bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of COX‐2, mPGE‐synthase1, MDR‐1 (P‐gp), and Bcl‐xL: a molecular pathway of H pylori‐related gastric carcinogenesis
Authors: Nardone Gerardo , Rocco Alba , Vaira Dino , Staibano Stefania , Budillon Alfredo , Tatangelo Fabiana , Sciulli Maria G. , Perna Federico , Salvatore Gaetano , Di Benedetto Maria , De Rosa Gaetano , Patrignani Paola 
Published: February 2004

AbstractHelicobacter pylori up‐regulates cyclo‐oxygenase‐2 (COX‐2) expression, which in turn is involved in tumourigenesis. Recently, a causal link between COX‐2 and multidrug resistance 1 (MDR‐1) gene expression, implicated in cancer chemoresistance, has been demonstrated. Thus, the expression of COX‐2 and the downstream enzyme involved in PGE2 biosynthesis, microsomal PGE‐synthase1 (mPGES1), was correlated with P‐gp, the product of MDR‐1, and the anti‐apoptotic protein, Bcl‐xL, in gastric biopsies from patients with H pylori infection and in patients with gastric cancer. In a retrospective analysis of endoscopic and pathology files, 40 H pylori‐negative patients (Hp−), 50 H pylori‐positive patients who responded to eradication therapy (Hp+R), 84 H pylori‐positive patients who did not respond to eradication therapy (Hp+NR), and 30 patients with gastric cancer (18 intestinal and 12 diffuse types) were selected. COX‐2, mPGES1, P‐gp, and Bcl‐xL were detected by immunohistochemistry. COX‐2, mPGES1, P‐gp, and Bcl‐xL expression was undetectable in gastric mucosa from Hp− patients. By contrast, COX‐2 and mPGES1 expression was detected in 42% and 44% of Hp+R patients, respectively, and in up to 66% (range 63–66%) of Hp+NR patients (p < 0.05). The expression of COX‐2 and mPGES1 correlated significantly (p < 0.0001) with that of P‐gp and Bcl‐xL. High levels of COX‐2, mPGES1, P‐gp, and Bcl‐xL expression were found in intestinal‐type gastric cancer samples. In conclusion, H pylori‐dependent induction of COX‐2 and mPGES1 is associated with enhanced production of P‐gp and Bcl‐xL that may contribute to gastric tumourigenesis and resistance to therapy. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
KIT (CD117) is frequently overexpressed in thymic carcinomas but is absent in thymomas
Authors: Pan Chin‐Chen , Chen Paul Chih‐Hsueh , Chiang Hung 
Published: February 2004

AbstractKIT (CD117), a tyrosine kinase receptor, has not been widely studied in epithelial tumours. In a systematic immunohistochemical survey of KIT expression on tissue arrays incorporating 671 cases, it was found that thymic carcinomas frequently express KIT. Twenty‐two thymic carcinomas, 110 thymomas, and 16 non‐neoplastic thymus glands were retrieved for further analyses. Immunohistochemically, 19 (86%) thymic carcinomas revealed heterogeneous to diffuse membranous positivity, whereas no thymomas or normal thymus glands contained positive epithelial cells. Using reverse transcriptase‐polymerase chain reaction (RT‐PCR), c‐kit transcripts could be demonstrated in all immunohistochemically positive cases. PCR amplification and direct sequencing of the c‐kit juxtamembrane domains (exons 9 and 11) and tyrosine kinase domain (exons 13 and 17) were also performed on the thymic carcinomas but mutations were not found. Some non‐thymic epithelial tumours showed frequent KIT expression including adenoid cystic carcinomas of the salivary gland (100% positive), chromophobe renal cell carcinomas (94%), renal oncocytomas (67%), and neuroendocrine tumours (34%). Other carcinomas were infrequently immunoreactive for KIT. The findings of this study suggest that KIT is involved in the pathogenesis of thymic carcinomas. The overexpression of KIT in thymic carcinomas has potential diagnostic utility in differentiating these tumours from thymomas and carcinomas arising from other sites, which express KIT infrequently. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Molecular analysis of the INK4A/INK4A‐ARF gene locus in conventional (central) chondrosarcomas and enchondromas: indication of an important gene for tumour progression
Authors: van Beerendonk Hetty M , Rozeman Leida B , Taminiau Antonie HM , Sciot Raf , Bovée Judith VMG , Cleton‐Jansen Anne‐Marie , Hogendoorn Pancras CW 
Published: February 2004

AbstractLoss of heterozygosity (LOH) at chromosomal band 9p21 is one of the few consistent genetic aberrations found in conventional chondrosarcoma. This locus harbours two cell‐cycle regulators, CDKN2A/p16/INK4A and INK4A‐p14ARF, which are inactivated in various human malignancies. It was therefore hypothesized that this locus also plays a role in the development of chondrosarcoma and this locus was investigated at protein, genetic, and epigenetic levels. Loss of p16 protein expression was detected by immunohistochemistry in 12 of 73 central chondrosarcomas and it correlated with increasing histological grade (p = 0.001). Loss of p16 protein expression was not found in 51 enchondromas, which are presumed to be potential precursors of conventional central chondrosarcoma. LOH at 9p21 was found in 15 of 39 chondrosarcomas (38%) but it did not correlate with loss of p16 protein expression. SSCP analysis of p16 did not reveal any mutations in 47 cases. Also, p14 was not the target of LOH, since it gave no aberrant bands on SSCP. To investigate whether an epigenetic mechanism was operating, methylation‐specific PCR was used to look at p16 promotor methylation, which was identified in 5 of 30 tumours. However, this did not correlate with protein expression, or with LOH at 9p21. Cytogenetic data were available in a subset of cases. All tumours that showed chromosome 9 alterations also showed LOH and loss of INK4A/p16 protein expression. It is concluded that although some alterations were found at the DNA level and at the promoter expression level, the lack of correlation between LOH, promotor methylation, and protein expression indicates that a locus other than CDKN2A/p16 must be the target of LOH at 9p21. The correlation between INK4A/p16 protein expression and tumour grade, and the retention of expression in enchondromas, indicates that loss of INK4A/p16 protein expression may be an important event during tumour progression from enchondroma to conventional central chondrosarcoma, and in the progression in grade after recurrence of chondrosarcoma. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Phosphorylated KDR is expressed in the neoplastic and stromal elements of human renal tumours and shuttles from cell membrane to nucleus
Authors: Fox Stephen B , Turley Helen , Cheale Michelle , Blázquez Cristina , Roberts Helen , James Neil , Cook Nathan , Harris Adrian , Gatter Kevin 
Published: February 2004

AbstractVascular endothelial growth factor (VEGF)‐A is an important angiogenic factor in establishing the vasculature in renal cell carcinomas (RCCs). Since little is known about VEGF signalling in RCCs, the profile of phosphorylated KDR (pKDR) has been investigated and the intracellular location of the receptor has been examined in the present study. Using two monoclonal antibodies raised against the phosphorylated KDR epitopes (Y1059 and Y1214) known to mediate different VEGF functions, together with a commercial anti‐KDR antibody and immunohistochemistry, the expression of pKDR was investigated in a series of normal (n = 25) and neoplastic kidneys (n = 54; clear cell n = 35; papillary n = 10; oncocytomas n = 8). pKDR was present in many tissue elements of both normal and neoplastic renal tissues, with strong expression in the cell membrane, cytoplasm, and nuclei of normal kidney and tumour cells, as well as endothelial cells in tumours of all histological types. Patterns and intensity were similar using both anti‐pKDR antibodies. There was no significant correlation in clear cell carcinomas between pKDR expression and age (p = 0.57), tumour size (p = 0.2), gender (p = 0.59), grade (p = 0.2) or histological type (p = 0.36). To delineate further the intracellular processing that might account for the cellular distribution, confocal microscopy was also performed. Antibodies to the different phosphorylated epitopes demonstrated different intracellular staining patterns. This study shows that pKDR is present in a wide variety of renal tumours, suggesting that anti‐VEGF therapy might have direct effects on tumour cells. It further suggests that cells traffic pKDR depending on the precise KDR tyrosines that are autophosphorylated in a manner that enables receptor activation to result in different functions. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
In ovarian neoplasms, BRAF, but not KRAS, mutations are restricted to low‐grade serous tumours
Authors: Sieben Nathalie LG , Macropoulos Patricia , Roemen Guido MJM , Kolkman‐Uljee Sandra M , Jan Fleuren Gert , Houmadi Rifat , Diss Tim , Warren Bretta , Al Adnani Mudher , de Goeij Anton PM , Krausz Thomas ,   The Cancer Genome Project, Flanagan Adrienne M 
Published: February 2004

AbstractGenes of the RAF family, which mediate cellular responses to growth signals, encode kinases that are regulated by RAS and participate in the RAS/RAF/MEK/ERK/MAP‐kinase pathway. Activating mutations in BRAF have recently been identified in melanomas, colorectal cancers, and thyroid and ovarian tumours. In the present study, an extensive characterization of BRAF and KRAS mutations has been performed in 264 epithelial and non‐epithelial ovarian neoplasms. The epithelial tumours ranged from adenomas and borderline neoplasms to invasive carcinomas including serous, mucinous, clear cell, and endometrioid lesions. It is shown that BRAF mutations in ovarian tumours occur exclusively in low‐grade serous neoplasms (33 of 91, 36%); these included serous borderline tumours (typical and micropapillary variants), an invasive micropapillary carcinoma and a psammocarcinoma. KRAS mutations were identified in 26 of 91 (29.5%) low‐grade serous tumours, 7 of 49 (12%) high‐grade serous carcinomas, 2 of 6 mucinous adenomas, 22 of 28 mucinous borderline tumours, and 10 of 18 mucinous carcinomas. Of note, two serous borderline tumours were found to harbour both BRAF and KRAS mutations. The finding that at least 60% of serous borderline tumours harbour mutations in two members of the ERK‐MAP‐kinase pathway (BRAF 36%, KRAS 30%) compared with 12% of high‐grade serous carcinomas (BRAF 0%, KRAS 12%) indicates that the majority of serous borderline tumours do not progress to serous carcinomas. Furthermore, no BRAF mutations were detected in the other 173 ovarian tumours in this study. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Comparative multi‐methodological measurement of ERBB2 status in breast cancer
Authors: Ginestier Christophe , Charafe‐Jauffret Emmanuelle , Penault‐Llorca Frédérique , Geneix Jeannine , Adélaïde José , Chaffanet Max , Mozziconacci Marie‐Joëlle , Hassoun Jacques , Viens Patrice , Birnbaum Daniel , Jacquemier Jocelyne 
Published: February 2004

AbstractThe ERBB2 transmembrane tyrosine kinase receptor is both a prognostic marker and a therapeutic target in breast cancer. Accurate determination of ERBB2 status is a prerequisite for the establishment of prognostic significance and for the selection of ERBB2‐overexpressing breast tumours for specific treatment. Unfortunately, there is no complete agreement on how this determination should be performed. This study has compared four methods of assessment of ERBB2 status. Two global, extraction‐based methods using real‐time quantitative PCR on DNA (Q‐PCR) or RNA (RQ‐PCR) and two non‐global, tissue‐based methods, ie fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC), were used. The 94 breast cancers tested were enriched in cases scoring 2+ using the IHC scoring system currently in use and for which the actual ERBB2 status remains ill defined. To determine the best parameters and reagents for assessment, two protocols for FISH and five anti‐ERBB2 antibodies were used, and both FISH and IHC were carried out on the same tissue microarrays (TMAs). It is shown that the combination of the two tissue‐based methods gives the best results. The use of either PCR‐based method did not improve the results significantly. A new combined IHC score based on the association of two selected anti‐ERBB2 antibodies (HercepTest™ and TAB250) and a dual scale for improved assessment of ERBB2 protein expression, particularly in 2+ cases, are proposed. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Distribution of laminins in the basement membranes of the upper gastrointestinal tract and Barrett's oesophagus
Authors: Dave U , Thursz MR , Ebrahim HY , Burke MM , Townsend ER , Walker MM 
Published: February 2004

AbstractBarrett's oesophagus predisposes to oesophageal adenocarcinoma. In vitro, laminin, a component of the epithelial basement membrane (BM), is important in regulation of cell differentiation. There is limited information on the distribution of laminin chains in the upper gastrointestinal tract (GIT) and none in Barrett's oesophagus. This study aimed to investigate qualitatively the distribution of laminins in the normal upper GIT mucosa and Barrett's oesophagus in order to understand the role of laminins in metaplasia. Immunoperoxidase staining for laminin chains α1, α2, α3, α5, β1, β2, β3, γ1, and γ2 was performed on frozen endoscopic squamous and Barrett's oesophageal biopsies and surgical resection specimens from squamous oesophagus (in resection specimens for oesophageal cancer), and in oesophageal and gastric biopsies from control subjects. α1 laminin was expressed in the BM of submucosal glands and ducts in squamous oesophagus and Brunner's glands in the duodenum, but not in Barrett's oesophagus or elsewhere in the upper GIT. α2 laminin chain was expressed in a granular distribution in the BM of squamous epithelium. In columnar epithelium, including Barrett's oesophagus, α2 laminin chain was expressed continuously in the BM of glands and deeper pits, but expression was reduced and granular in the surface epithelial BM. β2 laminin was continuous in squamous epithelial BM, but in Barrett's and cardia, gastric body, and duodenum, it was expressed faintly in the surface but continuously in the BM of glands and deeper pits. The constituents of laminin‐5 were continuously expressed in the BM of squamous epithelium, but in the cardia, gastric body, duodenum, and Barrett's, they were expressed only in the BM of surface epithelium, with a sharp decline in the glandular and deeper pit BM. Site‐specific distribution of the α2 and β2 laminin chains may therefore have an important role in Barrett's metaplasia. However, the absence of α1 laminin in Barrett's mucosa suggests that this is unlikely to play an important role in columnar metaplasia. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Vascular endothelial growth factor (VEGF) induces matrix metalloproteinase expression in immortalized chondrocytes
Authors: Pufe Thomas , Harde Viola , Petersen Wolf , Goldring Mary B , Tillmann Bernhard , Mentlein Rolf 
Published: February 2004

AbstractVEGF (vascular endothelial growth factor), an important angiogenesis factor, appears also to be involved in inflammatory processes. Recent studies have shown that VEGF and its receptors (VEGFR) are expressed on osteoarthritic, but not on normal adult, chondrocytes. To elucidate possible functions of VEGF in osteoarthritic cartilage, the effects of VEGF were studied on immortalized human chondrocytes. Activated matrix metalloproteinase (MMP)‐1, MMP‐3, MMP‐13, tissue inhibitor of metalloproteinases (TIMP)‐1, TIMP‐2, interleukin (IL)‐1β, IL‐6, and tumour necrosis factor‐α (TNF‐α) were measured in culture supernatants by enzyme‐linked immunosorbent assays, nitric oxide with the Griess reagent, and cell proliferation by [3H]thymidine incorporation. VEGFR‐2 mRNA was quantified by real‐time reverse transcription‐polymerase chain reaction and the protein was identified by immuno‐gold electron microscopy. Intracellular signal transduction effects were determined by western blots and electrophoretic mobility shift assays. The chondrocyte cell lines C28/I2, C20/A4, and T/C28a2/a4 expressed functionally active VEGFR‐2. VEGF stimulation induced receptor phosphorylation, activation of the mitogen‐activated protein kinases ERK 1/2, and long‐lasting activation of the transcription factor AP‐1 (activator protein‐1). VEGF increased secreted MMP‐1, MMP‐3, and especially MMP‐13, which could be effectively reduced by an inhibitor of VEGFR‐2 kinase activity. Interestingly, VEGF diminished the expression of TIMP‐1 and especially TIMP‐2. Under hypoxic conditions, as occur in cartilage, the reduction in TIMP levels was even greater. Furthermore, VEGF induced IL‐1β, IL‐6, TNF‐α, and nitric oxide expression to a small extent and stimulated the proliferation of immortalized chondrocytes. These findings indicate that VEGF is an autocrine stimulator of immortalized chondrocytes that mediates mainly destructive processes in osteoarthritis. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Distribution and significance of 14‐3‐3σ, a novel myoepithelial marker, in normal, benign, and malignant breast tissue
Authors: Simpson Peter T , Gale Theodora , Reis‐Filho Jorge S , Jones Chris , Parry Suzanne , Steele Dawn , Cossu Antonio , Budroni Mario , Palmieri Giuseppe , Lakhani Sunil R 
Published: February 2004

Abstract14‐3‐3σ is a candidate tumour suppressor gene transactivated by p53 in response to DNA damage. In gene expression analysis of normal luminal and myoepithelial cells, 14‐3‐3σ was preferentially expressed by myoepithelial cells. This study has analysed the immunohistochemical distribution and subcellular localization of 14‐3‐3σ in normal breast tissue and in a large series of benign and malignant breast lesions on whole tissue sections and by tissue microarray. Immunohistochemistry demonstrated that 14‐3‐3σ was consistently expressed in the cytoplasmic compartment and occasionally in the nuclei of myoepithelial cells arranged as a continuous layer around normal ducts and lobular units, whereas luminal epithelial, stromal, endothelial, pericytic, lipomatous, and neural cells showed no staining. Myoepithelial cells of benign proliferations and pre‐invasive lesions were consistently positive for 14‐3‐3σ. Strong expression of 14‐3‐3σ was evident in one case of ductal carcinoma in situ (5.5%) and in 105/554 invasive cancers (18.9%). Survival data were available for 452 patients with invasive breast carcinoma. 14‐3‐3σ cytoplasmic subcellular localization was a statistically significant prognostic factor for the whole series of invasive carcinomas, as well as for those positive for oestrogen (ER) or progesterone receptors (PR). This analysis demonstrates the utility of 14‐3‐3σ as a new adjunct antibody for characterization of myoepithelial cells and myoepithelial lesions and it may be a novel prognostic factor for breast cancer patients. Copyright © 2004 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
H1‐Antihistaminika als Allergene? Pharmakophore und Epitope
Authors: Siebert C. D. 
Published: February 2004

AbstractBeim Vergleich der beschriebenen H1‐Antihistaminika ist offensichtlich, dass Hautreaktionen in verschiedenen Erscheinungsformen die am häufigsten auftretenden allergischen Nebenwirkungen sind. Sie werden von allen hier erwähnten Arzneistoffen verursacht, vermutlich mit Ausnahme von Levocetirizin, haben aber nur sehr selten eine schwere Verlaufsform (wie z.B. das Stevens‐Johnson‐Syndrom bei Ketotifen). Bei etwa der Hälfte aller H1‐Blocker sind ein allergisches Asthma mit Bronchospasmus und damit verbunden Atemprobleme beschrieben worden. Gleiches trifft auch für den anaphylaktischen Schock zu, der durch Organversagen zum Tode führen kann. Quincke‐Ödeme bzw. angioneurotische Ödeme sind bei den Antihistaminika der ersten Generation nicht beschrieben worden, mit Ausnahme des auch strukturell abweichenden Dimetindens. Damit wird deutlich, dass die IgE‐vermittelten Reaktionen vom Soforttyp die größten Risiken darstellen. Die allergische Rhinitis spielt eine untergeordnete Rolle und tritt als einzige allergische Nebenwirkung bei Levocabastin auf. Mit einer Photosensibilität muss vor allem bei den Antihistaminika der ersten Generation und bei Promethazin gerechnet werden. Auffallend ist, dass zu Levocetirizin keine Angaben zu allergischen Reaktionen gefunden wurden, so dass vermutet werden kann, dass die für das racemische Cetirizin beschriebenen Allergien dem weniger wirksamen Enantiomer zugeschrieben werden können. Eine Auffälligkeit gilt es noch für die Typ‐II‐Allergien (Agranulozytose, aplastische Anämie und thrombozytopenische Purpura) zu erwähnen. Sie wurden ausschließlich bei den Dexchlorpheniramin‐ verwandten Substanzen gefunden. Es konnte exemplarisch gezeigt werden, dass die vergleichende Strukturanalyse ein probates Hilfsmittel zur Bewertung von auftretenden Allergien ist. Wie die Beispiele von Ibuprofen und Disopyramid zeigen, muss das Epitop nicht immer deckungsgleich mit dem Pharmakophor sein, was bedeutet, dass Allergien auf Arzneistoffe unterschiedlicher Indikation chemisch und nicht pharmakologisch klassifiziert werden sollten. Konsequent weiter gedacht bedeutet dies, dass die Gesamtzahl von in der Literatur beschriebenen verschiedenen Arzneistoffallergien deutlich abnimmt, was zugleich hilfreich für eine Systematisierung ist.
Differential protein expression assessed by two‐dimensional gel electrophoresis for two wheat varieties grown at four nitrogen levels
Authors: Bahrman Nasser , Le Gouis Jacques , Negroni Luc , Amilhat Laurence , Leroy Philippe , Lainé Anne‐Lyse , Jaminon Odile 
Published: February 2004

AbstractTo limit N‐fertilizer applied on wheat, cultivars that use N more efficiently are needed. Our objective was to investigate differences of nitrogen utilization in varieties by studying qualitative and quantitative proteins expression. Two wheat varieties, ‘Arche’ and ‘Récital’, were grown under controlled conditions at four N levels (0, 2, 8, and 20 mg N/plant/day) with two replicates. The number of tillers/plant, aerial dry weight/plant and total N content were measured after two months. Two‐dimensional gel electrophoresis was also performed on leaf protein extracts. Analyses of variance showed that the N level effect was highly significant for the number of tillers/plant, aerial dry weight and N content. The variety×N level interaction was significant for N content. Analyses of variance on % volume carried out for 524 spots showed a significant variety effect for 55 spots and a significant N treatment effect for 76 spots. Twenty spots showed a significant variety×N treatment interaction. Fourteen proteins were identified by liquid chromatography‐tandem mass spectrometry (LC‐MS/MS). The possible role of these proteins, eight of which belong to the carbon metabolism, is discussed.