bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐6 is a cofactor for the growth of myeloid cells from human bone marrow aspirates but does not affect the clonogenicity of myeloma cells in vitro
Authors: Montes Borinaga A. , Millar B. C. , Bell J. B. G. , Joffe J. K. , Millar J. L. , Gooding R. , Riches P. , McElwain T. J. 
Published: March 2008

Summary Several groups have claimed that IL‐6 is a growth factor for human myeloma cells in vitro. Bone marrow aspirates from 30 patients at different stages of treatment with VAMP/high dose melphalan, were examined for myeloma colony formation (MY‐CFU,) using a clonogenic assay in vitro. Myeloma cells from 16/30 patients produced MY‐CFUc in our assay system, which uses heavily irradiated HL60 cells as an underlay in soft agar. These heavily irradiated cells were shown to be essential for the inhibition of granulocyte‐macrophage colonies (GM‐CFUc). The addition of recombinant human IL‐6 (10 ng/plate) reduced the number of bone marrow samples which produced MY‐CFUc from 16 to six. Furthermore, the addition of antibody to IL‐6 (1 μg/plate) failed to inhibit MY‐CFUc from 6/7 samples.Conditioned medium from human peripheral blood mono‐nuclear cells (PBMC‐CM) contains approximately 2 ng/ml IL‐6 and can be used to stimulate the growth and maintenance of the B9 murine IL‐6 dependent hybridoma cell line. Kecombinant human IL‐6 supported the growth of B9 cells in a clonogenic assay and growth was inhibited by anti‐IL‐h in the presence of rhIL‐6 or PBMC‐CM. Mononuclear cells from a second group of myeloma patients were cultured in soft agar in a mixture of PBMC‐CM and fresh growth medium. Nine of the 10 samples produced myeloid colonies which consisted of granulocytes, monocytes and macrophages and the number of colonies was reduced by at least 50% in 6/8 samples when anti‐IL‐6 was added to the cultures. In no instance were MY‐CFUc produced. Also, conditioned medium from the bladder carcinoma cell line 5637. which is used routinely as a source of granulocyte‐macrophage colony stimulating factor (GM‐CSF), contains approximately 4 ng/ml IL‐6. Although rhIL‐6 failed to stimulate GM‐CFUc in the absence of other growth factors, addition of anti‐IL‐6 to cultures containing a suboptimal amount of 5637‐CM reduced the number of colonies by 50%.These data provide evidence that IL‐6 is a cofactor for the growth of myeloid precursors but does not affect the proliferation of human myeloma cells in vitro.
Expression of coagulation factor V gene by normal adult human hepatocytes in primary culture
Authors: Mazzorana Marlene , Baffet Georges , Kneip Bernard , Launois Bernard , Guguen‐Guillouzo Christiane 
Published: March 2008

Summary Normal human adult hepatocytes were examined for their ability to synthesize and secrete factor V using primary culture. The culture medium contained both factor V and factor Va as determined by bioassay and activation experiments. Immunoprecipitation of newly synthesized labelled factor V showed the presence of both native factor V (m.w. 330000) and two fragments of respective molecular weight 300000 and 265000. Northern blot analysis revealed the presence of a single 7 kb factor V mRNA in cultured human hepatocytes as in liver biopsies, together with fibrinogen β and albumin transcripts. Relative levels of factor V, fibrinogen β and albumin mRNAs differed when the cells cultured, suggesting that expression of the three corresponding genes might in part be independently regulated. Furthermore, addition of glucocorticoids enhanced factor V and fibrinogen β mRNA levels 1·6‐ and 5‐fold respectively, but did not significantly increase that of albumin.These results provide evidence that human hepatocytes actively participate in the synthesis of plasma factor V and constitute a valuable model to study the common and specific regulations involved in the control of the expression of this gene in human liver.
Haemophilia B mutations in a complete Swedish population sample: a test of new strategy for the genetic counselling of diseases with high mutational heterogeneity
Authors: Green P. M. , Montandon A. J. , Ljung R. , Bentley D. R. , Nilsson I.‐M. , Kling S. , Giannelli F. 
Published: March 2008

Summary. Carrier and prenatal diagnosis based on the identification of the gene defect (direct diagnosis) increases the proportion of haemophilia B families that can be offered precise genetic counselling from the 50–60% attainable by DNA markers, to 100%, and they also provide information on the molecular biology of the disease. We propose that in order to maximize the practical and scientific benefits of direct diagnosis the gene defect of complete (possibly national) populations of patients should be characterized and the information stored in appropriate confidential databases.We demonstrate the feasibility of such a strategy by characterizing the mutations of all the patients registered with the Malmö haemophilia centre.These patients (44♂ and 1♀) are from 45 unrelated families and 24 (53%) have negative family history. The 25 patients with similar reduction of factor IX:C and factor IX:Ag (24♀+1♂) have: two gross deletions, three frame‐shifts, four translation stops, six mutations expected to affect pre‐mRNA splicing and 10 amino acid substitutions. The six patients with greater reduction of factor IX:C than factor IX:Ag and the seven with reduced IX:C and normal IX:Ag have only amino acid substitutions. Patients with inhibitors have: one complete deletion, one frameshift and three translation stops. One patient has both a translation stop and a functionally neutral amino acid substitution (His257→Tyr). Characterization of the factor IX mutation was successful in every case, usually entailed 4 person‐days work, and has led to the identification of 12 amino acid residues essential for the factor IX structure and function.
Thioguanine used in maintenance therapy of chronic myeloid leukaemia causes non‐cirrhotic portal hypertension. RESULTS FROM MRC CML II TRIAL COMPARING BUSULPHAN WITH BUSULPHAN AND THIOGUANINE
Authors: Shepherd P. C. A. , Fooks J. , Gray R. , Allan N. C. 
Published: March 2008

Summary Portal hypertension with varices developed in 18/675 patients with chronic myeloid leukaemia (CML) in a randomized trial comparing busulphan with busulphan and thioguanine. All 18 had received the drug combination and none busulphan alone (P<0.0001). Ascites was also seen significantly more often in the combination arm (P>0.05). These results strongly suggest that the addition of thioguanine was responsible for the development of portal hypertension. The histological features were predominantly those of non‐cirrhotic portal hypertension—either idiopathic portal hypertension with minimal morphological abnormalities, nodular regenerative hyperplasia or in two cases leukaemic infiltration only was noted. Cirrhosis was present in 3/16 cases studied.Both treatment groups developed abnormal liver function tests during the chronic phase, but particularly with progression of the disease. During chronic phase abnormalities were significantly more frequent in those receiving busulphan and thioguanine‐alkaline phosphatase (P<0.02), transaminases (P<0.04), bilirubin (P<0.05), multiple abnormalities (P<0.01). The development of portal hypertension was often associated with abnormalities of these tests; however, lack of specificity precludes their use as a predictor of subsequent clinical problems. Thioguanine confers no survival advantage in this disease. In view of its hepatotoxicity it should not be used routinely for maintenance of control in chronic phase CML.
The Corfu δβ thalassaemia mutation in Greece: haematological phenotype and prevalence
Authors: Traeger‐Synodinos Joanne , Tzetis Maria , Kanavakis Emmanuel , Metaxotou‐Mavromati Anna , Kattamis Christos 
Published: March 2008

Summary The Corfu δβ thalassaemia mutation, a 7.2 kb deletion partially removing the (δ‐globin gene and a single nucleotide mutation (GA) at intervening sequence I (IVSI‐n5) in the β‐globin gene in cis, was first described in a family from Corfu; the carriers for this mutation had the unusual haematological phenotype of heterozygous β‐thalassaemia with normal levels of HbA2.To investigate the frequency and haematological characteristics of Corfu δβ thalassaemia in Greece we analysed 25 unrelated normal HbA2 type 2 β‐thalassaemia heterozygotes and their 23 clinically affected offspring. Gene mapping demonstrated that nine (36%) of the 25 normal HbA2β‐thalassaemia heterozygotes were in fact Corfu δβ thalassaemia heterozygotes and of the 23 patients, two were Corfu δβ thalassaemia homozygotes and five compound heterozygotes for Corfu δβ thalassaemia and another β‐thalassaemia defect.Detailed haematological analysis demonstrated that: the Corfu δβ thalassaemia mutation does not completely abolish the expression of the β‐globin gene; the HbA2 levels are slightly lower (P<0.01) and the HbF levels slightly higher (P<0.01) in Corfu δβ thalassaemia heterozygotes compared to β‐thalassaemia heterozygotes with the normal HbA2‐type 2 phenotype who do not have the Corfu δβ chromosome.
Increased intraplatelet levels of platelet‐derived growth factor and transforming growth factor‐β in patients with myelofibrosis with myeloid metaplasia
Authors: Martyré Marie‐Claire , Magdelenat Henri , Bryckaert Marie‐Claude , Laine‐Bidron Christine , Calvo Fabien 
Published: March 2008

Summary. Platelet‐derived growth factor (PDGF) is thought to play some role in the genesis of fibrosis associated with myeloproliferative disorders. In addition, transforming growth factor‐β (TGF‐β) has been confirmed to promote fibrotic process. Both PDGF and TGF‐β have been shown to cooperate with epidermal growth factor (EGF) in regulating the growth of human marrow fibroblasts. All three are contained in platelet α‐granules.We report the results of a study in patients with myelofibrosis with myeloid metaplasia (MMM). We evaluated PDGF, TGF‐β and EGF‐like activities in circulating platelets from patients compared to healthy subjects. In contrast to EGF‐like intraplatelet levels which were similar in patients and in normal donors (1‐4 ng/109 platelets), we found constantly higher values for both PDGF and TGF‐β in MMM patients. In both radioimmunoassay (RIA) and assay for mitogenic activity on human bone marrow fibroblasts, PDGF levels were increased on the average 2‐3·5‐fold over the levels found in normal donors (P<0·01 and P<0·001, respectively). PDGF serum levels in patients were consistent with those found in platelets. In platelet‐poor plasma (PPP), PDGF concentrations were undetectable or ≃ 2 ng/ml in patients and in control donors as well. The total TGF‐β activity in platelet lysates, determined using a competitive radioreceptor binding assay on Swiss 3T3 mouse cells and an inhibition growth assay on CCL64 cells, was found 2‐3‐fold increased in patients with MMM as compared to control subjects (P<0·003).These results emphasize that, not only PDGF, but also TGF‐β are implicated in the myelofibrosis with myeloid metaplasia.
Pharmacokinetics and biodistribution of technetium 99m labelled standard heparin and a low molecular weight heparin (enoxaparin) after intravenous injection in normal volunteers
Authors: Laforest M. D. , Colas‐Linhart N. , Guiraud‐Vitaux F. , Bok B. , Bara L. , Samama M. , Marin J. , Imbault F. , Uzan A. 
Published: March 2008

SummaryFor a better understanding of low molecular weight heparin pharmacokinetics, 99m technetium labelled heparin and enoxaparin were injected intravenously to four normal volunteers, after approval by the Ethics Committee and preliminary animals studies. In vitro and in vivo, the labelled products proved to be stable and identical to the non‐labelled drugs.Radioactivity curves in blood, organs and urines were similar for both products. Anti Xa plasma half‐life was 3 times longer for enoxaparin than for heparin. Anti Ha plasma half‐lives were similar. However, radioactivity persisted much longer than biological activities for both products. After chromatography, most of the radioactivity was bound to AT III, where an anti Xa activity peak was also detected. The anti Xa activity peak seen after adding AT III to plasma was much higher with heparin than with enoxaparin. In urine, biological activities, measured with AT III supplementation, were higher with enoxaparin than with heparin.These results suggest that phenomena other than biodistribution are responsible for the differences in pharmacokinetics observed between these two products. The two most likely explanations are differences in metabolism and/or a release of an endogenous factor.
Clinical experience with the combined use of recombinant interleukin‐2 (IL2) and interferon alfa‐2a (IFNα) in metastatic melanoma
Authors: Kruit W. H. J. , Goey S. H. , Monson J. R. T. , Stahel R. A. , Calabresi F. , Mertelsmann R. , Holdener E. E. , Eggermont A. M. M. , Bolhuis R. L. H. , de Mulder P. H. M. , Stoter G. 
Published: March 2008

A multicentre study of IL2 and IFNα has been performed in 58 patients with metastatic melanoma. The scheme consisted of IL2 30 BRMP MU/m2/d as a continuous infusion for 4 d combined with subcutaneous administration of IFNα 6 MU/m2/d, day 1 + 4. The cycle was repeated every 2 weeks for a maximum duration of 26 weeks. 54 patients were evaluable for response. One (2%) achieved a complete and 10 (19%) a partial response. 19 (35%) patients were stable and 24 (44%) showed progressive disease. Common side‐effects included fever, chills, fatigue, skin rash, anorexia, nausea and diarrhoea. Hypothyroidism was noted in 10% of the patients. These results show that this regimen of IL2 and IFNα is active but, in contrast to what could be expected, not superior to IL2 alone possibly due to suboptimal dosing.In an ongoing study in Rotterdam and Nijmegen, a more intense schedule was chosen, consisting of three daily i. v. doses of IL2 45 BRMP MU/m2 and IFNα 30 MU/m2 for 5 d. This regimen is repeated at intervals of 3 weeks for a total of three cycles. Presently, nine patients have been entered. One patient achieved a complete response, four a partial response (overall 56%), three had stable disease and one progressed. Toxicity was severe and treatment was prematurely stopped in five patients: myocardial infarction (one patient), atrial fibrillation (one patient), negative T waves and myocardial hypokinesia (one patient) and psychosis (two patients). This regimen can only be justified if the therapeutic results are superb, which has yet to be awaited.
Effects of low doses of recombinant human granulocyte‐macrophage colony stimulating factor (GM‐CSF) in patients with myelodysplastic syndromes
Authors: Estey Elihu H. , Kurzrock Razelle , Talpaz Moshe , McCredie Kenneth B. , O'Brien Susan , Kantarjian Hagop M. , Keating Michael J. , Deisseroth Albert B. , Gutterman Jordan U. 
Published: March 2008

SummaryThere has been no previously published experience with granulocyte‐macrophage colony stimulating factor (GM‐CSF) doses < 12 μg/m2 daily in patients with myelodysplastic syndromes, and most observations have been made at doses ≥ 120 μg/m2 daily. We administered 5 μg/m2 daily by subcutaneous injection to 29 such patients increasing the dose in patients who did not show a haemato‐logic response. Doses of 5 or 10 μg/m2 (‘low‐dose GM‐CSF”) produced an increase in neutrophils in 14/29 patients. Response was significantly (P=0·03) more frequent in patients who had a higher pre‐treatment neutrophil count (e.g. 11/16 in patients with ≥0·5 × 109/1). A rise in blasts followed administration of low‐dose GM‐CSF in five patients, all with either refractory anaemia with excess blasts (RAEB) or refractory anaemia with excess blasts in transformation (RAEBT). Platelets decreased in five patients, four of whom had no change in blasts, reverting to baseline when GM‐CSF was discontinued. We and others have previously observed simliar rises in blasts or decreases in platelets at doses of 120 μg/m2 daily. Low‐dose GM‐CSF produced no constitutional side effects. Our results suggest that low doses of GM‐CSF might be initially employed in neutropenic patients with myelodysplastic syndromes who present with pre‐treatment neutrophil counts > 0·5 × 109/1, increasing the dose, and hence the risk of extramedullary toxicity, only in patients who do not respond to the low dose. Patients who present with lower pre‐treatment neutrophil counts might begin treatment at doses above 10 μg/m2, but below the 120 μg/m2 commonly employed, which may be necessary in relatively few patients.
Leukaemia as a manifestation of large cell lymphoma
Authors: Bain Barbara , Matutes Estella , Robinson Danièle , Lampert I. A. , Brito‐Babapulle Vasanta , Morilla K. , Catovsky D. 
Published: March 2008

SummaryA leukaemic phase is uncommon in large cell lymphoma, particularly at presentation of the disease, and very few cases have been reported since immunological markers became available. We have studied 24 cases presenting over a period of 1 5 years. I h were H‐lineage and eight T‐lineage. In five patients the large cell lymphoma represented a transformation of a preceding low grade, small cell lymphoproliferative disease. Three other patients with T‐lineage large cell lymphoma presented with skin infiltration (two cases) or lymphoma‐associated nephrotic syndrome (one case) 3‐9 months before leukaemia occurred. The other 16 patients (12 B‐lineage and four T‐lineage) presented with de novo large cell leukaemia/lymphoma. With the exception of skin infiltration, clinical features did not differ between T and B‐lineage cases. Prognosis was generally poor although a minority of patients lived 1‐2 years. Median survival was 7 months. In the B‐cell lymphomas immunological markers were those expected but among the T‐cell cases there were many unusual immunophenotypes with frequent failure to express markers which are usually positive in peripheral T cells. Without the availability of immunological markers diagnosis would have been difficult, with acute myeloid leukaemia being the most important differential diagnosis. T‐lineage and B‐lineage cases could not be distinguished on cytological features. In the majority of cases the cells were very pleomorphic with nuclear lobulation, prominent nucleoli and marked cytoplasmic basophilia being commonly observed. Marked nuclear lobulation was not confined to T‐lineage cases but was seen also in seven of 12 cases of de novo B‐lineage leukaemia/lymphoma; it was readily apparent in histological sections and on ultrastructural examination.
The effect of human T cell leukaemia virus type I infection on a herpes simplex virus‐specific CD8+ cytotoxic T cell clone
Authors: Inatsuki Akira , Yasukawa Masaki , Kobayashi Yuzuru 
Published: March 2008

SummaryIn an effort to clarify the effect of human T cell leukaemia virus type I (HTLV‐I) infection on virus‐specific CD8+ cytotoxic T cells, a herpes simplex virus‐specific CD8+ cytotoxic T cell clone was infected with HTLV‐I in vitro. The cytotoxic activity of the clone was found to have declined early after HTLV‐I infection when the expression of T cell receptor‐CD 3 complex on the cell surface still showed no difference in comparison with that of uninfected parent cells. After 16 weeks of HTLV‐I infection, expression of T cell receptor‐CD3 complex on HTLV‐I‐infected clone cells became decreased. This phenomenon is similar to the effect of HTLV‐I infection on CD4+ cytotoxic T cells as we previously reported, and suggests that there are common mechanisms of declined cytotoxic activity mediated by both CD4+ and CD8+ cytotoxic T cells following infection with HTLV‐I. Such functional alterations of cytotoxic effector cells might be one of the mechanisms underlying immunodeficiency caused by HTLV‐I infection.
Non‐Hodgkin's lymphomas with t(11;14)(q13;q32): a subset of mantle zone/intermediate lymphocytic lymphoma?
Authors: Leroux Dominique , Marc'hadour F. Le , Gressin R. , Jacob Marie‐Christine , Keddari E. , Monteil Michèle , Caillot P. , Jalbert P. , Sotto J. J. 
Published: March 2008

SummaryWe here describe 13 patients with non‐Hodgkin's lymphoma (NHL) and a translocation t(11;14)(q13;q32). They were part of a series of 163 patients with NHL and an abnormal karyotype. serially referred to our institution between January 1984 and 1990. Patients with t(11;14) seem to present several common and interesting features. Males are more frequently affected than females, and old people more than young. They present at diagnosis with advanced disease and usually show involvement of epithelium and bone marrow. With respect to histologic diagnoses, these patients are usually considered to be of low‐grade malignancies. However, most of them do very poorly, have short complete remission and frequent relapses whatever the treatment. As a whole, the median survival rate is rather low. The cytologic, histologic as well as the immunologic patterns tend to be uniform: tumours are composed of small cells and display features of mantle zone/intermediate lymphocytic lymphoma. They express high IgM and low IgD levels and more commonly bear Ig lambda light chains. They also express all pan‐B antigens (except CD23) as well as the CD 5 antigen, but usually lack the CD10. According to these characteristics, these tumours could be placed in between lymphocytic lymphomas (which usually express CD23) and follicular lymphomas (which commonly lack IgD and CD5 and bear CD 10 as well as a t(14:18)).
Detection of activity of P‐glycoprotein in human tumour samples using rhodamine 123
Authors: Ludescher Christof , Thaler Josef , Drach Doris , Drach Johannes , Spitaler Martin , Gattringer Claus , And Heinz Huber , Hofmann Johann 
Published: March 2008

Summary Based on the fluorescent properties of the dye rhodamine 123 (Rh123), which is transported by the membrane efflux pump P‐glycoprotein (P‐gp), we developed a functional flow cytometric assay for the detection of multidrug‐resistant (MDR) cells. Using drug sensitive cell lines (KB‐3–1) and MDR mutants (KB‐8–5, KB‐C1) experimental conditions were established that enabled demonstration of significant differences in Rhl23 efflux and accumulation. Subsequently we investigated the applicability of this functional assay for the prediction of MDR in human peripheral blood and bone marrow samples. Using two‐colour flow cytometry, the leukaemic blast cells of six patients suffering from acute myeloid leukaemia (AML) were analysed. In three cases the blast cells showed a rapid and marked Rh123 efflux. In the presence of MDR inhibitors these cells retained Rh123. To determine whether the efflux of Rhl23 was associated with P‐gp expression, the leukaemic cells were stained with the monoclonal antibody MRK‐16. In addition extracted RNA was analysed by polymerase chain reaction to evaluate the expression of mdr 1 mRNA. In all three Rh123+ cases mdr 1 mRNA was detectable whereas only one AML case expressed P‐gp. In comparing Rh123 with daunorubicin, which also allows the detection of MDR cells, accumulation studies proved Rh123 to be the more sensitive drug for flow cytometric MDR screening. Additionally, two‐colour flow cytometry was much easier to perform with Rh123 than with daunorubicin.Our results indicate that flow cytometric measurement of Rh123 accumulation/efflux proves applicable to detect MDR cells in heterogenous clinical samples.