bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mechanisms of inactivation of the p16INK4a gene in leiomyosarcoma of soft tissue: decreased p16 expression correlates with promoter methylation and poor prognosis
Authors: Kawaguchi Ken‐ichi , Oda Yoshinao , Saito Tsuyoshi , Yamamoto Hidetaka , Tamiya Sadafumi , Takahira Tomonari , Miyajima Kimitaka , Iwamoto Yukihide , Tsuneyoshi Masazumi 
Published: October 2003

AbstractThe p16INK4a tumour suppressor gene, encoding p16 protein, plays a crucial role in regulation of the G1 cell‐cycle phase. To investigate the potential role of p16 in soft tissue leiomyosarcoma (LMS), an immunohistochemical analysis was performed of 77 LMSs for p16 expression. Decreased expression of the p16 protein was identified in 25 of 77 LMSs (32%). Decreased expression of p16 correlated significantly with large tumour size (p = 0.0038). In a univariate analysis, large tumour size and decreased expression of p16 were statistically significant adverse prognostic factors (p = 0.025 and p = 0.0021, respectively). In a multivariate analysis including conventional clinicopathological parameters, decreased expression of p16 protein was revealed as the only independent unfavourable prognostic factor (p = 0.012). To elucidate the mechanisms of inactivation of the p16INK4a gene, 49 LMSs for which genomic DNA was available were examined; analysis for homozygous deletion, mutation, and promoter hypermethylation was conducted using differential PCR, PCR–SSCP, and methylation‐specific PCR, respectively. Promoter hypermethylation was detected in 11 of 49 LMS cases (22%); homozygous deletion was detected in 3 of 49 cases (6%); and mutation was not recognized in any of the cases studied. Eight of 15 cases (53%) with decreased expression of p16 protein revealed methylation of the p16INK4a gene promoter. Promoter hypermethylation correlated closely with decreased expression and poor prognosis (p = 0.0014 and p = 0.0088, respectively). These results suggest that decreased expression of p16 protein can be considered as an independent reliable prognostic parameter in patients with soft tissue LMS. Furthermore, promoter methylation was more frequent than either homozygous deletion or mutation in this tumour, and promoter methylation was also shown to have a strong association with inactivation of the p16INK4a gene. Copyright © 2003 John Wiley & Sons, Ltd.
NF‐κB expression in oral and cutaneous lichen planus
Authors: Santoro Amerigo , Majorana Alessandra , Bardellini Elena , Festa Silvana , Sapelli Pierluigi , Facchetti Fabio 
Published: October 2003

AbstractLichen planus (LP) is a chronic inflammatory disorder involving cutaneous and mucosal surfaces, characterized by a T‐cell‐mediated immune response against epithelial cells, with persistent accumulation of T lymphocytes and epithelial cell damage. The mechanisms involved in this chronic inflammatory disease are largely unknown. A pivotal role in the pathogenesis of long‐lasting inflammatory processes is played by the activation of nuclear factor kappa B (NF‐κB), a primary transcription factor which upon translocation to the nucleus, binds to promoter regions of different genes encoding immune and pro‐inflammatory mediators. Using immunohistochemistry, the present study analysed the expression of NF‐κB in 25 cases of cutaneous LP (CLP) and 28 cases of oral LP (OLP) and correlated this with the recruitment of cytotoxic T‐cells (expressing Tia‐1 or perforin) in the inflammatory infiltrate. Nuclear NF‐κB was expressed on basal and suprabasal keratinocytes in all cases of LP, while normal epithelium was consistently negative; OLP contained significantly higher numbers of NF‐κB‐positive keratinocytes than CLP (means: 89.32 versus 22.6; p < 0.05). Furthermore, nuclear NF‐κB expression by epithelial cells correlated with the amount of cytotoxic cell infiltration (p < 0.02). These data suggest that increased NF‐κB activity may represent the basis of maintenance of the inflammatory response. The differences observed between NF‐κB expression on epithelial cells in OLP and CLP and their correlation with the degree of cytotoxic inflammatory infiltrate might explain the different clinical courses of the two variants of the disease, since OLP is typically more recalcitrant than CLP. As proposed for other chronic inflammatory disorders associated with increased NF‐κB activity, the involvement of NF‐κB in the pathogenesis of LP could be considered for selective therapeutic inhibitory targeting. Copyright © 2003 John Wiley & Sons, Ltd.
Expression of the thioredoxin system in interstitial lung disease
Authors: Tiitto Leena , Kaarteenaho‐Wiik Riitta , Sormunen Raija , Holmgren Arne , Pääkkö Paavo , Soini Ylermi , Kinnula Vuokko L 
Published: October 2003

AbstractThe thioredoxin system containing thioredoxin (Trx) and thioredoxin reductase (TrxR) has profound effects on cell proliferation and protection against exogenous oxidants. The significance of the Trx system in human lung and lung diseases is, however, largely unresolved. Altogether, 66 specimens of human lung were investigated by immunohistochemistry for their expression of Trx and TrxR. The diseases included interstitial pneumonias such as usual interstitial pneumonia (UIP), desquamative interstitial pneumonia (DIP), and UIP associated with collagen vascular diseases (CVD‐ILD), and granulomatous diseases such as sarcoidosis and allergic alveolitis. The ultrastructural localization of Trx and TrxR was analysed by immunoelectron microscopy. In healthy lung, Trx and TrxR were expressed in bronchial epithelium and alveolar macrophages. Trx and TrxR were highly concentrated in areas of metaplastic epithelium in UIP and in alveolar macrophages in DIP, though fibrotic areas in UIP were mainly negative. The expression of both enzymes was clearly weaker in CVD‐ILD than in UIP. Granulomas of sarcoidosis showed moderate to intense Trx immunoreactivity. Ultrastructurally, Trx and TrxR were expressed diffusely in the cytosolic compartment and plasma membrane of metaplastic type II pneumocytes, macrophages, and bronchial epithelial cells. This study highlights the importance of Trx and TrxR in primary defence in bronchial epithelium, alveolar epithelium, and macrophages in human lung, but also indicates that elevated expression of these proteins may serve as markers of ongoing cell regeneration and inflammation. Copyright © 2003 John Wiley & Sons, Ltd.
Tissue‐specific p53 responses to ionizing radiation and their genetic modification: the key to tissue‐specific tumour susceptibility?
Authors: Coates Philip J , Lorimore Sally A , Lindsay Kirsten J , Wright Eric G 
Published: October 2003

AbstractAlthough little is understood of the underlying mechanisms, there are tissue‐specific responses to tumourigenic and therapeutic agents and these responses are influenced by genetic factors. Ionizing radiation is an important tumourigenic and therapeutic agent for which there is substantial evidence for such tissue‐dependent and genotype‐dependent responses. Because the p53 tumour suppressor protein is a major determinant of cellular responses to radiation, the present study has investigated whether modification of the p53 pathway contributes to tissue‐dependent and genotype‐dependent responses using inbred strains of mice. Comparison of responses in haemopoietic and epithelial cells in irradiated C57BL/6 and DBA/2 mice revealed significant differences in p53 and apoptotic responses in different cell types and in different cells of the same type, reflecting the complexity of damage responses operating in the whole organism. The data suggest that p53‐mediated up‐regulation of Bax is a major determinant of apoptosis in the spleen, but not in the intestine, whereas p53‐mediated induction of p21waf1 plays an anti‐apoptotic role in the spleen, but not in the intestine. It is also shown that p53 stabilization and differential transactivational activities towards Bax or p21waf1 are influenced by genetic factors that act in a tissue‐specific manner. Analysis of ATM, a potential mediator of differential p53 activation, indicates that this key regulator of radiation responses is preferentially induced in epithelial cells, but is unlikely to account for genetic modification of p53 or apoptotic responses in the mouse strains studied. Polymorphisms in the p53 or DNA‐PKcs genes are also unlikely to account for the genetic modifications that are reported here. There are numerous further potential modifiers of the p53 pathway, but analysis of backcross and inter‐cross mice demonstrates that genes responsible for the complex modification of these in vivo responses can be identified by linkage analysis. This approach has the potential to reveal new or unexpected interactions involving the p53 pathway that determine both short‐term and long‐term effects of radiation exposure and the basis of tissue‐specific responses and tumour susceptibility. Copyright © 2003 John Wiley & Sons, Ltd.
Alterations of chromosomal copy number during progression of diffuse‐type gastric carcinomas: metaphase‐ and array‐based comparative genomic hybridization analyses of multiple samples from individual tumours
Authors: Peng Dun‐Fa , Sugihara Hiroyuki , Mukaisho Ken‐ichi , Tsubosa Yasuhiro , Hattori Takanori 
Published: October 2003

AbstractThe application of comparative genomic hybridization (CGH) has led to the rapid accumulation of cytogenetic information on gastric carcinoma (GC), but there is little information on the time sequence of cytogenetic changes. In the present study, degenerate oligonucleotide‐primed polymerase chain reaction (DOP‐PCR) and CGH were applied to multiple samples microdissected from 19 diffuse‐type GCs including eight early cancers. Recurrent gains were detected at 8q, 3q, 7q, and 8p, and loss at 17p (in more than 50% of the cancers), the frequencies of which were fairly similar between the samples with (SIG) and those without (POR) abundant signet ring cells. Earlier stemline changes (8q+, 8p+, 1q+, 17p−, etc), with breakpoints that were common to all the samples, were discriminated from later sideline changes (2q+, 11q+, 17q−, 21q−, etc) in individual tumours. The changes were generally common to early and advanced cancers, except for 7p+, 15q+, 3p−, and 18q−, which were largely sideline changes and more frequently detected in advanced cancers (p < 0.05). Because the samples with 7p+ had a greater number of copy‐number changes than those without 7p+ (p < 0.01), 7p+ may play a role in tumour progression by acceleration of chromosomal instability. Fifteen different chromosomal loci with amplification were detected in ten cases, mostly as sideline changes in advanced cancers. By microarray‐based CGH, KRAS, MDM2, and FGFR2 were confirmed in the amplicons at 12p, 12q, and 10q, and FES at 15q26, for the first time in GC. These results support the notion that SIG and POR are of a genetically single lineage in both early and advanced diffuse‐type GC and that the majority of advanced cancers derive from early cancers through the accumulation of various sideline changes in addition to stemline changes. Copyright © 2003 John Wiley & Sons, Ltd.
Is high‐grade adenomatous hyperplasia an early bronchioloalveolar adenocarcinoma?
Authors: Ullmann R , Bongiovanni M , Halbwedl I , Fraire AE , Cagle PT , Mori M , Papotti M , Popper Helmut H 
Published: October 2003

AbstractAtypical adenomatous hyperplasia (AAH) is a probable forerunner of bronchioloalveolar carcinoma (BAC) and pulmonary adenocarcinoma (AC) of mixed type. The present study analysed four low‐grade AAHs, 13 high‐grade AAHs, two BACs, nine mixed ACs, and one squamous cell carcinoma derived from 13 patients using comparative genomic hybridization. The average number of chromosomal aberrations was 1.2 in low‐grade AAH, 9.6 in high‐grade AAH, and 12.5 in AC. A high degree of overlap of genetic changes was found in high‐grade AAH, BAC, and AC within individual patients. The high number of aberrations and the degree of shared aberrations found in high‐grade AAH and AC raises questions about the separation of these two entities. In addition, in view of the monoclonal origin of multiple foci within the same patient, AAH may not be a precursor of AC in some cases, but rather may represent intraepithelial spread. Copyright © 2003 John Wiley & Sons, Ltd.
Apoptotic gene expression in Paget's disease: a possible role for Bcl‐2
Authors: Brandwood Craig P , Hoyland Judith A , Hillarby M Chantal , Berry Jacqueline L , Davies Michael , Selby Peter L , Mee Andrew P 
Published: October 2003

AbstractPaget's disease of bone is characterized by an increase in both the size and the number of bone‐resorbing osteoclasts. An important regulator of osteoclast activity is the process of apoptosis, and any aberration in this process could lead to increased osteoclasis. Analysis using human apoptosis cDNA expression arrays revealed that the apoptotic suppressor, Bcl‐2, showed a marked increase in expression in Pagetic bone. In situ hybridization (ISH) and computer‐assisted image analysis confirmed that the levels of Bcl‐2 transcripts were significantly (p < 0.0001) increased in Pagetic osteoclasts. The Bcl‐2 : Bax transcript ratios were similarly elevated. These findings were confirmed by immunohistochemistry. The Bcl‐2 gene promoter sequence from 20 Pagetic patients and controls was analysed. Single nucleotide mutations were identified in three of the Paget's patients and one of the controls. Luciferase reporter analysis showed that the mutations induced a basal 12‐fold increase and hydrogen peroxide‐induced 19‐fold increase in luciferase expression, compared with the normal construct. It is concluded that in Paget's disease, there is an increase in the expression of genes that are involved in the inhibition of apoptosis, notably Bcl‐2. The increase in Bcl‐2 may be explained in some patients by mutations in the Bcl‐2 gene promoter. These results provide a potential explanation for the dramatic increase in osteoclasis seen in patients with Paget's disease. Copyright © 2003 John Wiley & Sons, Ltd.
Expression of p27kip1 in breast cancer and its prognostic significance
Authors: Barnes A , Pinder SE , Bell JA , Paish EC , Wencyk PM , Robertson JFR , Elston CW , Ellis IO 
Published: October 2003

Abstractp27kip1 is a member of the KIP/CIP family of cyclin‐dependent kinase inhibitors and is a negative cell‐cycle regulator that is thought to play a role in tumour suppression. Reduced levels of this protein have been observed in a number of human cancers. However, evidence is conflicting as to whether p27kip1 has a role to play in breast cancer, including predicting behaviour and prognosis. The present investigation aimed to provide a definitive study of 830 breast cancer cases with median patient follow‐up of 104 months to determine the true prognostic significance, if any. Immunohistochemical analysis of tissue microarrays and three scoring methods were used to assess p27kip1 expression. Univariate analysis showed a significant relationship between reduced p27kip1 expression and increasing tumour grade, nuclear pleomorphism, mitosis, and decreasing tubule formation (allp< 0.001). Significant associations between reduced p27, negative oestrogen receptor status, and ductal/no special type tumours were also observed. Survival analysis demonstrated that patients with tumours with high p27kip1 levels had an improved survival compared with those with cancers with low expression. On multivariate analysis, when compared with existing factors, p27kip1 was not, however, an independent prognostic factor. It is concluded that the inverse relationship between p27kip1 levels and histological grade and individual grade components suggests a role for p27kip1 in both cell proliferation and differentiation, but is not clinically useful. Copyright © 2003 John Wiley & Sons, Ltd.
Gastric cancer: the role of insulin‐like growth factor 2 (IGF 2) and its receptors (IGF 1R and M6‐P/IGF 2R)
Authors: Pavelić Krešimir , Kolak Toni , Kapitanović Sanja , Radošević Senka , Spaventi Šime , Krušlin Božo , Pavelić Jasminka 
Published: October 2003

AbstractInsulin‐like growth factor 2 (IGF 2) appears to be involved in the progression of many tumours. It binds to at least two different types of receptor: IGF type 1 (IGF 1R) and mannose 6‐phosphate/IGF type 2 (M6‐P/IGF 2R). Ligand binding to IGF 1R provokes mitogenic and anti‐apoptotic effects. M6‐P/IGF 2R has a tumour suppressor function—it mediates IGF 2 degradation. Mutation of M6‐P/IGF 2R causes both diminished growth suppression and augmented growth stimulation. The aim of this study was to investigate the role of IGF 2 and its receptors (IGF 1R and IGF 2R) in human gastric cancer. The expression of IGF 2 and its receptors was measured in order to analyse the possible correlation between the activity of these genes and cell proliferation in two different gastric tumour types: diffuse and intestinal. The effect of IGF 1 receptor blockage on cell proliferation and anchorage‐independent cell growth was also examined. Increased expression of IGF 2 and IGF 1R genes (at the mRNA and protein level) was found in gastric cancer when compared with non‐tumour tissue. Furthermore, there was a significant difference between IGF 2 expression in the more aggressive diffuse type and that in the intestinal type of gastric cancer. Moreover, the IGF 2 peptide level in the culture media obtained from the diffuse type of cancer cells was significantly higher when compared with the intestinal type. The level of IGF 2 peptide in the conditioned media strongly correlated with [3H]thymidine incorporation and cell proliferation. On the contrary, IGF 2R mRNA expression was much higher in the intestinal type of cancer than in the diffuse type. In addition, IGF 2R protein expression was substantially lower with progression of the diffuse cancer type to a higher stage. The αIR3 monoclonal antibody strongly inhibited [3H]thymidine incorporation and decreased the number of colonies in soft agar of cells overexpressing IGF 2. These findings suggest that members of the IGF family are involved in the pathogenesis of gastric cancer, probably by autocrine/paracrine stimulation of cell growth. Such tumours might be excellent candidates for therapeutic strategies aimed at interference with this pathway. Copyright © 2003 John Wiley & Sons, Ltd.
Chromosomal imbalances: a hallmark of tumour relapse in primary cutaneous CD30+ T‐cell lymphoma
Authors: Prochazkova Martina , Chevret Edith , Beylot‐Barry Marie , Sobotka Jiri , Vergier Béatrice , Delaunay Michèle , Turmo Michèle , Ferrer Jacky , Kuglik Petr , Merlio Jean‐Philippe 
Published: October 2003

AbstractPrimary cutaneous CD30+ large T‐cell lymphoma (CD30+ CTCL) is a subset of non‐epidermotropic primary cutaneous T‐cell lymphoma. Although frequent spontaneous regression may be observed, skin relapses occur frequently. Cytogenetic abnormalities that could play a role in CD30+ CTCL tumour pathogenesis and relapses remain unknown. The identification of recurrent cytogenetic abnormalities is hampered by difficulty in culturing tumours and the lack of CD30+ CTCL serial studies comparing genetic changes both at diagnosis and at relapse. The purpose of this study was to investigate the cytogenetic abnormalities present in a series of 13 CD30+ CTCL samples obtained from nine patients fulfilling both EORTC and WHO diagnostic criteria, by the use of comparative genomic hybridization (CGH). CGH analysis revealed a non‐random distribution of genetic imbalances between relapsing and non‐relapsing disease. In relapsing disease, chromosomal abnormalities were detected both in the primary tumour and in relapses. The mean number of changes in non‐relapsing disease was 0.33 (range 0–1), compared with 6.29 (range 1–16) in relapsing disease. The recurrent chromosomes involved in relapsing disease were chromosomes 6 (86%), 9 (86%), and 18 (43%). While chromosome 9 was mostly affected by gain, chromosomes 6 and 18 mainly contained regions of loss, exclusively on 6q and 18p. The common regions of deletion were 6q21 and 18p11.3. In one patient, we successfully cultured tumour cells from a skin biopsy from a second relapse. The G‐banded karyotype was concordant with both CGH and fluorescence in situ hybridization (FISH) results. Although further studies are required to strengthen these data, this CGH analysis demonstrates chromosomal imbalances that may be involved in the pathogenesis of relapsing CD30+ CTCL. Copyright © 2003 John Wiley & Sons, Ltd.
Loss of parental‐specific methylation at the IGF2 locus in human hepatocellular carcinoma
Authors: Poirier Karine , Chalas Céline , Tissier Frédérique , Couvert Philippe , Mallet Vincent , Carrié Alain , Marchio Agnès , Sarli Dario , Gicquel Christine , Chaussade Stanislas , Beljord Cherif , Chelly Jamel , Kerjean Antoine , Terris Benoit 
Published: October 2003

AbstractSignificant production of the growth factor IGF2 has been reported in human hepatocellular carcinomas (HCCs). Disturbances associated with changes in methylation at this locus or affecting the 11p15.5 imprinting domain as a whole can be postulated in HCCs. In the present study, the methylation status of differentially methylated regions of the imprinted genes TSSC5, LIT1, and IGF2, which span the 11p15 domain, was analysed in 71 liver tissues from virus‐associated and non‐virus‐associated HCCs compared with six normal liver tissues. Altered methylation of TSSC5 and LIT1 was observed in only 6% and 8% of HCCs, respectively, compared with 89% at the IGF2 locus, suggesting that these loci were not concomitantly dysregulated. These observations suggest that loss of parental‐specific methylation at the IGF2 locus may be specifically associated with HCC, whether virus‐associated or non‐virus‐associated, and arising in cirrhotic or non‐cirrhotic livers. Copyright © 2003 John Wiley & Sons, Ltd.
Stellenwert der CSE‐Hemmer: Prophylaxe und Therapie der KHK
Authors: Kostner Karam 
Published: October 2003

AbstractMan kann festhalten, dass es keinen Zweifel am klinischen Benefit einer LDL‐C‐Senkung mittels Statinen geben kann. Die im letzten Jahr veröffentlichten ATP‐III‐Richtlinien stellen eine gute und praxisnahe Hilfestellung für die Therapieentscheidung dar. Die Entscheidung ist aber immer individuell zu treffen und obliegt letztendlich der klinischen Beurteilung des behandelnden Arztes. Die wichtige Frage, ob eine noch aggressivere LDL‐C‐Senkung zu niedrigeren Zielwerten (unter 80 mg/dL) einen zusätzlichen Nutzen bringt, ist noch nicht beantwortet. Wenn ein solcher Zusatznutzen besteht, so muss er jedenfalls gegen das möglicherweise erhöhte Nebenwirkungs‐Risiko einer besonders aggressiven, hochdosierten Statintherapie abgewogen werden. Es ist zu erwarten, dass die Ergebnisse laufender randomisierter Doppelblind‐Studien zur Klärung dieser Frage wesentlich beitragen werden. Die Ergebnisse der HPS‐Studie legen den Schluss nahe, dass bei Hochrisikopatienten eine LDL‐Senkung im Ausmaß von 30 bis 40 % in jedem Fall erfolgen sollte, auch wenn ein niedriger Ausgangswert des LDL‐C vorliegt. Zusammenfassend kann gesagt werden, dass Statine eine sehr wichtige Rolle in der Primär‐ und Sekundärprävention der Koronaren Herzkrankheit spielen und daher gewissermaßen das Penicillin der Atherosklerosetherapie darstellen.
Riboflavin als Sonnenschutz
Authors: Gießen Hannelore 
Published: October 2003

AbstractVitamine werden in großer Menge gebraucht. Nicht nur in der Humanmedizin für Arzneimittel, Vitaminsupplemente und Nahrungsergänzungsmittel, sondern auch für die Futtermittelindustrie. Eines der B‐Vitamine, das Riboflavin, wird inzwischen auf einem interessanten Weg von Mikroorganismen hergestellt.