bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of methotrexate treatment on expression levels of multidrug resistance protein 2, breast cancer resistance protein and organic anion transporters Oat1, Oat2 and Oat3 in rats
Authors: Shibayama Yoshihiko , Ushinohama Kazami , Ikeda Ryuji , Yoshikawa Yoshimi , Motoya Toshiro , Takeda Yasuo , Yamada Katsushi 
Published: August 2006

The ATP binding cassette (ABC) transporters, multidrug resistance protein 2 (Mrp2; Abcc2) and breast cancer resistance protein (Bcrp; Abcg2), and organic anion transporters (Oats) mediate excretion of methotrexate (MTX) and many other drugs. However, it is not known whether MTX treatment leads to any changes in the expression of these transporters. We examined the effect of MTX treatment on expression of Mrp2, Bcrp and Oats in rats. MTX was single injected intraperitoneally at doses of 10, 50 and 150 mg/kg, and then Western blot analysis was performed. The levels of Mrp2, Oat1 and Oat2 on day 1 after the treatment showed no significant change. Four days after injection of 150 mg/kg MTX, the Mrp2 levels in the liver and ileum, but not in the kidney, were markedly down‐regulated to 20 ± 3.6% and 8.9 ± 3.8% (mean ± SEM) of controls, respectively. Renal Oat1 and Oat3 were also down‐regulated to 56.4 ± 4.3% (Oat1) and 54.3 ± 5.5% (Oat3) of controls. These effects of MTX were almost recovered by leucovorin which rescues normal cells from MTX toxicity. MTX treatment also decreased mRNA levels of constitutive androstane receptor (CAR) and pregnane X receptor (PXR) to 65.5 ± 17.9% and 59.6 ± 14.5% of controls in the liver, respectively. MTX treatment has no apparent effect on expression levels of Bcrp, cytochrome P450 2B6 and 3A1. In conclusion, these data indicate that MTX treatment down‐regulates expression levels of Mrp2, Oat1 and Oat3, and its effects are recovered by leucovorin. (Cancer Sci 2006; 97: 1260–1266)
Review article: induction therapy for patients with active ulcerative colitis
Authors: TRAVIS S. P. L. 
Published: August 2006

Summary5‐aminosalicylic acid (mesalazine) is considered first‐line therapy for active mild–moderate, left‐sided or extensive ulcerative colitis. With modern delayed‐release formulations, conventional doses are very well tolerated, and there is accumulating evidence that increasing the dose, to >4 g/day, leads to higher response rates and earlier symptom relief in patients with ulcerative colitis.There is evidence that combining oral and rectal (enema) formulations of 5‐aminosalicylic acid leads to faster and higher remission rates. Despite the fact that clinical trials in ulcerative colitis have often used different endpoints, making it difficult to make objective comparisons, the evidence now strongly suggests that it is appropriate to start patients with mild or moderately active ulcerative colitis on doses of 5‐aminosalicylic acid of at least 4 g/day.For those with extensive disease, adding rectal 5‐aminosalicylic acid improves remission rates; the same seems likely to be true for limited disease, but robust evidence is lacking. Rectal 5‐aminosalicylic acid may in fact be sufficient on its own for patients with active proctitis. Patients with mild–moderate ulcerative colitis who do not improve within 2 weeks of high‐dose 5‐aminosalicylic acid should have treatment augmented by oral steroids.
Review article: maintenance therapy in patients with ulcerative colitis
Authors: ORCHARD T. , PROBERT C. S. , KESHAV S. 
Published: August 2006

SummaryBritish Society of Gastroenterology guidelines recommend that all patients with ulcerative colitis should receive long‐term therapy with a 5‐aminosalicylic acid compound to maintain remission.Recent studies have shown that time spent in remission is longer when the maintenance dose is increased from 1.2 to 2.4 g/day, with patients with extensive disease benefiting most from an increase with dosage. A retrospective analysis also found that the frequency of relapse was lower in patients taking more than the median dose of 5‐aminosalicylic acid (1.6 g/day) compared with those taking less than the median dose. Similarly, when 5‐aminosalicylic acids are used to induce remission, continuing the induction dosage for an extra 4 weeks prolongs remission and reduces the frequency of relapse. However, patients rarely comply fully with the prescribed dose regimen, which can lead to effective under‐dosing.The recent discovery that 5‐aminosalicylic acids may act in ulcerative colitis by activating peroxisome proliferator‐activated receptor‐γ, a nuclear receptor that plays a role in the control of cell proliferation and apoptosis, has given new impetus to the idea that long‐term therapy with 5‐aminosalicylic acid may reduce the risk of colorectal cancer. Epidemiological studies are beginning to provide evidence to support this view.Accumulating evidence suggests that the next revision of the clinical guidelines should suggest life‐long doses of 5‐aminosalicylic acid of ≥2 g/day for maintenance of remission in patients with ulcerative colitis.
Immune reconstitution after purified autologous and allogeneic blood stem cell transplantation compared with unmanipulated bone marrow transplantation in children
Authors: Schwinger Wolfgang , Weber‐Mzell Daniela , Zois Birgit , Rojacher Tanja , Benesch Martin , Lackner Herwig , Dornbusch Hans Juergen , Sovinz Petra , Moser Andrea , Lanzer Gerhard , Schauenstein Konrad , Ofner Petra , Handgretinger Rupert , Urban Christian 
Published: August 2006

SummaryImmune reconstitution is critical for the long‐term success of haematopoietic stem cell transplantation (HSCT). We prospectively analysed immune reconstitution parameters after transplantation of autologous (group 1; n = 10) and allogeneic (group 2; n = 12) highly purified CD34+ peripheral blood stem cells (PBSC) and unmanipulated allogeneic bone marrow (BM) (group 3; n = 9) in children. Median follow‐up after HSCT was 56 (group 1), 61 (group 2), and 40·5 months (group 3). Median CD34‐cell dose transplanted in the three groups was 9·4 × 106/kg, 20·3 × 106/kg, and 4·25 × 106/kg recipient's body weight (BW) respectively. Complete haematopoietic engraftment was seen in all patients without any significant differences between the three groups. T‐cell reconstitution at 6 months was significantly delayed in autologous peripheral blood stem cell transplantation (PBSCT) compared with allogeneic BM transplantation (P < 0·028) and allogeneic PBSCT (P < 0·034). At 3 months after transplantation numbers of CD56+/3− natural killer cells were higher in the allogeneic PBSC group (P < 0·01) compared with the BM group. The numbers of proven bacterial and viral infections were equally distributed between the three groups. In conclusion, recipients of allogeneic highly purified CD34+ PBSC or unmanipulated BM have higher lymphocyte subset counts at 6 months after transplantation than recipients of autologous CD34‐selected PBSC. Infection rates and outcome, however, were not significantly different.
Reversal of immune thrombocytopenia in mice by cross‐linking human immunoglobulin G with a high‐affinity monoclonal antibody
Authors: Bazin Renée , Lemieux Réal , Tremblay Tony 
Published: August 2006

SummaryIntravenous immunoglobulins (IVIgs) are used to treat an increasing number of autoimmune diseases, but their exact mechanism of action remains unknown. This study showed that cross‐linking of human IgG present in IVIg preparations using a mouse monoclonal anti‐human IgG generated complexes that prevented or reversed thrombocytopenia in mice more efficiently than IVIg. Furthermore, biologically active complexes were obtained simply by adding the monoclonal antibody to human serum. These results suggest the possible development of an IVIg‐free substitute through the ex vivo, and possibly in vivo, formation of immune complexes containing autologous IgG of immune thrombocytopenic purpura patients.
The heat shock protein 90 inhibitor 17‐AAG induces cell cycle arrest and apoptosis in mantle cell lymphoma cell lines by depleting cyclin D1, Akt, Bid and activating caspase 9
Authors: Georgakis Georgios V. , Li Yang , Younes Anas 
Published: August 2006

SummaryMantle cell lymphoma (MCL), a distinct type of non‐Hodgkin lymphoma, is characterised by the overexpression of cyclin D1. Heat shock protein 90 (HSP90) is a molecular chaperon to proteins that regulate cell cycle and survival. 17‐allylamino‐17‐demethoxy‐geldanamycin (17‐AAG), a HSP90 small molecule inhibitor, induced G0/1 cell cycle arrest and cell death in a dose‐ and time‐dependent manner in MCL cell lines. This effect was associated with the downregulation of cyclin D1, cdk4 and Akt, depletion of Bid, and activation of the intrinsic/mitochondrial caspase pathway. These data suggest that 17‐AAG may have a potential therapeutic value in patients with MCL.
Inherited and de novo von Willebrand disease ‘Vicenza’ in UK families with the R1205H mutation: diagnostic pitfalls and new insights
Authors: Lester William A. , Guilliatt Andrea M. , Surdhar Gurcharan K. , Enayat Said M. , Wilde Jonathan T. , Willoughby Sara , Grundy Pam , Cumming Anthony M. , Collins Peter W. , Hill Frank G. H. 
Published: August 2006

Summaryvon Willebrand disease (VWD) caused by the R1205H mutation has distinct and reproducible clinical and laboratory features. This report describes the phenotypic and molecular investigation of seven kindreds with VWD Vicenza R1205H. All affected individuals have historically been diagnosed with moderate to severe type 1 VWD. Amongst all families with highly penetrant type 1 VWD investigated at our centre, heterozygosity for the R1205H mutation was found to be the most common underlying molecular defect. A severe laboratory phenotype associated with a bleeding history that was milder than expected was commonly observed, consistent with previous published case reports; however, abnormal ultralarge high molecular weight multimers were not detected in resting plasma samples. We also provide evidence that the R1205H mutation may arise de novo– evidence that a common genetic origin for this mutation is unlikely.
The evolution towards ambulatory and day‐case management of febrile neutropenia
Authors: Chisholm Julia C. , Dommett Rachel 
Published: August 2006

SummaryFebrile neutropenia (FN) is only second to chemotherapy administration as a cause of hospital admission during treatment for cancer. As FN may signify serious or life‐threatening infection, management protocols have focussed on trying to prevent adverse outcomes in these patients. However, it is now possible to identify a subset of patients with FN at low risk of life‐threatening complications in whom duration of hospitalisation and intensity of therapy can be reduced safely. This review discusses how the management of FN has evolved to enable patients identified as low risk to be treated on specific low risk management strategies, with an emphasis on some of the practical considerations for the implementation of such strategies.
Didox, a ribonucleotide reductase inhibitor, induces apoptosis and inhibits DNA repair in multiple myeloma cells
Authors: Raje N. , Kumar S. , Hideshima T. , Ishitsuka K. , Yasui H. , Chhetri S. , Vallet S. , Vonescu E. , Shiraishi N. , Kiziltepe T. , Elford H.L. , Munshi N.C. , Anderson K.C. 
Published: August 2006

SummaryRibonucleotide reductase (RR) is the enzyme that catalyses the rate‐limiting step in DNA synthesis, the production of deoxynucleotides. RR activity is markedly elevated in tumour tissue and is crucial for cell division. It is therefore an excellent target for cancer chemotherapy. This study examined the anti‐myeloma activity of Didox (3,4‐Dihydroxybenzohydroxamic acid), a novel RR inhibitor (RRI). Our data showed that Didox induced caspase‐dependent multiple myeloma (MM) cell apoptosis. Didox, unlike other RRIs that mainly target the pyrimidine metabolism pathway, targets both purine and pyrimidine metabolism pathways in MM, as demonstrated by transcriptional profiling using the Affymetrix U133A 2·0 gene chip. Specifically, a ≥2‐fold downregulation of genes in these anabolic pathways was shown as early as 12 h after exposure to Didox. Furthermore, apoptosis was accompanied by downregulation of bcl family proteins including bcl‐2, bclxl, and XIAP. Importantly, RR M1 component transcript was also downregulated, associated with decreased protein expression. Genes involved in DNA repair mechanisms, specifically RAD 51 homologue, were also downregulated. As Didox acts on MM cells by inhibiting DNA synthesis and repair, combination studies with melphalan, an agent commonly used in MM, were performed. A strong in vitro synergism was shown, with combination indices of <0·7 as determined by the Chou–Talalay method. These studies therefore provide the preclinical rationale for evaluation of Didox, alone and in combination with DNA‐damaging agents, to improve patient outcome in MM.
The use of intermediate purity factor VIII concentrate BPL 8Y as prophylaxis and treatment in congenital thrombotic thrombocytopenic purpura
Authors: Scully Marie , Gattens Michael , Khair Kate , Liesner Ri 
Published: August 2006

SummaryThis report presents seven children with congenital thrombotic thrombocytopenic purpura (TTP). Six had a history of severe neonatal unconjugated hyperbilirubinaemia and thrombocytopenia. The seventh child had no neonatal problems but has suffered three episodes of acute TTP. The subsequent clinical course of the children varied. Five had a relapsing–remitting course and one had chronic microangiopathic haemolytic anaemia. The five oldest children initially received plasma infusions but, because of viral safety issues and easier administration, they now receive intermediate purity US‐sourced plasma‐derived factor VIII concentrate: BPL 8Y. Effective prophylaxis and treatment is possible in congenital TTP using BPL 8Y.
Fracture risk in patients with monoclonal gammopathy of undetermined significance
Authors: Gregersen Henrik , Jensen Paw , Gislum Mette , Jørgensen Birgit , Sørensen Henrik Toft , Nørgaard Mette 
Published: August 2006

SummaryLittle information is available on the risk of fractures in patients with monoclonal gammopathy of undetermined significance (MGUS). We identified 1535 patients with MGUS between 1978 and 2003 in North Jutland County, Denmark. The population control group consisted of 15 350 persons selected from the Danish Central Population Registry, matched by age and sex. Data on fractures in the two groups were obtained from the regional Hospital Discharge Registry. In the MGUS cohort, 187 first‐time fractures were identified during 9754 person‐years of follow‐up, corresponding to an incidence rate of 19/1000 person‐years. The adjusted relative risk for fractures among MGUS patients compared with population controls was 1·4 [95% confidence interval (CI), 1·2–1·6]. After 5 years of follow‐up, the risk difference was 1·8% (95% CI, 0·5–3·0). Six of the 187 MGUS patients with fractures were later diagnosed with malignant transformation. Relative risks for fractures were increased in IgG‐type MGUS [1·3 (95% CI,1·1–1·6)], IgM‐type MGUS [1·6 (95% CI, 1·1–2·2)] and MGUS with kappa light chain [1·4 (95% CI, 1·1–1·7)]. MGUS patients had an increased risk of fractures, which could not be explained by comorbidity, advanced age, gender or malignant transformation.
Early apoptosis in CD34+ cells as a potential heterogeneity in quality of cryopreserved umbilical cord blood
Authors: Shim Jae‐Seung , Cho Bin , Kim Myungshin , Park Gyeong‐Sin , Shin Jong‐Chul , Hwang Hong‐Kyu , Kim Tae‐Gyu , Oh Il‐Hoan 
Published: August 2006

SummaryThe increased use of umbilical cord blood (UCB) raises issues regarding the quality of cryopreserved UCB. This study investigated whether early apoptosis of CD34+ cells is part of the functional heterogeneity of cryopreserved UCB. Annexin V binding of CD34+PI(−) cells showed wide variations in both fresh and cryopreserved UCBs, with greater variation among units frozen for >5 years. Xenotransplantation of sorted cells into non‐obese diabetic severe combined immunodeficient mice demonstrated that the Annexin V assay identified most repopulating activities in UCB units. Thus, early apoptosis of CD34+ cells could influence the outcome of transplantation using cryopreserved UCB.
Effect of repeated apotransferrin administrations on serum iron parameters in patients undergoing myeloablative conditioning and allogeneic stem cell transplantation
Authors: Parkkinen Jaakko , Sahlstedt Leila , Von Bonsdorff Leni , Salo Hanna , Ebeling Freja , Ruutu Tapani 
Published: August 2006

SummaryMyeloablative conditioning prior to allogeneic stem cell transplantation causes a rapid increase in transferrin saturation and potentially toxic non‐transferrin‐bound iron (NTBI) in plasma. We have studied the ability of repeatedly administered apotransferrin to maintain this iron in a transferrin‐bound form. Twenty adult patients undergoing myeloablative conditioning and allogeneic stem cell transplantation were enrolled to receive apotransferrin with one of three dosage regimens. Ten consecutive patients with the same preconditioning were studied as controls. At the highest dose level, full transferrin saturation and appearance of NTBI were prevented in five of the eight patients. Serum iron increased significantly more in the patients receiving apotransferrin than in the controls and remained elevated until erythropoietic recovery. From the increment of iron saturation and the amount of endogenous and administered apotransferrin, an average 180 μmol of iron per day was bound to transferrin during the first 4 d after the start of the conditioning therapy. Thereafter, iron accumulation levelled off in most patients. The results suggested that about half of the amount of iron normally transported to erythropoiesis was initially released to plasma after induction of the erythroid arrest. Complete iron binding with apotransferrin would apparently require very high apotransferrin doses.
Lignin turnover in arable soil and grassland analysed with two different labelling approaches
Authors: Heim A. , Schmidt M. W. I. 
Published: August 2006

SummaryWhen modelling the carbon dynamics of temperate soils, soil organic carbon (SOC) is often represented by three kinetic pools, i.e. fast, slow and passive/inert. Lignin is often considered to be relatively resistant to decomposition, thus possibly contributing to the passive SOC pool. One way to assess SOC turnover under natural conditions is to follow the fate of 13C‐labelled biomass in soils. We used compound‐specific isotope analysis to analyse CuO oxidation products of lignin from grassland topsoils and from an arable topsoil that had received a natural (by C3‐C4 vegetation change) or an artificial (by fumigation with labelled CO2) isotopic label for 9–23 years. Results indicate faster apparent turnover for lignin (5–26 years in grassland, 9–38 years in arable soil) compared with bulk SOC (20–26 years in grassland, 51 years in arable soil). Although these calculated lignin turnover times cannot be extrapolated to the whole soil profiles, this paper provides isotopic evidence that lignin in soils is not preferentially preserved, which is a consistent result from both ways of isotopic labelling. It also demonstrates, however, that a considerable proportion of lignin in temperate soils can be stabilized for at least a few decades.
3D‐visualization and analysis of macro‐ and meso‐porosity of the upper horizons of a sodic, texture‐contrast soil
Authors: Jassogne L. , McNeill A. , Chittleborough D. 
Published: August 2006

SummaryThe lower E and upper B horizons of sodic, texture‐contrast soils are a formidable barrier to most annual and many perennial crops. The research presented here is part of a wider study into the nature of subsoil constraints to root exploration. The aim of this study was to characterize in three dimensions the macro‐ and meso‐porosity across the E horizon–Btn horizon interface of a sodic, texture‐contrast soil using X‐ray computed tomography (CT). Intact soil cores of 50‐cm length and 15‐cm diameter were scanned with a medical CT X‐ray machine. The pore volume reconstructed from these scans had a resolution of 0.3 × 0.3 × 0.4 cm (in the x, y, z dimensions, respectively). This resolution allowed visualization and quantification of the macroporosity of the intact cores. Undisturbed samples of 1.5‐cm diameter and 4‐cm length were carefully excised from the interface and scanned with micro‐CT X‐ray equipment. The reconstructed pore volumes had an isotropic resolution of 19 μm that allowed analysis of the mesoporosity just on the boundary between the E and Btn horizons. Mesoporosity decreased across the interface and increased lower in the Btn horizon. The distribution of the pores at the macro‐ and meso‐scales showed the importance of the smaller pores in the A and E horizons, whereas most of the porosity in the Btn horizon was attributed to the larger pores. Pores in this sodic, texture‐contrast soil were not distributed homogeneously at either the macro‐ or meso‐scale. A greater proportion of the pores in the E–B interface were horizontal than in the upper A1, upper E and lower Btn horizons. Some ‘coiling’ of the pores was also apparent in the interface. The shape of some pores (long tubular pores) suggested formation by roots as they drilled through the soil. The orientation of these pores was a function of physical (and possibly chemical) impedance at the interface.
Formation of 2,4–D complexes on montmorillonites – an ab initio molecular dynamics study
Authors: Tunega D. , Gerzabek M. H. , Haberhauer G. , Lischka H. 
Published: August 2006

SummarySorption of the anionic form of the pesticide 2,4–D (2,4–dichlorophenoxyacetic acid) on the surface of the clay mineral montmorillonite was investigated using a short‐time ab initio molecular dynamics (MD) simulation at room temperature. Three different situations were modelled: sorption on a dry surface, on a hydrated surface and an intercalation between montmorillonite layers. In all three cases, the calcium cation compensates the excess negative charge of the montmorillonite layer and the negative charge of the 2,4–D anion. It was found that in all models with direct contact of the Ca2+ cation with the montmorillonite layer, the most stable position of Ca2+ is above the ditrigonal hole of the mineral layer. While in the case of a dry surface very stable bidentate binding is created between the 2,4–D anion and the Ca2+ cation, the formation of the monodentate complexes is preferred in all models that include water molecules. Hydrogen bonds formed between water molecules and the 2,4–D anion make a considerable contribution to the formation of the monodentate complexes. Tetrahedral substitutions in the montmorillonite layer have a significant effect on the formation of the complexes of any type. However, the MD simulations did not support the role of Ca2+ as a cation bridge in the adsorption mechanism. Calculations showed that hydrated 2,4–D···Ca2+ complexes are thermodynamically more stable than complexes in which the Ca2+ cation acts as a bridge to the surface. On the other hand, it is possible that phyllosilicates with a greater concentration of isomorphic substitutions (e.g. mica) will be able to form stable surface complexes with a cation bridge mechanism.