bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antithrombotic activity of a fucosylated chondroitin sulphate from echinoderm: sulphated fucose branches on the polysaccharide account for its antithrombotic action
Authors: Mourão Paulo A. S. , Guimarães Marco A. M. , Mulloy Barbara , Thomas Stephen , Gray Elaine 
Published: March 2003

The antithrombotic activity of a fucosylated, chondroitin‐sulphate‐like polysaccharide extracted from the body wall of sea cucumber, and of chemically modified derivatives of the same polysaccharide, have been assessed using a stasis thrombosis model in rabbits. Intravenous administration of the native polysaccharide reduced thrombosis in a dose‐dependent manner and, at a dose of 1.5 mg/kg (60 IU/kg) body weight, completely prevented thrombosis after 10 min stasis. Removal of the sulphated fucose branches of the polysaccharide abolished antithrombotic effectiveness.After intravenous injection of an antithrombotic dose of radioactively labelled polysaccharide, a correlation was observed between removal of radioactivity from the plasma and decrease in ex vivo APTT values, demonstrating that antithrombotic effectiveness depends on the level of circulating polysaccharide rather than on an indirect effect of the polysaccharide on the vascular endothelium.Reduction of the glucuronic acid carboxyl groups in the polysaccharide did not affect its in vitro and in vivo activities. Both partial defucosylation and desulphation of the polysaccharide abolished all its anticoagulant or antithrombotic action.
Anti‐B4‐blocked ricin: a phase II trial of 7 day continuous infusion in patients with multiple myeloma
Authors: Grossbard Michael L. , Fidias Panos , Kinsella Jeanne , O'toole John , Lambert John M. , Blattler Walter A. , Esseltine Dixie , Braman Ginny , Nadler Lee M. , Anderson Kenneth C. 
Published: March 2003

This phase II trial was undertaken to determine the toxicities, response rate, pharmacokinetics and frequency of human anti‐mouse antibody (HAMA) and anti‐ricin antibody (HARA) when the B‐cell restricted immunotoxin anti‐B4‐bR was administered to patients with previously treated multiple myeloma (MM).Five patients with MM were scheduled to receive a 7 d continuous infusion of anti‐B4‐bR. The initial four patients received therapy at 40 μg/kg lean body weight (LBW)/d. Two patients received a 7 d infusion, one patient received 6 d, and another patient 5 d of therapy. The fifth patient was treated for 7 d at a lower dose of 30 μg/kg LBW/d because of the side‐effects observed in the initial patients.Pharmacokinetic studies demonstrated a peak serum level >2.6 n M in three of the patients. Side‐effects of therapy included hepatic transaminase elevations, myalgias, thrombocytopenia, nausea, vomiting, decrease in performance status, and capillary leak syndrome. One patient developed HAMA and two patients HARA. One patient developed neurologic toxicity with akinetic mutism, and died following therapy. No patient demonstrated a significant decline in M‐component during therapy.We concluded that anti‐B4‐bR can be administered by continuous infusion to patients with multiple myeloma, although immunotoxin levels >3 n M were associated with increased incidence of toxicity and required dose adjustment. Future trials using anti‐B4‐bR in MM will be needed to determine the optimal dose and administration schedule in this patient population, and to determine whether there is evidence of biologic activity.
Two M‐components in a single cell lineage in a patient with a dual isotype secretory B‐cell tumour
Authors: Sakashita Chizuko , Saito Takako , Kurosu Tetsuya , Yoshinaga Haruhiko , Kumagai Takasi , Yamamoto Koh , Miki Tohru , Koyama Takatoshi , Miura Osamu , Nemoto Tetsuo , Asakawa Hideo , Hirosawa Shinsaku 
Published: March 2003

We describe a case of Waldenström's macroglobulinaemia with two M‐components (IgM and IgG) with the same λ light chain. Southern blot analysis of bone marrow cells showed rearrangements of immunoglobulin heavy and λ light chain genes.Sequencing of the complementarity determining region 3 of the two γ and μ transcripts showed 100% homology. Immunofluorescence study showed that most cells stained for both IgG and IgM. These findings indicated that a single population of cells was expressing two isotypic variants of IgG and IgM, as the genes responsible for production of both components had the same origin.
Extensive phenotypic analysis of CD34 subsets in successive collections of mobilized peripheral blood progenitors
Authors: Perey Lucien , Peters Rowayda , Pampallona Sandro , Schneider Philippe , Gross Nicole , Leyvraz Serge 
Published: March 2003

The transplantation of mobilized progenitor cells after high‐dose chemotherapy shortens haemopoietic engraftment. CD34 cell subsets were examined in 20 consecutive mobilized progenitor cell collections obtained from patients with solid tumours that had not been previously treated. The analysis of CD34 cells was based on the expression of intracellular antigens, surface antigens including CD38, and cell size using multi‐dimensional flow cytometry. We also correlated the numbers of stem cell subsets reinfused to haemopoietic recovery.The majority of CD34+ cells expressed CD13 and CD33. A significant proportion was cytoplasmic myeloperoxidase (cMPO) positive. CD34+ MPO+ cells increased significantly in late collections. MPO expression was related to cell size. Cells expressing CD13 also increased in late collections in parallel to CFU‐GM count. Small subpopulations of CD34+ CD38+ were committed to B cells, T cells and erythroid cell lineages. A small population expressing the megakaryocytic antigen had a small size and were predominantly CD38−. A minor subpopulation expressed stem cells antigens. These were significantly higher in late collections (CD34+ Thy‐1+ and CD34+ CD33−). After mobilization, patients received three cycles of intensive chemotherapy followed by reinfusion of mobilized progenitors (5.45 × 106/kg CD34+ cells, range 3.4–11.88). The numbers of reinfused CD34 cells or the individual subsets did not influence recovery of leucocytes (9 d) or platelets (9 d).In conclusion, the numbers of stem cells and their subsets differed between collections and, in unpretreated patients receiving intensive chemotherapy, there was no delayed engraftment when sufficient numbers of stem cells were reinfused. The recovery period was short and not correlated to any stem cell subsets.
Use of standardized flow cytometric determinants of multidrug resistance to analyse response to remission induction chemotherapy in patients with acute myeloblastic leukaemia
Authors: Pallis M. , Turzanski J. , Harrison G. , Wheatley K. , Langabeer S. , Burnett A. K. , Russell N. H. 
Published: March 2003

We have used a combination of flow cytometric assays to define multidrug resistance (MDR) positive and negative blasts in cryopreserved samples from 47 MRC trial patients with acute myeloblastic leukaemia (AML). Our primary test is a standardized assay for daunorubicin accumulation. Confirmatory assays for MDR comprised the cyclosporin modulation assay for rhodamine‐123 uptake as a measure of functional P‐glycoprotein and the measurement of lung resistance protein and multidrug resistance associated protein (with LRP‐56 and MRPr1 respectively).57% of samples had both low accumulation and at least one positive confirmatory test. 32% were MDR negative in all four assays. 15% of patients had primary chemo‐resistant disease. Resistant disease rates were 22% for confirmed MDR‐positive patients and 0% for confirmed MDR‐negative patients (P = 0.07). Complete remission was achieved in 74% of patients, with rates of 63% in confirmed MDR‐positive patients and 93% in confirmed MDR‐negative patients (P = 0.06). The use of a standardized method for daunorubicin uptake, combined with the use of confirmatory tests, should reduce the uncertainty that is currently characteristic of MDR evaluation in leukaemia. In comparison with daunorubicin uptake, p‐gp expression, measured using MRK‐16 antibody, was more closely associated with remission rates (P = 0.01). This suggests an additional role for p‐glycoprotein in mediating drug resistance beyond that of a drug efflux pump.
Chronic lymphocytic leukaemia and neuroendocrine cancer
Authors: Russo F. , Guadagni S. , Corazzelli G. , Frigeri F. , Monda V. M. , Abate G. 
Published: March 2003

We report a unique association between neuroendocrine cancer and chronic lymphocytic leukaemia (CLL) in a 63‐year‐old man. Neuroendocrine cancer was resistant to various conventional treatments and following loco‐regional progression we treated the patient with hypoxic pelvic perfusion of cisplatin 100 mg/m2 plus mitomycin 40 mg/m2, using the stopflow method, for three cycles: a dramatic and surprising reduction of > 75% in the evaluable lesions was observed. The cumulative effect of treatment produced a complete response from CLL.At cytogenetic examination the neuroendocrine cells were diploid, whereas CLL cells showed trisomy 12. Moreover, deletion of the short arm of chromosome 3 was found in both neoplastic populations. Whether the abnormality seen on chromosome 3 in the two diseases represents a critical event is not known.
Prognosis for fludarabine therapy of chronic lymphocytic leukaemia based on ex vivo drug response by DiSC assay
Authors: Bosanquet Andrew G. , Johnson Stephen A. , Richards Sue M. 
Published: March 2003

The cytotoxic antimetabolite fludarabine is a widely used active agent in chronic lymphocytic leukaemia (CLL). However, cost and occasional adverse side‐effects necessitate careful use. Identifying before treatment patients not likely to benefit from fludarabine could advance disease management both clinically and financially.We used the DiSC (differential staining cytotoxicity) assay, an ex vivo apoptotic drug response test, to identify the sensitivity or resistance to fludarabine of lymphocytes from B‐cell CLL patients and compared the results with subsequent patient treatment, response and survival. Patients were grouped thus: those receiving fludarabine within 1 year of assay (± other cytotoxic drugs), and those receiving other chemotherapy (excluding fludarabine) within 1 year of assay.Fludarabine‐test‐resistance was found in 12/100 (12%) of untreated patients and 45/143 (31%) of previously treated patients (17/32 (53%) of patients previously treated with fludarabine). Treating fludarabine‐test‐resistant patients with fludarabine resulted in poor response compared with fludarabine‐test‐sensitive patients (7% v 69%) and short survival (median 7.9 v 41.7 months; relative risk (RR) = 14.8; P < 0.0001). 81% of fludarabine‐test‐resistant patients were test sensitive to other regimens. If treated with chemotherapy other than fludarabine, test‐resistant patients responded better and survived substantially longer than those treated with fludarabine (RR = 2.9; P = 0.001).Not all CLL patients should receive fludarabine. Fludarabine‐test‐resistance by DiSC assay is a powerful independent prognostic factor. Pretreatment DiSC assay results could enable the toxic, clinical and financial costs of fludarabine treatment to be avoided in fludarabine‐test‐resistant patients. Disease management, response, survival and use of financial resources might be significantly improved if therapy choice in CLL patients was guided by DiSC assay.
Flt3L induces the ex‐vivo amplification of umbilical cord blood committed progenitors and early stem cells in short‐term cultures
Authors: De Felice Lidia , Di Pucchio Tiziana , Grazia Mascolo Maria , Agostini Francesca , Breccia Massimo , Guglielmi Cesare , Rosaria Ricciardi Maria , Tafuri Agostino , Screnci Maria , Mandelli Franco , Arcese William 
Published: March 2003

Umbilical cord blood (UCB) has been successfully used for haemopoietic stem cell transplantation, although its use has been cautiously limited to paediatric patients because of the reduced volume produced. The clinical results have confirmed that either engraftment or survival significantly correlate with cell dose infused. We have standardized a culture method providing in a short time a significant amplification of both committed progenitors and primitive stem cells for clinical use.Eight‐day culture of UCB cells with flt3L/SCF/PIXY 321 induced a 10‐fold amplification of CD34+ cells and the expansion of multipotent (CFU‐GEMM) and committed (CFU‐GM, BFU‐E) progenitors respectively of 5‐, 7‐ and 9‐fold over input cells. As to the early stem cell pool, the primitive CD34+Thy‐1+ cell fraction increased 6‐fold and the LTC‐IC were amplified 17‐fold. Furthermore, the in vitro proliferation was detected by the gradual loss of fluorescence of the CD34+ cells tracked at day 0 with the dye PKH26. After 8 d of amplification >6% of the CD34+ cells remained intensely fluorescent. This subpopulation represents a deeply quiescent cell fraction unresponsive to cytokines and very enriched of primitive stem cells. These cells are most likely to be responsible for long‐term reconstitution after transplant.
Clonotypic CD20+ and CD19+ B cells in peripheral blood of patients with multiple myeloma post high‐dose therapy and peripheral blood stem cell transplantation
Authors: Rottenburger Christof , Kiel Katja , Bösing Tobias , Cremer Friedrich W. , Moldenhauer Gerhard , Ho Anthony D. , Goldschmidt Hartmut , Moos Marion 
Published: March 2003

The number of circulating clonotypic B cells in patients with multiple myeloma (MM) after high‐dose therapy (HDT) with peripheral blood stem cell transplantation (PBSCT) was investigated. Peripheral CD19+ B cells have been reported to persist throughout conventional and HDT and might resemble a source of relapse in patients with MM. We assessed the proportion of malignant cells in CD20+ and CD19+ cell fractions of 14 peripheral blood (PB) samples from 12 patients after HDT and PBSCT. Nine samples were obtained from patients in continuous remission, and five patients were in progressive disease or beginning relapse.The CD20+ fractions obtained had a mean purity of 96.8%. The percentages of tumour cells were determined using a quantitative allele‐specific oligonucleotide PCR assay based on the method of limiting dilutions. In the group of patients in continuous remission the median number of tumour cells in the CD20+ cell fractions was 1.9/ml (range 0–7.2 tumour cells/ml PB) higher than in the CD20− fractions (median 0; range 0–29 tumour cells/ml PB). Higher tumour cell numbers in both fractions, particularly pronounced in the negative ones, were found in patients with progressive disease or beginning relapse (CD20+: range 3.8–585; median 32 tumour cells/ml PB; CD20−: range 25–25527; median 334 tumour cells/ml PB). Enrichment with the anti‐CD19 antibody as a second pan B‐cell marker revealed comparable tumour cell numbers.In conclusion, an anti‐CD20 antibody treatment could be a promising approach for the eradication of malignant cells in the PB of patients in continuous remission after HDT and PBSCT with low amounts of tumour cells in the B‐cell compartment and an almost complete absence of tumour cells in the CD20− fractions.
Comparative serial quantitative measurements of chimaerism following unmanipulated allogeneic transplantation of peripheral blood stem cells and bone marrow
Authors: Miflin G. , Stainer C. J. , Carter G. I. , Byrne J. L. , Haynes A. P. , Russell N. H. 
Published: March 2003

Serial samples were collected from 38 patients following allogeneic transplantation using either unmanipulated peripheral blood stem cells (PBSC) (n = 18) or bone marrow (BM) (n = 20) to assess the incidence of mixed chimaerism using PCR amplification of five VNTR regions. After amplification, products were analysed using the Applied Biosystems ABI PRISM 377 Automated DNA Sequencer and GeneScan software GenoTyper program to determine a quantitative measure of chimaerism. The sensitivity of detection using this method was 0.1%.In the immediate post‐transplant period (up to day 30) a significantly lower incidence of mixed chimaerism (MC) occurred in recipients of PBSC compared to BM (P < 0.0005). Between 1 and 6 months there was a significantly lower incidence of low‐level MC in patients receiving PBSCT compared to BMT (4/14 v 8/11 respectively, P = 0.04) in patients who had not rejected their grafts or relapsed. Similarly, beyond 6 months 0/9 PBSCT patients compared to 4/9 BMT patients showed MC (P = 0.02). Beyond day 30 13/33 (39%) patients showed intermittent low‐level MC, but this was not predictive for subsequent relapse. A rapidly increasing proportion of recipient haemopoiesis was predictive of graft rejection or relapse. Stable continuous MC without relapse was seen in one patient transplanted with PBSC for severe aplastic anaemia. These results suggest that the incidence of intermittent low‐level MC is relatively high in the first 6 months following unmanipulated haemopoietic stem cell transplantation but reduces with time and is significantly lower in recipients of PBSC.
Preliminary experience of allogeneic stem cell transplantation for lymphoproliferative disorders using BEAM–CAMPATH conditioning: an effective regimen with low procedure‐related toxicity
Authors: Cull G. M. , Haynes A. P. , Byrne J. L. , Carter G. I. , Miflin G. , Rebello P. , Hale G. , Waldmann H. , Russell N. H. 
Published: March 2003

Autologous transplantation has an established role in the treatment of lymphoproliferative disorders, but allogeneic transplantation remains controversial. In an attempt to reduce the high procedure‐related mortality reported with allografting in lymphoma, we have used BEAM (BCNU, etoposide, cytarabine and melphalan), a standard conditioning regimen for autologous transplantation. As BEAM may be insufficiently immunosuppressive to permit durable engraftment in the allogeneic setting, patients received additional pretransplant immunosuppression with the anti‐CD52 antibody CAMPATH‐1G from day −5 to day −1.Twelve patients (median age 46 years) underwent allogeneic transplantation for lymphoma (n = 11) or chronic lymphocytic leukaemia (n = 1) from HLA‐identical (n = 9) or mismatched (n = 3) sibling donors. Cyclosporin A and methotrexate were used as graft‐versus‐host disease (GVHD) prophylaxis. One patient died of progressive lymphoma at day +12, the remaining 11 patients engrafted rapidly, with eight demonstrating full donor chimerism. One patient had an episode of rejection and received a further stem cell infusion with sustained recovery. Only one patient developed GVHD (grade I). The low incidence of acute GVHD may be in part related to persisting levels of in vivo CAMPATH‐IG at the time of transplantation. Of 11 evaluable patients, nine achieved complete remission (CR), and a further patient achieved CR after donor lymphocyte infusion at 5 months.Our preliminary experience is that this regimen was well tolerated with a low risk of GVHD and appears no more toxic than a BEAM autograft. Further follow‐up is required to see whether the low incidence of GVHD impacts upon relapse risk.
Two novel and one recurrent missense mutation in the factor XIII A gene in two Dutch patients with factor XIII deficiency
Authors: Gómez García E. B. , Poort S. R. , Stibbe J. , Sturk A. , Schaap M. C. L. , Kappers M. , Bertina R. M. 
Published: March 2003

Congenital factor XIII (FXIII) deficiency is a rare autosomal recessive disorder, usually attributed to a defect in the FXIII A subunit, whose genetic basis has been studied in a number of cases. We describe here the genetic variations found in two unrelated patients with FXIII deficiency. Both patients, under prophylactic substitution with FXIII concentrate, showed low plasma FXIII A subunit antigen levels with undetectable A subunit antigen in the platelets and normal plasma B antigen levels, which indicate that the defects are present in the A subunit of the molecule. Both probands were heterozygous for a previously reported G→A transversion in exon 8 of the FXIII A subunit gene (Arg326Gln substitution). Proband 1 was also heterozygous for a novel G→T transversion in exon 7, which predicts a Val316Phe substitution. Two of her sons were heterozygous for this mutation and showed low FXIII activity and FXIII A subunit antigen levels. Val316 is a well‐conserved amino acid among the transglutaminase family, located within the core domain, close to the Cys314 member of the catalytic triad. Proband 2 had a unique 2‐bp (TT) insertion in one of the alleles within or adjacent to the −7 to −20 T tail of intron A. This insertion was not found in 50 healthy individuals, which supports this being the second mutation in this patient.
Insertional events as well as translocations may arise during aberrant immunoglobulin switch recombination in a patient with multiple myeloma
Authors: Pratt G. , Fenton J. A. L. , Davies F. E. , Rawstron A. C. , Richards S. J. , Collins J. E. , Owen R. G. , Jack A. S. , Smith G. M. , Morgan G. J. 
Published: March 2003

The majority of patients with multiple myeloma have translocations involving the immunoglobulin heavy chain switch regions on chromosome 14q32 and a promiscuous range of partner chromosomes. We describe a patient with an insertion of 132 bp of chromosome 22q12 sequence into the 5′ region flanking Sμ on chromosome 14q32. The 132 bp region from chromosome 22q12 contains the whole of exon 3 from a novel gene of unknown function in man. The significance of such insertional events remains unclear. The description of insertional events occurring as a result of abnormal switch recombination suggests that, in myeloma, dysregulation of oncogenes may occur by a mechanism other than chromosomal translocation.
Molecular characterization of a myelodysplasia‐associated chromosome 7 inversion
Authors: Todd Roger , Bia Britta , Johnson Emma , Jones Chris , Cotter Finbarr 
Published: March 2003

Chromosome 7 abnormalities are observed in a wide range of myeloid disorders, particularly myelodysplasia (MDS) and acute myeloid leukaemia (AML). Monosomy 7 and 7q deletions are the most frequent abnormalities, although translocations and inversions involving 7q also occur. The region 7q22–q34 may contain as many as four distinct minimal regions of deletion (MDRs), which are thought to contain one or more myeloid tumour‐suppressor genes. We have defined previously the proximal breakpoint of a constitutional 7q22–q34 inversion, carried in a cell line derived from a member of a family with a history of MDS. A YAC clone spanning this breakpoint was identified. Both inversion breakpoints have now been cloned and sequenced, placing the proximal breakpoint 40 kb centromeric to the TAC2 (tachykinin 2) gene and the distal breakpoint 42 kb telomeric to the SSBP (mitochondrial single‐stranded DNA‐binding protein) gene. Sequence alignments revealed small (3–4 bp) duplications at the inversion breakpoints, suggesting that the mechanism of inversion involved the creation of staggered breaks and filling in of the overhanging ends. A 190‐bp Alu–Alu deletion close to the distal breakpoint was also detected and may have contributed to the inversion.