central

    Queiroz, Karla C. S.; Milani, Renato; Ruela-de-Sousa, Roberta R.; Fuhler, Gwenny M.; Justo, Giselle Z.; Zambuzzi, Willian F.; Duran, Nelson; Diks, Sander H.; Spek, C. Arnold; Ferreira, Carmen V.; Peppelenbosch, Maikel P.

    2012-01-01

    It is now generally recognised that different modes of programmed cell death (PCD) are intimately linked to the cancerous process. However, the mechanism of PCD involved in cancer chemoprevention is much less clear and may be different between types of chemopreventive agents and tumour cell types involved. Therefore, from a pharmacological view, it is crucial during the earlier steps of drug development to define the cellular specificity of the candidate as well as its capacity to bypass dysfunctional tumoral signalling pathways providing insensitivity to death stimuli. Studying the cytotoxic effects of violacein, an antibiotic dihydro-indolone synthesised by an Amazon river Chromobacterium, we observed that death induced in CD34+/c-Kit+/P-glycoprotein+/MRP1+ TF1 leukaemia progenitor cells is not mediated by apoptosis and/or autophagy, since biomarkers of both types of cell death were not significantly affected by this compound. To clarify the working mechanism of violacein, we performed kinome profiling using peptide arrays to yield comprehensive descriptions of cellular kinase activities. Pro-death activity of violacein is actually carried out by inhibition of calpain and DAPK1 and activation of PKA, AKT and PDK, followed by structural changes caused by endoplasmic reticulum stress and Golgi apparatus collapse, leading to cellular demise. Our results demonstrate that violacein induces kinome reprogramming, overcoming death signaling dysfunctions of intrinsically resistant human leukaemia cells. PMID:23071514

  3. CCR4 frameshift mutation identifies a distinct group of adult T cell leukaemia/lymphoma with poor prognosis.

    PubMed

    Yoshida, Noriaki; Miyoshi, Hiroaki; Kato, Takeharu; Sakata-Yanagimoto, Mamiko; Niino, Daisuke; Taniguchi, Hiroaki; Moriuchi, Yukiyoshi; Miyahara, Masaharu; Kurita, Daisuke; Sasaki, Yuya; Shimono, Joji; Kawamoto, Keisuke; Utsunomiya, Atae; Imaizumi, Yoshitaka; Seto, Masao; Ohshima, Koichi

    2016-04-01

    Adult T cell leukaemia/lymphoma (ATLL) is an intractable T cell neoplasm caused by human T cell leukaemia virus type 1. Next-generation sequencing-based comprehensive mutation studies have revealed recurrent somatic CCR4 mutations in ATLL, although clinicopathological findings associated with CCR4 mutations remain to be delineated. In the current study, 184 cases of peripheral T cell lymphoma, including 113 cases of ATLL, were subjected to CCR4 mutation analysis. This sequence analysis identified mutations in 27% (30/113) of cases of ATLL and 9% (4/44) of cases of peripheral T cell lymphoma not otherwise specified. Identified mutations included nonsense (NS) and frameshift (FS) mutations. No significant differences in clinicopathological findings were observed between ATLL cases stratified by presence of CCR4 mutation. All ATLL cases with CCR4 mutations exhibited cell-surface CCR4 positivity. Semi-quantitative CCR4 protein analysis of immunohistochemical sections revealed higher CCR4 expression in cases with NS mutations of CCR4 than in cases with wild-type (WT) CCR4. Furthermore, among ATLL cases, FS mutation was significantly associated with a poor prognosis, compared with NS mutation and WT CCR4. These results suggest that CCR4 mutation is an important determinant of the clinical course in ATLL cases, and that NS and FS mutations of CCR4 behave differently with respect to ATLL pathophysiology. PMID:26847489

  4. The seroepidemiology of human herpesvirus-6 (HHV-6) from a case-control study of leukaemia and lymphoma.

    PubMed

    Clark, D A; Alexander, F E; McKinney, P A; Roberts, B E; O'Brien, C; Jarrett, R F; Cartwright, R A; Onions, D E

    1990-05-15

    Sera from an epidemiological case-control study of leukaemias and lymphomas conducted between 1980 and 1986 were examined for reactivity to human herpesvirus-6 (HHV-6) by an indirect immunofluorescence assay. Statistical analyses of the data revealed higher HHV-6 seroprevalence and antibody titres in the cases, particularly evident in the disease subtypes acute myeloid leukaemia, Hodgkin's disease (HD), and low-grade non-Hodgkin's lymphoma. Within the control group alone, HHV-6 seroprevalence was placed at 55% at a serum dilution of 1:40. The controls also displayed higher seropositivity in females as compared with males. Further analyses suggest an association of increased HHV-6 seropositivity and geometric mean titre ratio with HD among young adults lacking social contact in the family group. This finding might indicate late exposure to HHV-6 in such persons and could possibly signify late exposure to a number of viruses, including those hypothesized as playing a role in the aetiology of HD. Previous reports have nominated Epstein-Barr virus as a possible candidate. Our results suggest that HHV-6 should be included in further investigations of the aetiology of HD. PMID:2159435

  5. Novel small-molecule SIRT1 inhibitors induce cell death in adult T-cell leukaemia cells

    PubMed Central

    Kozako, Tomohiro; Suzuki, Takayoshi; Yoshimitsu, Makoto; Uchida, Yuichiro; Kuroki, Ayako; Aikawa, Akiyoshi; Honda, Shin-ichiro; Arima, Naomichi; Soeda, Shinji

    2015-01-01

    Adult T-cell leukaemia/lymphoma (ATL) is an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukaemia virus (HTLV)-1. The identification of new molecular targets for ATL prevention and treatment is desired. SIRT1, a nicotinamide adenine dinucleotide+ -dependent histone/protein deacetylase, plays crucial roles in various physiological processes, including aging and apoptosis. We previously reported that ATL patients had significantly higher SIRT1 protein levels than healthy controls. Here, we demonstrate that two novel small-molecule SIRT1 inhibitors, NCO-01/04, reduced cell viability and enhanced apoptotic cells in peripheral blood monocyte cells of patients with acute ATL, which has a poor prognosis. NCO-01/04 also reduced the cell viability with DNA fragmentation, Annexin V-positive cells, and caspase activation. However, a caspase inhibitor did not inhibit this caspase-dependent cell death. NCO-01/04 enhanced the endonuclease G level in the nucleus with loss of the mitochondrial transmembrane potential, which can promote caspase-independent death. Interestingly, NCO-01/04 increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation as well as autophagy. Thus, NCO-01/04 simultaneously caused caspase activation and autophagy. These results suggest that NCO-01/04 is highly effective against ATL cells in caspase-dependent or -independent manners with autophagy, and that its clinical application might improve the prognosis of patients with this fatal disease. PMID:26091232

  6. Participation in IAEA-TEL-201304/28 ALMERA Proficiency Test Exercise on Determination of Anthropogenic Radionuclides in Water and Flour Samples.

    PubMed

    Visetpotjanakit, S; Kaewpaluek, S; Udomsomporn, S

    2016-03-01

    The Office of Atoms for Peace (OAP) participated in the IAEA-TEL-201304/28 ALMERA Proficiency Test Exercise, "Determination of Anthropogenic Radionuclides in Water and Flour Samples," organized by the ALMERA network. There were three test samples sent together with one known activity sample for quality control purpose. Two of the test samples were spiked water: one contained (134)Cs and (137)Cs and the other contained (90)Sr, (60)Co, (152)Eu and (241)Am. The third sample was wheat flour spiked with (134)Cs and (137)Cs. OAP submitted all results to IAEA after determining (134)Cs, (137)Cs, (60)Co, (152)Eu and (241)Am activities by direct gamma-ray counting and (90)Sr by chemical separation and Cerenkov measurement. Our results with critical comments and statistical analysis are described in this paper. PMID:26688353

  7. [The complex travel of cinchona barks between Peru and Québec Hôtel-Dieu, in the middle of the eighteenth century].

    PubMed

    Simon, Lorène; Lafont, Olivier

    2016-03-01

    Duplessis sisters, who were religious nuns in Hôtel-Dieu (Quebec hospital), were exchanging letters with a French apothecary from Dieppe in Normandy, named Jacques-Tranquilain Féret. They asked him to send them in Quebec the drugs and medicines their apothecary needed. Amongst these drugs were cinchona barks that came from Callao in Peru by boat, passed Cape Horn and then sailed to Cadiz, the great Spanish port. Then they embarked to Rouen, which was the French port for goods coming from overseas. The goods from Peru had then to be transported on little fishing boats to Dieppe, where Féret received the barks. The apothecary sent these drugs to Quebec by boats sailing either from Rouen or from La Rochelle. So these Peruvian drugs had to cross two times the Ocean before accessing to North America. PMID:27281933

  8. A new fibroblast growth stimulating activity from the human megakaryoblastic leukaemia cell line ELF-153: in vitro and in vivo findings.

    PubMed Central

    Hassan, H. T.; Hanauske, A. R.; Lux, E.; Kleine, H. D.; Freund, M.

    1995-01-01

    Although the exact mechanism for the progression of myelofibrosis in acute megakaryoblastic leukaemia is unclear, certain humoral factors released from the proliferating megakaryoblasts that are unable to store these factors in their defective alpha-granules, including platelet derived growth factor (PDGF), fibroblast growth factors (FGF), platelet factor-4 (PF-4), transforming growth factor-beta (TGF-beta) and beta-thromboglobulin, could result in increased collagen synthesis by bone marrow fibroblasts. Recently, the human megakaryoblastic leukaemia cell line MEG-01 has been shown to produce both TGF-beta and PF-4 which have enhanced the growth of bone marrow fibroblasts. Therefore, we have examined the presence of a fibroblast growth stimulating activity and the humoral factors that might be responsible for it in the supernatant of the human megakaryoblastic leukaemia cell line ELF-153 recently established in our laboratory from a patient with acute myelofibrosis. A new fibroblast growth stimulating activity has been identified in the supernatant of the ELF-153 human megakaryoblastic leukaemia cell line that is independent of the percentage of fetal calf serum in NRK-49F fibroblast agar clonogenic assays and is not due to any of the known fibroblast growth stimulating humoral factors including PDGF, epithelial growth factor, TGF-alpha or beta, tumour necrosis factor-alpha, interleukin-1, 2, 4 or 6, FGF, fibronectin, PF-4 and factor VIII AG. Also, in vivo, subcutaneous injection of ELF-153 megakaryoblastic leukaemia cells into nude mice formed, in three out of the five mice after 6 weeks, subcutaneous tumours with a very rigid texture whose histological examination revealed dense infiltration by blast cells and pronounced reticular fibrosis. Immunohistochemistry demonstrated exclusive deposition of collagen III in the extracellular matrix whereas laminin and collagen IV were absent.(ABSTRACT TRUNCATED AT 250 WORDS) Images Figure 1 Figure 2 PMID:7488550

  9. Taking control: findings of a prospective study of an educational course for patients with leukaemia.

    PubMed

    McGrath, P

    2000-09-01

    The challenge of coping with a chronic and life-threatening diagnosis such as a haematological malignancy, with the associated repeated, lengthy, and often invasive treatment interventions, can have a profound effect on all aspects of life. Patients and their families not only need information to help them understand the cancer experience, but also need support to generate coping strategies as the demands of the illness and its treatment exceed the individual's resources. Structured psycho-educational interventions, based on a strong informational component that aim to improve participants' adaptation to the disease and cancer situation, are one approach to providing such support. This article presents the findings from a recent prospective evaluation of the Leukaemia Foundation of Queensland's educational support course, Taking Control, which is designed for patients with a haematological malignancy and their families. The aim of this study was to record the participants' understanding of the positive and negative aspects and outcomes of course attendance. This is a prospective study of participants' perceptions of their experience with the 'Taking Control' course during the first half of 1999 (n =35; response rate 74.3%), using an author-designed, self-report questionnaire. The findings indicate that participants experience a high level of satisfaction, gain substantially in terms of knowledge, coping skills, and a positive framework within which to view their illness. Many obtain great value from the opportunity to meet and talk with others in similar situations. This study, which builds on previous retrospective research, affirms that this course has much to offer those who are confronted with the life-altering diagnosis of a haematological malignancy. However, the work also points to the need for special consideration to be given to a consistent minority of participants who will find socialising with their peers difficult whilst they are feeling so vulnerable

  10. Guidelines for the diagnosis and management of acute myeloid leukaemia in pregnancy.

    PubMed

    Ali, Sahra; Jones, Gail L; Culligan, Dominic J; Marsden, Philippa J; Russell, Nigel; Embleton, Nicholas D; Craddock, Charles

    2015-08-01

    Pregnant women should be managed by a multidisciplinary team that includes haematologists, obstetricians, neonatologists and anaesthetists (Grade 1C) As for non-pregnant patients, acute myeloid leukaemia (AML) should be diagnosed using the World Health Organization (WHO) classification (Grade 1A) Women diagnosed with AML in pregnancy should be treated without delay (Grade 1B) When the diagnosis of AML is made in the first trimester, a successful pregnancy outcome is unlikely and spontaneous pregnancy loss in this situation carries considerable risks for the mother. The reasons for and against elective termination should be discussed with the patient (Grade 2C) In the case of presentation beyond 32 weeks gestation, it may be reasonable to deliver the foetus prior to commencement of chemotherapy (Grade 2C) Between 24 and 32 weeks, risks of foetal chemotherapy exposure must be balanced against risks of prematurity following elective delivery at that stage of gestation (Grade 1C) The risk-benefit ratio must be carefully considered before using any drugs in pregnancy (Grade 1C) Where AML induction chemotherapy is delivered, a standard daunorubicin, cytarabine 3 + 10 schedule should be used (Grade 1B) Chemotherapy should be dosed according to actual body weight and adjustments made for weight changes during treatment (Grade 1C) Quinolones, tetracyclines and sulphonamide use should be avoided in pregnancy (Grade 1B) Amphotericin B or lipid derivatives are the antifungal of choice in pregnancy (Grade 2C) Cytomegalovirus (CMV)-negative blood products should be administered during pregnancy regardless of CMV serostatus (Grade 1B) A course of corticosteroids should be considered if delivery is anticipated between 24 and 35 weeks gestation, given over a 48-h period during the week prior to delivery (Grade 1A) Use of magnesium sulphate should be considered in the 24 h prior to delivery if this is before 30 weeks gestation (Grade 1A) Where possible, delivery should be

  11. Temporal association between childhood leukaemia and population growth in Swiss municipalities.

    PubMed

    Lupatsch, Judith E; Kreis, Christian; Zwahlen, Marcel; Niggli, Felix; Ammann, Roland A; Kuehni, Claudia E; Spycher, Ben D

    2016-08-01

    The population mixing hypothesis proposes that childhood leukaemia (CL) might be a rare complication of a yet unidentified subclinical infection. Large population influxes into previously isolated rural areas may foster localised epidemics of the postulated infection causing a subsequent increase of CL. While marked population growth after a period of stability was central to the formulation of the hypothesis and to the early studies on population mixing, there is a lack of objective criteria to define such growth patterns. We aimed to determine whether periods of marked population growth coincided with increases in the risk of CL in Swiss municipalities. We identified incident cases of CL aged 0-15 years for the period 1985-2010 from the Swiss Childhood Cancer Registry. Annual data on population counts in Swiss municipalities were obtained for 1980-2010. As exposures, we defined (1) cumulative population growth during a 5-year moving time window centred on each year (1985-2010) and (2) periods of 'take-off growth' identified by segmented linear regression. We compared CL incidence across exposure categories using Poisson regression and tested for effect modification by degree of urbanisation. Our study included 1500 incident cases and 2561 municipalities. The incident rate ratio (IRR) comparing the highest to the lowest quintile of 5-year population growth was 1.18 (95 % CI 0.96, 1.46) in all municipalities and 1.33 (95 % CI 0.93, 1.92) in rural municipalities (p value interaction 0.36). In municipalities with take-off growth, the IRR comparing the take-off period (>6 % annual population growth) with the initial period of low or negative growth (<2 %) was 2.07 (95 % CI 0.95, 4.51) overall and 2.99 (1.11, 8.05) in rural areas (p interaction 0.52). Our study provides further support for the population mixing hypothesis and underlines the need to distinguish take-off growth from other growth patterns in future research. PMID:27251152

  12. Dipeptide species regulate p38MAPK–Smad3 signalling to maintain chronic myelogenous leukaemia stem cells

    PubMed Central

    Naka, Kazuhito; Jomen, Yoshie; Ishihara, Kaori; Kim, Junil; Ishimoto, Takahiro; Bae, Eun-Jin; Mohney, Robert P.; Stirdivant, Steven M.; Oshima, Hiroko; Oshima, Masanobu; Kim, Dong-Wook; Nakauchi, Hiromitsu; Takihara, Yoshihiro; Kato, Yukio; Ooshima, Akira; Kim, Seong-Jin

    2015-01-01

    Understanding the specific survival of the rare chronic myelogenous leukaemia (CML) stem cell population could provide a target for therapeutics aimed at eradicating these cells. However, little is known about how survival signalling is regulated in CML stem cells. In this study, we survey global metabolic differences between murine normal haematopoietic stem cells (HSCs) and CML stem cells using metabolomics techniques. Strikingly, we show that CML stem cells accumulate significantly higher levels of certain dipeptide species than normal HSCs. Once internalized, these dipeptide species activate amino-acid signalling via a pathway involving p38MAPK and the stemness transcription factor Smad3, which promotes CML stem cell maintenance. Importantly, pharmacological inhibition of dipeptide uptake inhibits CML stem cell activity in vivo. Our results demonstrate that dipeptide species support CML stem cell maintenance by activating p38MAPK–Smad3 signalling in vivo, and thus point towards a potential therapeutic target for CML treatment. PMID:26289811

  13. Quality of different in-clinic test systems for feline immunodeficiency virus and feline leukaemia virus infection.

    PubMed

    Hartmann, Katrin; Griessmayr, Pascale; Schulz, Bianka; Greene, Craig E; Vidyashankar, Anand N; Jarrett, Os; Egberink, Herman F

    2007-12-01

    Many new diagnostic in-house tests for identification of feline immunodeficiency virus (FIV) and feline leukaemia virus (FeLV) infection have been licensed for use in veterinary practice, and the question of the relative merits of these kits has prompted comparative studies. This study was designed to define the strengths and weaknesses of seven FIV and eight FeLV tests that are commercially available. In this study, 536 serum samples from randomly selected cats were tested. Those samples reacting FIV-positive in at least one of the tests were confirmed by Western blot, and those reacting FeLV-positive were confirmed by virus isolation. In addition, a random selection of samples testing negative in all test systems was re-tested by Western blot (100 samples) and by virus isolation (81 samples). Specificity, sensitivity, positive and negative predictive values of each test and the quality of the results were compared. PMID:17604205

  14. T-chronic lymphocytic leukaemia presenting as primary hypogammaglobulinaemia--evidence of a proliferation of T-suppressor cells.

    PubMed Central

    Thien, S L; Catovsky, D; Oscier, D; Goldman, J M; van der Reijden, H J; Melief, C J; Rümke, H C; Ten Berge, R J; von dem Borne, A E

    1982-01-01

    A 63 year old man with late onset hypogammaglobulinaemia is described. Splenectomy, carried out because of marked splenomegaly and pancytopenia, demonstrated marked T lymphocytic infiltration in the splenic red pulp with prominent germinal centres. A persistent peripheral blood and bone marrow lymphocytosis ensued (10 X 10(9)/l and 40% respectively) and this was consistent with T-chronic lymphocytic leukaemia (T-CLL). Over 88% of his blood lymphocytes were E+, OKT3+, OKT8+ and OKT11+; 54% of the T lymphocytes had receptors for IgG (T gamma cells). Functional studies showed that the T lymphocytes of this patient lacked killer and natural killer cell function but they effectively suppressed the differentiation of normal B cells in a PWM stimulated system. It is suggested that the T-CLL in this patient resulted from the proliferation of the T suppressor subset which was responsible for his hypogammaglobulinaemia. Images Fig. 1 Fig. 2 PMID:6211309

  15. Can chronic myeloid leukaemia in children and adolescents be successfully treated without haematopoietic stem cell transplant? A single centre experience.

    PubMed

    Giona, Fiorina; Moleti, Maria L; De Benedittis, Daniela; Santopietro, Michelina; Nanni, Mauro; Testi, Anna M; Orlando, Sonia; Iori, Anna P; Piciocchi, Alfonso; Gottardi, Enrico; Barberi, Walter; Diverio, Daniela; Saglio, Giuseppe; Foà, Robin

    2016-06-01

    We analysed the long-term outcome of 35 children and adolescents (<20 years at diagnosis) with chronic myeloid leukaemia (CML) in chronic phase: 20 patients had received interferon-alpha and/or tyrosine kinase inhibitors (TKIs), and 15 underwent a haematopoietic stem cell transplant. The 10-year survival probabilities were similar in transplanted and non-transplanted patients (73·3% vs. 72·1%, respectively), whereas the survival probability was significantly lower in patients diagnosed before 1999 compared to those diagnosed afterwards (62·1% vs. 100%, P = 0·0384). The availability of TKIs and the standardized molecular monitoring have significantly improved treatment, management and outcome in children and adolescents with CML. PMID:26913809

  16. Clinical efficacy of second generation tyrosine kinase inhibitor and 5-azacytidine combination in chronic myelogenous leukaemia in myeloid blast crisis.

    PubMed

    Ghez, David; Micol, Jean-Baptiste; Pasquier, Florence; Auger, Nathalie; Saada, Véronique; Spentchian, Marc; Ianotto, Jean-Christophe; Bourhis, Jean-Henri; Bennaceur-Griscelli, Anelyse; Terré, Christine; Castaigne, Sylvie; Rigaudeau, Sophie; Rousselot, Philippe; de Botton, Stéphane

    2013-11-01

    Even in the tyrosine kinase inhibitors era, the prognosis of patients with chronic myeloid leukaemia in myeloid blast crisis remains dismal with few patients surviving longer than 6 months. Here we report the cases of 5 patients treated with the combination of 5-azacytidine and tyrosine kinase inhibitors for myeloid blast crisis CML. All patients achieved a complete haematological response including two with a complete cytogenetic and major molecular response. Two patients underwent an allogeneic stem cell transplantation. One died from relapse 34 months from diagnosis. The second is alive and free from disease at 11 months from diagnosis. The other 3 patients are still in complete haematological response after 15, 24 and 33 months of follow-up. These results suggest that the combination has a significant activity in myeloid blast crisis and may increase survival. PMID:23968731

  17. Development of chronic myeloid leukaemia in patients treated with anti-VEGF therapies for clear cell renal cell cancer.

    PubMed

    Czarnecka, Anna M; Oborska, Sylwia; Rzepecki, Piotr; Szczylik, Cezary

    2015-01-01

    Tyrosine kinase inhibitors are novel therapies targeting specific cellular signalling pathways. Sunitinib and sorafenib primarily block tyrosine kinase receptors involved in the progression of many tumours, including clear cell renal cell cancer (ccRCC). Although developed to target selected receptors, it is becoming apparent that they inhibit other kinases; this may result in the development of unexpected side effects. This is potentially dangerous as kinases on noncancerous cells are also inhibited. TKI off-target effects contributing to cardiotoxicity, hypothyroidism, hypertension, fatigue, hair depigmentation, hand-foot syndrome and gastrointestinal perforation have been described. We report three patients (3/412) treated with sunitinib and sorafenib who developed chronic myeloid leukaemia (CML) during treatment for ccRCC, proposing a molecular mechanism of tyrosine kinase inhibitors action on bone marrow cells that might be co-responsible for CML development. PMID:24953672

  18. IgA and IgM cytoplastic inclusions in a series of cases of chronic lymphocytic leukaemia.

    PubMed Central

    Cawley, J C; Smith, J; Goldstone, A H; Emmines, J; Hamblin, J; Hough, L

    1976-01-01

    Seventy-two cases of typical chronic lymphocytic leukaemia were screened by electron microscopy for the presence of intracytoplasmic immunoglobulin crystals. Immunoglobulin inclusions were found in four cases. Immunofluorescent studies showed that the inclusions contained IgA in two cases and IgM in the other two patients. Lambda light chain specificity was demonstrated in all four cases. The ultrastructure of the inclusions was identical in each patient except that in one of the IgA cases the inclusions were found in the perinuclear cistern in addition to the more usual location within cisternae of rough endoplasmic reticulum. Surface immunofluorescence showed mu heavy chains in the two cases displaying IgM crystal formation, but in the two IgA patients, no alpha heavy chains were demonstrable at the cell surface. The possible significance of these findings is discussed in relation to the existing literature. PMID:816582

  19. SWOG S0910: A Phase 2 Trial of Clofarabine/Cytarabine/Epratuzumab for Relapsed/Refractory Acute Lymphocytic Leukaemia

    PubMed Central

    Advani, Anjali S.; McDonough, Shannon; Coutre, Steven; Wood, Brent; Radich, Jerald; Mims, Martha; O’Donnell, Margaret; Elkins, Stephanie; Becker, Michael; Othus, Megan; Appelbaum, Frederick R.

    2014-01-01

    Summary Precursor B-acute lymphoblastic leukaemias (pre-B ALLs) comprise the majority of ALLs and virtually all blasts express CD22 in the cytoplasm and on the cell surface. In the present study (Southwestern Oncology Group S0910), we evaluated the addition of epratuzumab, a humanized monoclonal antibody against CD22, to the combination of clofarabine and cytarabine in adults with relapsed/refractory pre-B ALL. The response rate [complete remission and complete remission with incomplete count recovery ] was 52%, significantly higher than our previous trial with clofarabine/cytarabine alone, where the response rate was 17%. This result is encouraging and suggests a potential benefit to adding epratuzumab to chemotherapy for ALL; however, a randomized trial will be needed to answer this question. PMID:24579885

  20. SWOG S0910: a phase 2 trial of clofarabine/cytarabine/epratuzumab for relapsed/refractory acute lymphocytic leukaemia.

    PubMed

    Advani, Anjali S; McDonough, Shannon; Coutre, Steven; Wood, Brent; Radich, Jerald; Mims, Martha; O'Donnell, Margaret; Elkins, Stephanie; Becker, Michael; Othus, Megan; Appelbaum, Frederick R

    2014-05-01

    Precursor B-acute lymphoblastic leukaemias (pre-B ALLs) comprise the majority of ALLs and virtually all blasts express CD22 in the cytoplasm and on the cell surface. In the present study (Southwestern Oncology Group S0910), we evaluated the addition of epratuzumab, a humanized monoclonal antibody against CD22, to the combination of clofarabine and cytarabine in adults with relapsed/refractory pre-B ALL. The response rate [complete remission and complete remission with incomplete count recovery] was 52%, significantly higher than our previous trial with clofarabine/cytarabine alone, where the response rate was 17%. This result is encouraging and suggests a potential benefit to adding epratuzumab to chemotherapy for ALL; however, a randomized trial will be needed to answer this question. PMID:24579885

  1. A Novel Three-Colour Fluorescence in Situ Hybridization Approach for the Detection of t(7;12)(q36;p13) in Acute Myeloid Leukaemia Reveals New Cryptic Three Way Translocation t(7;12;16)

    PubMed Central

    Naiel, Abdulbasit; Vetter, Michael; Plekhanova, Olga; Fleischman, Elena; Sokova, Olga; Tsaur, Grigory; Harbott, Jochen; Tosi, Sabrina

    2013-01-01

    The t(7;12)(q36;p13) translocation is a recurrent chromosome abnormality that involves the ETV6 gene on chromosome 12 and has been identified in 20–30% of infant patients with acute myeloid leukaemia (AML). The detection of t(7;12) rearrangements relies on the use of fluorescence in situ hybridization (FISH) because this translocation is hardly visible by chromosome banding methods. Furthermore, a fusion transcript HLXB9-ETV6 is found in approximately 50% of t(7;12) cases, making the reverse transcription PCR approach not an ideal screening method. Considering the report of few cases of variant translocations harbouring a cryptic t(7;12) rearrangement, we believe that the actual incidence of this abnormality is higher than reported to date. The clinical outcome of t(7;12) patients is believed to be poor, therefore an early and accurate diagnosis is important in the clinical management and treatment. In this study, we have designed and tested a novel three-colour FISH approach that enabled us not only to confirm the presence of the t(7;12) in a number of patients studied previously, but also to identify a cryptic t(7;12) as part of a complex rearrangement. This new approach has proven to be an efficient and reliable method to be used in the diagnostic setting. PMID:24216708

  2. The rapamycin sensitivity of human T-cell leukaemia virus type I-induced T-cell proliferation is mediated independently of the polypyrimidine motifs in the 5' long terminal repeat.

    PubMed

    Rose, N; Lever, A

    2001-02-01

    The immunosuppressant rapamycin can regulate the translation of a subset of messenger RNAs, a phenotype which has been linked to the presence of a polypyrimidine motif [C(N)(4-14)] downstream of the mRNA cap structure. T-cell clones naturally infected with transcriptionally active human T-cell leukaemia virus, type I (HTLV-I) undergo autologous proliferation; this phenotype is inhibited by rapamycin but not FK506, which reverses the rapamycin effect. Within the R region of the HTLV-I 5' long terminal repeat (LTR) there are seven polypyrimidine motifs. We sought to determine if these were involved in the sensitivity of proliferation to the presence of rapamycin. Here we illustrate the generation of an in vitro model of this rapamycin-sensitivity and the analysis of LTR mutants which were created to determine the importance of the polypyrimidine motifs. Reporter gene assays suggest the effect is independent of the polypyrimidine motifs in the virus leader sequence. PMID:11161283

  3. Perforin- and granulysin-mediated cytotoxicity and interleukin 15 play roles in neurocognitive impairment in patients with acute lymphoblastic leukaemia.

    PubMed

    Petranovic, Duska; Pilcic, Gorazd; Valkovic, Toni; Sotosek Tokmadzic, Vlatka; Laskarin, Gordana

    2014-07-01

    Acute lymphoblastic leukaemia (ALL) is an aggressive disease. The course of disease is regulated by pro-inflammatory agents, and malignant cell infiltration of tissues plays a deleterious role in disease progression, greatly impacting quality of life, especially in the cognitive domains. Our hypothesis is that significant serum concentrations of interleukin 15 (IL-15) are responsible for higher expression of adhesion molecules on endothelial cells of blood-brain barrier (BBB) which allow leukaemia cells and/or normal lymphocytes the infiltration into the brain. In brain tissue these cells could be stimulated to release perforin and granulysin causing induction of apoptosis in brain cells that are involved in complex neural signalling mediated by neurotransmitters, and consequent fine cognitive impairment. Such changes could be detected early, even before notable clinical psycho-neurological or radiological changes in patients with ALL. To evaluate this hypothesis we propose measuring cognitive function using Complex Reactiometer Drenovac (CRD) scores in patients with ALL. The expression of different adhesion molecules on BBB as well as presence and distribution of different lymphocytes in brain tissue will be analyzed. We will then correlate CRD scores with levels of IL-15 and the percentages of T cells, natural killer T cells, and natural killer cells expressing perforin and/or granulysin proteins. CRD is a scientifically recognised and highly sensitive psychometric laboratory test based on the complex chronometric mathematical measuring of speed of reaction to various stimuli. It provides an objective assessment of cognitive functions from the most complex mental activities to the simplest reaction reflexes. Early recognition of cognitive dysfunction might be important when selecting the most appropriate chemotherapy and/or radiotherapy regimens, and could allow for the implementation of preventive measures against further deterioration in cognitive function and

  4. β-Arrestin1 promotes the progression of chronic myeloid leukaemia by regulating BCR/ABL H4 acetylation

    PubMed Central

    Qin, R; Li, K; Qi, X; Zhou, X; Wang, L; Zhang, P; Zou, L

    2014-01-01

    Background: β-Arrestins are scaffold proteins that interact with various cellular signals. Although β-arrestin2 mediates the initiation and progression of myeloid leukaemia, the critical role of β-arrestin1 in the chronic myeloid leukaemia (CML) is still unknown. The aim of this study is to investigate the essential function of β-arrestin1 in CML. Methods: The expressions of β-arrestin1 and BCR/ABL in CML patients, animal models and K562 cells were measured by RT–PCR, immunofluorescence and western blotting. The effect of β-arrestin1 on CML animal models and K562 cells by colony formation, MTT and survival analysis were assessed. BCR/ABL H4 acetylation was analysed through the use of Chromatin-immunoprecipitation (ChIP) -on-chip and confirmed by ChIP respectively. Co-immunoprecipitation and confocal were examined for the binding of β-arrestin1 with enhancer of zeste homologue 2 (EZH2). Results: The higher expression of β-arrestin1 is positively correlated with clinical phases of CML patients. Depletion of β-arrestin1 decelerates progression of K562 and primary cells, and increases survival of CML mice. Importantly, silenced β-arrestin1 results in the decrease of BCR/ABL H4 acetylation level in K562 cells. Further data illustrate that nuclear β-arrestin1 binds to EZH2 to mediate BCR/ABL acetylation and thus regulates cell progression in K562 cells and the survival of CML mice. Conclusions: Our findings reveal a novel function of β-arrestin1 binding to EZH2 to promote CML progression by regulating BCR/ABL H4 acetylation. PMID:24937675

  5. NALP1 is a transcriptional target for cAMP-response-element-binding protein (CREB) in myeloid leukaemia cells

    PubMed Central

    2004-01-01

    NALP1 (also called DEFCAP, NAC, CARD7) has been shown to play a central role in the activation of inflammatory caspases and processing of pro-IL1β (pro-interleukin-1β). Previous studies showed that NALP1 is highly expressed in peripheral blood mononuclear cells. In the present study, we report that expression of NALP1 is absent from CD34+ haematopoietic blast cells, and its levels are upregulated upon differentiation of CD34+ cells into granulocytes and to a lesser extent into monocytes. In peripheral blood cells, the highest levels of NALP1 were observed in CD3+ (T-lymphocytes), CD15+ (granulocytes) and CD14+ (monocytes) cell populations. Notably, the expression of NALP1 was significantly increased in the bone marrow blast cell population of some patients with acute leukaemia, but not among tissue samples from thyroid and renal cancer. A search for consensus sites within the NALP1 promoter revealed a sequence for CREB (cAMP-response-element-binding protein) that was required for transcriptional activity. Moreover, treatment of TF1 myeloid leukaemia cells with protein kinase C and protein kinase A activators induced CREB phosphorylation and upregulated the mRNA and protein levels of NALP1. Conversely, ectopic expression of a dominant negative form of CREB in TF1 cells blocked the transcriptional activity of the NALP1 promoter and significantly reduced the expression of NALP1. Thus NALP1 is transcriptionally regulated by CREB in myeloid cells, a mechanism that may contribute to modulate the response of these cells to pro-inflammatory stimuli. PMID:15285719

  6. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF).

    PubMed

    Rittchen, Sonja; Boyd, Amanda; Burns, Alasdair; Park, Jason; Fahmy, Tarek M; Metcalfe, Su; Williams, Anna

    2015-07-01

    Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS. PMID:25934281

  7. Myelin repair in vivo is increased by targeting oligodendrocyte precursor cells with nanoparticles encapsulating leukaemia inhibitory factor (LIF)

    PubMed Central

    Rittchen, Sonja; Boyd, Amanda; Burns, Alasdair; Park, Jason; Fahmy, Tarek M.; Metcalfe, Su; Williams, Anna

    2015-01-01

    Multiple sclerosis (MS) is a progressive demyelinating disease of the central nervous system (CNS). Many nerve axons are insulated by a myelin sheath and their demyelination not only prevents saltatory electrical signal conduction along the axons but also removes their metabolic support leading to irreversible neurodegeneration, which currently is untreatable. There is much interest in potential therapeutics that promote remyelination and here we explore use of leukaemia inhibitory factor (LIF), a cytokine known to play a key regulatory role in self-tolerant immunity and recently identified as a pro-myelination factor. In this study, we tested a nanoparticle-based strategy for targeted delivery of LIF to oligodendrocyte precursor cells (OPC) to promote their differentiation into mature oligodendrocytes able to repair myelin. Poly(lactic-co-glycolic acid)-based nanoparticles of ∼120 nm diameter were constructed with LIF as cargo (LIF-NP) with surface antibodies against NG-2 chondroitin sulfate proteoglycan, expressed on OPC. In vitro, NG2-targeted LIF-NP bound to OPCs, activated pSTAT-3 signalling and induced OPC differentiation into mature oligodendrocytes. In vivo, using a model of focal CNS demyelination, we show that NG2-targeted LIF-NP increased myelin repair, both at the level of increased number of myelinated axons, and increased thickness of myelin per axon. Potency was high: a single NP dose delivering picomolar quantities of LIF is sufficient to increase remyelination. Impact statement Nanotherapy-based delivery of leukaemia inhibitory factor (LIF) directly to OPCs proved to be highly potent in promoting myelin repair in vivo: this delivery strategy introduces a novel approach to delivering drugs or biologics targeted to myelin repair in diseases such as MS. PMID:25934281

  8. Archaeogeophysical data acquisition and analysis at Tel Burna, Israel: a valuable opportunity for ongoing ground-truth investigation and collaboration (Invited)

    NASA Astrophysics Data System (ADS)

    Pincus, J. A.

    2013-12-01

    Tel Burna is a site in the Shephelah breadbasket region of the southern part of Israel. It dates to the Bronze and Iron Age periods, 13th - 7th c. BCE. It has been suggested by scholars to be the Biblical site of Libnah. Libnah is mentioned in the Old Testament as an Israelite desert camp that Joshua encamped and fought against (Joshua 10:29-31; Joshua 12:15). Later it was given as a city to the children of Aaron, it joined the Edomites in a revolt against the King of Judah, and finally during the reign of Hezekiah, Libnah was besieged by Sennacherib (2 Kings 19:8, Isaiah 37:8). Today the tel has a flat-topped shape, has an extensive size, and there are clear casemate wall fortifications dating to the 7th c. BCE surrounding it. Thus far silos, floors, a Late Bronze period cultic area, figurines, and other intriguing artifacts have been unearthed at the site. The site is ideal for a case-study in archaeological geophysics method and interpretation in the region because (1) we are involving the method early in what is expected to be a long timeline of ongoing excavations; (2) it appears we have only a few occupation layers with significant architecture built directly on the bedrock; and (3) there is a relatively unconvoluted geological and pedological context. After conversations with the Director of the Tel Burna Archaeological Project, Itzick Shai, it was decided that out of the three areas actively being excavated a ground penetrating radar (GPR) survey of Area B would be most optimal at this time. The goal was to locate the extent of the archaeological material on the leveled area, while also providing better insight to the cultic area presently being excavated. Area B has proven to have been occupied during the Late Bronze Age IIB (13th c. BCE), as evidenced by the large public building associated with cultic remains, and a complex of walls. Using a 400 MHz antenna, a 30x20 meter grid was surveyed in June 2013. The spacing between each profile was 0.30 meters

  9. Genes and Gene Therapy

    MedlinePlus

    ... a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  10. Genes and Gene Therapy

    MedlinePlus

    ... correctly, a child can have a genetic disorder. Gene therapy is an experimental technique that uses genes to ... or prevent disease. The most common form of gene therapy involves inserting a normal gene to replace an ...

  11. Identification and developmental expression of the ets gene family in the sea urchin (Strongylocentrotus purpuratus).

    PubMed

    Rizzo, Francesca; Fernandez-Serra, Montserrat; Squarzoni, Paola; Archimandritis, Aristea; Arnone, Maria I

    2006-12-01

    A systematic search in the available scaffolds of the Strongylocentrotus purpuratus genome has revealed that this sea urchin has 11 members of the ets gene family. A phylogenetic analysis of these genes showed that almost all vertebrate ets subfamilies, with the exception of one, so far found only in mammals, are each represented by one orthologous sea urchin gene. The temporal and spatial expression of the identified ETS factors was also analyzed during embryogenesis. Five ets genes (Sp-Ets1/2, Sp-Tel, Sp-Pea, Sp-Ets4, Sp-Erf) are also maternally expressed. Three genes (Sp-Elk, Sp-Elf, Sp-Erf) are ubiquitously expressed during embryogenesis, while two others (Sp-Gabp, Sp-Pu.1) are not transcribed until late larval stages. Remarkably, five of the nine sea urchin ets genes expressed during embryogenesis are exclusively (Sp-Ets1/2, Sp-Erg, Sp-Ese) or additionally (Sp-Tel, Sp-Pea) expressed in mesenchyme cells and/or their progenitors. Functional analysis of Sp-Ets1/2 has previously demonstrated an essential role of this gene in the specification of the skeletogenic mesenchyme lineage. The dynamic, and in some cases overlapping and/or unique, developmental expression pattern of the latter five genes suggests a complex, non-redundant function for ETS factors in sea urchin mesenchyme formation and differentiation. PMID:16997294

  12. The effect of weekly short message service communication on patient retention in care in the first year after HIV diagnosis: study protocol for a randomised controlled trial (WelTel Retain)

    PubMed Central

    van der Kop, Mia L; Ojakaa, David I; Patel, Anik; Thabane, Lehana; Kinagwi, Koki; Ekström, Anna Mia; Smillie, Kirsten; Karanja, Sarah; Awiti, Patricia; Mills, Edward; Marra, Carlo; Kyomuhangi, Lennie Bazira; Lester, Richard T

    2013-01-01

    Introduction Interventions to improve retention in care after HIV diagnosis are necessary to optimise the timely initiation of antiretroviral therapy (ART) and HIV/AIDS control outcomes. Widespread mobile phone use presents new opportunities to engage patients in care. A randomised controlled trial (RCT), WelTel Kenya1, demonstrated that weekly text messages led to improved ART adherence and viral load suppression among those initiating ART. The aim of this study was to determine whether the WelTel intervention is an effective and cost-effective method of improving retention in care in the first year of care following HIV diagnosis. Methods and analysis WelTel Retain is an open, parallel group RCT that will be conducted at the Kibera Community Health Centre in Nairobi, Kenya. Over a 1-year period, we aim to recruit 686 individuals newly diagnosed with HIV who will be randomly allocated to an intervention or control arm (standard care) at a 1:1 ratio. Intervention arm participants will receive the weekly WelTel SMS ‘check-in’ to which they will be instructed to respond within 48 h. An HIV clinician will follow-up and triage any problems that are identified. Participants will be followed for 1 year, with a primary endpoint of retention in care at 12 months. Secondary outcomes include retention in stage 1 HIV care (patients return to the clinic to receive their first CD4 results) and timely ART initiation. Cost-effectiveness will be analysed through decision-analytic modelling. Ethics and dissemination Ethical approval has been obtained from the University of British Columbia and the African Medical and Research Foundation. This trial will test the effectiveness and cost-effectiveness of the WelTel intervention to engage patients during the first year of HIV care. Trial results and economic evaluation will help inform policy and practice on the use of WelTel in the early stages of HIV care. Trial registration ClinicalTrials.gov NCT01630304. PMID:23794578

  13. Co-Incidence or Co-Existence? Acute Lymphoblastic Leukaemia in HbE-alpha Thalassaemia: A Case Report with Review of Literature

    PubMed Central

    Rajendran, Rithika; Rajendran, Aruna; Scott, Julius Xavier

    2015-01-01

    Haemoglobin E (HbE) is a Haemoglobin variant that commonly occurs in many places in Asia. As β thalassaemia and α thalassaemia also occur in the same regions, the co-inheritance of these conditions leads to various phenotypic forms. HbE α thalassaemia is less common and of a milder phenotype than HbE β thalassaemia. Though malignancies are one of the complications in thalassaemia, occurrence of leukaemia is a rare event. Here we present a case of a two-year-old male child co-presenting with pre B acute lymphoblastic leukaemia (ALL) with MLL rearrangement and HbE alpha thalassaemia. The child is on remission 12 months post-therapy with standard ALL high risk protocol with no minimal residual disease (MRD). Haematological and oncological conditions coexisting at presentation is a challenge to therapy. This case is described for its rarity. Informed consent has been obtained from the parents. PMID:26672845

  14. Abundant macroscopic fat in intra-abdominal lymph nodes involved in the course of a patient with chronic lymphocytic leukaemia: presentation of imaging findings with biopsy correlation

    PubMed Central

    Karaosmanoglu, A D; Blake, M A; Lennerz, J K

    2012-01-01

    The presence of a small amount of macroscopic fat is not unusual in the hilar region of normal lymph nodes. However, abundant replacement of the lymph node with fat is highly unusual and may appear as metastatic lymph node disease in the course of fat-predominant liposarcomas or in the case of coeliac disease complicated by cavitating lymph node syndrome. In this case report, a patient with chronic lymphocytic leukaemia/small lymphocytic lymphoma who demonstrated an increasing abundance of macroscopic fat in the diseased lymph nodes is presented. To the best of our knowledge, the imaging findings of abundant fat in lymph nodes in the course of lymphoma have not been reported before. The presence of macroscopic fat may be seen in the presence of actively involved lymph nodes in the presence of chronic lymphocytic leukaemia. PMID:22457415

  15. Acute promyelocytic leukaemia (APL) in a patient with Crohn's disease and exposure to infliximab: a rare clinical presentation and review of the literature.

    PubMed

    Mohammad, Farhan; Vivekanandarajah, Abhirami; Haddad, Housam; Shutty, Christopher M; Hurford, Matthew T; Dai, Qun

    2014-01-01

    With the introduction of potent immunosuppressive and chemotherapeutic medications for various diseases, there is an increased incidence of therapy-related myeloid neoplasms. They are the result of mutational rearrangement and historically, have a grave prognosis compared with de novo myeloid neoplasms. We did a short review on various types of myeloid leukaemias reported after therapy with antitumour necrosis factor and also report, to the best of our knowledge, one among the very few cases of therapy-related acute promyelocytic leukaemia in a patient on infliximab therapy for refractory Crohn's disease. The patient responded well to the traditional treatment and is in complete remission for more than 5 years. PMID:24842356

  16. Apoptosis induced by paclitaxel via Bcl-2, Bax and caspases 3 and 9 activation in NB4 human leukaemia cells is not modulated by ERK inhibition.

    PubMed

    Morales-Cano, Daniel; Calviño, Eva; Rubio, Virginia; Herráez, Angel; Sancho, Pilar; Tejedor, M Cristina; Diez, José C

    2013-11-01

    We have studied the role of pivotal bio-molecules involved in signalling of cytotoxic effects induced by paclitaxel (Ptx) on acute promyelocytic human leukaemia NB4 cells. A time-dependent increase in cell death and DNA cleavage was observed after 30μM Ptx treatment. Cell death induction by Ptx proceeds mainly as programmed cell death as shown by annexin V-FITC, reaching up to 30% of apoptotic cells after 24h. Significant reductions of p53, changes in Bax and Bcl-2 and activation of caspases 3 and 9 were observed as the treatment was applied for long times. Ptx treatments produced NFkB depletion with expression levels abolished at 19h what could be involved in reduction of survival signals. Phosphorylation of intracellular kinases showed that pERK1/2 decreased significantly at 19h of Ptx treatment. When these cells were preincubated for 90min with 20μM PD98059, 2'-amino-3'-methoxyflavone, an inhibitor of ERK phosphorylation, a slight reduction of cell viability was observed in comparison to that produced by Ptx alone. Pretreatment with PD98059 neither activated caspases nor significantly increased the apoptotic effect of Ptx. Taken together, our data reveal that the inhibition of ERK phosphorylation does not seem to be an essential pathway for bursting an increased induction of apoptosis by Ptx. Decrease of p53 and Bcl-2, fragmentation of DNA, increase of Bax and, finally, activation of caspases 3 and 9 in NB4 leukaemia cells make the apoptotic process induced by Ptx irreversible. Application of Ptx in leukaemia cells shows therefore a promising potential with particular effects on different leukaemia cell types. PMID:23735541

  17. Activating and inhibitory killer immunoglobulin-like receptors (KIR) in haploidentical haemopoietic stem cell transplantation to cure high-risk leukaemias.

    PubMed

    Moretta, A; Pende, D; Locatelli, F; Moretta, L

    2009-09-01

    A number of experimental studies have shown that natural killer (NK) cells can eliminate cancer cells and the mechanisms involved in this effect have been uncovered during the last two decades. Clinical data from haploidentical haematopoietic stem cell transplantation (haplo-HSCT) revealed that NK cells were responsible for remarkably favourable effects in both adult and paediatric high-risk leukaemias. NK receptors specific for major histocompatibility complex (MHC) class I molecules, including killer immunoglobulin (Ig)-like receptors (KIR) and CD94/NKG2A, play a major role in the anti-leukaemia effect (mediating either inhibitory or activating signals). Haplo- HSCT requires a heavy conditioning regimen for the patient and the use of large numbers of T cell-depleted HSC to be grafted. After transplantation, natural killer cells develop from HSC shortly after engraftment and may include 'alloreactive' NK cells that kill leukaemic cells and prevent graft-versus-host disease (GvHD). Alloreactive NK cells are characterized by the expression of KIR that are not engaged by any of the human leucocyte antigen (HLA) class I alleles expressed by the patient. Their generation is dependent upon the existence of a KIR/HLA class I mismatch between donor and recipient. Novel important information on the function and specificity of different KIR has been obtained recently by the analysis of donor-derived alloreactive NK cells in a cohort of paediatric patients given haplo-HSCT to cure acute, high-risk leukaemias. PMID:19664139

  18. The Beginning of Metallurgy in the Southern Levant: A Late 6th Millennium CalBC Copper Awl from Tel Tsaf, Israel

    PubMed Central

    Garfinkel, Yosef; Klimscha, Florian; Shalev, Sariel; Rosenberg, Danny

    2014-01-01

    The beginning of metallurgy in the ancient Near East attracts much attention. The southern Levant, with the rich assemblage of copper artifacts from the Nahal Mishmar cave and the unique gold rings of the Nahal Qanah cave, is regarded as a main center of early metallurgy during the second half of the 5th millennium CalBC. However, a recently discovered copper awl from a Middle Chalcolithic burial at Tel Tsaf, Jordan Valley, Israel, suggests that cast metal technology was introduced to the region as early as the late 6th millennium CalBC. This paper examines the chemical composition of this item and reviews its context. The results indicate that it was exported from a distant source, probably in the Caucasus, and that the location where it was found is indicative of the social status of the buried individual. This rare finding indicates that metallurgy was first defused to the southern Levant through exchange networks and only centuries later involved local production. This copper awl, the earliest metal artifact found in the southern Levant, indicates that the elaborate Late Chalcolithic metallurgy developed from a more ancient tradition. PMID:24671185

  19. The beginning of metallurgy in the southern Levant: a late 6th millennium CalBC copper awl from Tel Tsaf, Israel.

    PubMed

    Garfinkel, Yosef; Klimscha, Florian; Shalev, Sariel; Rosenberg, Danny

    2014-01-01

    The beginning of metallurgy in the ancient Near East attracts much attention. The southern Levant, with the rich assemblage of copper artifacts from the Nahal Mishmar cave and the unique gold rings of the Nahal Qanah cave, is regarded as a main center of early metallurgy during the second half of the 5th millennium CalBC. However, a recently discovered copper awl from a Middle Chalcolithic burial at Tel Tsaf, Jordan Valley, Israel, suggests that cast metal technology was introduced to the region as early as the late 6th millennium CalBC. This paper examines the chemical composition of this item and reviews its context. The results indicate that it was exported from a distant source, probably in the Caucasus, and that the location where it was found is indicative of the social status of the buried individual. This rare finding indicates that metallurgy was first diffused [corrected] to the southern Levant through exchange networks and only centuries later involved local productionThis copper awl, the earliest metal artifact found in the southern Levant, indicates that the elaborate Late Chalcolithic metallurgy developed from a more ancient tradition. PMID:24671185

  20. Inositol pyrophosphates mediate the DNA-PK/ATM-p53 cell death pathway by regulating CK2 phosphorylation of Tti1/Tel2

    PubMed Central

    Rao, Feng; Cha, Jiyoung; Xu, Jing; Xu, Risheng; Vandiver, M. Scott; Tyagi, Richa; Tokhunts, Robert; Koldobskiy, Michael A.; Fu, Chenglai; Barrow, Roxanne; Wu, Mingxuan; Fiedler, Dorothea; Barrow, James C.; Snyder, Solomon H.

    2014-01-01

    The apoptotic actions of p53 require its phosphorylation by a family of phosphoinositide-3-kinase-related-kinases (PIKKs), which include DNA-PKcs and ATM. These kinases are stabilized by the TTT (Tel2, Tti1, Tti2) co-chaperone family, whose actions are mediated by CK2 phosphorylation. The inositol pyrophosphates, such as 5-diphosphoinositol pentakisphosphate (IP7), are generated by a family of inositol hexakisphosphate kinases (IP6Ks) of which IP6K2 has been implicated in p53-associated cell death. In the present study we report a novel apoptotic signaling cascade linking CK2, TTT, the PIKKs, and p53. We demonstrate that IP7, formed by IP6K2, binds CK2 to enhance its phosphorylation of the TTT complex thereby stabilizing DNA-PKcs and ATM. This process stimulates p53 phosphorylation at serine-15 to activate the cell death program in human cancer cells and in murine B cells. PMID:24657168