15 research outputs found
Association of peripheral edema on body composition analysis in patients with heart failure
No full textGenome Wide Analysis of Acute Myeloid Leukemia Reveal Leukemia Specific Methylome and Subtype Specific Hypomethylation of Repeats
No full textPMCID: PMC3315563This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited
TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma
No full textProliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor {kappa}B (NF-{kappa}B). NF-{kappa}B activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV+) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV– cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-{kappa}B target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-{kappa}B activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-{kappa}B activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV– than EBV+ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis
Short-run pain, long-run gain : the effects of financial liberalization
No full textThe authors examine the short- and long-run effects of financial liberalization on capital markets. To do so, they construct a new comprehensive chronology of financial liberalization in 28 developed and emerging economies since 1973. The authors also construct an algorithm to identify booms and busts in stock market prices. The results indicate that financial liberalization is followed by more pronounced boom-bust cycles in the short run. But financial liberalization leads to more stable markets in the long run. Finally, the authors analyze the sequencing of liberalization and institutional reforms to understand the contrasting short- and long-run effects of liberalization.Insurance Law,Insurance&Risk Mitigation,Fiscal&Monetary Policy,Economic Theory&Research,Payment Systems&Infrastructure,Financial Economics,Economic Theory&Research,Insurance&Risk Mitigation,Insurance Law,Financial Intermediation
The investigation and design of a piezoelectric active vibration control system for vertical machining centres
No full textThe clinical and biological consequences of different FLT3 mutations in patients with AML
No full textCharacterisation of pathogenic markers in acute myeloid leukaemia (AML) may benefit
patients through refinement of risk stratification, application of molecularly targeted
therapy and improved understanding of AML biology. Whilst the presence of an
internal tandem duplication (ITD) within the fms-like tyrosine kinase-3 (FLT3) gene is
known to predict adverse outcome in young adults with AML, the clinical significance
of activating mutations in the tyrosine kinase domain (TKD) of FLT3 is unclear.
Therefore, a highly sensitive and specific denaturing-HPLC technique was developed to
screen for FLT3/TKDs in 1339 young adult patients with AML. Mutations were
detected in 161 (12%) cases, with a high incidence in patients with inv(16) (24%;
P=.009), a group in which FLT3/ITDs are uncommon. Unlike FLT3/ITDs, FLT3/TKDs
were associated with a favourable long-term outcome with a 10-year overall survival
(OS) of 36% for FLT3 WT, 51% for FLT3/ITD-TKD+ and 24% for FLT3/ITD+TKDpatients
(P<.001). The relative FLT3/TKD mutant level was highly variable with the
favourable prognosis residing in those patients with greater than 25% mutant alleles
(10-year OS of 59%), possibly reflecting the stage at which the mutation is acquired.
The mechanism of FLT3 activation also influenced sensitivity to FLT3-inhibitor
induced cytotoxicity, with FLT3/ITD+ blast cells more sensitive than FLT3/TKD+ cells.
Following lentiviral transduction, FLT3/ITD-transduced 32Dcl3 and Ba/F3 cells
demonstrated more rapid proliferation than FLT3/TKD-transduced cells. In an NB4 cell
line model of ATRA-induced myeloid differentiation, the presence of a FLT3/ITD
inhibited differentiation unlike a FLT3/TKD mutation which increased differentiation.
Furthermore, FLT3/ITD-transduced CD34 positive haematopoietic stem cells showed
greater cytokine-free survival of colony forming cells than FLT3/TKD-transduced cells.
Signalling studies also revealed that a FLT3/ITD induced stronger STAT5 activation
than a FLT3/TKD mutation. This unexpected genotype-phenotype relationship is of
direct relevance to current clinical decision making in AML, and may also provide
insights into mechanisms of chemoresistance
Continued low-dose decitabine (DAC) is an active first-line treatment in all cytogenetic subgroups of older AML patients: Results of the FR00331 multicenter phase II study
No full textCharacterisation of T cell defects in acute myeloid leukaemia
No full textPhDUnderstanding the immune system in patients with cancer and how it interacts with malignant cells is critical for the development of successful immunotherapeutic strategies at a time when novel cancer treatment approaches are required. Acute myeloid leukaemia (AML) results in widespread interaction between the malignant cells and T cells and as such, offers an opportunity to study these interactions. A flow cytometric analysis of T cells in the peripheral blood of patients presenting with AML illustrated that the absolute number of T cells is increased in AML compared with healthy controls. Furthermore, a large population of CD3+56+ cells was identified. These cells are not natural killer T cells but effector T cells that may represent a failing immunosurveillance mechanism. Two technical issues were explored: how to separate T cells from the peripheral blood of newly diagnosed AML patients and the impact of the method of immunomagnetic cell separation on the gene expression profile of healthy T cells. Gene expression profiling was subsequently performed on T cells from AML patients compared with healthy controls. Global differences in transcription were observed suggesting aberrant T cell activation patterns in AML. As differentially regulated genes involved in actin cytoskeletal formation were noted, a functional assessment of the ability of T cells from AML patients to form immunological synapses was performed. This illustrated that although T cells from AML patients can form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signalling molecules to that signalling interface is impaired. Taken together, these findings demonstrate that numerically T cells are plentiful in AML however they are abnormal in terms of the genes they are transcribing and in their interactions with tumour cells. Targeting immunological synapse formation may represent an important means of improving T cell recognition of tumour cells across a range of cancers
A multicenter phase ii trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy
No full textBackground. Acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large prospective studies have been performed in this indication. With the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (Decitabine) in MDS and acute myeloid leukemia with 20-30% bone marrow blasts, we asked whether this drug is also active in patients with >30% blasts.Design and Methods. To evaluate efficacy and toxicity of Decitabine in untreated acute myeloid leukemia patients >60 years ineligible for induction chemotherapy, 227 patients (median age 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome (MDS) were treated. During the initial Decitabine treatment (135 mg/m2 total dose infused intravenously over 72 hours every 6 weeks), a median of 2 cycles was administered (range 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients completing 4 cycles of treatment subsequently received a median of 5 maintenance courses (range 1-19) with a lower dose of Decitabine (20 mg/m2) infused over 1 hour on 3 consecutive days every 4-6 weeks.Results. The complete and partial remission rate was 26% (95% CI: 20%, 32%), an antileukemic effect was noted in 26%. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes responded also. Median overall survival from start of Decitabine was 5.5 months (range, 0-57.5+), 1-year survival 28% (95%CI: 22%, 34%). Toxicities were predominantly hematologic.Conclusions. Decitabine is well tolerated by older, medically non-fit acute myeloid leukemia patients, myelosuppression being the major toxicity. Response rate and overall survival were not adversely influenced by poor-risk cytogenetics or MDS. Because of these encouraging results, randomized studies evaluating single-agent Decitabine versus conventional treatment are warranted. The study is registered with WHO primary registry German Clinical Trials Registry, number DRKS00000069.sponsorship: Acknowledgements: we would like to express our gratitude to the dedicated clinical study teams of all participating Centers, with special thanks to Christine Kalkhof, Cordula Heers, Petra Kinzel, Jessica Baumer, Ljudmila Bogatyreva and Dr. Roland Weis in Freiburg. We thank Guillermo Garcia-Manero for sharing unpublished data, and Drs. Hartmut Henss, Roland Mertelsmann and Michael Cullen for continued helpful discussions. This work was supported in part by the German Jose Carreras Leukemia Foundation (grant F06/04 to BD), and the European LeukemiaNet (WP5, WP8). (German Jose Carreras Leukemia Foundation|F06/04, European LeukemiaNet|WP5, European LeukemiaNet|WP8)status: Publishe
Hematopoietic stem cell allografting for chronic lymphocytic leukemia: A focus on reduced-intensity conditioning regimens
No full textBackground: Allogeneic hematopoietic cell transplantation (allo-HCT) remains the only known treatment modality that currently offers a potential cure to patients with chronic lymphocytic leukemia (CLL). A better understanding of the role of adoptive immunotherapy and its consequent bona fide graft-vs-leukemia (GVL) effect has resulted in a reduction of the ablative intensity and toxicity of preparative allo-HCT regimens. Methods: The authors review the published data of reduced-intensity conditioning (RIC) allo-HCT in patients with CLL. Results: RIC allo-HCT has reduced the transplant associated morbidity and mortality of the procedure and has consequently broadened applicability of allo-HCT to patients with CLL who are generally of more advanced age ( 60 years) and who often have associated comorbidities. Conclusions: Published literature supports the use of RIC allo-HCT for these patients once a suitable donor is identified, provided they fulfill acceptable consensus criteria for hematopoietic stem cell allografting. Several studies have shown that T-cell-replete RIC allo-HCT is also capable of overcoming the adverse effect of poor prognostic factors in CLL such as del(17p), unmutated IgVH, or ZAP-70 expression. Continued clinical trials to identify the optimal regimen for RIC allo-HCT for patients with CLL are warranted.Bacigalupo A, 2009, BIOL BLOOD MARROW TR, V15, P1628, DOI 10.1016-j.bbmt.2009.07.004; Brown JR, 2006, BIOL BLOOD MARROW TR, V12, P1056, DOI 10.1016-j.bbmt.2006.06.004; Caballero D, 2005, CLIN CANCER RES, V11, P7757, DOI 10.1158-1078-0432.CCR-05-0941; CANNONALBRIGHT LA, 1994, CANCER RES, V54, P2378; Crespo M, 2003, NEW ENGL J MED, V348, P1764, DOI 10.1056-NEJMoa023143; Delgado J, 2009, ANN ONCOL, V20, P2007, DOI 10.1093-annonc-mdp259; Delgado J, 2006, BLOOD, V107, P1724, DOI 10.1182-blood-2005-08-3372; Dohner H, 2000, NEW ENGL J MED, V343, P1910, DOI 10.1056-NEJM200012283432602; Doney KC, 2002, BONE MARROW TRANSPL, V29, P817, DOI 10.1038-sj-bmt-1703548; Dreger P, 2005, LEUKEMIA, V19, P1029, DOI 10.1038-sj.leu.2403745; Dreger P, 2010, BLOOD, V116, P2438, DOI 10.1182-blood-2010-03-275420; Dreger P, 2003, LEUKEMIA, V17, P841, DOI 10.1038-sj.leu.2402905; Dreger P, 2007, LEUKEMIA, V21, P12, DOI 10.1038-sj.leu.2404441; Elter T, 2005, J CLIN ONCOL, V23, P7024, DOI 10.1200-JCO.2005.01.9950; Fischer K, 2009, BLOOD, V114, P205; Goldin LR, 2009, HAEMATOL-HEMATOL J, V94, P647, DOI 10.3324-haematol.2008.003632; Gribben JG, 2005, BLOOD, V106, P4389, DOI 10.1182-blood-2005-05-1778; Hamblin TJ, 2002, BLOOD, V99, P1023, DOI 10.1182-blood.V99.3.1023; Kay NE, 2007, BLOOD, V109, P405, DOI 10.1182-blood-2006-07-033274; Kharfan-Dabaja MA, 2007, BRIT J HAEMATOL, V139, P234, DOI 10.1111-j.1365-2141.2007.06773.x; Khartan-Dabaja MA, 2008, CANCER, V113, P897, DOI 10.1002-cncr.23671; Kharfan-Dabaja MA, 2007, BIOL BLOOD MARROW TR, V13, P373, DOI 10.1016-j.bbmt.2007.01.075; Khouri IF, 2007, BRIT J HAEMATOL, V137, P355, DOI 10.1111-j.1365-2141.2007.06591.x; Khouri IF, 2001, BLOOD, V98, P3595, DOI 10.1182-blood.V98.13.3595; KOLB HJ, 1990, BLOOD, V76, P2462; Lamanna N, 2006, J CLIN ONCOL, V24, P1575, DOI 10.1200-JCO.2005.04.3836; Malhotra P, 2008, LEUKEMIA LYMPHOMA, V49, P1724, DOI 10.1080-10428190802263535; Michallet M, 1996, ANN INTERN MED, V124, P311; Michallet MM, 2003, BLOOD, V102, p474A; Nishida T, 2009, CLIN CANCER RES, V15, P4759, DOI 10.1158-1078-0432.CCR-09-0199; Pavletic ZS, 2005, J CONTRACEPT FERTIL, V23, P5788; Pavletic ZS, 2000, BONE MARROW TRANSPL, V25, P717, DOI 10.1038-sj.bmt.1702237; Peres E, 2009, BONE MARROW TRANSPL, V44, P579, DOI 10.1038-bmt.2009.61; Ritgen M, 2004, BLOOD, V104, P2600, DOI 10.1182-blood-2003-12-4321; Ritgen M, 2008, LEUKEMIA, V22, P1377, DOI 10.1038-leu.2008.96; Schetelig J, 2003, J CLIN ONCOL, V21, P2747, DOI 10.1200-JCO.2003.12.011; Schetelig J, 2008, J CLIN ONCOL, V26, P5094, DOI 10.1200-JCO.2008.16.2982; Slavin S, 1995, EXP HEMATOL, V23, P1553; Sorror ML, 2008, J CLIN ONCOL, V26, P4912, DOI 10.1200-JCO.2007.15.4757; Stem Cell Trialists' Collaborative Group, 2005, J CONTRACEPT FERTIL, V23, P5074; Tam CS, 2008, BLOOD, V112, P975, DOI 10.1182-blood-2008-02-140582; Toze CL, 2005, BONE MARROW TRANSPL, V36, P825, DOI 10.1038-sj.bmt.1705130; Wierda W, 2005, J CLIN ONCOL, V23, P4070, DOI 10.1200-JCO.2005.12.5168121
