bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of PML as novel PAX5 fusion partner in childhood acute lymphoblastic leukaemia
Authors: Nebral Karin , König Margit , Harder Lana , Siebert Reiner , Haas Oskar A. , Strehl Sabine 
Published: September 2007

Summary PAX5 encodes the B‐cell lineage specific activator protein (BSAP) and is required for B‐cell development and maintenance. In B‐cell precursor acute lymphoblastic leukaemia (ALL), PAX5 is involved in several chromosome translocations that fuse the N‐terminal paired DNA‐binding domain of PAX5 with the C‐terminal regulatory sequences of ETV6, FOXP1, ZNF521 or ELN. Herein, we describe the identification of a novel recurrent t(9;15)(p13;q24) in two cases of childhood ALL, which results in an in‐frame fusion of PAX5 to the promyelocytic leukaemia (PML) gene. The putative PAX5‐PML fusion gene encodes a chimaeric protein that retains the paired domain, the octapeptid and the partial homeodomain of PAX5, and virtually the whole PML protein. The steadily increasing number of PAX5 rearrangements suggests that PAX5 is not only crucial for B‐cell lymphopoiesis but also for the development of B‐cell malignancies.
In vitro expansion of gamma delta T cells with anti‐myeloma cell activity by Phosphostim and IL‐2 in patients with multiple myeloma
Authors: Burjanadzé Maka , Condomines Maud , Reme Thierry , Quittet Philippe , Latry Pascal , Lugagne Cécile , Romagne François , Morel Yanis , Rossi Jean François , Klein Bernard , Lu Zhao Yang 
Published: September 2007

SummaryT‐cell‐mediated immunotherapy is a promising therapeutic option for multiple myeloma (MM). Gamma‐delta T cells (γδ T cells) recognize phosphoantigens and display strong anti‐tumour cytotoxicity. The synthetic agonist Phosphostim (bromohydrin pyrophosphate, BrHPP) has been shown to selectively activate Vγ9Vδ2 T cells. This study aimed to evaluate the expansion capacity and anti‐myeloma cell cytotoxicity of circulating γδ T cells from MM patients at different time points throughout the disease, using Phosphostim and interleukin 2 (IL‐2). Circulating γδ T cell counts in patients with newly diagnosed MM or in relapse did not differ from those in healthy donors. A 14‐d culture of peripheral blood mononuclear cells with Phosphostim and IL‐2 triggered a 100‐fold expansion of γδ T cells in 78% of newly diagnosed patients. γδ T cells harvested at the time of haematopoietic progenitor collection or in relapsing patients expanded less efficiently. Expanded γδ T cells killed 13/14 myeloma cell lines as well as primary myeloma cells, but not normal CD34 cells. Their killing efficiency was not affected by 2‐d IL‐2 starvation. This study demonstrated the ability of Phosphostim and IL‐2 to expand γδ T cells from MM patients, and the efficient and stable killing of human myeloma cells by gd T cells.
M4 and M5 acute myeloid leukaemias display a high sensitivity to Bortezomib‐mediated apoptosis
Authors: Riccioni Roberta , Senese Mara , Diverio Daniela , Riti Viviana , Buffolino Sonia , Mariani Gualtiero , Boe Alessandra , Cedrone Michele , Lo‐Coco Francesco , Foà Robin , Peschle Cesare , Testa Ugo 
Published: September 2007

SummaryThe present study explored the sensitivity of leukaemic blasts derived from 30 acute myeloid leukaemia (AML) patients to Bortezomib. Bortezomib induced apoptosis of primary AML blasts: 18/30 AMLs were clearly sensitive to the proapoptotic effects of Bortezomib, while the remaining cases were moderately sensitive to this molecule. The addition of tumour necrosis factor‐related‐apoptosis‐inducing ligand, when used alone, did not induce apoptosis of AML blasts and further potentiated the cytotoxic effects of Bortezomib. The majority of AMLs sensitive to Bortezomib showed immunophenotypic features of the M4 and M5 French–American–British classification subtypes and displayed myelomonocytic features. All AMLs with mutated FLT3 were in the Bortezomib‐sensitive group. Biochemical studies showed that: (i) Bortezomib activated caspase‐8 and caspase‐3 and decreased cellular FLICE [Fas‐associated death domain (FADD)‐like interleukin‐1β‐converting enzyme]‐inhibitory protein (c‐FLIP) levels in AML blasts; (ii) high c‐FLIP levels in AML blasts were associated with low Bortezomib sensitivity. Finally, analysis of the effects of Bortezomib on leukaemic cells displaying high aldehyde dehydrogenase activity suggested that this drug induced in vitro killing of leukaemic stem cells. The findings of the present study, further support the development of Bortezomib as an anti‐leukaemic drug and provide simple tools to predict the sensitivity of AML cells to this drug.
Circulating DNA: a potential marker of sickle cell crisis
Authors: Vasavda Nisha , Ulug Pinar , Kondaveeti Sheila , Ramasamy Karthik , Sugai Taku , Cheung Gordon , Rees David C. , Awogbade Moji , Bannister Sybil , Cunningham Juliette , Menzel Stephan , Thein Swee Lay 
Published: September 2007

SummaryFree circulating DNA is present in the plasma of healthy subjects, and is elevated in conditions characterized by increased cell death, such as cancer and physical trauma. Analysis of circulating DNA in plasma could provide a useful biomarker in sickle cell disease (SCD) in view of the increased cell turnover through chronic ongoing haemolysis, recurrent vaso‐occlusion and inflammation. Plasma DNA was determined by real‐time quantitative polymerase chain reaction (PCR) amplification of the β‐globin gene (HBB) in 154 patients with SCD [105 haemoglobin (Hb)SS, 46 HbSC and three HbS/β0 thalassaemia] and 53 ethnically matched controls. Blood samples were obtained from all patients in steady state; 21 of the 154 patients were also sampled during admission to hospital for acute pain. Median concentration of circulating plasma DNA in acute pain was more than 10‐fold that in steady state and in controls – 10070 vs. 841 and 10070 vs. 933 genome equivalents/ml respectively (P < 0·0001, in both cases). During steady state, patients had plasma DNA levels similar to controls. Plasma DNA levels in SCD correlated with C‐reactive protein levels (P < 0·005) and total white cell counts (P < 0·05) in steady state. The study shows that plasma DNA concentration may have potential as a biomarker in sickle cell patients.
Picogram doses of lipopolysaccharide exacerbate antibody‐mediated thrombocytopenia and reduce the therapeutic efficacy of intravenous immunoglobulin in mice
Authors: Tremblay Tony , Aubin Éric , Lemieux Réal , Bazin Renée 
Published: September 2007

SummaryExacerbation of antibody‐mediated thrombocytopenia following infection with viruses has recently been demonstrated in a mouse model of the disease. The phenomenon was caused by an increased activation of phagocytes through gamma‐interferon secretion in response to infection. Endotoxins from Gram‐negative bacteria are also known to be potent activators of phagocytic cells. The objective of the present work was to determine whether lipopolysaccharide (LPS) could exacerbate antibody‐mediated thrombocytopenia in vivo and so alter the therapeutic efficacy of intravenous immunoglobulin (IVIg), using a mouse model of thrombocytopenia. Very low doses of LPS (picogram range) and of anti‐platelet antibodies (nanogram range), which did not induce thrombocytopenia individually, could synergize in vivo, resulting in significant decreases in platelet counts. The therapeutic efficacy of IVIg in antibody‐mediated thrombocytopenia was significantly reduced in presence of LPS. These in vivo observations further support a role for bacterial infections in the aetiology of immune thrombocytopenic purpura (ITP) and may contribute to better understand the recognized lack of efficacy of IVIg in a significant proportion of patients with ITP.
Loss of expression of LyGDI (ARHGDIB), a rho GDP‐dissociation inhibitor, in Hodgkin lymphoma*
Authors: Ma Liya , Xu Gaixiang , Sotnikova Anna , Szczepanowski Monika , Giefing Maciej , Krause Kristina , Krams Matthias , Siebert Reiner , Jin Jie , Klapper Wolfram 
Published: September 2007

SummaryThe guanosine triphosphatase (GTPase) inhibitor LyGDI (ARHGDIB, Ly/D4‐GDI, RhoGDIb or RhoGDI 2) is abundantly expressed in haematopoetic cells and possibly plays a role in the onset of apoptosis. Gene expression profiling of Hodgkin cell lines revealed that LyGDI expression was downregulated in these cell lines. The present study evaluated the expression of LyGDI in Hodgkin cells in vivo and studied the function of LyGDI in Hodgkin cell lines in vitro. Our results showed that virtually all Hodgkin and Reed‐Sternberg cells in classical Hodgkin lymphoma lacked LyGDI protein expression. On the other hand, almost all non‐Hodgkin lymphomas, except for anaplastic large cell lymphomas, expressed LyGDI protein. Transfection of the classical Hodgkin cell line L428 with a vector containing full‐length LyGDI‐induced apoptosis in a subset of cells. However, the majority of Hodgkin cells with transgenic expression of LyGDI escaped apoptosis. Our data show that lack of LyGDI expression is a frequent feature of cHL but that it is not of vital importance for the growth and survival of these cells.
Unbalanced protein S deficiency due to warfarin treatment as a possible cause for thrombosis
Authors: Haran Michal Z. , Lichman Inna , Berebbi Alain , Weinmann Eran , Rosenberg Nurit 
Published: September 2007

SummaryThe prothrombin time/International Normalized Ratio is an accurate parameter for following most warfarin‐treated patients. However, it reflects mostly factor VII levels, and significant disproportionate alterations in other vitamin K‐dependent factors may not be reflected properly. We report a rare case of a woman who developed arterial thrombosis whilst receiving therapeutic doses of warfarin, and was found to have a significant and unbalanced protein S deficiency. Discontinuation of warfarin resulted in complete normalization of coagulation factors, and no further thrombotic events under treatment with enoxaparin, with a follow‐up of 2.5 years.
Effect of standardization and normalization on imprecision of calibrated automated thrombography: an international multicentre study
Authors: Dargaud Yesim , Luddington Rodger , Gray Elaine , Negrier Claude , Lecompte Thomas , Petros Sirak , Hogwood John , Bordet Jean‐Claude , Regnault Veronique , Siegemund Annelie , Baglin Trevor 
Published: September 2007

SummaryCalibrated automated thrombography (CAT) enables continuous measurement of thrombin generation (TG). Initial clinical studies using the CAT method showed large variability of normal values, indicating the necessity for a standardized CAT protocol. This international study assessed the intra‐ and inter‐assay imprecision of CAT as well as the inter‐centre variability of results in five European centres using locally available reagents and conditions (study 1) and a standardized protocol in which results were normalized (study 2). Samples with and without corn trypsin inhibitor from six healthy volunteers, two haemophilia patients and one protein C deficient patient were assayed. Study 1 confirmed that the use of different sources and concentrations of tissue factor (TF) and different phospholipid (PL) mixtures produced large variability in results. The second study demonstrated that, using the same source and concentration of TF, PL and the same test procedure, this variability could be significantly reduced. Normalization of results improved the inter‐centre variability. The benefit of contact factor inhibition prior to TG measurement was confirmed. These results demonstrated that standardization of CAT reduces the variability of results to acceptable limits. Standardization and normalization should be considered in future clinical studies which apply TG testing to clinical decision making.
Mesenchymal content of fresh bone marrow: a proposed quality control method for cell therapy
Authors: Veyrat‐Masson Richard , Boiret‐Dupré Nathalie , Rapatel Chantal , Descamps Stéphane , Guillouard Laurent , Guérin Jean‐Jacques , Pigeon Pascale , Boisgard Stéphane , Chassagne Jacques , Berger Marc G. 
Published: September 2007

SummaryThe scarcity of mesenchymal stem cells (MSC) in bone marrow (BM) has justified their ex vivo expansion before therapeutic use, but a method to evaluate the quality of initial mesenchymal content and track the modifications induced by graft processing has not yet been proposed. The aim of this study was to establish such a procedure. Flow cytometric and functional assay methods were modified to count CD45− CD14−/CD73+ subsets containing all MSC and used them to study BM from spongy bone (SB) and iliac crest aspirate (ICA). These methods detected the target subsets in all BM suspensions derived from SB (n = 154) and ICA, (n = 44) with a satisfactory correlation between immuno‐phenotyping and functional tests by low‐density plating. We noted a higher overall MSC frequency in SB cell suspensions but a lower plating efficiency of CD45− CD14−/CD73+ SB cells under standard culture conditions.We propose a cell quality control on un‐manipulated BM cell suspensions to quantify the mesenchymal compartment with regard to varying donor factors, such as age and sampling site, that influence expansion and define a therapeutic threshold value. Furthermore, we were able to confirm differences in plating efficiency and proliferative capacity between two BM origins.
Functional regulation of D‐type cyclins by insulin‐like growth factor‐I and serum in multiple myeloma cells
Authors: Glassford Janet , Rabin Neil , Lam Eric W.‐F. , Yong Kwee L. 
Published: September 2007

SummaryD‐type cyclin genes are universally dysregulated in multiple myeloma (MM), but the functional consequences are unclear as D‐type cyclin gene expression does not correlate with proliferation or disease progression. We examined the protein expression and regulation of D‐type cyclins and other cell cycle regulators in human myeloma cell lines and primary CD138+ plasma cells (PCs). Cyclin D1, cyclin D2, cyclin dependent kinase (CDK) 4, CDK6, p27Kip1 p18INK4C and retinoblastoma protein (pRb) were absent in normal PCs, heterogeneously expressed in primary MM cells and positively correlated with disease activity/progression. Cyclins D1 and D2 complexed with both CDK4 and CDK6, suggesting that both phosphorylate pRb in MM. Furthermore, cyclin D2 expressed via either t(14;16) or t(4;14) IgH translocations was functionally upregulated by fetal calf serum or insulin‐like growth factor‐I, leading to pRb phosphorylation and cell cycle entry/progression, and in some cases inversely correlated with p27Kip1. However, pRb phosphorylation and cell cycle progression mediated by cyclin D1 expressed via t(11;14) was less dependent on exogenous stimuli. These data suggest that the presence or absence of specific IgH translocations underlying aberrant D‐type cyclin expression may influence their response to mitogens in the bone marrow microenvironment. We showed for the first time that D‐type cyclins are functionally regulated in MM, differentially responsive to exogenous growth factors and upregulated with disease progression.
Sickle‐cell haemoglobin polymerization: is it the primary pathogenic event of sickle‐cell anaemia?
Authors: Vekilov Peter G. 
Published: September 2007

SummarySickle cell anaemia is associated with a mutant haemoglobin, HbS, which forms polymers in the red blood cells of patients. The primary role of the HbS polymerization for the pathophysiology has been questioned: observations in patients and model organisms contradict deterministic scenarios of sickling crises triggered by polymerization. However, results with knock‐out sickle‐cell mice, which were cured by delaying HbS polymerization, reconfirm polymerization's primary role. To reconcile the contradictory observations, this article reviews recent findings on two steps in polymerization: homogeneous nucleation of fibres, and their growth. The fibre growth is faster by far than for any other protein ordered structure. This is due to a negligible free‐energy barrier for incorporation into a fibre, determined by an entropy gain, stemming from the release of water molecules structured around HbS. The kinetics of fibre nucleation have shown that the formation of the polymer nucleus is preceded by a metastable droplet of a dense liquid. The properties of the dense liquid are sensitive functions of solution composition, including components in micro‐ and nanomolar amounts. This mechanism allows low‐concentration solution components to strongly affect the nucleation kinetics, accounting for the high variability of the disease. These insights can potentially be utilized for control of HbS polymerization and treatment of the disease.
In vitro evidence of the inhibitory capacity of chloroquine on arginase activity in sickle erythrocytes
Authors: Iyamu Efemwonkiekie W. , Ekekezie Chiazotam , Woods Gerald M. 
Published: September 2007

SummaryIncreased levels of erythrocyte arginase activity are believed to play a key role in the pathogenesis of sickle cell disease (SCD). Because increased arginase activity has been implicated in the exacerbation of pulmonary hypertension in SCD, this enzyme is considered an important therapeutic target for identifying new drugs to treat and manage SCD and other inflammatory disorders. Although chloroquine (CQ) is prescribed as an anti‐malarial and anti‐rheumatoid drug, the mechanism of its anti‐inflammatory activity is largely unknown. The present study found that CQ inhibited arginase in a dose‐dependent manner, and also displayed a linear competitive inhibition on sickle erythrocyte arginase. The apparent KM values in the presence of inhibitor were considerably reduced at both physiological and slightly acidic pHs. Slope replots of the double reciprocal plots at pH 6·8 and 7·4 also indicated simple competitive inhibitory mechanism of CQ, and Ki values for CQ were within micromolar levels. To our knowledge, this is the first example of an anti‐malarial and anti‐inflammatory agent displaying competitive inhibition kinetics on arginase. The outcome of this study may provide a template for the rational design of specific agents either alone or in combination with CQ for the inhibition of arginase activity.
Toll‐like receptors: key activators of leucocytes and regulator of haematopoiesis
Authors: McGettrick Anne F. , O'Neill Luke A. J. 
Published: September 2007

AbstractToll‐like receptors (TLRs) play a critical role in the induction of the immune response to invading pathogens. The detection of pathogens by TLRs initiates a signalling cascade that results in the activation of transcription factors such as nuclear factor (NF)‐κB and interferon regulatory factors leading to the production of pro‐inflammatory cytokines and type 1 interferons. Five cytoplasmic adaptors, MyD88, Mal, Trif, TRAM and SARM, are utilized by the TLRs to activate these signalling pathways. Through the years the main focus of research has been on the activation and function of TLRs in monocytic cells. This review discusses several additional roles of TLRs. TLR activation plays a role in influencing the differentiation of haematopoietic stem cells. Their activation also prevents apoptosis in neutrophils following pathogen invasion. B cells and T cells proliferation and differentiation is influenced by TLR activation and the possible therapeutic benefits of using TLR ligands for the treatment of chronic lymphocytic leukaemia will also be discussed.
Outcome of haematopoietic stem cell transplantation for paediatric acute lymphoblastic leukaemia in third complete remission: a vital role for graft‐versus‐host‐disease/ graft‐versus‐leukaemia effect in survival
Authors: Gassas Adam , Ishaqi M Kashif , Afzal Samina , Dupuis Annie , Doyle John 
Published: September 2007

SummaryChildren with acute lymphoblastic leukaemia (ALL) receiving haematopoietic stem cell transplantation (HSCT) in third complete remission (CR3) are at high risk for transplant‐related mortality (TRM) and relapse. Twenty‐two consecutive children with ALL in CR3 received HSCT between January 1994 and August 2005. Ten patients died of TRM, seven patients relapsed, six did not have graft‐versus‐host disease (GVHD). Five patients were long‐term survivors, (median follow‐up, 5·8 years; range 2·9–11·7). Three‐year event‐free survival was 0·32 (95% confidence interval 0·19 and 0·59). Survivors had moderate to severe GVHD. Allowing some GVHD or exploring means of inducing GVHD should be considered in CR3 patients.
Bilan de 9 ans de suivis des déprédations de Hamsters communs (Cricetus cricetus) sur les cultures alsaciennes
Authors: Losinger I. 
Published: September 2007

En France, le hamster commun (Cricetus cricetus) n’est présent que dans la plaine du Rhin. Classé nuisible jusqu’en 1993 en raison des dommages qu’il causait aux cultures, il est aujourd’hui menacé de disparition dans l’ouest de l’Europe. Il fait l’objet d’un programme de conservation à la demande du Ministère de l’Environnement depuis 1998. En raison des déprédations que quelques individus peuvent causer au printemps dans les cultures spécialisées, C. cricetus entre en conflit avec les exploitants agricoles. Pour éviter des destructions illicites, une procédure de constats de dommages a été mise en place dès 1998. Elle aboutit à la capture des animaux en cause ou à une compensation financière correspondant au manque à gagner à la récolte. En 9 ans, 48 exploitants alsaciens ont fait appel à cette procédure. 107 constats ont été dressés pour 270 terriers et 49 animaux ont été capturés et déplacés. Enfin, les dommages liés à la présence de 126 terriers ont été indemnisés pour une valeur totale d’environ 8100 EUR. Cet article met en évidence que les déprédations causées par C. cricetus s’effectuent principalement en mai, pendant une dizaine de jours, sur 3 cantons. Les campagnes d’information et la prise en compte des dommages ont contribuéà faire accepter l’espèce par la majeure partie des exploitants agricoles. Pour que cette tendance perdure, il est impératif de maintenir le système existant, mais aussi de restaurer l’habitat de l’espèce et de sensibiliser les exploitants à l’importance de ce petit rongeur alsacien.
Surveillance for whiteflies on greenhouse roses and chrysanthemums in northern Tanzania
Authors: Ndomba O. A. 
Published: September 2007

A specific monitoring survey for whiteflies was conducted in greenhouse‐grown roses and chrysanthemums in northern Tanzania from October to December 2005. The survey objectives were to appraise the suitability of yellow traps made from locally available materials, to suggest action threshold levels, and to see if the area could be considered an Area of Low Pest Prevalence. Three farms, one growing roses and two growing chrysanthemums, were sampled in the major growing areas and Pest Management Units (PMUs) of 700 m2 were formed from maps of the farmland. Twelve yellow traps were placed at intervals of 1.5 traps per PMU in the sampled farms and monitored weekly. Insects trapped included whiteflies, aphids, and occasionally fungus gnats and shore flies. The traps held insects during the period of exposure. Exposure of longer than five days in the field resulted in changes in the texture of the trap. Based on the results of these surveys, farmers are advised to take action when 1.5 whiteflies per trap in each PMU are recorded. The results show that Post Entry Plant Quarantine Inspectors could consider and recommend the area to be an Area of Low Pest Prevalence due to its tight pest management measures and routine inspections.