bluuebunny/crossref_metadata_2025_split huggingface dataset:
Philadelphia positive acute lymphoblastic leukaemia of childhood
Authors: Jones Louise K. , Saha Vaskar 
Published: July 2005

SummaryOn current chemotherapeutic regimens, children with Philadelphia positive acute lymphoblastic leukaemia show a heterogeneous response to treatment. A few respond quickly to treatment and achieve long‐term remission. Some fail to achieve remission after induction and the majority respond slowly to treatment. Relapse on treatment is common and remission is sustained in a proportion of cases only after allogeneic stem cell transplantation (allo‐SCT). The use of imatinib along with conventional cytoreductive therapy, prior to allo‐SCT appears to be the most promising strategy. The future lies in the molecular evaluation of response to treatment and combination targeted chemotherapy.
Isolated central nervous system involvement in adult T‐cell lymphoma/leukaemia
Authors: Dungerwalla M. , Osuji N. , Waldman A. D. , Al Jehani F. , Mehta A. , Taylor R. , Wotherspoon A. , Cogill G. , Matutes E. 
Published: July 2005

SummaryCentral nervous system (CNS) presentation of adult T‐cell lymphoma/leukaemia is rare, and almost invariably associated with systemic disease. We report an unusual manifestation of adult T‐cell lymphoma/leukaemia, with isolated CNS involvement and unusual imaging findings. We also describe objective response to antiviral therapy. To our knowledge, this is the first report of such presentation and response.
Gene expression profiling of mantle cell lymphoma cells reveals aberrant expression of genes from the PI3K‐AKT, WNT and TGFβ signalling pathways
Authors: Rizzatti Edgar Gil , Falcão Roberto Passetto , Panepucci Rodrigo Alexandre , Proto‐Siqueira Rodrigo , Anselmo‐Lima Wilma Terezinha , Okamoto Oswaldo Keith , Zago Marco Antonio 
Published: July 2005

SummaryMicroarray studies have revealed the differential expression of several genes in mantle cell lymphoma (MCL), but it is unknown which of these differences are dependent on the transformed MCL cell itself or on the tumour microenvironment. To investigate which genes and signalling pathways are aberrantly expressed in MCL cells we used oligonucleotide microarrays to perform gene expression profiling of both purified leukaemic MCL cells and their normal counterparts, the naive B cells. A total of 106 genes were differentially expressed at least threefold in MCL cells compared with naive B cells; 63 upregulated and 43 downregulated. To validate the microarray results in a larger set of samples, we selected 10 differentially expressed genes and quantified their expression by real‐time polymerase chain reaction in peripheral blood of MCL patients (n = 21), purified MCL cells (n = 6) and naive B cells (n = 4), obtaining fully concordant results. A computer‐assisted approach was used to procure specific molecular signalling pathways that were aberrantly expressed in MCL cells. Several genes related to apoptosis and to the PI3K/AKT, WNT and tumour growth factor β signalling pathways were altered in MCL cells when compared with naive B cells. These pathways may play a significant role in the pathogenesis of MCL and deserve further investigation as candidates for new therapeutic targets.
Viscum album agglutinin‐I induces apoptosis and degradation of cytoskeletal proteins via caspases in human leukaemia eosinophil AML14.3D10 cells: differences with purified human eosinophils
Authors: Lavastre Valérie , Chiasson Sonia , Cavalli Hélène , Girard Denis 
Published: July 2005

SummaryAlthough there are several agents that induce neutrophil apoptosis, few are known as inducers of eosinophil apoptosis. As eosinophils are potent effector cells contributing to allergic inflammation and asthma, we investigated whether the pro‐apoptotic agent Viscum album agglutinin‐I (VAA‐I) could induce eosinophil apoptosis. VAA‐I was found to induce apoptosis in eosinophilic AML14.3D10 (3D10) cells and that these cells expressed caspases‐1, ‐2, ‐3, ‐4, ‐7, ‐8, ‐9 and ‐10. VAA‐I‐induced gelsolin degradation was reversed by the pan‐caspase inhibitor N‐benzyloxycarbonyl‐V‐A‐D‐O‐methylfluoromethyl ketone (z‐VAD). Also, paxillin, vimentin and lamin B1 were cleaved by caspases in VAA‐I‐induced 3D10 cells. VAA‐I activated caspase‐3 and ‐8 in 3D10 cells but, unlike z‐VAD, treatment with a caspase‐8 inhibitor slightly reversed apoptosis. Treatment of purified human eosinophils with VAA‐I was found to induce apoptosis, degradation of gelsolin and lamin B1, but unlike 3D10 cells, cleavage of lamin B1 and cell apoptosis was not reversed by z‐VAD. We conclude that VAA‐I is a potent inducer of eosinophil apoptosis and that proteases other than those inhibited by z‐VAD in 3D10 cells are involved in VAA‐I‐induced peripheral blood eosinophil apoptosis and lamin B1 cleavage. Thus, VAA‐I represents a potential candidate for the reduction of the number of eosinophils in diseases where they play important roles.
Comparison of CHOP versus CIOP in good prognosis younger patients with histologically aggressive non‐Hodgkin lymphoma
Authors: Burton C. , Smith P. , Vaughan‐Hudson G. , Qian W. , Hoskin P. , Cunningham D. , Hancock B. , Linch D. 
Published: July 2005

SummaryCHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone) has been the standard chemotherapy regimen used for diffuse large cell lymphomas for over 30 years. Idarubicin is a 4‐demethoxy‐anthracycline analogue of daunorubicin that has proven activity in non‐Hodgkin lymphoma, and has been reported to cause less cardiotoxicity. We therefore initiated a randomised trial of standard dose CHOP versus CIOP (cyclophosphamide, idarubicin, vincristine and prednisolone), in which doxorubicin 50 mg/m2 was substituted by idarubicin 10 mg/m2, a dose thought to have equivalent anti‐lymphoma activity. This trial was closed prematurely after 211 patients had completed therapy when a lower complete remission (CR) rate was noted in the CIOP arm. The formal results with long‐term follow up are now reported. Overall response rate was 84% in the CHOP arm and 78% in the CIOP arm, CR rates were 70% and 52% respectively in all patients (P = 0·013) and 73% and 52% respectively for the eligible patients (P = 0·0084). At a median of 8 years follow‐up, 4‐year progression‐free survival for all patients was 56% in the CHOP arm and 40% in the CIOP arm (P = 0·0096). Overall survival for all patients was 65% in the CHOP arm and 56% in the CIOP arm (P = 0·14). Results for eligible patients were comparable. CIOP containing idarubicin at a dose of 10 mg/m2 is clearly inferior to standard CHOP.
Efficacy and tolerability of peginterferon alpha‐2a with or without ribavirin in thalassaemia major patients with chronic hepatitis C virus infection
Authors: Inati Adlette , Taher Ali , Ghorra Sandy , Koussa Suzanne , Taha Marwan , Aoun Elie , Sharara Ala I. 
Published: July 2005

SummaryThalassaemia patients with genotype 1 or 4 chronic hepatitis C virus (HCV) infection were randomised to receive peginterferon alpha‐2a 180 mg/week ribavirin for 48 weeks. Primary efficacy variable was sustained viral response (SVR) at 72 weeks. Thirty‐two patients were evaluated; 20 enrolled. Baseline characteristics were comparable. SVR occurred in four of 12 and five of eight patients in the monotherapy and combination groups (30% and 62·5%; P = 0·19), respectively. Undetectable RNA at 12 weeks and age <18 years were associated with improved SVR (P < 0·05). Transfusion requirements rose by 34% in the combination arm (P = 0·08). Peginterferon/ribavirin was effective in thalassaemics with HCV and moderate iron overload.
Allogeneic haematopoietic stem cell transplantation as a promising treatment for natural killer‐cell neoplasms
Authors: Murashige Naoko , Kami Masahiro , Kishi Yukiko , Kim Sung‐Won , Takeuchi Masami , Matsue Kosei , Kanda Yoshinobu , Hirokawa Makoto , Kawabata Yoshinari , Matsumura Tomoko , Kusumi Eiji , Hirabayashi Noriyuki , Nagafuji Koji , Suzuki Ritsuro , Takeuchi Kengo , Oshimi Kazuo 
Published: July 2005

SummaryThe efficacy of allogeneic haematopoietic stem‐cell transplantation (allo‐HSCT) for natural killer (NK)‐cell neoplasms is unknown. We investigated the results of allo‐HSCT for NK‐cell neoplasms between 1990 and 2003 through questionnaires. After reclassification by a haematopathologist, of 345 patients who underwent allo‐HSCT for malignant lymphoma, 28 had NK‐cell neoplasms (World Health Organization classification): extranodal NK/T‐cell lymphoma (n = 22), blastic NK‐cell lymphoma (n = 3), and aggressive NK‐cell leukaemia (n = 3). Twelve were chemosensitive and 16 chemorefractory. Twenty‐two had matched‐related donors. Stem‐cell source was bone marrow in eight and mobilised peripheral blood in 20. Conditioning regimens were myeloablative (n = 23) and non‐myeloablative (n = 5). Grade 2–4 acute graft‐versus‐host disease (GVHD) and chronic GVHD developed in 12 and 8 respectively. Eight died of disease progression, three of infection, two of acute GVHD, one of veno‐occlusive disease, one of interstitial pneumonitis, and one of thrombotic microangiopathy. Two‐year progression‐free and overall survivals were 34% and 40% respectively (median follow‐up, 34 months). All patients who did not relapse/progress within 10 months achieved progression‐free survival (PFS) during the follow‐up. In multivariate analysis, stem cell source (BM versus peripheral blood; relative risk 3·03), age (≥40 years vs. <40 years; relative risk 2·85), and diagnoses (extranodal NK/T‐cell lymphoma versus others; relative risk 3·94) significantly affected PFS. Allo‐HSCT is a promising treatment for NK‐cell neoplasms.
C‐reactive protein and D‐dimer with clinical probability score in the exclusion of pulmonary embolism
Authors: Steeghs N. , Goekoop R. J. , Niessen R. W. L. M. , Jonkers G. J. P. M. , Dik H. , Huisman M. V. 
Published: July 2005

SummaryThis study evaluated the diagnostic value of C‐reactive protein (CRP) combined with a clinical decision rule in the exclusion of pulmonary embolism (PE) and compared this with D‐dimer. In 363 consecutive outpatients CRP and D‐dimer test were performed and clinical probability of PE was assessed. Patients with D‐dimer levels <500 μg/l and clinical probability indicating ‘PE unlikely’ were followed for 3 months. Ventilation‐perfusion scan or spiral computerized tomography was performed in patients with D‐dimer levels ≥500 μg/l or clinical probability indicating ‘PE likely’. The CRP had a sensitivity of 95·7% [95% confidence interval (CI): 90–100] and negative predictive value (NPV) of 98·4% (96–100). CRP <5 mg/l with clinical probability score indicating ‘PE unlikely’ (n = 108, 30%), had a sensitivity of 96·7% (90–100), a specificity of 43·0% (37–49) and NPV of 99·1% (97–100). D‐dimer <500 μg/l with clinical probability score indicating ‘PE unlikely’ (n = 170, 51%), had a sensitivity of 96·7% (90–100), a specificity of 67·9% (62–74) and NPV of 99·4% (98–100). Based on retrospective data it was concluded that a standard CRP test can potentially be used to safely exclude PE, either as a sole test or combined with clinical probability assessment. Prospective studies are needed to confirm these findings.
The lipid A palmitoyltransferase PagP: molecular mechanisms and role in bacterial pathogenesis
Authors: Bishop Russell E. 
Published: July 2005

SummaryPalmitoylated lipid A can both protect pathogenic bacteria from host immune defences and attenuate the activation of those same defences through the TLR4 signal transduction pathway. A palmitate chain from a phospholipid is incorporated into lipid A by an outer membrane enzyme PagP, which is an 8‐stranded antiparallel β‐barrel preceded by an amino‐terminal amphipathic α‐helix. The PagP barrel axis is tilted by 25° with respect to the membrane normal. An interior hydrophobic pocket in the outer leaflet‐exposed half of the molecule functions as a hydrocarbon ruler that allows the enzyme to distinguish palmitate from other acyl chains found in phospholipids. Internalization of a phospholipid palmitoyl group within the barrel appears to occur by lateral diffusion from the outer leaflet through non‐hydrogen‐bonded regions between β‐strands. The MsbA‐dependent trafficking of lipids from the inner membrane to the outer membrane outer leaflet is necessary for lipid A palmitoylation in vivo. The mechanisms by which bacteria regulate pagP gene expression strikingly reflect the corresponding pathogenic lifestyle of the bacterium. Variations on PagP structure and function can be illustrated with the known homologues from Gram‐negative bacteria, which include pathogens of humans and other mammals in addition to pathogens of insects and plants. The PagP enzyme is potentially a target for the development of anti‐infective agents, a probe of outer membrane lipid asymmetry, and a tool for the synthesis of lipid A‐based vaccine adjuvants and endotoxin antagonists.
Cell cycle arrest during S or M phase generates polarized growth via distinct signals in Candida albicans
Authors: Bachewich Catherine , Nantel Andre , Whiteway Malcolm 
Published: July 2005

SummaryTreatments that perturb DNA synthesis or mitosis will activate checkpoints that prevent cell cycle progression and cell proliferation. In yeast‐form cells of the fungal pathogen Candida albicans, exposure to hydroxyurea (HU) or shutting off expression of the polo‐like kinase CaCDC5 blocked nuclear division and spindle elongation, but activated a highly polarized growth mode. We have used transcription profiling both to characterize the initiation and progression of this polar growth pattern and to determine how cell elongation may be linked to the cell cycle in C. albicans. Different gene expression patterns during early stages of cell elongation support the concept that CaCdc5p‐depleted and HU‐exposed cells were blocked at different stages of the cell cycle, and suggest that different signals may generate the common polarized growth phenotype. Consistent with this, BUB2 expression was modulated in CaCdc5p‐depleted cells, and absence of BUB2 prevented the maintenance of cell polarization, resulting in multibudded, pseudohyphal cells with constrictions. In contrast, HU‐induced filaments did not modulate or require BUB2, but were dependent on the GTPase Ras1p. However, at later stages of cell elongation, transcription profiles were more similar, and comparisons with serum‐induced hyphae revealed that the cell cycle‐arrested filaments expressed several targets of the hyphal signalling pathways. Thus, arresting the yeast cell cycle in S or M phase generates a polarized growth pattern through different mechanisms in C. albicans, and maintenance of the polar growth mode can ultimately lead to the expression of hyphal‐associated cell wall and virulence‐related factors, in the absence of any external stimuli.
Paralysis and killing of Caenorhabditis elegans by enteropathogenic Escherichia coli requires the bacterial tryptophanase gene
Authors: Anyanful Akwasi , Dolan‐Livengood Jennifer M. , Lewis Taiesha , Sheth Seema , DeZalia Mark N. , Sherman Melanie A. , Kalman Lisa V. , Benian Guy M. , Kalman Daniel 
Published: July 2005

SummaryPathogenic Escherichia coli, including enteropathogenic E. coli (EPEC), enterohaemorrhagic E. coli (EHEC), enteroinvasive E. coli (EIEC) and enterotoxigenic E. coli (ETEC) are major causes of food and water‐borne disease. We have developed a genetically tractable model of pathogenic E. coli virulence based on our observation that these bacteria paralyse and kill the nematode Caenorhabditis elegans. Paralysis and killing of C. elegans by EPEC did not require direct contact, suggesting that a secreted toxin mediates the effect. Virulence against C. elegans required tryptophan and bacterial tryptophanase, the enzyme catalysing the production of indole and other molecules from tryptophan. Thus, lack of tryptophan in growth media or deletion of tryptophanase gene failed to paralyse or kill C. elegans. While known tryptophan metabolites failed to complement an EPEC tryptophanase mutant when presented extracellularly, complementation was achieved with the enzyme itself expressed either within the pathogen or within a cocultured K12 strains. Thus, an unknown metabolite of tryptophanase, derived from EPEC or from commensal non‐pathogenic strains, appears to directly or indirectly regulate toxin production within EPEC. EPEC strains containing mutations in the locus of enterocyte effacement (LEE), a pathogenicity island required for virulence in humans, also displayed attenuated capacity to paralyse and kill nematodes. Furthermore, tryptophanase activity was required for full activation of the LEE1 promoter, and for efficient formation of actin‐filled membranous protrusions (attaching and effacing lesions) that form on the surface of mammalian epithelial cells following attachment and which depends on LEE genes. Finally, several C. elegans genes, including hif‐1 and egl‐9, rendered C. elegans less susceptible to EPEC when mutated, suggesting their involvement in mediating toxin effects. Other genes including sek‐1, mek‐1, mev‐1, pgp‐1,3 and vhl‐1, rendered C. elegans more susceptible to EPEC effects when mutated, suggesting their involvement in protecting the worms. Moreover we have found that C. elegans genes controlling lifespan (daf‐2, age‐1 and daf‐16), also mediate susceptibility to EPEC. Together, these data suggest that this C. elegans/EPEC system will be valuable in elucidating novel factors relevant to human disease that regulate virulence in the pathogen or susceptibility to infection in the host.
A tertiary structural element in S box leader RNAs is required for S‐adenosylmethionine‐directed transcription termination
Authors: McDaniel Brooke A. , Grundy Frank J. , Henkin Tina M. 
Published: July 2005

SummaryThe S box transcription termination control system regulates expression of genes involved in methionine metabolism. Expression of the S box regulon, comprised of 11 transcriptional units in Bacillus subtilis, is induced in response to starvation for methionine. We previously demonstrated that S‐adenosylmethionine (SAM) is the molecular effector sensed by the S box leader RNAs during transcription. A secondary structure model for S box leader RNAs was developed based on conservation of primary sequence elements and sequence covariation in helical domains. Covariation of nucleotides in two distantly spaced unpaired regions in the S box leader RNAs suggested that these two domains might interact in the RNA tertiary structure. In this study, site‐directed mutagenesis of the covarying residues in two B. subtilis S box leader sequences was employed to test the hypothesis that base‐pairing between these regions may be important. The effect of these mutations on in vivo expression, transcription termination in vitro, SAM binding, and leader RNA structure strongly supported the model that interaction between these two regions plays a key role in S box leader function. This provides the first insight into the three‐dimensional arrangement of structural elements within the S box RNAs.
Identification of a fibronectin‐binding domain within the Campylobacter jejuni CadF protein
Authors: Konkel Michael E. , Christensen Jeffrey E. , Keech Amy M. , Monteville Marshall R. , Klena John D. , Garvis Steve G. 
Published: July 2005

SummaryThe binding of Campylobacter jejuni to fibronectin (Fn), a component of the extracellular matrix, is mediated by a 37 kDa outer membrane protein termed CadF for Campylobacter adhesion to Fn. Previous studies have indicated that C. jejuni binds to Fn on the basolateral surface of T84 human colonic cells. To further characterize the interaction of the CadF protein with Fn, enzyme‐linked immunosorbent assays were performed to identify the Fn‐binding domain (Fn‐BD). Using overlapping 30‐mer and 16‐mer peptides derived from translated cadF nucleotide sequence, maximal Fn‐binding activity was localized to four amino acids (AA 134–137) consisting of the residues phenylalanine‐arginine‐leucine‐serine (FRLS). A mouse α‐CadF peptide polyclonal antibody (M α‐CadF peptide pAb) was generated using FRLS containing peptides and found to react with viable C. jejuni as judged by indirect fluorescent microscopy, suggesting that the FRLS residues are surface‐exposed. Binding of CadF to purified Fn and INT 407 human epithelial cells was significantly inhibited with peptides containing the Fn‐BD. Moreover, a CadF recombinant variant protein, in which the Phe‐Arg‐Leu residues (CadF AA 134–136) were altered to Ala‐Ala‐Gly, exhibited a 91% decrease in Fn‐binding activity as compared with the wild‐type CadF protein. Collectively, these data indicate that the FRLS residues (CadF AA 134–137) of the C. jejuni CadF protein possess Fn‐binding activity.
The conserved flaF gene has a critical role in coupling flagellin translation and assembly in Caulobacter crescentus
Authors: Llewellyn Midge , Dutton Rachel J. , Easter Jesse , O'Donnol Danielle , Gober James W. 
Published: July 2005

SummaryThe expression of the flagellin proteins in Caulobacter crescentus is regulated by the progression of flagellar assembly both at the transcriptional and post‐transcriptional levels. An early basal body structure is required for the transcription of flagellin genes, whereas the ensuing assembly of a hook structure is required for flagellin protein synthesis. Previous experiments have shown that the negative regulatory protein, FlbT, operates this second post‐transcriptional checkpoint by associating with the 5′ untranslated region (UTR) of the fljK flagellin transcript, inhibiting translation and destabilizing the mRNA. In this paper we examine the role of flaF in flagellar biogenesis. The flaF gene, which is conserved in several speices of flagellated α‐proteobacteria, is required for motility and flagellin protein synthesis. A deletion of flbT in a ΔflaF strain restored flagellin protein expression, but not motility, indicating that FlaF functions in filament assembly. Mutant strains with a deletion in flaF had no detectable fljK mRNA, the levels of which were restored by an additional mutation in flbT. Assay of fljK gene expression using transcription and translation reporter fusions indicated that FlaF was essential for the translation of fljK mRNA. FlaF protein levels were under cell cycle control, peaking during the period of flagellin expression and filament assembly, whereas FlbT was present throughout the cell cycle. These results suggest that FlbT and FlaF activities oppose one another in the regulation of flagellin expression in response to both the progression of flagellar assembly and the cell cycle.