bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ubiquitin Lysine 63 Chain–Forming Ligases Regulate Apical Dominance inArabidopsis
Authors: Yin Xiao-Jun , Volk Sara , Ljung Karin , Mehlmer Norbert , Dolezal Karel , Ditengou Franck , Hanano Shigeru , Davis Seth J. , Schmelzer Elmon , Sandberg Göran , Teige Markus , Palme Klaus , Pickart Cecile , Bachmair Andreas 
Published: June 2007

AbstractLys-63–linked multiubiquitin chains play important roles in signal transduction in yeast and in mammals, but the functions for this type of chain in plants remain to be defined. The RING domain protein RGLG2 (for RING domain Ligase2) from Arabidopsis thaliana can be N-terminally myristoylated and localizes to the plasma membrane. It can form Lys-63–linked multiubiquitin chains in an in vitro reaction. RGLG2 has overlapping functions with its closest sequelog, RGLG1, and single mutants in either gene are inconspicuous. rglg1 rglg2 double mutant plants exhibit loss of apical dominance and altered phyllotaxy, two traits critically influenced by the plant hormone auxin. Auxin and cytokinin levels are changed, and the plants show a decreased response to exogenously added auxin. Changes in the abundance of PIN family auxin transport proteins and synthetic lethality with a mutation in the auxin transport regulator BIG suggest that the directional flow of auxin is modulated by RGLG activity. Modification of proteins by Lys-63–linked multiubiquitin chains is thus important for hormone-regulated, basic plant architecture.
Heat‐shock induction of T‐cell lymphoma/leukaemia in conditional Cre/lox‐regulated transgenic zebrafish
Authors: Feng Hui , Langenau David M. , Madge Jennifer A. , Quinkertz Andre , Gutierrez Alejandro , Neuberg Donna S. , Kanki John P. , Thomas Look A. 
Published: June 2007

SummaryThe zebrafish is an ideal vertebrate model system to investigate the complex genetic basis of cancer because it has the capacity for in vivo tumour‐cell imaging and forward genetic screens, and the molecular mechanisms regulating malignancy are remarkably conserved when compared with human. Our laboratory has previously generated transgenic zebrafish models that overexpress the mouse c‐Myc gene fused to enhanced green fluorescent protein (EGFP) and develop T‐cell acute lymphoblastic leukaemia (T‐ALL) that recapitulates the human disease both molecularly and pathologically. Our previous models have been limited by disease onset prior to sexual maturity and by the low disease penetrance when conditional transgenic embryos are injected with Cre RNA. Here, we report a novel system in which compound transgenic fish expressed both Cre controlled by the heat‐shock promoter and a rag2‐promoter‐regulated lox‐dsRED2‐lox‐EGFP‐mMyc cassette rag2‐LDL‐EMyc in developing T cells. After heat‐shock treatment at 3 d postfertilisation (dpf) for 45 min at 37°C, 81% of compound transgenic fish developed T‐lymphoblastic lymphoma (T‐LBL, mean latency 120 ± 43 (standard deviation) days of life), which rapidly progressed to T‐ALL. Heat‐shock‐regulated transgenic technology in zebrafish provides the missing link necessary to exploit the powerful genetic capacity of this organism to probe the multi‐step molecular pathogenesis of leukaemia.
Platelets release active matrix metalloproteinase‐2 in vivo in humans at a site of vascular injury: lack of inhibition by aspirin
Authors: Falcinelli Emanuela , Giannini Silvia , Boschetti Enrico , Gresele Paolo 
Published: June 2007

SummaryWhen stimulated in vitro, human platelets release matrix metalloproteinase‐2 (MMP‐2) that, in turn, potentiates platelet activation. The present study investigated if MMP‐2 is released from activated platelets in vivo in humans and whether aspirin inhibits this release. MMP‐2 levels were measured by zymography, immunoblotting, flow‐cytometry and an activity assay system, in plasma prepared from blood emerging from a skin wound inflicted for the measurement of the bleeding time (shed blood) and simultaneously from venous blood in 27 healthy human volunteers. In a subgroup, the same measurements were carried out before and 1 h after aspirin intake. MMP‐2 was significantly higher in shed blood than in venous blood and increased progressively, consistent with ongoing platelet activation. A significant correlation was evident between platelet number and MMP‐2 in shed blood; platelet MMP‐2 content in shed blood was lower than that of platelets in venous blood. The level of active MMP‐2 released by activated platelets in vivo was within the range of concentrations that potentiate platelet activation. Aspirin did not reduce MMP‐2 release in vivo. In conclusion, MMP‐2 is released from platelets in vivo in humans at a localised site of vessel wall damage in amounts sufficient to potentiate platelet aggregation; aspirin does not reduce this release.
Biphenotypic acute leukaemia: a case series
Authors: Aribi Ahmed , Bueso‐Ramos Carlos , Estey Eli , Estrov Zeev , O'Brien Susan , Giles Francis , Faderl Stefan , Thomas Deborah , Kebriaei Partow , Garcia‐Manero Guillermo , Pierce Sherry , Cortes Jorge , Kantarjian Hagop , Ravandi Farhad 
Published: June 2007

SummaryBiphenotypic acute leukaemia (BAL) is a rare type of leukaemia. Whether patients with BAL should be treated with regimens designed for acute myeloid leukaemia (AML), acute lymphocytic leukaemia (ALL) or both remain unclear.We have reviewed the clinical data for 31 BAL patients. Most patients co‐expressed B‐lymphoid and myeloid markers. No specific chromosomal abnormality was identified. The majority of the patients were treated with regimens devised for treating ALL. Seven patients were treated with regimens designed for AML. Complete remission (CR) rates of 78% and 57% were noted respectively. The overall survival probability at 2 years was 60%.
Trisomy 19 is associated with trisomy 12 and mutated IGHV genes in B‐chronic lymphocytic leukaemia
Authors: 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 
Published: June 2007

SummaryThe 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.
Hepcidin, a key regulator of iron metabolism, is transcriptionally activated by p53
Authors: Weizer‐Stern Orly , Adamsky Konstantin , Margalit Ofer , Ashur‐Fabian Osnat , Givol David , Amariglio Ninette , Rechavi Gideon 
Published: June 2007

SummaryHepcidin is an iron‐regulatory protein that is upregulated in response to increased iron or inflammatory stimuli. Hepcidin reduces serum iron and induces iron sequestration in the reticuloendothelial macrophages – the hallmark of anaemia of inflammation. Iron deprivation is used as a defense mechanism against infection, and it also has a beneficial effect on the control of cancer. The tumour‐suppressor p53 transcriptionally regulates genes involved in growth arrest, apoptosis and DNA repair, and perturbation of p53 pathways is a hallmark of the majority of human cancers. This study inspected a role of p53 in the transcriptional regulation of hepcidin. Based on preliminary bioinformatics analysis, we identified a putative p53 response‐element (p53RE) contained in the hepcidin gene (HAMP) promoter. Chromatin immunoprecipitation (ChIP), reporter assays and a temperature sensitive p53 cell‐line system were used to demonstrate p53 binding and activation of the hepcidin promoter. p53 bound to hepcidin p53RE in vivo, andthis p53RE could confer p53‐dependent transcriptional activation. Activation of p53 increased hepcidin expression, while silencing of p53 resulted in decreased hepcidin expression in human hepatoma cells. Taken together, these results define HAMP as a novel transcriptional target of p53. We hypothesise that hepcidin upregulation by p53 is part of a defence mechanism against cancer, through iron deprivation. Hepcidin induction by p53 might be involved in the pathogenesis of anaemia accompanying cancer.
Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3
Authors: Barlogie Bart , Anaissie Elias , Van Rhee Frits , Haessler Jeffrey , Hollmig Klaus , Pineda‐Roman Mauricio , Cottler‐Fox Michele , Mohiuddin Abid , Alsayed Yazan , Tricot Guido , Bolejack Vanessa , Zangari Maurizio , Epstein Joshua , Petty Nathan , Steward Douglas , Jenkins Bonnie , Gurley Jennifer , Sullivan Ellen , Crowley John , Shaughnessy John D. 
Published: June 2007

SummaryTotal therapy 3 incorporated bortezomib into a melphalan‐based tandem transplant regimen for 303 newly diagnosed patients with myeloma. Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD‐PACE (bortezomib, thalidomide, dexamethasone and 4‐d continuous infusions of cis‐platin, doxorubicin, cyclophosphamide, etoposide); 3‐year maintenance comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A minimum of 20 × 106CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment‐related death. At 24 months, 83% had achieved near‐complete remission, which was sustained in 88% at 2 years from its onset. With a median follow‐up of 20 months, 2‐year estimates of event‐free and overall survival were 84% and 86% respectively. The 44 patients who experienced an event more often had a high‐risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase, beta‐2‐microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo‐embolic events in 27% and peripheral neuropathy in 12%. Results of this phase‐2 study demonstrated that bortezomib could be safely combined with multi‐agent chemotherapy, effecting near‐complete remission status and 2‐year survival rates in more than 80% of patients.
Molecular analysis of the human thrombin‐activatable fibrinolysis inhibitor gene promoter
Authors: Garand Mathieu , Bastajian Nazareth , Nesheim Michael E. , Boffa Michael B. , Koschinsky Marlys L. 
Published: June 2007

SummaryThrombin‐activatable fibrinolysis inhibitor (TAFI) is a carboxypeptidase B‐like pro‐enzyme that, once activated, attenuates fibrinolysis. Little is presently known of the factors that regulate expression of CPB2, the gene encoding TAFI. This study identified 10 potential transcription factor binding sites (denoted A–J) within the proximal promoter region of CPB2, spanning nucleotides −425 to +21; two of these represent previously‐described binding sites for CCAAT/enhancer binding protein and glucocorticoid receptor. We identified additional transcription factors that bind within the proximal CPB2 promoter, namely, nuclear factor‐Y (NF‐Y) and hepatocyte nuclear factor‐1α (HNF‐1α). Binding of NF‐Y to the region between nucleotides −76 to −59 (Site B) is important for basal CPB2 promoter activity; NF‐Y may be a key factor for the recruitment of the transcriptional machinery to the TAFI gene promoter. HNF‐1α binds at the interface between Sites C and B. Transient transfections of CPB2 promoter‐reporter constructs showed that HNF‐1α binding is essential for the activity of this promoter in HepG2 cells, indicating that HNF‐1α is involved in the liver‐specific expression of CPB2.
A strategic framework for novel drug development in multiple myeloma
Authors: Anderson Kenneth C. , Hannah Alison L. , Pazdur Richard , Farrell Ann T. 
Published: June 2007

SummaryAlthough multiple myeloma remains incurable, recent advances in research have created a new paradigm for the development of novel agents for myeloma treatment. Biological insights are being translated rapidly from bench to bedside, with an increasing number of agents available at all stages of disease. Concomitantly, the drug development and approval process has become more challenging. Defining optimal clinical dosing schedules and therapeutic regimens is increasingly dependent on insights derived from genomic, proteomic and cell signaling studies. Because the maximum tolerated dose of a novel agent may not be the same as the optimal biological dose, designing phase I trials is more complex. Evaluation of new agents in patients who have relapsed is more challenging because the number of effective therapies has increased. Finally, choosing a ‘standard therapy’ control arm for randomised trials is more difficult because of the increased number of potential comparator regimens. In June 2005, the Multiple Myeloma Research Foundation (MMRF) sponsored a roundtable symposium in Washington, DC, to define the strategies and guidelines for phases I, II and III development of new myeloma agents, with the ultimate goal of speeding delivery of new therapies to myeloma patients.
The linear effects of α‐thalassaemia, the UGT1A1 and HMOX1 polymorphisms on cholelithiasis in sickle cell disease
Authors: Vasavda Nisha , Menzel Stephan , Kondaveeti Sheila , Maytham Emma , Awogbade Moji , Bannister Sybil , Cunningham Juliette , Eichholz Andrew , Daniel Yvonne , Okpala Iheanyi , Fulford Tony , Thein Swee Lay 
Published: June 2007

SummarySerum bilirubin levels and predisposition to gallstones in sickle cell disease (SCD) are influenced by genetic variation in the hepatic uridine diphosphate (UDP)‐glucuronosyltransferase (UGT1A1) gene, but the association is not consistent. This study investigated whether variation in the gene encoding haem oxygenase (HMOX1), a rate‐limiting enzyme upstream of UGT1A in the haem catabolic pathway, and α‐thalassaemia could explain some of the inconsistent effects. The UGT1A1 [TA]n and HMOX1 [GT]n promoter polymorphisms and α globin genotypes were determined in 263 SCD patients (199 HbSS, 5 HbS/β0, 59 HbSC). Detection of gallstones was based on ultrasound of the liver/biliary tree. Regression analysis showed that serum bilirubin levels and the incidence of gallstones were strongly associated with the number of UGT1A1 [TA] repeats in all subjects (P < 0·0001 and P < 0·01, respectively). While HMOX1 genotype had no effect, co‐inheritance of α‐thalassaemia reduced serum bilirubin levels in all SCD patients independently of the number of UGT1A1 [TA] repeats. Each additional [TA] repeat is associated with an increase in mean serum bilirubin levels of 21% and cholelithiasis risk of 87% in SCD.
Characterisation of genomic translocation breakpoints and identification of an alternative TCF3/PBX1 fusion transcript in t(1;19)(q23;p13)‐positive acute lymphoblastic leukaemias
Authors: Paulsson Kajsa , Jonson Tord , Øra Ingrid , Olofsson Tor , Panagopoulos Ioannis , Johansson Bertil 
Published: June 2007

SummaryThe t(1;19)(q23;p13), one of the most common translocations in childhood and adult acute lymphoblastic leukaemias (ALLs), usually results in fusion of exons 1–16 of TCF3 (previously E2A) and exons 3–9 of PBX1. However, some t(1;19)‐positive ALLs are negative for this chimaera. We here report an alternative TCF3/PBX1 transcript, fusing exon 17 of TCF3 with exon 5 of PBX1, in a paediatric t(1;19)‐positive ALL. The different breakpoints made this hybrid undetectable by reverse transcription polymerase chain reaction using standard TCF3 and PBX1 primers. Hence, ALLs with t(1;19) that test negative for TCF3/PBX1 should be analysed further before excluding this alternative fusion. Furthermore, we have characterised the genomic translocation breakpoints in eight TCF3/PBX1‐positive ALLs; four cases with a balanced t(1;19) and four with an unbalanced der(19)t(1;19). It has previously been suggested that the breakpoints are clustered, particularly in TCF3, and that N‐nucleotides are frequently present in the fusion junctions. Three of seven investigated TCF3 intron 16 breakpoints were within the previously described 14 base pair‐cluster, and all but two junctions harboured N‐nucleotides. The PBX1 breakpoints were more dispersed, although still clustered in two regions. This confirms that most t(1;19) rearrangements may arise by a combination of illegitimate V(D)J recombination and non‐homologous end joining.
Adding low‐dose gemtuzumab ozogamicin to fludarabine, Ara‐C and idarubicin (MY‐FLAI) may improve disease‐free and overall survival in elderly patients with non‐M3 acute myeloid leukaemia: results of a prospective, pilot, multi‐centre trial and comparison with a historical cohort of patients
Authors: Clavio Marino , Vignolo Luana , Albarello Alessandra , Varaldo Riccardo , Pierri Ivana , Catania Gioacchino , Balocco Manuela , Michelis Gianluca , Miglino Maurizio , Manna Annunziata , Balleari Enrico , Carella A. Michele , Sessarego Mario , Van Lint Maria Teresa , Bacigalupo Andrea , Gobbi Marco 
Published: June 2007

SummaryWe report the final results of a prospective multi‐centre trial testing the combination of chemotherapy (fludarabine, cytosine arabinoside and idarubicin; FLAI) followed by low‐dose gemtuzumab ozogamicin (GO), for induction treatment of patients with CD33+ acute myeloid leukaemia (AML). Forty‐six consecutive patients were treated: the median age was 66 (range: 60–80) years; the karyotype was unfavourable in 12 patients (26%), intermediate in 33 (71%) and favourable in one (3%). Eleven major infectious complications were recorded. There was one early death. Of the 45 evaluable patients, 24 achieved a complete response (CR; 52%), 66% and 33% in good‐intermediate/poor karyotype patients. Median duration of CR was 7 (3–24) months. The cumulative incidence of relapse was 37% with an actuarial 2‐year survival of 54%. These results were compared with 47 patients matched for age and karyotype who received FLAI, without GO. The proportion of patients achieving CR was comparable. However, patients with de novo AML receiving GO (n = 26) had a significantly lower risk of relapse at 2 years when compared with patients not receiving GO (n = 35) (40% vs. 80%, P = 0·01) and significantly better overall 2‐year survival (40% vs. 14%P = 0·02). Patients with secondary AML had comparable outcome whether or not they received GO. This GO‐based induction chemotherapy has a good toxicity profile. In keeping with a recent prospective randomised trial, the addition of GO seems to prolong disease‐free survival.
Expression of functional soluble human leucocyte antigen‐G molecules in lymphoproliferative disorders
Authors: Sebti Yasmine , Le Maux Amélie , Gros Frédéric , De Guibert Sophie , Pangault Céline , Rouas‐Freiss Nathalie , Bernard Marc , Amiot Laurence 
Published: June 2007

SummaryMembrane‐bound and soluble human leucocyte antigen‐G (sHLA‐G) molecules display immunotolerant properties favouring tumour cell escape from immune surveillance. sHLA‐G molecules have been detected in several tumour pathologies; this study aimed to evaluate sHLA‐G expression in lymphoproliferative disorders. sHLA‐G plasma level was significantly increased in 110 of 178 newly diagnosed lymphoid proliferations cases i.e. 59% of chronic lymphocytic leukaemia, 65% of B non‐Hodgkin lymphomas (NHL) and 58% of T‐NHL. To assess the mechanisms involved in this secretion, the differential effect of cytokines was tested in in vitro cultures of NHL cells. A significant induction of sHLA‐G level was shown in T‐NHL in contrast with B‐NHL and normal equivalent cells, after cytokine stimulation with (i) interferonγ (IFNγ), interleukin‐2 (IL‐2) and granulocyte‐macrophage colony‐stimulating factor, (ii) IL‐10 and (iii) transforming growth factor β. An impact of microenvironment on sHLA‐G expression was found in B‐NHL as shown by the in vitro effect of addition of normal monocytes. Finally, a functional effect of sHLA‐G molecules purified from pathologic plasma was demonstrated by their strong capacity to inhibit T‐cell proliferation at concentrations currently observed during these disorders. These results suggest that functional sHLA‐G molecules are upregulated in lymphoproliferative disorders which can support their potential immunomodulatory role during this pathology.
The management and outcome of chronic graft‐versus‐host disease
Authors: Fraser Christopher J. , Scott Baker K. 
Published: June 2007

SummaryChronic graft‐versus‐host disease (cGVHD) is a common complication following allogeneic haematopoietic cell transplantation (HCT). It is the leading cause of non‐relapse mortality in transplant survivors and has a significant impact upon their functional status and quality of life. Despite significant advances being made in the field of HCT over the past 25 years, there has been little change in the incidence, morbidity and mortality of cGVHD. This is partly because of a lack of understanding about the pathogenesis of the disorder but also because a lack of well validated grading systems and outcome measures has hindered clinical research. Strategies for prophylaxis have largely been unsuccessful and may compromise the graft‐versus‐leukaemia (GVL) effect. Standard primary treatment remains a combination of corticosteroids and calcineurin inhibitors. There is no standard therapy for those who fail to respond to corticosteroids. Many agents have been studied but there is an urgent need for systematic research to compare the efficacy of different approaches. Infection is the leading cause of death among patients with cGVHD so antimicrobial prophylaxis is mandatory. A multidisciplinary approach to the care of patients with cGVHD is essential to adequately address its effects on both physical and psychological functioning.
Review of the value of colony stimulating factors for prophylaxis of febrile neutropenic episodes in adult patients treated for haematological malignancies
Authors: Levenga Tjakiena Henriette , Timmer‐Bonte Johanna N. H. 
Published: June 2007

SummaryChemotherapy‐induced neutropenia is a major dose‐limiting toxicity of systemic cancer chemotherapy that can lead to fever and infection, requiring prompt analysis and in‐patient treatment with broad‐spectrum antibiotics. Complicated neutropenia may lead to reduction and/or delay of systemic anti‐cancer treatment, which may compromise outcome. Haematopoietic growth factors have the ability to augment haematopoietic cell cycling and are used to facilitate more dose‐intense treatments and to decrease treatment‐related complications. This review focuses on randomised trials that investigated the use of colony‐stimulating factors (CSF) to prevent treatment‐related febrile complications in haematological malignancies in (younger) adult patients. In general, these studies demonstrated that CSF reduced the duration of severe neutropenia but not always its febrile complications; therefore inconsistent results regarding clinically relevant reduction of hospitalisation, duration of therapeutic antibiotics, infection‐related or disease‐related mortality and economic effects were reported. Current developments in treatment of haematological malignancies will pose new challenges as a shift in infectious pathogens can be expected.