bluuebunny/crossref_metadata_2025_split huggingface dataset:
UTY‐specific TCR‐transfer generates potential graft‐versus‐leukaemia effector T cells
Authors: Ivanov Roman , Hol Samantha , Aarts Tineke , Hagenbeek Anton , Slager Elisabeth H. , Ebeling Saskia 
Published: July 2005

SummaryImmunotherapeutic approaches that target antigens that are differentially recognized on haematopoietic and non‐haematopoietic cells may specifically enhance the graft‐versus‐leukaemia (GVL) effect of donor lymphocyte infusion. In this study, we have characterized a new HLA‐B*5201‐restricted epitope of the UTY gene. Unusually, presentation of this epitope was restricted to lymphoblasts. As a result, a T cell clone specific to this epitope recognized normal and malignant male B and T lymphoblasts, while showing little reactivity towards male HLA‐B*5201+ fibroblasts. Transfer of its T cell receptor (TCR) into donor T cells led to the generation of large numbers of T cells, which acquired the specificity of the original clone, its avidity and the differential pattern of reactivity towards lymphoblasts and fibroblasts. Remarkably, the specific response of TCR‐transferred T cells was significantly higher than that of the original clone. This is the first demonstration of the possibility to preserve the specific pattern of a T cell response to a differentially expressed antigen after TCR‐transfer and to augment the amplitude of this response concomitantly. These results indicate that it may be feasible to enhance the GVL effect of donor lymphocyte infusions in lymphoproliferative malignancies by the transfer of TCRs specific to epitopes that are differentially recognized on lymphoblasts.
Chronic oxidative stress reduces the respiratory burst response of neutrophils from beta‐thalassaemia patients
Authors: Amer Johnny , Fibach Eitan 
Published: July 2005

SummaryBeta‐thalassaemia patients are susceptible to infections by mechanisms that are not fully understood. Polymorphonuclear neutrophils (PMN) destroy microbes by producing a burst of reactive oxygen species (ROS) (respiratory burst) in response to bacterial components, as well as to phorbol‐myristate‐acetate (PMA). In the present study, we compared ROS generation by normal and β‐thalassaemia PMN and assessed their response to PMA. Blood cells were subjected to gelatin separation, staining with dichlorofluorescin‐diacetate and flow cytometry. At basal level, the fluorescence (mean fluorescence channel) of normal and thalassaemia PMN were 12·7 ± 4·5 and 95·6 ± 19·8 respectively; it changed to 283·4 ± 72·5 and 39·5 ± 14·3, respectively, upon PMA stimulation, indicating that thalassaemia PMN have a higher basal ROS but a reduced response to PMA. When normal PMN were treated with the oxidants hydrogen peroxide and butyl‐hydroxyperoxide, as well as iron and haemin, which are elevated in thalassaemia, their basal ROS increased 5–22‐fold, but the PMA response was abolished. Treating thalassaemic PMN with antioxidants (N‐acetyl‐l‐cysteine or vitamins C and E) reduced their basal ROS but enhanced their PMA response. Our findings indicate that chronically stressed PMN, e.g. in thalassaemia, have reduced capacity to elicit a respiratory burst, which may compromise their antibacterial capacity, and imply prophylactic treatment with antioxidants for recurrent infections.
Haplotypes in the tumour necrosis factor region and myeloma
Authors: Morgan Gareth J. , Adamson Peter J. , Mensah Fiona K. , Spink Charlotte F. , Law Graham R. , Keen Leigh J. , Roman Eve , Davies Faith E. , Rollinson Sara , Child J. A. , Bidwell Jeffrey L. 
Published: July 2005

SummaryThis study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions −1031, −863, −857, −308 and −238 of the 5′ promoter region of TNF‐α gene, and 252 in the LT‐α gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF‐α−308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF‐α−308 variant allele A, odds ratio, 0·57; 95% confidence interval, 0·38–0·86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.
Oneversustwo high‐dose cytarabine‐based consolidation before autologous stem cell transplantation for young acute myeloblastic leukaemia patients in first complete remission
Authors: Jourdan Eric , Rigal‐Huguet Françoise , Marit Gerald , Vey Norbert , Dastugue Nicole , Fegueux Nathalie , Molina Lysiane , Gastaut Jean‐Albert , Legros Laurence , Zerazhi Hacene , Cailleres Sylvie , Bauduer Frédéric , Bordessoule Dominique , Attal Michel , Blaise Didier , Pigneux Arnaud ,   the BGMT Study Group
Published: July 2005

SummaryWe report on a randomized trial aimed to determine the impact of a second consolidative high‐dose cytarabine‐based chemotherapy (HiDAC) in patients with acute myeloid leukaemia prior to an autologous stem cell transplantation (ASCT). Patients aged 18–60 years, in complete remission (CR) received a first consolidation with daunorubicin and cytarabine at reduced dose. Patients not allocated to allogeneic transplantation received one course of HiDAC and then were randomized to receive an ASCT immediately (HiDAC 1 group) or after one more course of HiDAC (HiDAC 2 group). Out of the 437 initial patients, 351 achieved CR (80%), of those 277 (79%) were eligible for first HiDAC, and 128 (36%) were randomized (HiDAC 1: 65, HiDAC 2: 63). Overall survival, leukaemia‐free survival and cumulative incidence of relapse and non‐relapse deaths were 41% and 53% (P = 0·14), 39% and 48% (P = 0·12), 57% and 47% (P = 0·11), 8% and 8% (P = 0·95) for HiDAC 1 and HiDAC 2 groups, respectively. Further studies are warranted with a larger number of patients to test the place of a second course of HiDAC in this setting.
Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood
Authors: Beck Rose C. , Wlodarski Marcin , Gondek Lukasz , Theil Karl S. , Tuthill Ralph J. , Sobeck Ronald , Bolwell Brian , Maciejewski Jaroslaw P. 
Published: July 2005

SummaryGraft‐versus‐host disease (GVHD) causes severe morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) because of destruction of recipient tissues by donor alloreactive T cells. We hypothesized that GVHD‐specific T‐cell clones are expanded within affected tissue of HSCT patients and can also be detected in blood at the time of active disease. A multiplex polymerase chain reaction (PCR) was used to amplify T‐cell receptor (TCR) variable beta (VB) chain rearrangements in skin biopsies from eight allogeneic HSCT patients. Molecular analysis of the complementarity‐determining region 3 (CDR3) of amplified products defined expanded, potentially disease‐associated ‘clonotypes’ and enabled the design of clonotype‐specific PCR assays. We detected immunodominant clones in seven of eight GVHD‐positive skin biopsies. In serial skin biopsies from the same patient, the identical clone was found in each biopsy. In a patient who underwent two successive HSCTs from different donors, distinct clones were identified for each engraftment. Using clonotypic PCR assays, individual tissue‐derived clones could be identified in peripheral blood samples obtained during active GVHD. We hypothesize that clonotypic sequences derived from target tissue can serve as markers for GVHD and may have utility in diagnosis and monitoring response to therapy, as well as enable future therapies targeted against pathogenic clones.
The International Prognostic Index determines the outcome of patients with nodal mature T‐cell lymphomas
Authors: Sonnen Ruth , Schmidt Wolf‐Peter , Müller‐Hermelink Hans Konrad , Schmitz Norbert 
Published: July 2005

SummaryThe World Health Organization (WHO) lymphoma classification recognises anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoma (AIL) and peripheral T‐cell lymphoma, unspecified (PTCU) as nodal mature T‐cell lymphomas. Little is known about long‐term outcome and prognostic factors of these diseases. A retrospective analysis on 125 patients with ALCL, AIL or PTCU was performed to evaluate outcome parameters, taking into account histological subtype and the International Prognostic Index (IPI). Median age was 54 years (range 17–90 years). Complete remission (CR) was achieved in 51% of patients. Five‐year overall survival (OS) was 43%, and 5‐year relapse‐free survival was 69%. Five‐year OS was 61% for ALCL, 45% for PTCU and 28% for AIL. With regard to the IPI, 5‐year OS was 74%, 49%, 21% and 6% for the low, low‐intermediate, high‐intermediate and high risk groups, respectively. In the multivariate analysis, the IPI but not the histological subtype significantly predicted survival. To a large extent, the IPI score explains the differences in survival between histological subtypes of nodal mature T‐cell lymphomas. The IPI may therefore be used for risk stratification in clinical trials to identify patients who would benefit most from new treatment strategies, such as high‐dose chemotherapy followed by stem cell or bone marrow transplantation.
Cytokines and fungal infections
Authors: Antachopoulos Charalampos , Roilides Emmanuel 
Published: July 2005

SummaryThe very poor outcome of invasive fungal infections (IFI) in patients with haematological malignancies or recipients of haematopoietic stem cell transplantation is largely attributed to their compromised host defence mechanisms. The restoration or augmentation of immune responses in these patients is now considered as one of the cornerstones of effective antifungal therapy. Major advances in the field of experimental immunology have provided insight on the important regulatory role of cytokines in both innate and adaptive immunity to fungal pathogens. Preclinical studies have convincingly demonstrated that immunomodulation with cytokines can enhance the antifungal activity of neutrophils and monocytes/macrophages as well as upregulate protective T‐helper type 1 adaptive immune responses. Evidence on the clinical use of cytokines in immunocompromised hosts with IFI is, however, still scant and inconclusive. The present review summarizes experimental and clinical data on the role of cytokines in the immune response to fungal pathogens and on their potential use for prevention or treatment of fungal infections. Implications for future research are also briefly discussed.
Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis
Authors: Horne AnnaCarin , Janka Gritta , Maarten Egeler R. , Gadner Helmut , Imashuku Shinsaku , Ladisch Stephan , Locatelli Franco , Montgomery Scott M. , Webb David , Winiarski Jacek , Filipovich Alexandra H. , Henter Jan‐Inge ,   the Histiocyte Society
Published: July 2005

SummaryHaemophagocytic lymphohistiocytosis (HLH) poses major therapeutic challenges, and the primary inherited form, familial haemophagocytic lymphohistiocytosis (FHL), is usually fatal. We evaluated, including Cox regression analysis, survival in 86 children (29 familial) that received HLH‐94‐therapy (etoposide, dexamethasone, ciclosporin) followed by allogeneic stem cell transplantation (SCT) between 1995 and 2000. The overall estimated 3‐year‐survival post‐SCT was 64% [confidence interval (CI) = ±10%] (n = 86); 71 ± 18% in those patients with a matched related donor (MRD, n = 24), 70 ± 16% with a matched unrelated donor (MUD, n = 33), 50 ± 24% with a family haploidentical donor (haploidentical, n = 16), and 54 ± 27% with a mismatched unrelated donor (MMUD, n = 13). After adjustment for potential confounding factors, estimated odds ratios (OR) for mortality were 1·93 (CI =0·61–6·19) for MUD, 3·31 (1·02–10·76) for haploidentical, and 3·01 (0·91–9·97) for MMUD, compared with MRD. In children with active disease after 2‐months of therapy (n = 43) the OR was 2·75 (1·26–5·99), compared with inactive disease (n = 43). In children with active disease at SCT (n = 37), the OR was 1·80 (0·80–4·06) compared with inactive disease (n = 49), after adjustment for disease activity at 2‐months. Mortality was predominantly transplant‐related. Most HLH patients survived SCT using MRD or MUD, and survival with partially mismatched donors was also acceptable. Patients that responded well to initial pretransplant‐induction therapy fared best, but some persisting HLH activity should not automatically preclude performing SCT.
Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway
Authors: Bortul Roberta , Tazzari Pier Luigi , Billi Anna Maria , Tabellini Giovanna , Mantovani Irina , Cappellini Alessandra , Grafone Tiziana , Martinelli Giovanni , Conte Roberto , Martelli Alberto M. 
Published: July 2005

SummaryActivation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its downregulation, by means of PI3K inhibitors, lowers resistance to various types of therapy in tumour cell lines. Recently, it has been reported that deguelin, a naturally occurring rotenoid, is a powerful inhibitor of PI3K. We investigated whether or not deguelin could enhance the sensitivity to chemotherapeutic drugs of human U937 leukaemia cells and acute myeloid leukaemia (AML) blasts with an activated PI3K/Akt network. Deguelin (10 nmol/l) induced S phase arrest with interference of progression to G2/M, and at 100 nmol/l significantly increased apoptotic cell death of U937. At 10–100 nmol/l concentrations, deguelin downregulated Akt phosphorylation of leukaemia cells and markedly increased sensitivity of U937 cells to etoposide or cytarabine. A 10 nmol/l concentration of deguelin did not negatively affect the survival rate of human cord blood CD34+ cells, whereas it increased sensitivity of AML blasts to cytarabine. Deguelin was less toxic than wortmannin on erythropoietin‐ and stem cell factor‐induced erythropoiesis from CD34+ progenitor cells. Overall, our results indicate that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukaemia cells with an active PI3K/Akt signalling network.
A population‐based study of severity of comorbidity among patients with non‐Hodgkin's lymphoma: prognostic impact independent of International Prognostic Index
Authors: Janssen‐Heijnen Maryska L.G. , van Spronsen Dick Johan , Lemmens Valery E.P.P. , Houterman Saskia , Verheij Kees D.G.W. , Coebergh Jan Willem W. 
Published: July 2005

SummaryOver 60% of patients aged over 70 years, diagnosed with non‐Hodgkin's lymphoma (NHL) in the Netherlands have serious comorbidity. We studied the independent influence of comorbidity on choice of treatment, dose reductions, treatment‐related toxicity and prognosis, using data from a random sample of 381 patients from the population‐based Eindhoven Cancer Registry. About 45% of patients over 60 years of age with NHL had high impact comorbidity at the time of cancer diagnosis. The proportion of patients with aggressive NHL who received chemotherapy decreased from 85% in patients aged 40–60 years to 70% in those over 60 years. About 65% of systematically treated patients with aggressive NHL suffered from treatment‐related toxicity. Toxicity appeared to be more common among females and those with high‐intermediate or high International Prognostic Index (IPI) risk. Among patients with aggressive NHL, the chance of dying for those with high impact comorbidity was twice as high compared with those without comorbidity. This was independent of the IPI risk. Dose reductions are frequently unavoidable for patients with severe comorbidity, poor performance status or chemotherapy‐related toxicity. Whether the less frequent prescription of (full dose) chemotherapy for patients with advanced age and/or with comorbidity is justified remains a question for debate.
Reduced efficacy of clinical probability score and d‐dimer assay in elderly subjects suspected of having deep vein thrombosis
Authors: Schutgens Roger E. G. , Haas Fred J. L. M. , Biesma Douwe H. 
Published: July 2005

SummaryThe combined strategy of a pretest clinical probability (PCP) score and d‐dimer has shown to be of value in the diagnosis of deep vein thrombosis (DVT). As d‐dimer concentrations increase with age, the effect of age on the usefulness of this strategy was retrospectively investigated in outpatients suspected of having DVT. In all patients, participants of a prospective management trial, a PCP score and d‐dimer (Tina‐quant®) were performed. In a total of 812 patients, 317 (39%) had thrombosis. Patients were divided into quartiles according to their age. Sensitivity and negative predictive value of a low/moderate PCP score and a normal d‐dimer were 98–100% and did not differ between the different age quartiles. Specificity in the highest quartile was 17·4% compared with 49·2% in the youngest (P < 0·000001). The proportion of patients with a low/moderate PCP score and a normal d‐dimer decreased with age: 12% in the highest quartile (>73·8 years) versus 25% in younger patients (P = 0·00005). We therefore conclude that the combined strategy of a low/moderate PCP score with a normal d‐dimer test is safe for excluding DVT in all age groups, but is less useful in the elderly.
An elevated venous haemoglobin concentration cannot be used as a surrogate marker for absolute erythrocytosis: a study of patients with polycythaemia vera and apparent polycythaemia
Authors: Johansson Peter L. , Safai‐Kutti Soodabeh , Kutti Jack 
Published: July 2005

SummaryThe diagnosis of polycythaemia vera (PV) has been established upon sets of clinical criteria, which require the presence of absolute erythrocytosis (AE). The most recent clinical criteria for PV, published by the World Health Organization (WHO) in 2001, also required AE, and stated that the measured red cell mass (RCM) could be replaced by a surrogate marker for AE; a haemoglobin (Hb) value of >18·5 g/dl in males and >16·5 g/dl in females. The present study evaluated the potential of venous haematocrit (Hct) and Hb values as possible surrogate markers for AE in a series of 77 consecutive patients with PV and 66 patients with apparent polycythaemia (AP), in all of whom the RCM had been previously determined. In only 35% of the male PV patients would Hb values >18·5 g/dl indicate the presence of AE. Conversely, 14% of male AP patients would be misdiagnosed as having AE. A Hb > 16·5 g/dl would predict the presence of AE in 63% of the female PV patients, but 35% of female AP cases would be misdiagnosed as having AE. However, when the Hct was ≥0·60 an AE was always present, and this was true for both male and female subjects.
Molecular mechanisms of eosinophil activation in allergic diseases
Authors: Chihara J. 
Published: July 2005

SummaryEosinophils are major effector cells in allergic diseases. These cells possess a variety of membrane receptors that mediate their activation in the presence of pro‐inflammatory chemokines such as IL‐5, regulated on activation, normal T cell expressed and secreted, eotaxin, and intracellular adhesion molecule (ICAM)‐1. ICAM‐1 is also implicated in stimulating the production of reactive oxygen species and inducing degranulation of eosinophil granule proteins. Treatment with peroxisome proliferator‐activated receptor‐γ agonist inhibits IL‐5‐stimulated eosinophil survival and eotaxin‐directed eosinophil chemotaxis, suggesting that such agents could serve as a new therapeutic modality for the treatment of allergic diseases.
Eosinophils and rhinitis
Authors: Howarth P. H. 
Published: July 2005

SummaryAllergic rhinitis (AR) is typified by the nasal mucosal and luminal recruitment of eosinophils. These changes are evident in both seasonal and perennial disease, although the magnitude of these cellular changes is often greater with the more transient intense stimulation associated with seasonal allergen exposure than with the chronic persistent stimulation linked to perennial disease. Measures of eosinophil activation markers in nasal lavage such as eosinophil cationic protein and eosinophil protein X parallel the eosinophilic cellular changes and have been used serially to monitor allergic inflammation in association with intranasal allergen challenge and in therapeutic intervention studies. In both naturally occurring disease and laboratory allergen challenge, there is considerable inter‐subject variability in the magnitude of eosinophil airway recruitment and activation. Studies evaluating the mechanisms involved in nasal eosinophil recruitment identify systemic involvement of bone marrow stimulation and tissue recruitment of circulating progenitor cells. Interleukin‐5 (IL‐5) is a key cytokine involved in this process, acting on both marrow and circulating progenitors, with chemokines such as stromal cell derived factor‐1, RANTES (regulated on activation, normal T cell expressed and secreted) and eotaxin potentially being involved in tissue uptake and localization within the nasal airways. Inflammatory mediators such as leukotrienes acting through the cys‐LT1 receptor, in conjunction with IL‐5, and prostaglandin D2 acting through eosinophil‐expressed DP and CRTH2 cell surface receptors also contribute in animal models of allergic inflammation. The function of nasal eosinophils in AR can be debated. Genetic and nasal challenge models, with chemokines that promote eosinophil influx, support the relevance of eosinophils to symptom expression in rhinitis while the timing of the eosinophil recruitment following intranasal allergen challenge, the relationship between eosinophils and plasma protein exudation as well as the appreciation that clinical disease expression can arise in the apparent absence of nasal eosinophilia favour a restorative function for this cell. In the absence of specific eosinophil‐targeted intervention in rhinitis, it is not possible to conclusively apportion the relative involvement of eosinophils in these inductive and restorative processes but it has to be appreciated that the close association between eosinophils and clinical disease expression in rhinitis is not necessarily causal.
Analysis of Th1, Th2, Tc1 and Tc2 cells in patients with allergic rhinitis
Authors: Ohta N. , Sakurai S. , Yoshitake H. , Aoyagi M. 
Published: July 2005

SummaryAllergic rhinitis (AR) is an IgE‐mediated inflammatory disease of the nasal mucous membranes, characterized by paroxysms of sneezing, itching of the nose, eyes, palate, pharynx, and conjunctivae, nasal stuffiness with partial or total obstruction of airflow and mucous secretion often accompanied by post‐nasal drainage. A T helper (Th)1/Th2 cytokine imbalance with a predominance of Th2 cytokines has been suggested of pathogenic importance in AR. To evaluate the role of Th1/Th2 cytokines in AR, the subsets of Th1, Th2, T cytotoxic type 1 (Tc1) and Tc2 cells from patients with AR were examined by intracellular cytokine flow cytometry. The population of Tc1 cells (52.3±23.6%) in AR was significantly increased compared with that in control (35.4±14.6%, P<0.05). Th1, Th2 and Tc2 cells in AR were not significantly increased vs. control. However, the ratio of Th1/Th2 was significantly decreased and the ratio of Tc1/Tc2 was significantly higher in patients with AR compared with healthy individuals (P<0.05 and P<0.01, respectively). These results indicate that the predominance of Th2 and Tc1 cells might contribute to the pathogenetic mechanism in AR.