bluuebunny/crossref_metadata_2025_split huggingface dataset:
Troxacitabine and imatinib mesylate combination therapy of chronic myeloid leukaemia: preclinical evaluation
Authors: Orsolic Nada , Giles Francis J. , Gourdeau Henriette , Golemovic Mirna , Beran Miloslav , Cortes Jorge , Freireich Emil J , Kantarjian Hagop , Verstovsek Srdan 
Published: December 2004

SummaryThe in vitro and in vivo activity of a deoxycytidine analogue, troxacitabine, alone or in combination with imatinib mesylate (IM), was evaluated against human chronic myeloid leukaemia (CML) cell lines both sensitive (KBM5 and KBM7) and resistant (KBM5‐R and KBM7‐R) to IM. These cell lines differ in their sensitivity to IM but all showed similar sensitivity to treatment with troxacitabine (IC50 = 0·5–1 μmol/l). Combined treatment with troxacitabine and IM revealed additive or synergistic effects. Greater apoptotic response was seen with combined treatment than with either agent alone in KBM7‐R cells. In clonogenic assays, troxacitabine showed activity against mononuclear cells from CML patients (IC50 = 0·01 μmol/l) with either IM‐sensitive or resistant disease. In vivo efficacy studies were carried out in severe combined immunodeficient mice bearing KBM5 or KBM5‐R cells. Troxacitabine was administered i.p. daily for 5 d starting on day 20, at doses of 5, 10, 20, or 25 mg/kg. IM was administered i.p. twice a day for 10 d at a dose of 50 mg/kg starting on day 25. In this setting of late stage disease, troxacitabine led to a significant increase in life span, while IM did not. When IM was combined with troxacitabine at 10 and 25 mg/kg in the KBM5 xenograft model, a further increase in life span was observed and some mice achieved long‐term survival. These data indicate that the combination of troxacitabine and IM has significant preclinical activity in advanced CML and that clinical evaluation of this combination is warranted.
Thalassaemia mutations within the 5′UTR of the human β‐globin gene disrupt transcription
Authors: Sgourou Argyro , Routledge Samantha , Antoniou Michael , Papachatzopoulou Adamantia , Psiouri Lambrini , Athanassiadou Aglaia 
Published: December 2004

SummaryThe mechanisms by which mutations within the 5′ untranslated region (UTR) of the human β‐globin gene (HBB) cause thalassaemia are currently not well understood. We present here the first comprehensive comparative functional analysis of four ‘silent’ mutations in the human β‐globin 5′UTR, namely: +10(−T), +22(G → A), +33(C → G) and +(40–43)(−AAAC), which are present in patients with β‐thalassaemia intermedia. Expression of these genes under the control of the β‐globin locus control region in stable transfected murine erythroleukaemia cells showed that all four mutations decreased steady state levels of mRNA to 61·6%, 68%, 85·2% and 70·6%, respectively, compared with the wildtype gene. These mutations did not interfere with either mRNA transport from the nucleus to the cytoplasm, 3′ end processing or mRNA stability. Nuclear run‐on experiments demonstrated that mutations +10(−T) and +33(C → G) reduced the rate of transcription to a degree that fully accounted for the observed lower level of mRNA accumulation, suggesting a disruption of downstream promoter sequences. Interestingly, mutation +22(G → A) decreased the rate of transcription to a low degree, indicating the existence of a mechanism that acts post‐transcriptionally. Generally, our data demonstrated the significance of functionally analysing mutants of this type in the presence of a full complement of transcriptional regulatory elements within a stably integrated chromatin context in an erythroid cell environment.
Podocalyxin in human haematopoietic cells
Authors: Kerosuo Laura , Juvonen Eeva , Alitalo Riitta , Gylling Mikhail , Kerjaschki Dontscho , Miettinen Aaro 
Published: December 2004

SummaryPodocalyxin‐like protein (PCLP) is a sialomucin‐type membrane protein structurally related to CD34 and endoglycan. It was first described in glomerular podocytes and endothelial cells. In mice, PCLP is present in haemangioblasts, and in both chicken and mice it is a marker of early haematopoietic stem cells and lineage‐restricted haematopoietic progenitors. Its expression decreases during differentiation of haematopoietic cells. Of mature blood cells, only chicken and rat thrombocytes express PCLP protein. PCLP expression in human haematopoietic cells has not been studied. Here we demonstrate PCLP mRNA in human CD34+ cells, in lineage committed erythroid, megakaryocyte and myeloid progenitors, in K562 leukaemia cells, and in peripheral blood leucocytes. The mRNA expression level was higher in developing cells than in mature leucocytes. By Northern blotting and cDNA sequencing, the haematopoietic and renal PCLP mRNAs were identical. Of the mobilized CD34+ cells, 28% (mean; range 14–61%) expressed PCLP protein and the majority of PCLP+ cells were CD117+. Almost all of the K562 cells expressed PCLP protein. Surprisingly, PCLP protein was not detected in any mature blood cells. These results suggest that human PCLP may be a valuable marker for a subset of haematopoietic stem cells.
Randomized trial of effect of transdermal continuous combined hormone replacement therapy on cardiovascular risk markers
Authors: Stevenson John C. , Oladipo Ayotunde , Manassiev Nick , Whitehead Malcolm I. , Guilford Sandra , Proudler Anthony J. 
Published: December 2004

SummaryWhether hormone replacement therapy (HRT) is beneficial for coronary heart disease (CHD) is controversial. We hypothesized that continuous combined transdermal HRT may have benefits on CHD risk markers without the potential adverse effects seen with certain other HRT regimens. Sixty apparently healthy postmenopausal women, aged 40–65 years, entered a prospective, double‐blind, randomized, placebo‐controlled clinical trial; 55 women completed the 6‐month study. Women received either transdermal oestradiol 17β 0·05 mg and norethisterone acetate 0·125 mg daily, or identical placebo. Circulating markers of vascular function and remodelling, forearm blood flow, lipids and lipoproteins, glucose and insulin, and haemostatic safety parameters were measured at baseline and after treatment. Compared with placebo after 6 months, HRT administration resulted in decreased E‐selectin (P < 0·01), and angiotensin‐converting‐enzyme (ACE; P = 0·05). Cholesterol (P < 0·05), low‐density lipoproteins (LDL; P < 0·05), high‐density lipoprotein3 (HDL3; P < 0·05) and apolipoproteins AII (P < 0·05) and B (P < 0·05), and fasting insulin (P < 0·05) also decreased in the HRT group. Factor VII coagulation activity decreased (P < 0·01) and plasminogen activator inhibitor‐1 and fibrin D‐dimer increased (P < 0·05) in the HRT group, whilst prothrombin fragment 1 + 2 (P < 0·05) decreased, more so in the placebo group. There were no changes in matrix metalloproteinase (MMP)‐2, or in LDL particle size. This transdermal HRT had beneficial effects on vascular function and CHD risk markers.
Development and functional analysis of eosinophils from murine embryonic stem cells
Authors: Hamaguchi‐Tsuru Emi , Nobumoto Atsuya , Hirose Noriyuki , Kataoka Sayo , Fujikawa‐Adachi Kiyomi , Furuya Masato , Tominaga Akira 
Published: December 2004

SummaryWe have established a culture system for the development of eosinophils from murine embryonic stem (ES) cells. After transferring ES cells from embryonic fibroblast cells onto macrophage colony‐stimulating factor‐deficient stromal cells, OP9, ES cells were cultured in the presence of interleukin (IL)‐5 with either IL‐3 or granulocyte–macrophage colony stimulating factor (GM‐CSF) for 20 d to obtain approximately 50% eosinophils. Electron microscopy confirmed the presence of crystallized major basic protein (MBP) in the granules of some of these cells. Neither IL‐5, IL‐3, GM‐CSF nor eotaxin alone could induce eosinophils as efficiently as the conditions described above. Eotaxin induced eosinophil development in combination with either IL‐3 or IL‐5. Levels of GATA‐1, Friend of GATA (FOG)‐1, PU.1, CCAAT/enhancer binding protein (C/EBP)α, C/EBPβ, IL‐3 receptor α (IL‐3Rα), GM‐CSF receptor α (GM‐CSFRα), and MBP mRNAs were increased in ES cells 10 d after transfer onto OP9 cells. In contrast, C/EBPɛ, IL‐5Rα, and eosinophil peroxidase mRNAs were induced in response to IL‐3 and IL‐5 after transfer onto OP9 cells. Eosinophils that developed in this system expressed Gr‐1, F4/80, B220, CCR3, IL‐3Rα, IL‐5Rα, and DX5. Finally, eosinophils developed from ES cells produced reactive oxygen species in response to Leishmania as do peripheral blood eosinophils.
Computer‐based drug management in a bone marrow transplant unit: a suitable tool for multiple prescriptions even in critical conditions
Authors: Krampera Mauro , Venturini Francesca , Benedetti Fabio , Oliani Andrea , Carolei Simonetta , Visco Carlo , Aqel Haytam , Pizzolo Giovanni , Scroccaro Giovanna 
Published: December 2004

SummaryDrug prescription or administration errors are the most common causes of adverse events for hospital patients. Computer‐based systems can be effective in reducing these errors. The aim of this study was to assess whether computer‐based systems are easily exploitable even in critical conditions. The oral and handwritten system for drug management was completely replaced by a computer‐based system in our bone marrow transplant unit, chosen because: (i) the intensive treatments could test the efficiency of the system; (ii) the very frequent occurrence of complications and emergencies could test the flexibility of the system; and (iii) the pre‐existing system could be used as comparison. From May to November 2002, 41 patients were repeatedly admitted to undergo high‐dose chemotherapy, autologous/allogeneic stem cell transplantation or because of severe complications. In 27 consecutive admissions, 2264 drug prescriptions (average, 29 drugs/patient admission) and 36 786 drug administrations (39·8/patient/d) were carried out. Despite the large number of procedures, the computerized system effectively replaced the oral and handwritten transmission of information among medical staff, pharmacists and nurses, and lowered the error risks. In addition, it contributed to medical updating through warnings on potential problems in case of multiple drug prescriptions, and gave the pharmacy a valuable tool to monitor drug use.
Improved survival in steroid‐refractory acute graft versus host disease after non‐myeloablative allogeneic transplantation using a daclizumab‐based strategy with comprehensive infection prophylaxis
Authors: Srinivasan R. , Chakrabarti S. , Walsh T. , Igarashi T. , Takahashi Y. , Kleiner D. , Donohue T. , Shalabi R. , Carvallo C. , Barrett A. J. , Geller N. , Childs R. 
Published: December 2004

SummaryApproximately 15% of patients undergoing non‐myeloablative allogeneic haematopoietical cell transplantation (NMHCT) develop steroid‐refractory acute‐graft versus host disease (aGVHD), a usually fatal complication. We encountered 18 cases of steroid‐refractory aGVHD in 146 patients, undergoing NMHCT from a related human leucocyte antigen‐compatible donor following cyclophosphamide/fludarabine‐based conditioning. Our initial cohort of steroid‐refractory aGVHD patients treated with antithymocyte globulin (ATG) and mycophenolate mofetil (regimen‐1: n = 6) had high GVHD‐related mortality. Therefore, we investigated an alternative strategy for subsequent patients developing this complication (regimen‐2: n = 12), consisting of daclizumab (alone or combined with infliximab/ATG) and targeted broad spectrum antibacterial and aspergillus prophylaxis in conjunction with rapid tapering of steroids to minimize opportunistic infections. In a retrospective analysis, patients receiving regimen‐2 were significantly more likely to have complete resolution of GVHD compared with those receiving regimen‐1 [12/12 (100%) vs. 1/6 (17%); P < 0·001]. When compared with those receiving regimen‐1, regimen‐2 patients also had a higher probability of survival at day 100 (100% vs. 50%) and day 200 (73% vs. 17%) post‐transplant, and improved overall survival (median 453 d vs. 42 d from aGVHD onset; P < 0·0001). GVHD‐related mortality was 89% for regimen‐1 patients vs. 17% for regimen‐2 patients (P < 0·0001). These data suggest that a co‐ordinated approach using immunoregulatory monoclonal antibodies, pre‐emptive antimicrobial therapy and judicious steroid withdrawal can dramatically improve outcome in steroid‐refractory aGVHD.
Outcomes of an automated procedure for the selection of effective platelets for patients refractory to random donors based on cross‐matching locally available platelet products
Authors: Rebulla Paolo , Morelati Fernanda , Revelli Nicoletta , Villa Maria Antonietta , Paccapelo Cinzia , Nocco Angela , Greppi Noemi , Marconi Maurizio , Cortelezzi Agostino , Fracchiolla Nicola , Martinelli Giovanni , Deliliers Giorgio Lambertenghi 
Published: December 2004

SummaryIn 1999, we implemented an automated platelet cross‐matching (XM) programme to select compatible platelets from the local inventory for patients refractory to random donor platelets. In this study, we evaluated platelet count increments in 40 consecutive refractory patients (8·3% of 480 consecutive platelet recipients) given 569 cross‐match‐negative platelets between April 1999 and December 2001. XM was performed automatically with a commercially available immunoadherence assay. Pre‐, 1‐ and 24‐h post‐transfusion platelet counts (mean ± SD) for the 569 XM‐negative platelet transfusions containing 302 ± 71 × 109 platelets were 7·7 ± 5·5, 32·0 ± 21·0 and 16·8 ± 15·5 × 109/l respectively. Increments were significantly higher (P < 0·05, t‐test) than those observed in the same patients given 303 random platelet pools (dose = 318 ± 52 × 109 platelets) during the month before refractoriness was detected, when pre‐, 1‐ and 24‐h post‐transfusion counts were 7·0 ± 8·6, 15·9 ± 16·1 and 9·6 ± 12·8 × 109/l respectively. The cost of the platelet XM disposable kit per transfusion to produce 1‐h post‐transfusion platelet count increments >10 × 109/l was euro 447. This programme enabled the rapid selection of effective platelets for refractory patients, from the local inventory.
Efficacy of standard dose and 30 ml/kg fresh frozen plasma in correcting laboratory parameters of haemostasis in critically ill patients
Authors: Chowdhury Pratima , Saayman Anton G. , Paulus Ulrike , Findlay George P. , Collins Peter W. 
Published: December 2004

SummaryThis study assessed the effect on coagulation tests of fresh frozen plasma (FFP), given according to guidelines compared with higher doses in critically ill patients. Group 1 (10 patients) received 12·2 ml/kg and group 2 (12 patients) 33·5 ml/kg FFP. Prothrombin time, activated partial thromboplastin time and factors I–XII were measured before and after FFP infusion. Factor levels of 30 IU/dl (1 g/l for fibrinogen) were considered haemostatic. A retrospective review showed 10 of 22 (five in group 1 and five in group 2) patients had not required FFP. Of those that needed FFP, one of five in group 1 and seven of seven in group 2 had coagulation factor levels above the target post‐FFP. Increments for group 1 versus 2 were: fibrinogen 0·4 vs. 1·0 g/l, FII 16 vs. 41*, FV 10 vs. 28*, FVII 11 vs. 38*, FVIII 10 vs. 17, FIX 8 vs. 28*, FX 15 vs. 37*, FXI 9 vs. 23 and FXII 30 vs. 44 IU/dl* (*P < 0·01). In vivo recovery of coagulation factors was the same for both groups and the observed increments correlated with the dose of FFP. In conclusion, coagulation screens were poor predictors of coagulation factor levels and current guidelines on the use of FFP result in predictably small increments in coagulation factors in critically ill patients and should be reviewed.
The efficacy and safety of B‐cell depletion with anti‐CD20 monoclonal antibody in adults with chronic immune thrombocytopenic purpura
Authors: Cooper Nichola , Stasi Roberto , Cunningham‐Rundles Susanna , Feuerstein Michael A. , Leonard John P. , Amadori Sergio , Bussel James B. 
Published: December 2004

SummaryBecause of its B‐cell depleting effect, rituximab has entered clinical trials in several autoimmune conditions. This study assesses the efficacy and safety of rituximab in 57 adults with chronic immune thrombocytopenic purpura (ITP). All patients had platelet counts <30 × 109/l, all had received two or more previous ITP treatments and 31 had undergone splenectomy. Patients received rituximab 375 mg/m2 weekly for 4 weeks. Thirty‐one patients (54%) responded, achieving a platelet count >50 × 109/l: 18 achieved a complete response (CR: platelet count >150 × 109/l) and 13 a partial response (PR: platelet count 50–150 × 109/l). Twenty‐nine responses occurred within 8 weeks of the first infusion. Sixteen of 18 CR patients (28% overall), including eight who had failed splenectomy, continued in CR after a median of 72·5 weeks; 15 of 16 are >1 year from the first infusion. Only two of 13 maintained a PR. Thirty‐three patients experienced grade 1–2 adverse events and one a grade 3 event, but they all completed treatment. Circulating B cells fell to <0·03 × 109/l. No changes in immunoglobulin levels or infectious complications were seen. In summary, rituximab was well tolerated with no immediate complications and induced a lasting, substantial response in 32% of adults with chronic ITP.
A recombinant bispecific single‐chain Fv antibody against HLA class II and FcγRIII (CD16) triggers effective lysis of lymphoma cells
Authors: Bruenke Joerg , Fischer Barbara , Barbin Karin , Schreiter Katja , Wachter Yvonne , Mahr Kerstin , Titgemeyer Fritz , Niederweis Michael , Peipp Matthias , Zunino Susan J. , Repp Roland , Valerius Thomas , Fey Georg H. 
Published: December 2004

SummaryBispecific antibodies offer the possibility of improving effector‐cell recruitment for antibody therapy. For this purpose, a recombinant bispecific single‐chain Fv antibody (bsscFv), directed against FcγRIII (CD16) and human leucocyte antigen (HLA) class II, was constructed and tested in functional assays. RNA from the hybridomas 3G8 and F3.3, reacting with CD16 and HLA class II, respectively, was used to generate phage display libraries. From these libraries, reactive phages were isolated and the bsscFv was constructed by connecting both single‐chain Fv components through a 20 amino acid flexible linker. After expression in SF21 insect cells and chromatographic purification, the bsscFv bound specifically and simultaneously to both antigens. The affinities of the anti‐CD16 and the anti‐HLA class II scFv components of the bsscFv were 8·6 × 10−8 mol/l and 13·7 × 10−8 mol/l, respectively, which was approximately sevenfold lower than the F(ab) fragments of the parental antibodies. In antibody‐dependent cellular cytotoxicity experiments with human mononuclear cells as effectors, the bsscFv‐mediated specific lysis of both HLA class II‐positive, malignant human B‐lymphoid cell lines and primary cells from patients with chronic B‐cell lymphocytic leukaemia. Optimal lysis was obtained at bsscFv concentrations of approximately 400 ng/ml, similar to the concentration required for maximum lysis by the corresponding chemically linked bispecific antibody. Thus, this recombinant bsscFv‐antibody is an efficient molecule for effector‐cell mediated lysis of malignant human B‐lymphoid cells.
Results of imatinib mesylate therapy in chronic myelogenous leukaemia with variant Philadelphia chromosome
Authors: El‐Zimaity Maha M. T. , Kantarjian Hagop , Talpaz Moshe , O'Brien Susan , Giles Francis , Garcia‐Manero Guillermo , Verstovsek Srdan , Thomas Deborah , Ferrajoli Alessandra , Hayes Kimberly , Nebiyou Bekele B. , Zhou Xian , Rios Mary B. , Glassman Armand B. , Cortes Jorge E. 
Published: December 2004

SummaryFive to 10 per cent of patients with Philadelphia chromosome (Ph)‐positive chronic myelogenous leukaemia (CML) have variant translocations involving chromosomes other than 9 and 22. We investigated the characteristics and outcome of patients with variant translocations treated with imatinib. Among 721 patients, 44 (6%) had variant translocations, involving one (n = 39) or two (n = 4) additional chromosomes. Nineteen patients (44%) were in chronic (12 previously untreated), 24 (55%) in accelerated and one (2%) in blastic phase. A major cytogenetic response was achieved in 14 (74%) patients treated in chronic phase and in 14 (58%) treated in accelerated phase. Six of 13 (46%) evaluable patients had deletion of derivative chromosome 9, and there was a trend for a lower response rate in these patients. We compared the 43 patients in chronic or accelerated phase to 678 patients with classic Ph treated with imatinib. The only significant difference in clinical characteristics was a higher frequency of accelerated phase among those with variant translocations (56%) compared with those with classic translocations (38%). No differences in outcome were evident. In a multivariate analysis, variant Ph translocations had no impact in response rate, overall survival or duration of response. We conclude that patients with variant Ph translocations have a similar prognosis to those with classic Ph translocations when treated with imatinib.
CD21S antigen expression in tumour cells of diffuse large B‐cell lymphomas is an independent prognostic factor indicating better overall survival
Authors: Ogawa Shoko , Yamaguchi Motoko , Oka Kouji , Taniguchi Masanori , Ito Motohiro , Nishii Kazuhiro , Nakase Kazunori , Ohno Toshiyuki , Kita Kenkichi , Kobayashi Tohru , Shiku Hiroshi 
Published: December 2004

SummaryTo evaluate the clinical significance of CD21S expression of diffuse large B‐cell lymphoma (DLBCL) tumour cells, we compared their clinical features, immunophenotype, response to therapy and outcome in relation to CD21S expression. Between 1987 and 1999, frozen sections from 240 DLBCL cases were examined for CD21S expression by immunohistochemical methods. CD21S expression was detected on the tumour cells of 87 (36%) cases. The median age of the CD21S+ DLBCL cases was 65 years (range: 17–84 years), the male–female ratio was 42:45, and they showed the following clinical features: Eastern Cooperative Oncology Group score >1 in 14%, lactate dehydrogenase greater than normal levels in 38%, extranodal sites >1 in 14%, stages III/IV disease at diagnosis in 29%, B symptoms in 17%, and a high/high–intermediate International Prognostic Index (IPI) in 23%. They also showed a better overall survival (P = 0·00001, log‐rank test) and a better complete remission rate (P = 0·00004, chi‐square test) than CD21S− DLBCL. Moreover, CD21S+ DLBCL showed a better survival than CD21S− DLBCL for both low/low–intermediate and high/high–intermediate risk categories of IPI (P = 0·045 and P = 0·0016 respectively). Multivariate analysis identified CD21S expression as an independent factor for survival when compared with the five IPI factors. These findings indicate that CD21S expression of DLBCL tumour cells is a useful prognostic factor for survival.