bluuebunny/crossref_metadata_2025_split huggingface dataset:
Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression
Authors: Page Guillaume , Miossec Pierre 
Published: August 2004

AbstractThe aim of this study was to compare the cellular composition and organization of rheumatoid (RA) synovium, which has several of the characteristics of lymphoid organs, with lymph nodes. To clarify further whether RA synovium can be classified as an ectopic lymphoid organ, paired RA synovium and lymph node (LN) tissues from 11 patients were compared in terms of T‐cell–B‐cell and germinal centre (GC) organization, dendritic cell (DC) subsets, and chemokine expression. Tonsil, a normal secondary lymphoid organ, was used as a tissue control. In paired RA LN and synovium, more follicular DC‐positive GCs were observed in LN, but when observed in synovium, they shared the same T‐cell–B‐cell organization and mean GC size. In LN, a predominance of mature DC‐LAMP‐positive DCs of myeloid (CD11c‐positive) or lymphoid (CD123‐positive) origin was observed, whereas paired RA synovium was characterized by the relative accumulation of immature CD1a‐positive DCs. In the same way, CCL19–CCL21/CCR7, a chemokine/chemokine receptor complex involved in mature DC migration, was more frequently seen in LN than in paired RA synovium. In synovium, such expression was associated with lymphoid follicle formation, with or without a GC. Conversely, CCL20, a chemokine involved in immature DC migration, was expressed in RA synovium and tonsils but not in paired LNs. In conclusion, although similarities were observed, this study, using paired samples, indicates that the RA synovium lacks some of the features that are characteristic of a lymphoid organ. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Localization of degradative enzymes and their inhibitors in the degenerate human intervertebral disc
Authors: Le Maitre Christine Lyn , Freemont Anthony J , Hoyland Judith Alison 
Published: August 2004

AbstractThe histological and biochemical changes that occur in the extracellular matrix of the intervertebral disc (IVD) during ageing and degeneration have been investigated extensively. However, the mechanisms behind these changes are not fully understood. A number of studies have suggested the involvement of matrix metalloproteinases (MMPs) and ADAMTS in IVD degeneration, but few have localized the site of production of these enzymes to the cells of the degenerate disc. This study uses immunohistochemical techniques to localize and quantify the production of degrading enzymes (MMPs 1, 3, and 13, and ADAMTS 4) and their inhibitors (TIMPS 1, 2, and 3) within non‐degenerate and degenerate discs of varying severity of degeneration. In all discs investigated, the cells that produced the enzymes and their inhibitors were the chondrocyte‐like cells of the nucleus pulposus and inner annulus fibrosus (AF), with little immunopositivity in the outer AF. Non‐degenerate discs showed low numbers of cells expressing the degradative enzymes MMP 1 and ADAMTS 4, suggesting a role for these enzymes in normal homeostasis. No MMP 3 or MMP 13 immunopositivity was observed in non‐degenerate discs. In degenerate discs, the number of cells immunopositive for MMPs 1, 3, 13 and ADAMTS 4 increased with the severity of degeneration. This increase in degrading enzymes was also accompanied by increases in the number of cells immunopositive for TIMPs 1 and 2 but not TIMP 3. This study highlights that although the expression of a number of MMPs increases with degeneration, this is accompanied by an increase in their inhibitors. However, the increase in the number of cells immunoreactive for ADAMTS 4 with increasing degeneration was not paralleled by a rise in its inhibitor TIMP 3. This finding indicates that the aggrecanases, rather then the MMPs, are a possible therapeutic target for the inhibition of disc degeneration. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Altered cell kinetics in cultured placental villous explants in pregnancies complicated by pre‐eclampsia and intrauterine growth restriction
Authors: Crocker Ian P , Tansinda Dympna M , Baker Philip N 
Published: August 2004

AbstractPlacentae in pre‐eclampsia (PE) and intrauterine growth restriction (IUGR) are characterized by morphological variations, apoptosis, and syncytial shedding, features that are linked to inappropriate oxygen and inflammatory cytokines. Cell turnover within the placenta is dynamic. In this study, these cellular events have been investigated longitudinally using a placental explant model. Intrinsic variations between normal (n = 14), PE (n = 16) and IUGR pregnancies (n = 11), and their responses to oxygen (3% and 17%) and exogenous tumour necrosis alpha (TNFα), were recorded. Placental explants were assessed for apoptotic morphology, immunolocalization of MIB‐1 (a proliferation marker), lactate dehydrogenase (a necrosis marker), and human chorionic gonadotrophin (hCG, a marker of cytotrophoblast differentiation). Explants under TNFα and 17% O2 revealed progressive degeneration of syncytiotrophoblast (ST) followed by restoration of hCG, localized to newly differentiated cytotrophoblasts. This differentiation was significantly enhanced in PE and IUGR. Responses to 3% O2 were similar between groups: a sharp decline in hCG and failure to recover thereafter. Exaggerated cell death was recorded in PE and IUGR explants exposed to TNFα and 3% O2. All significant changes in apoptosis were confined to ST and stromal compartments. Enhanced cell death was predominantly apoptotic in PE and necrotic in IUGR. 3% O2 promoted cell proliferation in normal placentae but this response was not reciprocated in PE and IUGR. Elevated hCG in PE and IUGR explants may represent a placental predisposition to differentiation in vivo. In addition, the increased susceptibility of villous components to cell death, in the absence of stimulated proliferation, may provide a powerful mechanism for aberrant or adaptive placental cell turnover in utero. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
The role of PTEN and its signalling pathways, including AKT, in breast cancer; an assessment of relationships with other prognostic factors and with outcome
Authors: Panigrahi AR , Pinder SE , Chan SY , Paish EC , Robertson JFR , Ellis IO 
Published: August 2004

AbstractPTEN is a novel tumour suppressor gene located on chromosome 10. PTEN mutations are believed to exert their effects through the putative PI3K–AKT–mTOR signalling pathway. Specifically, loss of PTEN leads to activation of AKT, which in turn promotes anti‐apoptotic and pro‐cell cycle entry pathways believed to be essential in tumourigenesis. Whilst PTEN mutations are frequent in a variety of sporadic cancers and inherited cancer syndromes, it is not clear how frequently PTEN mutations and immunohistochemical loss of PTEN expression occur in sporadic breast cancer. This study used tissue microarrays (TMAs) to assess wild‐type PTEN and pAKT immunohistochemical staining in 670 and 691 cases, respectively, of primary operable breast cancer. Scores of 0, 1, and 2 were given for negative, weakly positive, and strongly positive degrees of immunoreactivity, respectively. In addition, immunohistochemical assessment of epidermal growth factor receptor (EGFR), Her2, and proliferation by MIB1 expression was performed on the same TMAs and the scores were compared with those of PTEN and pAKT. Eight per cent of cases did not express wild‐type PTEN. No correlation was observed between patient, tumour and outcome variables and PTEN. pAKT expression correlated inversely with adverse tumour variables such as tumour grade (p < 0.001) and correlated positively with ER status (p < 0.001). No correlation was seen between either PTEN or AKT and EGFR, Her2 or MIB1. No association of PTEN or pAKT was seen in Kaplan–Meier or multivariate analysis for overall survival. The results indicate that loss of PTEN expression is infrequent in breast cancer. PTEN and AKT do not appear to be prognostic markers. The study argues against the current model of a simple linear tumourigenic PTEN–PI3K–AKT–mTOR pathway in breast cancer. It also suggests that, in this group of breast cancers, the most common upstream regulator of AKT may be ER rather than PTEN, EGFR or Her2. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Evaluation of immunohistochemical markers in non‐small cell lung cancer by unsupervised hierarchical clustering analysis: a tissue microarray study of 284 cases and 18 markers
Authors: Au NHC , Cheang M , Huntsman DG , Yorida E , Coldman A , Elliott WM , Bebb G , Flint J , English J , Gilks CB , Grimes HL 
Published: August 2004

AbstractThis study has investigated a panel of immunomarkers in non‐small cell lung carcinoma (NSCLC). Unsupervised hierarchical clustering analysis was used to investigate the possibility of identifying different subgroups in NSCLC based on their molecular expression profile rather than morphological features. A tissue microarray consisting of 284 cases of NSCLC was constructed. Immunohistochemistry was used to detect the presence of 18 biomarkers including synaptophysin, chromogranin, bombesin, NSE, GFI1, ASH‐1, p53, p63, p21, p27, E2F‐1, cyclin D1, Bcl‐2, TTF‐1, CEA, HER2/neu, cytokeratin 5/6, and pancytokeratin. Univariate analysis of all 18 markers for prognostic significance was performed. Immunohistochemical scoring data for NSCLC were analysed by unsupervised hierarchical clustering analysis. Kaplan–Meier survival curves were plotted for the different cluster groups of lung tumours identified by this method. Analysis of the three different World Health Organization (WHO) subtypes (adenocarcinoma, squamous cell carcinoma, large cell carcinoma) of NSCLC individually showed that different markers were significant in different subtypes. For example, p53 and p63 were significant for squamous cell carcinoma (p = 0.007 and p = 0.03, respectively), whereas cyclin D1 and HER2/neu were significant prognostic markers for adenocarcinoma (p = 0.025 and p = 0.015, respectively). These markers were not significant prognostic predictors for NSCLC as a group. Hierarchical clustering analysis of NSCLC produced four separate cluster groups, although the vast majority of cases were found in two cluster groups, one dominated by squamous cell carcinoma and the other by adenocarcinoma. The clinical outcomes of cases from the four cluster groups were not significantly different. Prognostic indicators vary between different morphological subtypes of NSCLC. Unsupervised hierarchical clustering analysis, based on an extended immunoprofile, identifies two main cluster groups corresponding to adenocarcinoma and squamous cell carcinoma; cases of large cell carcinomas are assigned to one of these two groups based on their molecular phenotype. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Decreased expression of apical Na+ channels and basolateral Na+, K+‐ATPase in ulcerative colitis
Authors: Greig ER , Boot‐Handford RP , Mani V , Sandle GI 
Published: August 2004

AbstractImpaired absorption of sodium (Na+) and water is a major factor in the pathogenesis of diarrhoea in ulcerative colitis (UC). Electrogenic Na+ absorption, present mainly in human distal colon and rectum, is defective in UC, but the molecular basis for this is unclear. The effect of UC on the expression of apical Na+ channels (ENaC) and basolateral Na+, K+‐ATPase, the critical determinants of electrogenic Na+ transport, was therefore investigated in this study. Sigmoid colonic and/or proximal rectal mucosal biopsies were obtained from patients with mild to moderate UC, and patients with functional abdominal pain (controls). ENaC subunit expression was studied by immunohistochemistry, western blot analysis, and in situ hybridization, and Na+, K+‐ATPase isoform expression was studied by immunohistochemistry, western blotting, and northern blot analysis. UC was associated with substantial decreases in the expression of the ENaC β‐ and γ‐subunit proteins and mRNAs, whereas the decrease in ENaC α‐subunit protein detected by immunolocalization was less marked. The levels of expression of Na+, K+‐ATPase α1‐ and β1‐isoform proteins were also lower in UC patients than in controls, although there were no differences in Na+, K+‐ATPase α1‐ and β1‐isoform mRNA levels between the two groups. Taken together, these results show that UC results mainly in decreased expression of the apical ENaC β‐ and γ‐subunits, as well as the basolateral Na+, K+‐ATPase α1‐ and β1‐isoforms. In conclusion, these changes provide a basis for the low/negligible levels of electrogenic Na+ absorption seen in the distal colon and rectum of UC patients, which contribute to the pathogenesis of diarrhoea in this disease. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Inverse correlation of secreted frizzled‐related protein 4 and β‐catenin expression in endometrial stromal sarcomas
Authors: Hrzenjak Andelko , Tippl Michaela , Kremser Marie‐Luise , Strohmeier Bettina , Guelly Christian , Neumeister Doris , Lax Sigurd , Moinfar Farid , Tabrizi Ali Dastranj , Isadi‐Moud Narges , Zatloukal Kurt , Denk Helmut 
Published: August 2004

AbstractEndometrial stromal sarcomas are rare uterine tumours. Whereas the histology and immunohistochemistry of these tumours are well documented, almost nothing is known about the molecular mechanisms involved in their pathogenesis. To characterize the genes altered in these malignancies, a genome‐wide cDNA library was generated by suppression subtractive hybridization and a set of differentially expressed clones was isolated. These were then used to produce custom‐spotted cDNA arrays. Genes deregulated in endometrial stromal sarcomas were identified by cDNA array hybridization and were confirmed by quantitative real‐time PCR analyses and in situ hybridization. Following cDNA array analysis, more than 300 genes deregulated in endometrial stromal sarcoma were selected and sequenced. Among the most significantly deregulated genes were those of secreted frizzled‐related proteins (SFRPs), in particular secreted frizzled‐related protein 4 (SFRP4). SFRPs are putative modulators of the Wnt‐signalling pathway and play a role in different cellular events including cell proliferation. Compared with normal endometrium, the expression of SFRP4 was decreased in both low‐grade endometrial stromal sarcoma (ESS; n = 10) and undifferentiated endometrial sarcoma (UES; n = 4), being lower in the latter more aggressive form. These results were verified on paraffin wax‐embedded tissue by quantitative real‐time PCR analysis and in situ hybridization. Furthermore, the expression of β‐catenin, an important component of the Wnt‐signalling pathway, was regulated in an opposite manner to SFRP4, being particularly increased in undifferentiated sarcomas. The activation of the Wnt‐signalling pathway was additionally supported by the immunohistochemical demonstration that β‐catenin was translocated to the nucleus in UES. SFRP4 may therefore be a putative tumour suppressor involved in deregulation of the Wnt pathway and in the pathogenesis of ESS and UES. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Angiopoietins in tumours: the angiogenic switch
Authors: Tait Catherine R , Jones Pamela F 
Published: August 2004

AbstractOn first view, the literature pertaining to the expression of the angiopoietins in tumours is confusing and does not readily offer a consensus pattern. Apparently conflicting publications report increased, decreased or unchanged expression levels of both angiopoietin‐1 (Ang‐1) and angiopoietin‐2 (Ang‐2) in a wide range of tumours. However, closer scrutiny of the literature, taking into account relative increases or decreases of each factor, reveals a consensus pattern, seen in almost all instances of expression profiling of the angiopoietins in tumours. What becomes apparent is that although absolute levels of either angiopoietin may increase or decrease, the ratio of Ang‐1:Ang‐2 shifts in favour of Ang‐2. Given that Ang‐2 is a destabilization factor, rendering vasculature in a more plastic state amenable to sprouting (under the influence of vascular endothelial growth factor, VEGF) or regression, this analysis suggests that tumours shift the angiogenic balance towards a pro‐angiogenic state through altering the balance between the angiopoietins. This in turn implicates Ang‐2 as a candidate for the angiogenic switch and also as an important potential therapeutic target. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Increased CCL27–CCR10 expression in allergic contact dermatitis: implications for local skin memory
Authors: Moed Heleen , Boorsma Dick M , Tensen Cornelis P , Flier Jacoba , Jonker Maureen J , Stoof Tom J , von Blomberg B Mary E , Bruynzeel Derk P , Scheper Rik J , Rustemeyer Thomas , Gibbs Susan 
Published: August 2004

AbstractAllergic contact dermatitis (ACD) is a T‐cell‐mediated disease in which expression of a distinct repertoire of chemokines results in the recruitment of effector T cells into the skin. While it is becoming clear which chemokines and receptors determine the development of ACD, the mechanisms involved in the retention of T cells in the skin after resolution of inflammation are still unknown. Unravelling these mechanisms will help us to understand local skin memory as observed in retest reactivity and flare‐up reactions. This study was designed to evaluate the role of chemokine–chemokine receptor interactions in local T‐cell retention. The results show that expression of the CCR10 targeting ligand CCL27 is not only increased during inflammation, but also remains increased several weeks after clinical responsiveness to patch testing. In parallel with increased CCL27 expression, an increased number of infiltrating cells could still be detected in skin that, clinically, had returned to normal 21 days after patch testing. These persisting cells were characterized as CD4+ cells expressing CCR10, while no CD8+ CCR10+ cells could be detected. The presence of these cells is most likely an allergen‐mediated effect, as increased levels of CCL27 and CCR10 could not be detected 21 days after initiating an irritant contact dermatitis reaction. In contrast to CCL27, increased expression of CXCL9, CXCL10, and CXCL11 could only be observed during the clinically inflammatory phase of ACD. In conclusion, local CCL27‐mediated retention of CCR10+ CD4+ T cells in sites previously challenged by ACD could be responsible for phenomena such as local skin memory observed in retest reactions and flare‐up reactions in which the presence of persisting T cells results in an accelerated inflammatory response upon renewed allergen challenge. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Self‐organization of striped pattern of refractive indices in photopolymer film
Authors: Uematsu Takafumi , Watanabe Akira , Yamaguchi Yukio 
Published: August 2004

AbstractWe report on a self‐organized striped pattern of refractive indices in a photopolymer film. Silicon oxide (SiO2) particles (1.3‐μm diameter) were dispersed on a cover glass above a monomer mixture (bifunctional methacrylate monomer, cyanoethylmethacrylate, and 2,4,6‐trimethylbenzoyldiphenylphosphine oxide), and the sample was uniformly irradiated from a tube light source. The self‐organized striped pattern was observed inside a 0.45‐mm thickness photopolymer film. In contrast, no pattern was observed in a 0.45‐mm thickness sample photopolymerized without particles on a cover glass. The results suggest that the SiO2 particles acted as “lenses” and produced a light distribution reflecting the shape of the light source used during the irradiation. The photopolymerization extended in depth according to the light distribution, and then the striped pattern was generated inside a medium. The photopolymer film with the striped pattern has an angular dependence in the transmittance as a result of the microstructure and can be applied to a flexible optical transmission filter. © 2004 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 42: 3351–3358, 2004
Sequence‐based prediction of pathological mutations
Authors: Ferrer‐Costa C. , Orozco M. , de la Cruz X. 
Published: August 2004

AbstractThe development of methods to assess the impact of amino acid mutations on human health has become an important goal in biomedical research, due to the growing number of nonsynonymous SNPs identified. Within this context, computational methods constitute a valuable tool, because they can easily process large amounts of mutations and give useful, almost cost‐free, information on their pathological character. In this paper we present a computational approach to the prediction of disease‐associated amino acid mutations, using only sequence‐based information (amino acid properties, evolutionary information, secondary structure and accessibility predictions, and database annotations) and neural networks, as a model building tool. Mutations are predicted to be either pathological or neutral. Our results show that the method has a good overall success rate, 83%, that can reach 95% when trained for specific proteins. The methodology is fast and flexible enough to provide good estimates of the pathological character of large sets of nonsynonymous SNPs, but can also be easily adapted to give more precise predictions for proteins of special biomedical interest. Proteins 2004. © 2004 Wiley‐Liss, Inc.
Molecular recognition of aldehydes by aldehyde dehydrogenase and mechanism of nucleophile activation
Authors: Wymore Troy , Hempel John , Cho Samuel S. , MacKerell Alexander D. , Nicholas Hugh B. , Deerfield David W. 
Published: August 2004

AbstractExperimental structural data on the state of substrates bound to class 3 Aldehyde Dehydrogenases (ALDH3A1) is currently unknown. We have utilized molecular mechanics (MM) simulations, in conjunction with new force field parameters for aldehydes, to study the atomic details of benzaldehyde binding to ALDH3A1. Our results indicate that while the nucleophilic Cys243 must be in the neutral state to form what are commonly called near‐attack conformers (NACs), these structures do not correlate with increased complexation energy calculated with the MM‐Generalized Born Molecular Volume (GBMV) method. The negatively charged Cys243 (thiolate form) of ALDH3A1 also binds benzaldehyde in a stable conformation but in this complex the sulfur of Cys243 is oriented away from benzaldehyde yet yields the most favorable MM‐GBMV complexation energy. The identity of the general base, Glu209 or Glu333, in ALDHs remains uncertain. The MM simulations reveal structural and possible functional roles for both Glu209 and Glu333. Structures from the MM simulations that would support either glutamate residue as the general base were further examined with Hybrid Quantum Mechanical (QM)/MM simulations. These simulations show that, with the PM3/OPLS potential, Glu209 must go through a step‐wise mechanism to activate Cys243 through an intervening water molecule while Glu333 can go through a more favorable concerted mechanism for the same activation process. Proteins 2004. © 2004 Wiley‐Liss, Inc.