bluuebunny/crossref_metadata_2025_split huggingface dataset:
The angiogenic peptide vascular endothelial growth factor (VEGF) is expressed in chronic sacral pressure ulcers
Authors: Pufe Thomas , Paulsen Friedrich , Petersen Wolf , Mentlein Rolf , Tsokos Michael 
Published: April 2003

AbstractChronic decubital lesions have a limited potential to heal. Evidence suggests that a lack of local revascularization is involved in this aetiology. The present study investigated the expression of one of the most important angiogenic factors, the vascular endothelial growth factor (VEGF), in different regions of sacral chronic decubital lesions and in normal skin by immunohistochemical, biochemical, molecular, and cell biology methods. To elucidate some of the factors responsible for the induction of VEGF in chronic skin ulcers, cultured fibroblasts were exposed to hypoxia and/or growth factors. In the central part (zone I) of chronic ulcers and in normal skin, immunostaining for VEGF remained largely negative. However, VEGF could be immunostained in cells in the granulation tissue adjacent to central necrosis (zone II). VEGF receptor 2 (VEGFR‐2; KDR) could also be identified in microvessels. High VEGF levels were present in homogenates from granulation tissue by enzyme‐linked immunosorbent assay (ELISA) and western blot experiments: low concentrations were found in areas of central necrosis and negligible amounts were present in normal skin. Reverse transcriptase‐polymerase chain reaction (RT‐PCR) showed that only the splice variants VEGF121 and VEGF165 were expressed. In cultured fibroblasts, hypoxia or platelet‐derived growth factor (PDGF) raised VEGF production. The angiogenic peptide VEGF is present in all zones of chronic decubital ulcers. Its strong expression within the adjacent granulation tissue supports the view that there is no deficiency of VEGF. VEGF may be involved in the healing process of chronic skin lesions, but it seems that loss of another factor may be responsible for the poor healing response. Copyright © 2003 John Wiley & Sons, Ltd.
hnRNP B1 expression in benign and malignant lung disease
Authors: Snead DRJ , Perunovic B , Cullen N , Needham M , Dhillon DP , Satoh H , Kamma H 
Published: April 2003

AbstractEvidence is accumulating to suggest that hnRNP B1 expression may be a useful tool in the early diagnosis of lung cancer. This study examined the immunohistochemical expression of hnRNP B1 in archived sections of resected lung cancers and compared the patterns of expression with those seen in similar archived sections of non‐neoplastic lung. Particular attention was paid to the expression of hnRNP B1 in the benign bronchial cells in both cases, to establish if overexpression of this protein in respiratory epithelial cells is specific for malignancy. Nineteen cases of different types of non‐small cell carcinoma were examined (eight squamous cell, six adenocarcinomas, two carcinosarcomas, two undifferentiated large cell carcinomas, and one mucoepidermoid carcinoma) and compared with sections from 16 open lung biopsies (three cases of cryptogenic fibrosing alveolitis, two cases of sarcoidosis, two cases of organizing pneumonia, and one case each of tuberculosis, extrinsic allergic alveolitis, non‐specific interstitial pneumonitis, pneumocystis pneumonia, aspergilloma, respiratory bronchiolitis–interstitial lung disease, mineral dust disease, Sjögren's syndrome and systemic sclerosis vascular variant). All the tumours showed positive staining, with the vast majority, 16/19 (84%), showing strong diffuse nuclear staining. The background cells of these cases showed positive staining in alveolar macrophages, lymph node germinal centres, bronchial mucous glands, and bronchial epithelial cells. No significant difference was seen in the percentage of positive bronchial epithelial cells in bronchi adjacent to the tumour compared with the resection margins. In the benign lung cases, positive bronchial epithelial cells were seen in a small percentage, 3/16 (18%), of cases, but the majority of cases showed no or very focal staining. The levels of expression between benign epithelial cells of malignant cases, compared with benign, showed a significant difference when the staining was assessed in percentage of positive nuclei (p = 0.001, Fisher's exact test). The results confirm that hnRNP B1 is widely expressed in a range of lung carcinomas; that expression is seen in benign bronchial epithelial cells and inflammatory cells; and that expression in background bronchial epithelial cells appears to be higher in malignant than in benign lung disease. It is feasible that this biomarker may be of use in the detection of early lung cancer, provided that levels of expression can be accurately quantified. Copyright © 2003 John Wiley & Sons, Ltd.
Can p53 staining be used to identify patients with aggressive superficial bladder cancer?
Authors: Masters John RW , Vani Urvi D , Grigor Kenneth M , Griffiths Gareth O , Crook Angela , Parmar Mahesh KB , Knowles Margaret A 
Published: April 2003

AbstractApproximately 10% of patients with superficial bladder cancer (pTa/pT1) recur with life‐threatening muscle‐invasive disease. Identification of these patients has been a major goal of bladder cancer research. In 1994, it was suggested that p53 immunostaining could identify the cancers that would progress and it was proposed that tumours that stain for p53 should be treated aggressively with radiotherapy or cystectomy. Despite the hundreds of studies published since on the relationship between p53 and progression in superficial bladder cancer, the clinical utility of p53 immunostaining has not been resolved because of limitations concerning the numbers of patients and the length of follow‐up. This study set out to overcome these limitations by using tissue from a large multicentre trial that recruited 502 patients with a median follow‐up of 10 years. Each of 34 patients that had progressed with ≥ pT2 disease or had distant metastases or had died from bladder cancer was compared with one or two matched controls. Sections were stained with a mouse monoclonal antibody to p53, pAb1801. In agreement with many of the earlier studies, p53 immunostaining had prognostic significance. The adjusted hazard ratio for time to progression for the pAb1801‐positive versus negative group was 2.5, with 95% confidence intervals of 1.05–5.98 (p = 0.039). The other major risk factor that is associated with progression of superficial bladder cancer is pT1G3 disease. Of the 42 pT1G3 cancers, 14 (33%) progressed. The proportion of cancers with p53 staining that progressed was similar to the proportion of pT1G3 cancers that progressed, but neither the sensitivity nor the specificity of association of p53 staining with progression is sufficient to recommend cystectomy in individual patients. Copyright © 2003 John Wiley & Sons, Ltd.
Malignant phyllodes tumours show stromal overexpression of c‐myc and c‐kit
Authors: Sawyer Elinor J , Poulsom Richard , Hunt F Toby , Jeffery Rosemary , Elia George , Ellis Ian O , Ellis Paul , Tomlinson Ian PM , Hanby Andrew M 
Published: April 2003

AbstractPhyllodes tumours are fibroepithelial neoplasms of the breast, the stroma of which can undergo malignant progression to sarcoma. The frequency of malignant lesions varies in different series from 5% to 30%. The aim of this study was to elucidate potential molecular mechanisms in the progression to malignancy in phyllodes tumours. c‐myc and c‐kit were studied at the protein, RNA(c‐myc only) and DNA level. We chose to study c‐myc as we have previously shown that Wnt signalling is important in benign, but not malignant, phyllodes tumours. If c‐myc is constitutively activated in malignant tumours, this may provide an explanation for why the Wnt pathway is no longer important in these tumours. c‐kit is a membrane‐bound tyrosine kinase receptor and overexpression is characteristic of gastrointestinal stromal tumours. A previous report suggested that this may also be the case in malignant phyllodes tumours, and we wished to confirm this. We assessed expression of c‐myc and c‐kit in 30 phyllodes tumours (10 malignant) using in situ hybridization (c‐myc) and immunohistochemistry (c‐myc and c‐kit). 9/10 malignant tumours showed c‐myc expression in the stroma, compared to 7/20 benign tumours (p = 0.006, Fisher's exact test). Stromal c‐kit expression was found in 5/10 malignant tumours, compared to 1/20 benign tumours (p = 0.008, Fisher's exact test). One tumour had high‐level amplification of c‐myc, but we found no evidence of mutations of c‐kit. We hypothesize that the overexpression of c‐myc may drive stromal proliferation in malignant phyllodes tumours, and that c‐kit overexpression contributes to the growth of these lesions. c‐kit may also be a new therapeutic target in these tumours. Copyright © 2003 John Wiley & Sons, Ltd.
Cholesterol storage and tau pathology in Niemann–Pick type C disease in the brain
Authors: Distl Roland , Treiber‐Held Stephanie , Albert Frank , Meske Volker , Harzer Klaus , Ohm Thomas G 
Published: April 2003

AbstractNiemann–Pick type C disease is an inherited neurovisceral storage disorder with intracellular accumulation of cholesterol. In affected brains, many ballooned neurons are seen. Considerable nerve cell loss of unknown pathogenesis leads to neurological deterioration and dementia. Chemical examination of brains has failed to demonstrate increased levels of cholesterol. Using filipin fluorometry of neuronal cells in tissue slices, we found massive accumulation of cholesterol in neurons in four out of five human Niemann–Pick type C cases including adult patients. Neurofibrillary tangles composed of aggregates of the otherwise highly soluble protein tau were present in three Niemann–Pick type C cases and were also immunologically identical to those associated with Alzheimer's disease. However, only a thin slab of spinal cord or a tiny piece of isocortex was available for examination in the two cases without tangles. In a further semi‐quantitative analysis of 576 neurons, we determined higher cholesterol content in tangle‐bearing neurons than in adjacent tangle‐free neurons. The association of cholesterol accumulation with neurofibrillary degeneration in Niemann–Pick type C disease and Alzheimer's disease awakens interest in the role of impaired cholesterol metabolism in the development of neurofibrillary tangles in both diseases. Copyright © 2003 John Wiley & Sons, Ltd.
Sustained interleukin‐6 signalling leads to the development of lymphoid organ‐like structures in the lung
Authors: Goya Sho , Matsuoka Hiroto , Mori Masahide , Morishita Hiroshi , Kida Hiroshi , Kobashi Yoichiro , Kato Terufumi , Taguchi Yoshio , Osaki Tadashi , Tachibana Isao , Nishimoto Norihiro , Yoshizaki Kazuyuki , Kawase Ichiro , Hayashi Seiji 
Published: April 2003

AbstractA variety of pathological changes are seen in lymphoproliferative disorders of the lung but the histogenesis of these abnormalities is not yet fully understood. We previously showed that adenovirus vector‐mediated transient expression of both the human interleukin‐6 (IL‐6) and IL‐6 receptor (IL‐6R) genes, but not the IL‐6 gene alone, in the rat lung induced lymphocytic alveolitis. In the present study, we explored the lung pathology of human IL‐6 and IL‐6R double transgenic mice to elucidate the effects of prolonged IL‐6 signalling on the lung. The transgenic animals developed mononuclear cell accumulation in peribronchovascular regions, but little infiltration into alveolar spaces. Immunohistochemical analysis revealed that the cellular accumulations contained not only mixtures of inflammatory cells but also lymphoid tissue‐like structures. As the expression of CXCL13/BLC, the indispensable chemokine for lymphoid organogenesis, was recognized in the B cell follicles of the pulmonary lesions, we speculate that this chemokine plays an inductive role in the development of the lymphoid tissue‐like structures. These structures were distinguished from bronchus‐associated lymphoid tissues (BALTs) by their location and by the lack of lymphoepithelium, which is a characteristic of BALT. These findings imply that IL‐6 signalling may play a role in the pathogenesis of lymphoproliferative disorders of the lung. Copyright © 2003 John Wiley & Sons, Ltd.
Overexpression of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 in gastric cancer—association with tumour cell proliferation
Authors: Grabsch Heike , Takeno Shinsuke , Parsons Wendy J , Pomjanski Natalja , Boecking Alfred , Gabbert Helmut Erich , Mueller Wolfram 
Published: April 2003

AbstractThe mitotic spindle assembly checkpoint modulates the timing of anaphase initiation in response to improper alignment of chromosomes at the metaphase plate. The BUB gene family encodes proteins which are part of a large multi‐protein kinetochore complex and which are believed to be key components of the checkpoint regulatory pathway. Failure of this surveillance system can lead to genomic instability and could be responsible for the increased incidence of aneuploidy in gastric cancer. Since mutations of BUB genes have not been identified in gastric cancer to date, altered BUB expression levels may significantly impair mitotic checkpoint function. To explore this possibility, the expression levels of BUB1, BUBR1, and BUB3 were determined in 43 gastric carcinomas and corresponding normal gastric mucosa by reverse transcription‐polymerase chain reaction (RT‐PCR). Gene expression levels were compared with histopathological parameters and DNA ploidy, as well as with proliferative activity, measured by Ki‐67 mRNA expression. To the authors' knowledge, this is the first study to investigate the expression levels of mitotic checkpoint genes together with DNA ploidy in gastric cancer. BUB1 was overexpressed in 84%, BUBR1 in 68%, and BUB3 in 79% of gastric cancers. This study also revealed that all three genes were simultaneously overexpressed in 61% of the tumours and that there was a statistically significant positive correlation between overexpression of BUB1, BUBR1 or BUB3 and Ki‐67 expression (p < 0.001). Eighty‐one per cent of the tumours were classified as aneuploid. However, no correlation was found between ploidy and BUB transcript expression levels. These results suggest that inactivation of the mitotic checkpoint genes BUB1, BUBR1, and BUB3 by epigenetic silencing does not seem to play a role in gastric carcinogenesis. The strong correlation of BUB expression level and tumour cell proliferation suggests that BUB overexpression is a proliferation‐dependent phenomenon in gastric cancer. However, overexpression due to lack of normal BUB protein function or due to a yet unknown additional BUB function has to be considered. Copyright © 2003 John Wiley & Sons, Ltd.
Concerted promoter hypermethylation of hMLH1, p16INK4A, and E‐cadherin in gastric carcinomas with microsatellite instability
Authors: Kim Hyunki , Kim Yun Hee , Kim Sung Eun , Kim Nam‐Gyun , Noh Sung Hoon , Kim Hoguen 
Published: April 2003

AbstractIn most sporadic gastric carcinomas, microsatellite instability (MSI) originates from inactivation of the hMLH1 gene by promoter hypermethylation. However, the methylation patterns of other genes and their consequences in high MSI (MSI‐H) gastric carcinomas are not well characterized. To address the aberrant promoter methylation profiles of MSI‐H gastric carcinomas, promoter methylation of six genes (hMLH1, p16INK4A, E‐cadherin, Rb, RASSF1A, and VHL) and CpG island methylator phenotype (CIMP) were explored in 36 MSI‐H gastric carcinomas and the results were compared with those of 43 microsatellite‐stable (MSS) gastric carcinomas. Frequent promoter hypermethylation was found in hMLH1, p16INK4A, and E‐cadherin and the frequency was significantly higher in MSI‐H gastric carcinomas. Promoter hypermethylation of hMLH1, E‐cadherin, and p16INK4A was found in 89%, 78%, and 33% of MSI‐H gastric carcinomas and in 16%, 32%, and 11% of MSS carcinomas, respectively (p = 0.01). Selective absent or decreased expression of the gene product related to the hypermethylated promoter was found for hMLH1 and p16INK4A in MSI‐H carcinoma, whereas the expression of E‐cadherin was generally decreased both in the MSI‐H and in the MSS carcinomas. MSI‐H gastric carcinomas were also related to the high CIMP (CIMP‐H, three or more of the five loci examined showing methylation). Twenty‐two (61%) MSI‐H gastric carcinomas were CIMP‐H, compared with only seven (16%) MSS carcinomas (p = 0.001). These findings indicate that hMLH1 is one of the frequent methylation targets in CIMP‐H gastric carcinomas and that inactivation of hMLH1 through promoter hypermethylation results in tumours following the MSI pathway. Copyright © 2003 John Wiley & Sons, Ltd.
The role of E‐cadherin in low‐grade ductal breast tumourigenesis
Authors: Roylance Rebecca , Droufakou Stavroula , Gorman Patricia , Gillett Cheryl , Hart Ian R , Hanby Andrew , Tomlinson Ian 
Published: April 2003

AbstractGrade I invasive ductal breast carcinomas have a specific pattern of genetic aberrations, namely gain of 1q and loss of 16q. This pattern is very similar to the changes seen in invasive lobular breast carcinomas (ILCs). The gene on 16q involved in ILC is known to be E‐cadherin (CDH1). This study has investigated whether the same gene is responsible for grade I invasive ductal carcinoma (IDC), using allele imbalance analysis, mutation screening, and immunohistochemistry (IHC). The data suggest that despite the shared pattern of genetic aberrations seen in grade I IDC and ILC, CDH1 is not the target gene in low‐grade ductal tumourigenesis. Copyright © 2003 John Wiley & Sons, Ltd.
Promoter methylation of TGFβ receptor I and mutation of TGFβ receptor II are frequent events in MSI sporadic gastric carcinomas
Authors: Pinto Mafalda , Oliveira Carla , Cirnes Luis , Carlos Machado José , Ramires Maria , Nogueira Ana , Carneiro Fátima , Seruca Raquel 
Published: April 2003

AbstractTransforming growth factor beta (TGFβ) is a potent inhibitor of cell growth, whose action is transduced through interaction between type I (RI) and type II (RII) receptors. Abnormal expression of these receptors has been identified in several human cancers and was found to be associated with resistance to TGFβ. TGFβ RII mutations occur in many types of malignancy. TGFβ RI hypermethylation has been suggested as a cause of abnormal or absent expression of this receptor in cancer. This study has analysed the methylation status of the promoter region of the TGFβ RI gene using a methylation‐sensitive enzyme followed by polymerase chain reaction (PCR), and TGFβ RII mutations (BAT‐RII and a GT3) in order to determine the frequency of alteration of the TGFβ receptors in a series of 40 sporadic gastric carcinomas (SGCs), 25 of which showed microsatellite instability (MSI) and 15 of which were microsatellite stable (MSS). Methylation in the promoter region of the TGFβ RI gene was detected in 20 of the 40 (50%) SGCs (64% of the MSI cases and 26.7% of the MSS); 17 of the 40 (42.5%) cases had mutations in the BAT‐RII region of the TGFβ RII gene (68% in the MSI cases; 0% in the MSS). In total, 25 of the 40 (62.5%) SGCs had alterations in at least one of the TGFβ receptors (84% of the cases in the MSI group, in contrast with 16% of the MSS cases) (p = 0.0003). The clinicopathological features of the cases were also studied and significant associations were found between the presence of alterations in TGFβ receptors and the age of the patients (p = 0.046), size (p = 0.011), and proliferative rate of the tumours (p = 0.048). In conclusion, alterations in the receptors of TGFβ (TGFβ RI promoter hypermethylation and TGFβ RII mutations) are frequent events in MSI SGC and are associated with large size and high proliferative activity of the tumours, in keeping with loss of the growth inhibitory effects of TGFβ in this setting. Copyright © 2003 John Wiley & Sons, Ltd.
Age‐related pseudocapillarization of the human liver
Authors: McLean Allan J , Cogger Victoria C , Chong Guan C , Warren Alessandra , Markus Astrid MA , Dahlstrom Jane E , Le Couteur David G 
Published: April 2003

AbstractAge‐related changes in liver function are important because they may promote susceptibility to adverse drug reactions, neurotoxicity, atherosclerosis, and other important diseases in older people. Age‐related changes in the rat hepatic sinusoidal endothelium, termed pseudocapillarization, have been described recently and these may contribute to hepatic impairment. The present study has examined surgical and post‐mortem specimens with immunohistochemistry and transmission electron microscopy to determine whether pseudocapillarization also occurs in older humans. The age of the subject, independent of systemic disease or hepatic pathology in surgical and post‐mortem samples of human liver, was associated with increased peri‐sinusoidal expression of von Willebrand's factor, collagen I, collagen IV, and staining with Masson's trichrome. Electron microscopy revealed significant age‐related thickening of the sinusoidal endothelium (young 165 ± 17 nm, middle age 222 ± 11 nm, older 289 ± 9 nm, p < 0.001) with loss of fenestrations (young 7.7 ± 0.7 per 10 µm, middle age 3.6 ± 0.5 per 10 µm, older 1.5 ± 0.4 per 10 µm, p < 0.001), and age‐related deposition of basal lamina and collagen. In conclusion, ageing in humans is associated with morphological changes in the sinusoidal endothelium and space of Disse which are presumptively related to the ageing process and potentially represent an important link between the ageing process and disease susceptibility. Copyright © 2003 John Wiley & Sons, Ltd.
ALK‐negative systemic anaplastic large cell lymphoma: differential diagnostic and prognostic aspects–a review
Authors: ten Berge Rosita L , Oudejans Joost J , Ossenkoppele Gert J , Meijer Chris JLM 
Published: April 2003

AbstractAnaplastic large cell lymphoma (ALCL) can be divided into two major groups. The first is a spectrum of CD30+ T‐cell lymphoproliferative disorders including primary cutaneous ALCL and lymphomatoid papulosis, usually affecting older patients but characterized by an excellent prognosis. The second is systemic nodal ALCL, which on the basis of genetic and immunophenotypic features combined with clinical parameters can be divided into two subgroups: anaplastic lymphoma kinase (ALK)‐positive and ALK‐negative systemic ALCL. ALK expression, usually the result of a t(2;5) translocation, correlates with the expression of other markers such as EMA and a cytotoxic phenotype, and is strongly related to younger age groups, lower international prognostic index (IPI) risk groups, and a good prognosis. ALK‐negative ALCL, however, shows a more heterogeneous immunophenotype and clinical behaviour, and prognostic parameters are needed to determine treatment strategies in individual patients. Besides clinical parameters included in the IPI, recent studies have pointed out several biological prognosticators of potential value, such as the percentage of tumour‐infiltrating activated cytotoxic T‐lymphocytes. The expression of proteins involved in the execution or regulation of apoptosis, such as activated caspase 3, Bcl‐2, and PI9, was also found to be strongly related to clinical outcome. These studies indicate that inhibition of the apoptosis cascade in particular is an important mechanism that can explain the poor clinical outcome in therapy refractory ALCL. Functional studies are required to investigate whether disruption of one or more of the apoptosis pathways is the major factor in the fatal outcome of the disease and whether apoptosis resistance based on inhibition of one pathway can be overcome by activating another pathway that is still intact. Copyright © 2003 John Wiley & Sons, Ltd.