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  • Electronic Resource  (194)
  • 2000-2004  (194)
  • 1800-1809
  • apoptosis  (117)
  • Prognosis  (77)
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  • Electronic Resource  (194)
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  • 1
    Electronic Resource
    Electronic Resource
    Springer
    Virchows Archiv 436 (2000), S. 102-108 
    ISSN: 1432-2307
    Keywords: Key words Oral ; Squamous cell carcinoma ; Proliferation ; Apoptosis ; Tumour suppressor gene ; Oncogene ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tumour progression is characterised by an imbalance between cell proliferation and apoptosis. The aim of our study was to estimate the importance of proliferation and apoptosis associated parameters in primary squamous cell carcinomas (SCCs) of the oral cavity and oropharynx. For determination of apoptosis, the enzymatic labelling of DNA fragmentation with a terminal transferase reaction was used in 156 tissue samples of 107 patients, including corresponding lymph-node metastases in nine cases. P53, bcl-2, and Ki-67 were determined immunohistologically. P53 was detectable in 50.5% of the cases. Positive staining was associated significantly with decreased apoptosis (P〈0.003). Bcl-2 was upregulated in 31.8% of the cases depending on the tumour grading (P〈0.001) and correlated negatively with apoptosis (P〈0.001). Proliferation (P〈0.006) and apoptosis (P〈0.03) were enhanced in larger tumours, though a direct correlation between these two parameters was not proven. Nevertheless, in contrast to the conventional tumour staging and grading, neither the expression of p53 or bcl-2 nor the apoptosis or Ki-67 measurements were able to predict survival or recurrence-free survival of the patients suffering from a SCC in the oral cavity or oropharynx. Our observations suggest that the function of wild-type p53 to induce apoptosis is lost in at least half of the SCCs under study and that the physiological function of bcl-2 as potent inhibitor of apoptosis is widely preserved in oral SCC.
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  • 2
    ISSN: 1432-2307
    Keywords: Key words CD44 ; Adhesion molecules ; Prognosis ; Soft tissue sarcoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Recent studies have shown that expression of alternatively splicing variants of CD44 is correlated with prognosis for several kinds of malignant tumors. However, little is known about the expression of CD44 standard and variant isoforms in soft tissue sarcomas. In this study 47 cases of soft tissue sarcoma [18 malignant fibrous histiocytomas (MFHs), 13 synovial sarcomas (SSs), 7 malignant schwannomas (MSs), and 9 liposarcomas (LSs)] were examined immunohistochemically. The monoclonal antibodies to the standard form of CD44 (CD44H) and variant exons of CD44v3, 4, 5, 6, 7, 9, and v10 were used. We analyzed the membranous expression pattern of CD44H and CD44 variant exons and assessed the relation between expression of CD44s and metastasis-free survival rates (MFSR) of patients with soft tissue sarcoma. A few sarcomas expressed CD44v3 (2/47) and v7 (2/47), but none of the sarcomas expressed CD44v10. CD44v4 (5/47), v5 (4/47), v6 (10/47), and v9 (9/47) are relatively common types of variant isoforms in soft tissue sarcomas. Expression of CD44v6 is more frequently detected in high-grade than in low-grade tumors. CD44v6 or CD44v9 expression was correlated with metastasis-free survival of patients with soft tissue sarcomas.
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  • 3
    ISSN: 1432-2307
    Keywords: Keywords AgNORs ; Standardised AgNOR analysis ; Parathyroid tumour ; Proliferation ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Prediction of evolution of secondary hyperplasia and tumours of the parathyroid glands is still a problem in histopathology. To assess whether the quantity of silver-stained nucleolar organiser region (AgNOR) proteins might be used as a prognostic tool in parathyroid pathology, a standardised AgNOR analysis has been performed on 19 cases of parathyroid hyperplasia caused by secondary hyperparathyroidism (PH), 8 cases of adenoma (PA) and 10 cases of carcinoma (PC). Clinico-pathological data and follow-up information were available. On formalin-fixed and paraffin-embedded sections, the visualisation and quantification of AgNORs were achieved according to the 1995 guidelines of the Committee on AgNOR Quantification. Then, the mean area (square micrometres) of AgNORs per nucleus (NORA) was evaluated by means of an image analyser and specific softwares. After testing the normal distribution of NORA values, statistical parametric tests were utilised; Kaplan-Meier and Cox multivariate analyses were also performed. In parathyroid lesions, a progressive increase of mean NORA values was observed from PH (2.895 µm2; SE 0.171) through PA (3.638 µm2; SE 0.125) to PC (4.701 µm2; SE 0.179); these differences were highly significant (P〈0.001), although some degree of overlap was found among single NORA values. A significantly higher mean NORA value was revealed in PC with distant metastases than was noted in cases with no current clinical evidence of disease progression. Furthermore, a significantly (P〈0.001) higher mean NORA value was encountered in the group of PH with recurrences (3.600 µm2; SE 0.106) than in nonrecurrent PH (2.261 µm2; SE 0.087). Multivariate analyses indicated that the NORA value was an independent prognostic parameter determining the risk of recurrence in PH. We suggest that AgNOR quantity may be a promising additional tool for predicting the biological behaviour of parathyroid lesions.
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  • 4
    ISSN: 1432-1963
    Keywords: Schlüsselwörter Apoptose ; Proliferation ; Hämatopoetischer Zellumsatz ; Topoisomerase II α ; PCNA ; Chronische myeloproliferative Erkrankungen ; Prognose ; Reaktive Läsionen ; Key words Apoptosis ; Proliferation ; Hematopoietic turnover index ; Topoisomerase II α ; PCNA ; Chronic myeloproliferative disorders ; Prognosis ; Reactive lesions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Apoptosis and proliferation are important regulators of normal development and homeostasis in the bone marrow. Therefore, dynamics of hematopoiesis is mainly defined by these two parameters. However, since only few data are available from previous studies, we performed a retrospective analysis to elucidate some aspects of this complex pathomechanism. A total of 400 patients with chronic myeloproliferative disorders (CMPDs) and corresponding reactive bone marrow lesions were enrolled into this study. Apoptosis was detected in bone marrow tissue by the ISEL-technique and topoisomerase II α expression was demonstrated by the monoclonal antibody Ki-S1. Furthermore, by determination of the proliferating-cell nuclear antigen labeling (PCNA) index, we were able to calculate the proportion of cells in the G2/M phase, because both nuclear antigens are expressed in different phases of the cell cycle. Patients with IMF, PV, and ET revealed a normal range of apoptosis, whereas in chronic myeloid leukemia (CML) a significant increase could be observed. On the other hand, IMF and PV were characterized by a raised proliferative activity. Dynamics of hematopoiesis was assessed by calculation of the so called hematopoietic turnover index. In CML and reactive lesions no alterations of this parameter were detectable, but IMF and PV showed a significant increase. Survival analysis disclosed a relevant worsening of life expectancy for patients with reduced apoptosis and proliferation. In conclusion, our in-situ results confirm and extend previous experimental data on hematopoietic cell kinetics. In this context, a greater regenerative capacity of hematopoiesis may be reflected by an increased rate of apoptosis and/or proliferation and therefore is associated with a more favorable outcome.
    Notes: Zusammenfassung Apoptose und Proliferation stellen im Rahmen einer funktionsgerechten Regelung der Hämatopoese einen integralen Bestandteil für die Aufrechterhaltung des zellulären Gleichgewichts im Knochenmark dar. Insofern ist die Dynamik des hämatopoetischen Zellumsatzes durch diese beiden Parameter gekennzeichnet. Da weiterführende Untersuchungen in dieser Hinsicht lediglich vereinzelt am Knochenmark durchgeführt worden sind, haben wir im Rahmen einer retrospektiven Analyse versucht, einige Aspekte dieses komplexen Mechanismus zu beleuchten. Insgesamt wurden 400 Patienten mit chronischen myeloproliferativen Erkrankungen (CMPE) sowie korrespondierenden reaktiven Veränderungen in die Untersuchung aufgenommen. Neben dem direkten Nachweis der Apoptose im Knochenmark durch die ISEL-Technik haben wir die Topoisomerase II α Expression mittels des monoklonalen Antikörpers Ki-S1 gemessen. Zusätzlich konnten wir durch die Bestimmung der PCNA-Markierung aufgrund der Zellzyklus-spezifischen Färbereaktion beider nukleärer Antigene den Anteil der in G2-/M-Phase befindlichen Zellen ermitteln. Während die IMF, die PV sowie die ET eine im Normbereich liegende Apoptoserate erkennen ließen, war dieser Wert bei der CML signifikant erhöht. Auf der anderen Seite wiesen IMF und PV eine deutlich gesteigerte proliferative Aktivität im Knochenmark auf. Bei der Berechnung eines hämatopoetischen Zellumsatz Index (HZI) zeigten diese beiden CMPE-Subtypen einen signifikanten Anstieg, wohingegen bei der CML sowie den reaktiven Läsionen keine relevante Verschiebung dieses Parameters festzustellen war. Im Rahmen prognostischer Analysen hatten IMF und PV Patienten mit reduzierter Proliferation und Apoptoserate jeweils eine signifikant kürzere Überlebenszeit. Unsere in-situ Ergebnisse erweitern und bestätigen vorausgegangene experimentelle Studien zur hämatopoetischen Zellkinetik. Darüber hinaus lassen sich aus unseren Daten prognostische Überlegungen ableiten, da insbesondere bei der PV und IMF Apoptose und Proliferation signifikanten Einfluß auf das Überleben der Patienten hatten. In diesem Zusammenhang spiegelt eine vermehrte Apoptose- und Proliferationsrate im Knochenmark offenbar eine größere regenerative Kapazität der Hämatopoese wieder und könnte daher für einen günstigeren Verlauf verantwortlich gemacht werden.
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Springer
    Der Pathologe 21 (2000), S. 456-459 
    ISSN: 1432-1963
    Keywords: Schlüsselwörter Undifferenziertes kleinzelliges Hepatoblastom ; Immunhistochemie ; Keywords Undifferentiated small-cell hepatoblastoma ; Immunohistochemistry ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract Undifferentiated small-cell hepatoblastoma (HB) is a rare malignant tumor of childhood. The cell of origin is supposed to be a pluripotential, probably entodermal, stem-cell. Differential diagnosis of this type of HB is difficult among the group of small round and blue cell malignant tumors of children. The immunohistochemically determined coexpression of cytokeratin 8, 18, and 19 and of vimentin and actin, regularly in the absence of α-fetoprotein expression may be diagnostically helpful. We present the case of an undifferentiated small-cell HB of a 15-month-old girl with agenesis of the right kidney. As morphological peculiarity the tumor presented disseminated histiocytic giant cells.
    Notes: Zusammenfassung Undifferenzierte kleinzellige Hepatoblastome (HB) zählen zu den seltenen malignen Tumoren der Leber im Kindesalter. Da der Tumor in der Regel kein α-Fetoprotein exprimiert, ist der Nachweis von Zytokeratin 8, 18 und 19 sowie Vimentin und Aktin diagnostisch wegweisend. Als Ausgangszelle wird eine pluripotente, wohl entodermale Stammzelle vermutet. In der Gruppe der klein-, rund- und blauzelligen malignen Tumoren des Kindesalters bietet diese Variante des HB differenzialdiagnostische Schwierigkeiten. Wir berichten über ein undifferenziertes kleinzelliges HB eines 15 Monate alten weiblichen Kleinkindes mit Agenesie der rechten Niere. Als morphologische Besonderheit des Tumors werden disseminierte histiozytäre Riesenzellen beschrieben.
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  • 6
    ISSN: 1432-1963
    Keywords: Schlüsselwörter Gastrointestinaltrakt ; Karzinoid ; Neuroendokrine Tumoren ; DNA-Zytophotometrie ; Prognose ; Key words Gastrointestinal tract ; Carcinoid ; Neuroendocrine tumors ; DNA cytophotometry ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary A total of 123 manifestations (97 primary tumours and 26 metastases) of neuroendocrine tumours of the gastrointestinal tract observed in 95 patients was investigated for the prognostic value of clinical, histological and DNA cytophotometric parameters. Metastases almost exclusively occurred among ileal carcinoids, which also were responsible for all 14 cases of lethal outcome observed during the follow-up period of mean 42 months. Aneuploid DNA values could be determined significantly more frequently among ileal than in non-ileal carcinoids and showed – upon analysis of the total group of gastrointestinal neuroendocrine tumours – a significant correlation to lethal course of disease. In addition, among 18 cases with primary and secondary carcinoid manifestations available for DNA cytophotometry, an association between the DNA content of metastatic neuroendocrine tumours and prognosis came to light. When applicated to the group of ileal neoplasms, however, the parameter DNA content did not allow a better prognostic assessment.
    Notes: Zusammenfassung Untersucht wurden 123 Manifestationen (97 Primärtumoren und 26 Metastasen) von bei 95 Patienten beobachteten neuroendokrinen (NE-)Tumoren des Gastrointestinaltrakts auf die prognostische Bedeutung verschiedener klinischer, histologischer und DNA-zytophotometrischer Parameter. Metastasen traten fast ausschließlich bei ilealen Karzinoiden auf, denen auch sämtliche 14 während der durchschnittlichen Nachbeobachtungszeit von 42 Monaten aufgetretenen letalen Erkrankungsverläufe zuzuordnen waren. Aneuploide DNA-Verteilungsmuster wurden signifikant häufiger bei ilealen als bei nichtilealen Karzinoiden angetroffen und waren – bezogen auf die Gesamtgruppe – signifikant mit tödlichem Krankheitsausgang korreliert. Darüber hinaus zeigte sich bei 18 Fällen mit DNA-zytophotometrisch auswertbaren primären und sekundären Karzinoidmanifestationen eine Assoziation zwischen dem DNA-Histogrammtyp metastatischer Karzinoide und der Prognose. Innerhalb der Gruppe der Ileumtumoren erlaubte der Parameter DNA-Gehalt aber keine Verbesserung der Prognoseabschätzung.
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Journal of cancer research and clinical oncology 126 (2000), S. 48-52 
    ISSN: 1432-1335
    Keywords: Key words Enzyme-linked immunosorbent assay ; p53 protein ; WAF1 protein ; Lung cancer ; Prognosis ; AbbreviationsNSCLC non-small-cell lung cancer ; RR relative risk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: p21WAF1, a cyclin-dependent kinase inhibitor, is an important mediator of the cell-cycle arrest and tumor suppression induced by the protein p53. Although alterations of the p53 gene and its overexpression are frequent in most malignancies, including non-small-cell lung cancer (NSCLC), and may be associated with poor patient prognosis, the clinical utility of p21WAF1 expression in NSCLC has not been established. Methods: We have used a commercial enzyme-linked immunosorbent assay (ELISA) kit for p21WAF1 to test soluble extracts of 54 NSCLC specimens with known clinicopathological properties. Results: There was no correlation between p21WAF1 and p53 concentrations, the latter being determined by a time-resolved immunofluorometric assay developed in-house. Furthermore, p21WAF1 levels were not associated with patient age, tumor/node/metastasis (TNM) stage, lymph node metastasis, histological grade or type, or smoking history, in Mann-Whitney analysis. χ2-tests, based on cutoffs equal to the 25th, 50th, or 75th percentiles of the p21WAF1 distribution, similarly did not reveal any statistically significant associations between p21WAF1 and other clinicopathological variables. Because of the small number of patients and the median follow-up of only 18 months, a meaningful survival analysis could not be performed. Conclusion: In summary, this preliminary study suggests that ELISA-quantified p21WAF1 levels in NSCLC extracts are weaker than p53 in terms of prognostic value and do not contribute to the further subclassification of patients.
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  • 8
    ISSN: 1432-1335
    Keywords: Key words erbB-3 ; Colorectal carcinoma ; Survival ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background/aims: The family of erbB receptors includes four transmembrane glycoproteins with tyrosine kinase activity. These receptors are widely expressed in normal tissues, but they also have been implicated in the development of several human adenocarcinomas. c-erbB-3/HER-3 has been detected to a greater or lesser extent in many tissues from the digestive, urinary, reproductive and respiratory tracts. The overexpression of c-erbB-3/HER-3 protein has also been shown in 53%–88% of colorectal adenocarcinomas. In this study we investigated the expression of the c-erbB-3/HER-3 gene product in colorectal tumour samples, and compared the results obtained with several clinicopathological parameters, including the survival of patients. Methods: Paraffin-embedded tissue sections were analysed immunohistochemically, using monoclonal antibody RTJ1 to human erbB-3 protein. Antibody RTJ1 specificity was confirmed by immunoprecipitation followed by Western blotting analysis. Amplification of the erbB-3 oncogene was tested by dot-blot hybridization. Results: Adenocarcinomas of the colon were positive for erbB-3 protein in 78% of samples examined. Dot-blot analysis showed no amplification of the erbB-3 gene in colon adenocarcinomas. Statistical analysis showed that patients with tumours that could not be stained for erbB-3 protein survived significantly longer (P 〈 0.05) than patients with tumours staining positive for the erbB-3 protein. A Cox proportional-hazards model with stepwise variable selection identified age, sex and erbB-3 expression as important prognostic factors. Conclusion: These findings demonstrate that erbB-3 protein expression could serve as a prognostic factor in colorectal malignancies.
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  • 9
    ISSN: 1433-0385
    Keywords: Schlüsselwörter: Inkontinenz ; Rectumcarcinom ; Manometrie ; Prognose ; Anus. ; Keywords: Incontinence ; Rectal cancer ; Anorectal manometry ; Prognosis ; Anus.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract. Aim: To determine clinical and physiologic parameters enabling the prognosis of continence after protective ileostomy closure secondary to rectal resection for rectal cancer. Method: Patients who had undergone rectal resection (n = 65, of whom 24 had had radiochemotherapy) were evaluated by clinical examination, anorectal manometry and orthograde contrast enema before ileostomy closure. Continence was evaluated by clinical findings 91 ± 52 weeks after stoma closure with the help of standardized questionaires and classified according to the Wexner continence score. The relationship between findings before stoma closure and continence score was calculated with Pearson's correlation coefficient. Results: Correlations were found to be significant between the continence score and the level of anastomosis (r = –0.58, p 〈 0.001), median resting pressure (r = –0.52, p 〈 0.001), rectal compliance (r = –0.43, p 〈 0.001). Additionally, radiochemotherapy impairs continence (p = 0.0001). Correlations were not significant between continence and functional sphincter length, squeeze pressure, threshold for perception, urge and maximal tolerable volume, and continence for semiliquid contrast medium. Conclusion: Incontinence after rectum resection is multifactorial: the level of anastomosis, resting pressure, rectal compliance and radiochemotherapy all play a dominant role. Based on these findings, the continence score can be calculated before closure of a diverting ileostomy by applying multivariate analysis with the help of the following formula: Continence score = 18.23–0.94 · level of anastomosis – 0.18 · resting pressure + 3.72 · radiochemotherapy.
    Notes: Zusammenfassung. Ziel dieser Studie war eine Evaluation von klinischen und physiologischen Parametern zur Vorhersage des Kontinenzgrades nach Rückverlagerung der protektiven Loop-Ileostomie nach Rectumresektion wegen eines Carcinoms. Methode: 65 Patienten wurden klinisch mittels anorectaler Manometrie und orthograder Röntgenkontrastmitteldarstellung vor der Ileostomieresektion untersucht. Bei 24 Patienten war eine Radiochemotherapie durchgeführt worden. Der klinische Status wurden 91 ± 52 Wochen nach der Ileostomieresektion mittels eines standardisierten Fragebogens erhoben und der Kontinenzgrad nach dem Wexner-Kontinenzscore bewertet. Der postoperative Kontinenzscore wurde mit den Befunden vor Stomarückverlagerung korreliert und ein Pearson-Korrelationskoeffizient berechnet. Ergebnisse: Es ergab sich eine signifikante Korrelation des Kontinenzgrades mit der Anastomosenhöhe (r = –0,58, p 〈 0,001), dem mittleren Ruhedruck (r = –0,52, p 〈 0,001) und der rectalen Compliance (r = –0,43, p = 0,001). Die Kontinenz war nach Radiochemotherapie schlechter (p = 0,0001). Es fand sich keine signifikante Korrelation zwischen Kontinenzgrad und funktioneller Sphincterlänge, Kneifdruck, Perceptionsschwelle, Drangschwelle, maximal tolerablem Volumen und Kontinenz für semiliquides Kontrastmittel. Schlußfolgerung: Inkontinenz nach Rectumresektion ist multifaktoriell. Anastomosenhöhe, mittlerer Ruhedruck, rectale Compliance und Radiochemotherapie (RCT) spielen eine dominante Rolle. Basierend auf diesen Befunden ist über die Berechnung einer multivariaten Regressionsanalyse eine Abschätzung des Kontinenzgrades vor Ileostomieresektion mit folgender Formel möglich: Prognose-Wexner-Score = 18,23–0,94 · Anastomosenhöhe – 0,18 · Ruhedruck + 3,72 · RCT.
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  • 10
    ISSN: 1432-0851
    Keywords: Key wordsαvβ3 ; Integrins ; Melanoma ; Blood vessels ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The αvβ3 integrin has emerged as a key mediator in angiogenesis. Its role in tumor-induced angiogenesis is supported by its up-regulation in vivo in the vasculature of a number of different types of carcinoma. The potential clinical significance of αvβ3 expression on blood vessels in carcinomas is suggested by its association with tumor progression. Currently no information is available about the clinical significance of αvβ3 expression on the vasculature of lesions of melanocytic origin. Since we have previously found that αvβ3 expression on melanoma cells in primary lesions is associated with a poor prognosis, in the present study we have compared αvβ3 expression on blood vessels and on cells of melanocytic origin in nevi and in malignant melanoma lesions. In addition we have examined the lesions for expression of the αv subunit to gain information on the regulation of αvβ3 expression on endothelial cells and on cells of the melanocyte lineage. αvβ3 expression on endothelial cells and on melanocytic cells was a relatively sensitive and specific marker for malignant lesions. However, αvβ3 expression on endothelial cells in primary melanoma lesions was not associated with the prognosis of the disease. The αv subunit and the αvβ3 complex were differentially expressed on endothelial cells and on melanocytic cells, implying that different regulatory pathways control their expression. This finding may account for the differential clinical significance of αvβ3 expression on tumor vasculature and on melanoma cells we observed in our patient cohort. Lastly, αvβ3 may be a useful target for immunotherapeutic approaches in melanoma because of its high expression on the vasculature of all metastatic lesions tested and its restricted distribution in normal tissues.
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  • 11
    ISSN: 1432-0851
    Keywords: Key words IL-2 serum levels ; NSCLC ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Interleukin(IL)-2 is a T helper (Th) 1 type cytokine that has been shown to play an important role in antitumour immune responses. In this study, the prognostic significance of serum IL-2 levels was investigated in 60 advanced non-small-cell lung cancer (NSCLC) patients. IL-2 serum levels were determined before chemotherapy, at the end of chemotherapy and during follow-up, using a commercially available enzyme-linked immunoadsorbent assay kit. The results were analysed according to the response to therapy and were used to generate a model predicting overall survival and time to treatment failure. All 60 patients were shown to have higher IL-2 serum levels than controls (P 〈 0.0001). Stage IV patients had significantly lower IL-2 levels than stage III patients (P 〈 0.0001), although they were still significantly higher than controls (P 〈 0.0001). It is interesting that, when patients were divided into responders and non-responders according to the response to therapy, the former were shown to have significantly higher pre-chemotherapy levels than the latter (P 〈 0.0001). Moreover, a further significant increase in IL-2 serum levels (P=0.004) and a significant decrease (P 〈 0.0001) were shown in responders and non-responders, respectively at the end of the therapy. Using univariate and multivariate analyses, both overall survival and time to treatment failure were shown to be affected by the mean pathological levels of IL-2. Furthermore, the prognostic significance of the serum level of IL-2 was confirmed by the stepwise regression analysis. In conclusion, determination of pre-treatment IL-2 serum levels was shown to be of independent prognostic utility in patients with advanced NSCLC; therefore, its possible use for prediction of outcome is proposed.
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  • 12
    Electronic Resource
    Electronic Resource
    Springer
    European journal of orthopaedic surgery & traumatology 10 (2000), S. 199-202 
    ISSN: 1432-1068
    Keywords: Abscess ; Prognosis ; Spinal epidural abscess
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Five patients suffering from spinal epidural abscess associated with neurologic deficit are reported. Four patients underwent a decompressive procedure for abscess drainage, and one patient was medically treated. One of the patients showed a neurologic deterioration at the early postoperative period. The long-term follow-up showed a good outcome in all patients. It is concluded that epidural abscess associated with progressive neurologic deficit requires immediate decompression and administration of antibiotic. Postoperative neurological deterioration may be seen despite proper and immediate decompression and in such a case neurologic improvement is observed in the late postoperative period.
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  • 13
    Electronic Resource
    Electronic Resource
    Springer
    Archives of gynecology and obstetrics 264 (2000), S. 13-19 
    ISSN: 1432-0711
    Keywords: Key words Fallopian tube cancer ; Radiotherapy ; Chemotherapy ; Lymph node metastasis ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Objective: To contribute toward the understanding of the therapeutic management of fallopian tube cancer. Methods: Recent studies related to the treatment of fallopian tube cancer were reviewed. Results: Current evidence indicates that even patients in early stages have nodal disease, and often experience relapses in distant sites. In advanced stages, survival prolongation by the use of platinum-based chemotherapy has been demonstrated. Aggressive cytoreductive surgery followed by chemotherapy and negative second-look laparotomy offer the possibility of long-term survival. However, a significant fraction of patients eventually relapses after negative second-look laparotomy, and a poor survival rate after positive second-look laparotomy has been observed. Conclusions: This series suggests the need for thorough evaluation of lymph nodes at the time of surgery. The use of platinum-based chemotherapy is probably the best adjuvant therapy for both early stages and advanced stages. The clinical value of second-look laparotomy will remain limited until effective salvage therapy is developed. The potential benefits of neoadjuvant chemotherapy and the use of paclitaxel will be increasingly important.
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  • 14
    ISSN: 1432-1238
    Keywords: Key words Acute renal failure ; 80 years old ; Etiology ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: To determine the epidemiological trends, spectrum of etiologies, morbidity and mortality of acute renal failure (ARF) in patients over 80 years old.¶Design: Historical cohort analysis.¶Setting: Intensive care unit (ICU) of nephrology, Tenon Hospital, Paris.¶Patients and participants: The criteria of inclusion was ARF, defined on the basis of a creatinine value over 120 μmol/l, in patients over 80 years of age admitted between October 1971 and September 1996. When moderate chronic nephropathy was pre-existing, ARF was defined by the increase of at least 50 % over the basal creatininemia.¶Measurements and results: Three hundred and eighty-one patients over 80 years of age were included. The etiology and mechanism of ARF are detailed. 29 % of the patients received dialysis. Global mortality at the hospital was 40 %. Factors significantly associated with a poor prognosis are identified. Mean survival after hospitalization was 19 months.¶Conclusion: The frequency of admission to ICUs for ARF in patients older than 80 years seems to be on the increase. Mortality is less severe than expected. These patients could benefit from the renal replacement therapy of modern intensive care medicine.
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  • 15
    Electronic Resource
    Electronic Resource
    Springer
    Intensive care medicine 26 (2000), S. S064 
    ISSN: 1432-1238
    Keywords: Key words Bacteraemia ; Sepsis ; Septic shock ; Epidemiology ; Prognosis ; Risk factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: To examine the incidence, risk factors, aetiologies and outcome of the various forms of the septic syndromes (the systemic inflammatory response syndrome [SIRS] sepsis, severe sepsis, and septic shock) and their relationships with infection.¶Design: Review of published cohort studies examining the epidemiology of the septic syndromes, with emphasis on intensive care unit (ICU) patients.¶Results: The prevalence of SIRS is very high, affecting one-third of all in-hospital patients, and 〉 50 % of all ICU patients; in surgical ICU patients, SIRS occurs in 〉 80 % patients. Trauma patients are at particularly high risk of SIRS, and most these patients do not have infection documented. The prevalence of infection and bacteraemia increases with the number of SIRS criteria met, and with increasing severity of the septic syndromes. About one-third of patients with SIRS have or evolve to sepsis. Sepsis may occur in approximately 25 % of ICU patients, and bacteraemic sepsis in 10 %. In such patients, sepsis evolves to severe sepsis in 〉 50 % of cases, whereas evolution to severe sepsis in non-ICU patients is about 25 %. Severe sepsis and septic shock occur in 2 %–3 % of ward patients and 10 %–15 % or more ICU patients, depending on the case-mix; 25 % of patients with severe sepsis have shock. There is a graded severity from SIRS to sepsis, severe sepsis and septic shock, with an associated 28-d mortality of approximately 10 %, 20 %, 20 %–40 %, and 40 %–60 %, respectively. Mortality rates are similar within each stage, whether infection is documented or not, and microbiological characteristics of infection do not substantially influence outcome, although the source of infection does. While about three of four deaths occur during the first months after sepsis, the septic syndromes significantly impact on long-term outcome, with an estimated 50 % reduction of life expectancy over the following five years. The major determinants of outcome, both short-term and long-term, of patients with sepsis are the severity of underlying diseases and comorbidities, the presence of shock and organ failures at onset of sepsis or evolving thereafter. It has been estimated that two-thirds of the overall mortality can be attributed to sepsis.¶Conclusions: The prevalence of sepsis in ICU patients is very high, and most patients have clinically or microbiologically documented infection, except in specific subset of patients. The prognosis of septic syndromes is related to underlying diseases and the severity of the inflammatory response and its sequelae, reflected in shock and organ dysfunction/failures.
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  • 16
    ISSN: 1432-1084
    Keywords: Key words: MR imaging ; Non-small cell lung cancer ; Therapeutic effect ; Prognosis ; Survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The aim of this study was to evaluate the therapeutic effect more accurately and predict the prognosis of treated non-small cell lung cancer by using contrast-enhanced magnetic resonance imaging (CE-MRI). Contrast-enhanced computed tomography (CE-CT) and CE-MRI were examined 90 non-small cell lung cancer patients treated with conservative therapies. Enhancement patterns of CE-MRI were classified into three types: peripheral; mottled; and homogeneous. Reduction ratio of tumor size (RRT) based on the World Health Organization response criteria and a new response rate; reduction ratio of viable tumor size (RRVT) which evaluates not only the reduction of tumor size but also changes in necrosis and/or cavity size, were evaluated. Changes of enhancement pattern were compared and correlated with pathological diagnosis. The RRTs, RRVTs, and interobserver agreements evaluated by all modalities were compared. The RRTs and RRVTs in each subgroup were correlated and compared with prognoses. Change of enhancement pattern depended on therapy had no tendency (p = 0.06). Enhancement pattern had significant correlation with pathological diagnosis (p 〈 0.0001). Partial response (PR) case of RRVT had significant difference between imaging techniques (p = 0.04). The RRVT of other cases and RRT had no significant difference. Interobserver agreements of RRT and RRVT were almost perfect (ϰ≥ 0.93). Prognosis had better correlation with RRVT than with RRT. Differences of relapse-free survival and survival between patients considered as having no change (NC) by RRT and PR by RRVT (NC-PR) and patients considered as having NC by RRT and RRVT were significant (p = 0.03, p = 0.01). There were no significant differences of relapse-free survival and survival between NC-PR patients and patients considered as having PR by RRT and RRVT. The CE-MRI technique could accurately evaluate the therapeutic effect and predict the prognosis of treated non-small cell lung cancer.
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  • 17
    ISSN: 1279-8509
    Keywords: Acute myeloid leukemia ; Chemotherapy ; Allogenic transplantation ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to assess the place of HLA-identical allogeneic bone marrow transplantation (BMT) and to compare it to other post-induction therapies, we analyzed patient outcome in intention-to-treat based on the presence or not of an HLA-identical familial donor in young adults with de novo acute myeloid leukemia (AML) in first complete remission (CR). Between 1985 and 1998, 152 consecutive AML patients aged less than 41 years old, seen in our institution, were treated according to 3 different successive protocols (LYLAM85, LAM90, AML10). 144/152 patients entered our prospective study in which they were registered at time of diagnosis for presence or absence of HLA-identical donor and analyzed in intention-to-treat. In this study, 52 patients (36%), who had at least one identical sibling donor (group 1), were offered allogeneic BMT after CR achievement. The 92 patients without donor were allocated to group 2 and were assigned to receive chemotherapy or autologous transplantation as post-remission according to the protocol they were initially included in. Patients from both groups had similar disease characteristics at diagnosis. Karyotypes at diagnosis were defined as low risk (t(8;21) or t(15;17) or chromosome 16 abnormalities(, intermediate risk (normal karyotypes), or high risk (other abnormalities). Overall, 114/152 patients (75%) achieved a CR. Of the 144 eligible patients, 46/52 (88%) with a donor and 68/92 (74%) without a donor achieved a CR. The median follow-up duration of the 144 patients was 21.2 months. The relapse rate was higher in group 2 (56%) than in group 1 (31%). However, the overall survival was not different between patients with and without donor (median survival respectively at 16.7 months and 26.6 months with estimated survival at 5 years respectively at 32% and 34%). Thirty-four patients from group 1 (65%) were actually transplanted in first CR. The probability of 5-year survival for patients receiving effectively allogeneic BMT was 44% and was not significantly better than that of patients who did not. In univariate as in multivariate analysis, karyotypic status was the main prognostic factor for CR achievement (p = 0.002), CR duration (p 〈 0.0001), and overall survival (p 〈 0.0001). There were no significant differences between group 1 and group 2 when survivals were compared with adjustment for karyotypes. We conclude that the availability of an HLA-identical sibling donor did not confer any prognostic advantage in terms of outcome for young adults with AML in first CR. These results make allogeneic BMT process questionable as systemic post-remission therapy in patients with an HLA-identical familial donor.
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  • 18
    ISSN: 1279-8517
    Keywords: Gastric carcinomas ; Cardiac carcinomas ; TNM-classification ; Prognosis ; Lesser and greater omenta
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The problem of T classification of proximal gastric carcinomas is becoming increasingly important due to a rise in the incidence of these tumors. The aim of this study was to examine the gastric insertion of the lesser and greater omenta and its role in the T classification of gastric carcinomas. The stomach and greater and lesser omenta were removed from 76 fixed cadavers and 12 measurements each were done in defined localizations. The lesser omentum extended to the gastric wall in 98% of the cases. This junction as well as the omental thickness and thus the retroperitoneal part are especially pronounced in the cardiac region. According to the current UICC classification, even advanced tumors extending into the gastric wall can be classified T2 as long as they do not penetrate the visceral peritoneum. This results in « understaging » and a seemingly poorer prognosis for cardiac carcinomas. Our study results support the recommendation of Hermanek and Wittekind [5] to subdivide the T2 stage of gastric carcinomas on the basis of infiltration depth.
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  • 19
    Electronic Resource
    Electronic Resource
    Springer
    Annals of hematology 79 (2000), S. 455-458 
    ISSN: 1432-0584
    Keywords: Key words Anterior chamber ; Hypopyon ; Leukemia ; Extramedullary ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We encountered a patient with acute myelogenous leukemia (AML) who developed leukemic hypopyon. Leukemia initially spread into the pharynx, gingiva, lymphnode, and bone marrow. He achieved complete remission after chemotherapy but developed blurred vision and hypopyon. Anterior chamber paracentesis disclosed leukemic infiltration of the anterior chamber. Infiltration of the central nervous system also occurred. He received systemic chemotherapy, intrathecal chemotherapy, and local chemotherapy. However, he did not achieve prolonged remission. These findings suggest that these chemotherapy treatments have an inadequate effect for AML with anterior chamber infiltration. This rare complication is associated with extramedullary infiltration of leukemia.
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  • 20
    ISSN: 1248-9204
    Keywords: Hernia ; Strangulation ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary It is believed that direct hernias are less likely to strangulate because, in contrast to an indirect inguinal hernia, the neck of the direct hernia is wide. For this reason, some surgeons do not repair direct hernias in I elderly patients. We analyzed all incarcerated hernias repaired on an emergency basis during a 3-year period in order to discover the extent of incarcerated direct hernias in our practice. A total of 293 patients with incarcerated hernia were evaluated; of these, 222 were inguinal (193 indirect −86.9%- and 29 direct −13.1%-). The strangulation rate for inguinal hernias was found to be 29.7%. There was a significant difference between indirect and direct inguinal hernias in respect to strangulation rate (32.6% vs 10.3% p = 0.014). However, we did not find any difference between bowel resection rates in incarcerated-strangulated indirect and direct hernias (14/193 −7.3%- vs 2/29 −6.9%-, p = 0.95). Hospitalization time was significantly longer for the patients who developed strangulation than those who did not. The side of direct hernia had no effect on strangulation (10.5% for right-sided vs 10.0% for left-sided, p = 0.97). The only prognostic factor for strangulation and resection in regression analysis was the age-group of the patients (〈 60 vs. 60 or older). At operation the average diameter of the defect in the transversalis fascia was 23.8 mm. The diameter of the defect had no effect on strangulation.
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  • 21
    ISSN: 1432-2013
    Keywords: Key words vitamin C (L-ascorbic acid) ; apoptosis ; human articular chondrocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Chondrocytes present in articular cartilage survive as a resident cell population throughout the lifespan of the individual organism. However, articular chondrocytes as other cells also undergo apoptosis and there is an ever increasing list of diverse stimuli that can induce this phenomenon in vitro. Our main interest was to investigate potential cytotoxic effects of vitamin C (L-ascorbic acid) on human articular chondrocytes. The present study suggests that vitamin C can induce apoptosis in a cell culture of chondrocytes after 18 h of cultivation. Apoptosis-inducing activity of L-ascorbic acid is dose dependent and significantly affected by the presence of serum. The increased number of vitamin C induced apoptotic cells was associated with DNA fragmentation and morphological changes of the cells.
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  • 22
    ISSN: 1534-4681
    Keywords: Rectal cancer ; Intensive follow-up ; Local recurrence ; Reoperation ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Because more than 90% of local recurrences after curative surgery for rectal cancer appear within the first 36 months after surgery, an intensive and strict follow-up program during this period could improve early diagnosis and, thus, prognosis of patients. Methods: Of the 216 patients who underwent surgery for rectal cancer, 127 entered an intensive follow-up program (median follow-up: 42 months); the clinical outcome of the remaining 89 patients was reconstructed with the help of their general practitioners. Results: Fifty eight (26.8%) of the 216 patients who were treated with curative surgery alone developed a local recurrence; pelvic recurrences were prevalent. Eleven (30.5%) of the 36 patients who had recurrence during follow-up, and 6 of the 22 who had not undergone follow-up, had a reoperation with curative intent; the median survival was 19 months vs. 8 months, respectively (P 5 ns). Four (44.4%) curative reoperations were performed on the 9 asymptomatic patients and in 13 (26.5%) of the 49 cases with symptomatic local recurrences. Median survival was 15 months vs. 14 months, respectively (P 5 n.s). All patients except one (living after 42 months from reoperation) died within 48 months. Conclusions: In our study, adherence to a strict follow-up program unfortunately proved to be ineffective for improving long-term survival for patients who underwent reoperation with curative intent.
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  • 23
    ISSN: 1534-4681
    Keywords: Gastric cancer ; Prognosis ; Pepsinogen C ; Pepsinogen A
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: In this study we evaluated the expression and clinical significance of pepsinogen C, an aspartic proteinase involved in the digestion of proteins in the stomach, in patients with gastric cancer. Methods: Pepsinogen C expression was examined by immunohistochemical methods in a series of 95 gastric carcinomas. The prognostic value of pepsinogen C was retrospectively evaluated by multivariate analysis taking into account conventional prognostic parameters. Follow-up period of patients was 21.4 months. Results: A total of 25 (26.3%) gastric carcinomas stained positively for pepsinogen C. The percentage of pepsinogen C-positive tumors was higher in well-differentiated (50%) than in moderately differentiated (19.5%) and poorly differentiated (21.9%) tumors (P 〈 .05). Similarly, significant differences in pepsinogen C immunostaining were found between node-negative and node-positive tumors (47.1% vs. 14.7%; P 〈 .001). In addition, statistical analysis revealed that pepsinogen C expression was associated with clinical outcome in gastric cancer patients. Low pepsinogen C levels predicted short overall survival periods in the overall group of patients with gastric cancer (P 〈 .001), and in 71 patients with resectable carcinomas (P 〈 .005). Multivariate analysis according to Cox’s model indicated that pepsinogen C immunostaining was an independent predictor of outcome for both overall and resectable gastric cancer patients (P 〈 .05, for both). Conclusions: The expression of pepsinogen C in gastric cancer may represent a useful biological marker able to identify subgroups of patients with different clinical outcomes.
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  • 24
    ISSN: 1534-4681
    Keywords: Stomach ; Cancer ; Gastric cancer ; Lymph node metastasis ; Prognosis ; Survival rate ; Multivariate analysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: In gastric cancer, the level and number of lymph node metastases is useful for predicting survival, and there are several staging systems for lymph node metastasis. The aim of this study was to compare the several lymph node classifications and to clarify the most important lymph node information associated with prognosis using multivariate analysis. Methods: A total of 106 patients with histologically node-positive gastric cancer treated by radical gastrectomy and extended lymph node dissection (D2, D3) were studied. The level of lymph node metastasis was categorized simply as Level I nodes (perigastric, No.1–6), Level II nodes (intermediate, No.7–9), and Level III nodes (distant, No.10–16), irrespective of the tumor location. The Level II nodes included lymph nodes along the left gastric artery, common hepatic artery, and celiac trunk. Results: Overall 5-year survival rate was 51%. Univariate analysis showed that 5-year survival rate was significantly influenced by the level of positive nodes (P 〈 .01), total number of positive nodes (P 〈 .01), number of positive Level I nodes (P 〈 .01), and number of positive Level II nodes (P 〈 .01), in addition to the tumor location (P 〈 .05), tumor size (P 〈 .05), gross type (P 〈 .01), and depth of wall invasion (P 〈 .01). Of these, independent prognostic factors associated with 5-year survival rate were the number of positive Level II nodes (0–1 vs. ≥2) (62% vs. 19%, P 〈 .01) and the depth of wall invasion (within vs. beyond muscularis) (79% vs. 43%, P 〈 .01). Conclusions: Among several staging systems for lymph node metastases, the number of positive Level II nodes provided the most powerful prognostic information in patients with node-positive gastric cancer. When there were two or more metastases in the Level II nodes, prognosis was poor even after D2 or D3 gastrectomy.
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  • 25
    Electronic Resource
    Electronic Resource
    Springer
    Strahlentherapie und Onkologie 176 (2000), S. 513-516 
    ISSN: 1439-099X
    Keywords: Key Words: Breast cancer ; Zoster ; Radiotherapy ; Prognosis ; Schlüsselwörter: Mammakarzinom ; Zoster ; Radiotherapie ; Prognose
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Hintergrund: Wir haben in einer retrospektiven Analyse die Häufigkeit eines Herpes zoster bei Patientinnen mit Mammakarzinom und postoperativer Radiotherapie untersucht. Patientinnen und Methode: Von Januar 1985 bis Dezember 1993 erhielten 1 155 Patientinnen an unserer Klinik eine postoperative Bestrahlung nach Mastektomie (n = 961) oder brusterhaltende Operation (n = 194) in kurativer Intention. Das Alter betrug 34 bis 79 Jahre. 443 (38%) waren prä- und 712 (62%) postmenopausal, 21% hatten T3- bis T4-Tumoren, und 55% wiesen einen axillären Lymphknotenbefall auf. Alle Patientinnen erhielten eine Bestrahlung der Restbrust bzw. Thoraxwand bis 50 Gy, bei mastektomierten Patientinnen wurden zusätzlich die regionären Lymphknoten mit 44 Gy bestrahlt. 65% der Patientinnen erhielten eine zusätzliche Systemtherapie. Die Nachbeobachtungszeit betrug drei Monate bis 12,5 Jahre (Median 3,1 Jahre). Ergebnisse: 41/1 155 Patientinnen (3,7%) entwickelten im Nachbeobachtungszeitraum einen Herpes zoster. Alle Infektionen waren lokalisiert, eine generalisierte Hautinfektion oder systemische Infektionen traten nicht auf. Alter, Menopausenstatus, Erkrankungsstadium oder Art der Therapie (Brusterhaltung vs. Mastektomie, zusätzliche Chemotherapie) hatten keinen Einfluss auf die Frequenz von Zoster. Patientinnen mit starker akuter Hautreaktion waren ebenfalls nicht signifikant stärker betroffen als Patientinnen mit geringer Hautreaktion im Bestrahlungsfeld (5% vs. 2%). Das Auftreten eines Zosters nach Therapie hatte keinen Einfluss auf die Prognose hinsichtlich lokaler Kontrolle oder Überleben. Schlussfolgerungen: Die beobachtete Häufigkeit von Herpes zoster (etwa 4% nach drei Jahren Follow-up) lässt vermuten, dass ein Herpes zoster im untersuchten Kollektiv etwa drei- bis fünffach häufiger auftritt als anhand der Inzidenzen in der Normalbevölkerung erwartet. Dies ist nicht mit einer schlechteren Prognose assoziiert. Ob die erhöhte Frequenz auf die Radiotherapie zurückzuführen ist oder in Zusammenhang mit der Krebserkrankung steht, kann nich beurteilt werden.
    Notes: Background: We have studied the incidence of herpes zoster in patients with adjuvant radiotherapy for breast cancer with special emphasis on possible correlations with other prognostic factors or survival. Patients and Methods: From 1/1985 through 12/1993, 1 155 breast cancer patients received postoperative radiotherapy with curative interent in our department. After mastectomy 961 patients were irradiated and after breast-preserving treatment 194 patients. The age ranged from 34 to 79 years, the median follow-up was 3.1 years (range: 0.3 to 12.4 years). There were 443 women (38%) pre- and 712 (62%) postmenopausal. 21% had T3- to T4-tumors, 55% had axillary lymph node involvement, and 65% received additional systemic hormonal and/or cytotoxic therapy. In case of postmastectomy radiotherapy, the lateral chest wall and lymphatics (axilla, parasternal and supraclavicular nodes) were irradiated with an anterior photon field to 50 Gy (axilla 44 Gy) and most of the chest wall with an electron field to 44 Gy in 2-Gy fractions. After breast-preservation, the breast was irradiated via tangential fields with 6- to 8-MV photons up to 50 Gy plus 8 Gy electron boost to the tumor bed. Most of the patients were followed routinely in the department for 2 to 5 years. The frequency of zoster was determined retrospectively by reviewing the patients' records. Results: A zoster after radiotherapy occurred in 41/1 155 patients (3.7%), mostly within the first 2 years after completion of radiotherapy. All infections remained localized and there was no evidence for systemic infections. Type of treatment (mastectomy vs breast-preservation) had no impact on the frequency of herpes zoster (36/961 patients after mastectomy and 5/194 patients after breast-preservation). There was also no correlation with other prognostic factors such as age, menopausal status, stage of disease or the use of adjuvant chemotherapy, nor was the occurrence of zoster linked to the degree of acute skin reaction in the radiation field. Moreover, patients with zoster had the same prognosis as compared to patients without zoster with regard to local control and survival. Conclusions: The observed frequency of zoster (about 4% of patients after postoperative radiotherapy) in this retrospective study suggests that the risk of developing zoster in this patient group may be 3- to 5-fold higher as compared to the incidence in the general population. However, the occurrence of zoster was not linked to prognosis and treatment response.
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  • 26
    ISSN: 1436-3305
    Keywords: Key words Hypergastrinemia ; Carcinoid tumor ; Prognosis ; Autoimmune gastritis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Gastric carcinoid tumors associated with chronic atrophic gastritis type A have been reported to show good prognosis, because invasion and metastasis are rare. We report a case of gastric carcinoid tumor associated with hypergastrinemia that showed no malignant changes for 12 years. A 15-year-old man with abdominal discomfort underwent endoscopic examination. A polypoid lesion was detected on the atrophic mucosa of the fundus, and was diagnosed as a carcinoid tumor. Serological examination revealed a high level of anti-parietal-cell antibody, suggesting that the patient had chronic atrophic gastritis type A. The tumor was treated by endoscopic mucosal resection. Follow-up examinations were performed for 12 years, but showed no recurrence. This case confirms that gastric carcinoid tumors associated with chronic atrophic gastritis type A may have a good prognosis.
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  • 27
    ISSN: 1436-3305
    Keywords: Key words Stomach ; Cancer ; Gastric cancer ; Lymph node metastasis ; Prognosis ; Survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Background. Although many authors have investigated the prognostic factors of gastric cancer, there are few comprehensive studies on the prognosis of patients with extensive lymph node metastasis. The aim of this study was to clarify the prognostic factors of gastric cancer with extragastric lymph node metastasis, using multivariate analysis. Methods. The study population consisted of 121 patients who had undergone radical gastrectomy and extended lymph node dissection (D2, D3) for gastric cancer with extragastric lymph node metastasis. We examined 18 clinicopathologic factors, including the type of gastrectomy, tumor size, depth of wall invasion, status of lymph node metastasis, and stage of disease. Survival rates were analyzed by the Kaplan-Meier and Mantel-Cox methods, and multivariate analysis was done using the Cox proportional hazards model. Results. The overall 5-year survival rate was 32%, and the 5-year survival rate after curative gastrectomy was 37%. Overall survival rate was associated with the type of gastrectomy, stage of disease, operative curability, tumor size, depth of wall invasion, and anatomical distribution of positive nodes, whereas the survival rate after curative gastrectomy was correlated with the type of gastrectomy, stage of disease, tumor size, gross type, and depth of wall invasion. Independent prognostic factors were operative curability and depth of wall invasion, and survival after curative gastrectomy was influenced only by the depth of wall invasion (mucosa and submucosa [T1], muscularis and subserosa [T2] vs serosa [T3]). Conclusion. In patients with gastric cancer with extragastric lymph node metastasis, independent prognostic factors after gastrectomy were operative curability and depth of wall invasion. Long-term survival can be achieved when the patients have no serosal invasion (T1, T2) and are treated by curative gastrectomy.
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  • 28
    ISSN: 1530-0358
    Keywords: Microscopic peritoneal dissemination ; Colon-cancer ; Gastric cancer ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: We evaluated the incidence and prognostic relevance of microscopic intraperitoneal tumor cell dissemination of colon cancer in comparison with dissemination of gastric cancer as a rational for additive intraperitoneal therapy. METHODS: Peritoneal washouts of 90 patients with colon and 111 patients with gastric cancer were investigated prospectively. Sixty patients with benign diseases and 8 patients with histologically proven gross visible peritoneal carcinomatosis served as controls. Intraoperatively, 100 ml of warm NaCl 0.9 percent were instilled and 20 ml were reaspirated. In all patients hematoxylin and eosin staining (conventional cytology) was performed. Additionally, in 36 patients with colon cancer and 47 patients with gastric cancer, immunostaining with the HEA-125 antibody (immunocytology) was prepared. The results of cytology were assessed for an association with TNM category and cancer grade, based on all patients, and with patient survival, among the R0 resected patients. RESULTS: In conventional cytology 35.5 percent (32/90) of patients with colon cancer and 42.3 percent (47/111) of patients with gastric cancer had a positive cytology. In immunocytology 47.2 percent (17/36) of patients with colon cancer and 46.8 percent (22/47) of patients with gastric cancer were positive. In colon cancer, positive conventional cytology was associated with pT and M category (P=0.044 andP=0.0002), whereas immunocytology was only associated with M category (P=0.007). No association was found between nodal status and immunocytology in colon cancer and with the grading. There was a statistically significant correlation between pT M category and conventional and immunocytology in gastric cancer (P〈0.0015/P=0.007 andP〈0.001/P=0.009, respectively). Positive immunocytology was additionally associated with pN category (P=0.05). In a univariate analysis of R0 resected patients (no residual tumor), positive immunocytology was significantly related to an unfavorable prognosis in patients with gastric cancer only (n=30). Mean survival time was significantly increased in patients with gastric cancer with negative cytology compared with positive cytology (1,205 (standard error of the mean, 91)vs. 771 (standard error of the mean, 147) days;P=0.007) but not in patients with colon cancer (1,215 (standard error of the mean, 95)vs. 1,346 (standard error of the mean, 106) days;P=0.55). CONCLUSIONS: Because microscopic peritoneal dissemination influences survival time after R0 resections only in patients with gastric but not with colon cancer, our results may provide a basis for a decision on additive, prophylactic (intraperitoneal) therapy in gastric but not colon cancer.
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  • 29
    ISSN: 1530-0358
    Keywords: Abdominoperineal resection ; Laparoscopy ; Colorectal carcinoma ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: Although laparoscopic colorectal surgery is attracting ever more attention, its use for curative treatment of colorectal carcinoma in particular continues to be controversial. The present study was an attempt to analyze the results of the perioperative course, oncologic quality, and preliminary long-term results. METHOD: The data considered here were collected within the framework of a prospective, observational study initiated on August 1, 1995, and involving a total of 18 institutions in Germany and Austria. At the end of three years, the results are now being presented selectively,i.e., focusing only on abdominoperineal resection. RESULTS: A total of 116 patients underwent laparoscopic abdominoperineal resections, 98 (84.5 percent) of which were performed with curative intent. The mean operating time was 226 (confidence interval, 140–365) minutes. Seven patients (6 percent) experienced an intraoperative complication, which in more than one-half of the cases was a vascular injury involving the presacral venous plexus; the conversion rate was 3.4 percent. Postoperatively, 40 patients developed 97 complications—including those of a very minor nature—giving an overall morbidity rate of 34.4 percent. Reoperation in six patients (5.2 percent) had to be performed for an afterbleed in one-half of the cases and ileus in the other one-half. Postoperative mortality was a low 1.7 percent. In most of the curative resections, an oncologically radical operation with high transection of the inferior mesenteric artery and a complete dissection of the pelvis down to the floor was performed. The median number of lymph nodes investigated was 11.5, and there was wide fluctuation in the numbers among the individual institutions. Tumor cell dissemination occurred intraoperatively in five patients. In the meantime, 79 patients (81 percent) underwent at least one follow-up examination, the mean follow-up period being 491 days. Seven patients developed a local recurrence, and a further six patients developed distant metastases. For recurrence-free survival rate, the Kaplan-Meier estimation calculated a probability of 71 percent. CONCLUSION: Not all of the reservations about laparoscopic abdominoperineal resection, in particular with regard to resection with curative intent, have yet been eliminated. The present study does, however, show that a laparoscopic approach can in principle meet oncologic requirements of radicality and, with regard to the postoperative course, is associated with considerable benefits to the patient.
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  • 30
    Electronic Resource
    Electronic Resource
    Springer
    Diseases of the colon & rectum 43 (2000), S. 1222-1226 
    ISSN: 1530-0358
    Keywords: Colorectal neoplasms ; Young age ; Case-control study ; Pathology ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: Colorectal adenocarcinoma before the age of 40 is uncommon, and its prognosis is controversial, with many studies reporting a worse prognosis than in older patients and others showing no difference. The current study compared two groups of patients who had surgical resection for colorectal adenocarcinoma. METHODS: The case group was composed of 34 patients younger than 40 (34 ± 4) years. Detailed pathologic prognosis factors, tumor cell proliferation measured by proliferating cell nuclear antigen, survival, family history, and predisposing conditions were analyzed. Results were compared with a control group constituted of 34 patients older than 65 (75 ± 6) years matched by gender, cancer site, and Dukes stage. RESULTS: Tumor differentiation, presence of vascular and perineural neoplastic invasion, tumor growth pattern, tumor cell proliferation measured by proliferating cell nuclear antigen count, and survival according to the Kaplan-Meier method were not significantly different between younger and older patients. The only difference between the two groups was a higher prevalence of family history and predisposing conditions for colorectal cancer in younger patients (23vs. 3 percent;P=0.03). CONCLUSION: This case-control study documents that pathologic features and prognosis of colorectal adenocarcinoma are comparable in patients younger than 40 years compared with older patients for identical stages. The higher prevalence of positive family history in younger patients suggests a different genetic background compared with older patients.
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  • 31
    ISSN: 1534-4681
    Keywords: Gastric cancer ; Younger patients ; Elderly patients ; Comparative study ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Gastric cancer is one of the most common gastrointestinal malignancies worldwide. Some studies have suggested that it has a worse prognosis in young than in elderly patients. Methods: All young and elderly patients treated for gastric adenocarcinoma during the period 1988 to 1994 in a tertiary referral center in Mexico City were included. Demographic, clinical, and pathologic features of young patients (less than 40 years of age) with gastric cancer were compared with those of elderly patients (70 years of age or older) with the same diagnosis. Overall survival was the main outcome measure. Results: There were 38 patients in each group. The mean age of the young and elderly groups was 33 and 77 years, respectively. Family history of gastric cancer was reported by 6 patients of the younger group and by 1 patient in the older group (P 〈 .05). Most patients in both groups were symptomatic and had an advanced stage of the disease. With a mean follow-up of 17 months, the overall median survival for all patients was 12 months. By group, the median survival was 13 and 12 months for the young and elderly patients, respectively (P = .38). Variables with significant impact on survival were the stage of the disease, possibility of surgical resection, location of the tumor, and a family history of gastric cancer. Conclusions: Young patients represent a significant proportion of patients with gastric cancer in Hispanic populations. There were no significant differences in clinicopathological characteristics and outcome of gastric adenocarcinoma between young and elderly patients. Survival was determined by the stage of the tumor and the possibility of complete surgical resection.
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  • 32
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    Annals of surgical oncology 7 (2000), S. 520-525 
    ISSN: 1534-4681
    Keywords: Proximal gastric third ; Adenocarcinoma ; Total gastrectomy ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The incidence of proximal gastric third carcinoma (PGC) has been rising in recent years. Classification and surgical therapy remain controversial. Methods: Between May 1986 and October 1997, 532 patients were operated for primary gastric carcinoma. All patient data were analyzed retrospectively comparing findings in patients with PGC and those with distal gastric carcinoma (DGC). Results: Two hundred fifty patients had a PGC, and 282 patients had a DGC. The rate of R0 resections was 79.3% for PGC and 81.6% for DGC. In 93.9% of the patients with PGC total gastrectomy was performed; for DGC total gastrectomy was done in 74.5% of patients. Postoperative morbidity and mortality were 29.2% for PGC and 23.8% for DGC, and 3.2% for PGC and 3.5% for DGC, respectively. Patients with advanced tumor stages (stage III and IV) were more common in the PGC group (73.3% vs. 53.6% in DGC). After R0 resection, the 5-year survival rate was 33.2% for PGC and 59.7% for DGC. Conclusions: There was no significant difference between the rates of R0 resections for PGC and DGC. Total gastrectomy can be performed with low postoperative morbidity and mortality. PGC and DGC represent the same tumor entity, and prognosis is similar, but due to more advanced tumor stages, the long-term survival is worse for patients with PGC than for those with DGC. Left retroperitoneal lymphadenectomy may be indicated for PGC.
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  • 33
    ISSN: 1530-0358
    Keywords: Fistula-in-ano ; Surgery ; Imaging ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: Magnetic resonance imaging of fistula-in-ano has been shown to predict surgical anatomy accurately and identify complex features. In addition, fistula complexity has been correlated with poor outcome after surgical intervention. We investigated whether preoperative magnetic resonance imaging could predict clinical outcome after surgery for fistulous disease better than clinical examination under anesthetic. METHODS: Seventy patients with clinically suspected fistula-in-ano underwent preoperative dynamic contrast-enhanced magnetic resonance imaging before surgical exploration. Outcome was assessed at a minimum of one year after surgical exploration and correlated in a blinded fashion with the surgical and magnetic resonance grading of the severity of the fistulous disease. RESULTS: Of 70 patients, 12 were not operated on and 6 were lost to follow-up, making 52 patients eligible for analysis. Assessment by dynamic contrast-enhanced magnetic resonance imaging more accurately predicted outcome than the findings at initial surgical exploration. Dynamic contrast-enhanced magnetic resonance imaging had a sensitivity of 81 percent, specificity of 73 percent, and positive predictive value of 75 percent; surgery had a sensitivity of 77 percent, specificity of 46 percent, and positive predictive value of 59 percent. Surgical assessment of apparent disease severity bore no relation to final outcome. Dynamic contrast-enhanced magnetic resonance imaging could accurately predict whether patients were likely to have a satisfactory or unsatisfactory outcome after surgery. CONCLUSION: Dynamic contrast-enhanced magnetic resonance imaging better predicts clinical outcome of patients with fistula-in-ano than initial surgical exploration.
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  • 34
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    Diseases of the colon & rectum 43 (2000), S. 1227-1236 
    ISSN: 1530-0358
    Keywords: Rectal cancer ; Apoptosis ; p53 ; bcl-2 ; Prognosis ; Recurrence ; Survival
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract PURPOSE: The aim of this study was to evaluate the prognostic value of the apoptotic index for recurrence and disease-free survival after curative surgery for rectal cancer, particularly in relation to clinicopathologic variables, p53− and bcl-2 expression. METHODS: Formalin-fixed, paraffin-embedded tissue samples of rectal carcinomas resected curatively within a five-year period were used (N=160). Apoptotic cells with fragmented DNA were detected by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphatase-biotin nick-end-labeling method. The ratio of apoptotic tumor cells (in percent) was classified into low apoptotic index (less than 10 percent) and high apoptotic index (10 percent or more). Immunohistochemical analysis was performed using monoclonal antibodies (DO-1 for p53 and clone 124 for bcl-2). Statistics included univariate and multivariate analysis, and survival was calculated using the Kaplan-Meier method. RESULTS: Seventy-five percent of tumors showed a low apoptotic index, and 25 percent had a high apoptotic index. No correlation was found between apoptotic index and International Union Against Cancer stage (P〉0.05). However, significant correlations were documented with histologic differentiation (mean apoptotic index, 5.74 percent in moderatelyvs. 3.98 percent in poorly differentiated carcinomas; P=0.0173), lymph node involvement (mean apoptotic index, 6.11 percent in pN1vs. 3.72 percent in pN2; P=0.0074), p53 status (mean apoptotic index, 6.26 percent in p53−vs. 4.42 percent in p53+; P=0.0085), and bcl-2 expression (mean apoptotic index, 5.13 percent in bcl-2−vs. 6.51 percent in bcl-2+; P=0.0418). Tumors of the lower rectum had a lower apoptotic index than those of the upper rectum (P=0.0277). Neither univariate nor multivariate analysis assessed apoptotic index as predictor of prognosis: Recurrence rates did not differ between tumors related to apoptotic index (22 percent with low apoptotic indexvs. 15 percent with high apoptotic index; P〉0.05), and no significant differences were found regarding survival (P〉0.05). On multivariate analysis, International Union Against Cancer stage (P=0.0002), p53 (P=0.0002), gender (P=0.0136), and bcl-2 (P=0.0243) were independent predictors of recurrence. These variables, except for bcl-2, were also independently related to disease-free survival. CONCLUSIONS: Reflecting tumor biology, apoptotic index as single variable showed no prognostic significance, whereas p53 was an independent predictor for both recurrence and survival, and bcl-2 was independently related to recurrence, but not to survival. Clinically, International Union Against Cancer stage and gender were independent prognostic factors after curative surgery for rectal cancer.
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  • 35
    ISSN: 1534-4681
    Keywords: Colorectal hepatic metastases ; Liver neoplasm ; Liver resection ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: Hepatic resection is potentially curative in selected patients with colorectal metastases. It is a widely held practice that multiple colorectal hepatic metastases are not resected, although outcome after removal of four or more metastases is not well defined. Methods: Patients with four or more colorectal hepatic metastases who submitted to resection were identified from a prospective database. Number of metastases was determined by serial sectioning of the gross specimen at the time of resection. Demographic data, tumor characteristics, complications, and survival were analyzed. Results: From August 1985 to September 1998, 155 patients with four or more metastatic tumors (range 4–20) underwent potentially curative resection by extended hepatectomy (39%), lobectomy (42%), or multiple segmental resections (19%). Operative morbidity and mortality were 26% and 1%, respectively. Actuarial 5-year survival was 23% for the entire group (median 5 32 months) and there were 12 actual 5-year survivors. On multivariate analysis, only number of hepatic tumors (P = .005) and the presence of a positive margin (P = .003) were independent predictors of poor survival. Conclusions: Hepatic resection in patients with four or more colorectal metastases can achieve long-term survival although the results are less favorable as the number of tumors increases. Number of hepatic metastases alone should not be used as a sole contraindication to resection, but it is clear that the majority of patients will not be cured after resection of multiple lesions.
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  • 36
    ISSN: 1569-8041
    Keywords: 5-fluorouracil ; antifolates ; apoptosis ; DNA repair ; p53 ; thymidylate synthase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Thymidylate synthase (TS) is an essential enzyme for the de novo synthesis of thymidylate and subsequently DNA synthesis. TS has been usedas a target for cancer chemotherapy in the development of fluoropyrimidinessuch as 5-fluorouracil (5-FU) and 5-fluorodeoxyuridine and of novelfolate-based TS inhibitors such as ZD1694 (Tomudex, Raltitrexed), ZD9331,LY231514 (ALIMTA, Pemetrexed), AG337 (Thymitaq, Nolatrexed) and AG331.Although TS has been considered as a target for chemotherapy, the precisemechanism by which TS inhibition leads to cell death is still not completelyresolved. TS inhibition results in depletion of dTTP, an essential precursorfor DNA, and an increase in dUTP. This results in the so-called thymine-lessdeath due to misincorporation of dUTP into DNA; its excision, catalysed byuracil-DNA glycosylase, results in DNA damage. Both this imbalance indTTP/dUTP and DNA damage can result in induction of downstream events, leadingto apoptosis. On the other hand a specific interaction exists betweenoncogenes and TS, by binding of TS protein to the p53and c-mycRNA, while wt p53can also inhibit TS promotor activity. TSinhibition by either 5-FU or antifolates can also result in a depression ofTS protein mediated inhibition of TS mRNA translation leading to induction ofmore TS protein synthesis, and p53protein may further deregulatethis process. These complex indirect and direct interactions between oncogenesand TS may have as yet unclear clinical implications, since most data arebased on in vitroor in vivo studies and some results arecontradictive. In some preliminary clinical studies evidence was postulatedfor a combined prognostic role for TS and p53.This knowledge shouldbe used to design clinical studies with the aim to deliver effective treatmentto potentially sensitive patients both in the adjuvant setting and in advancedstage disease.
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  • 37
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    Virus genes 20 (2000), S. 143-147 
    ISSN: 1572-994X
    Keywords: equine arteritis virus ; cell infection ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Equine arteritis virus (EAV) is the etiological agent of equine viral arteritis, a contagious viral disease of equids. EAV is the prototype virus of the arteriviruses, a group of small enveloped viruses with positive single-stranded RNA genomes. Because apoptosis or programmed cell death is believed to play an important role in the biogenesis of several cytopathogenic viruses, we examined whether EAV was able to induce cell apoptosis in vitro. To do this, Vero cells were infected with EAV at a multiplicity of infection of 0.1 tissue culture infectious dose (TCID50) per cell, and analyzed at various time intervals for the appearance of apoptotic signs. Fragmentation of chromosomal DNA into nucleosomal oligomers and caspase activation were observed in the infected cells at the time (e.g. 24 h postinfection) where a noticeable cytopathic effect was observed. The kinetics of the DNA fragmentation correlated with that of the production of progeny virus, so that viral multiplication was not interrupted by the apoptotic cell damage. All these data provide evidence that EAV is able to induce apoptotic cell death in vitro.
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  • 38
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    Virus genes 21 (2000), S. 13-25 
    ISSN: 1572-994X
    Keywords: adenovirus E3 proteins ; E3 protein sequence comparison ; immune evasion ; interference with antigen presentation ; CD95 (Fas/APO-1) ; apoptosis ; receptor down-regulation ; TNF mediated lysis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Persistent viruses have evolved multiple strategies to escape the host immune system. One important prerequisite for efficient viral reproduction in the face of an ongoing immune response is prevention of premature lysis of infected cells. A number of viruses achieve this goal by interfering with antigen presentation and recognition of infected cells by cytotoxic T cells (CTL). Another viral strategy aims to block apoptosis triggered by host defense mechanisms. Both types of strategies seem to be realized by human adenoviruses (Ads). The early transcription unit E3 of Ads encodes proteins that inhibit antigen presentation by MHC class I molecules as well as apoptosis induced by tumor necrosis factor α (TNF-α) and Fas ligand (FasL). Here, we will describe the organization of the E3 regions of different Ad subgroups and compare the structure and functions of the known immunomodulatory E3 proteins.
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  • 39
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    Virus genes 21 (2000), S. 97-109 
    ISSN: 1572-994X
    Keywords: myxoma virus ; immuno-modulator ; viroceptor ; TNF receptor ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Myxoma virus, a member of the poxvirus family of DNA viruses, encodes many virulence factors to combat and evade the host immune responses. Among the virus-encoded immuno-modulators is M-T2, a tumor necrosis factor receptor (TNF-R) homologue. M-T2 is secreted as monomeric and dimeric species that bind and inhibit rabbit TNF in a species-specific manner. Deletion analysis indicates that the anti-TNF function is mediated by the first three of four cysteine rich domains (CRDs) of M-T2. In addition, the intracellular form of M-T2 has the ability to block virus-induced apoptosis in lymphocytes, and the first two CRDs appear to be sufficient for this function. Although the mechanisms for the anti-TNF and anti-apoptotic functions of M-T2 are not yet fully defined, we postulate that these dual activities of M-T2 are mediated through different functional motifs and abrogate distinct cellular responses to virus infection.
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  • 40
    ISSN: 1572-994X
    Keywords: apoptosis ; bZIP ; coiled body ; herpesvirus ; Jun ; nucleolus ; oncogene ; transactivation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In order to adapt to and to cope with an often hostile host environment, many viruses have evolved to encode products that are homologous to cellular proteins. These proteins exploit the existing host machinery and allow viruses to readily integrate into the host functional network. As a result, viruses are able to maneuver their journey seemingly effortlessly inside the host cell to achieve ultimate survival. Such molecular mimicries sometime go overboard, allowing viruses to overtake the cellular pathways or evade the immune system as do many of the retroviral oncogenes. Retroviral oncogenes are derived directly from host genes, and they are virtually identical to host genes in sequences except those mutations that make them unregulatable by host. Oncogenic herpesviruses also encode oncogenes, or transforming genes, which have independently evolved and are distantly related to host genes. However, these genes do share consensus structural motifs with cellular genes involved in cell growth and apoptosis and are functional analogues to host genes. The Marek's disease virus oncoprotein, MEQ, is one such example. MEQ is a basic region-leucine zipper (bZIP) transactivator which shares extensive homology with the Jun/Fos family of transcription factors within the bZIP domain, but not in other regions. Like all other bZIP proteins, MEQ is capable of dimerizing with itself and with a variety of bZIP partners including c-Jun, B-Jun, c-Fos, CREB, ATF-1, ATF-2, and SNF. MEQ-Jun heterodimers bind to a TRE/CRE-like sequence in the meq promoter region and have been shown to up-regulate MEQ expression in both chicken embryo fibroblasts and F9 cells. In addition, the bZIP and transactivation domains are interchangeable between MEQ and c-Jun in terms of transforming potential; i.e. MEQ can functionally substitute for c-Jun. These properties enable MEQ to engage in host cell processes by disguising itself as c-Jun. On the other hand, there are properties of MEQ notably different from c-Jun, which include its capability to bind RNA, to bind a CACAC-bent DNA structure as a homodimer, to inhibit apoptosis, and to interact with CDK2. MEQ’s subcellular localization in the nucleolus and coiled body, is also different from Jun/Fos family of transactivators. These unique features may provide the MEQ with additional facility in regulating MDV replication, establishing latency, and cellular transformation. In this review, we will attempt to summarize the past research progress on MDV meq, with a focused on the similarities and differences between MEQ and cellular proteins, and between MEQ and other viral oncoproteins.
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  • 41
    ISSN: 1436-3305
    Keywords: Key words EGC ; Prognosis ; Treatment
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Background. During the 1970s, a special type of Gastric Cancer with excellent prognosis (early gastric cancer; EGC) was identified by the Japanese Research Society for Gastric Cancer. EGC has been defined as a tumor which invades the mucosa and/or submucosa, regardless of the lymph node status. Using this definition, we identified an initial phase of tumor development which could be treated both endoscopically and surgically. Methods. We examined 412 EGC patients, recruited between 1976 and 1999, with an average follow-up of 9 years. All tumors were classified according to the macroscopic and microscopic criteria proposed by the Japanese Society of Gastroenterological Endoscopy (JSGE) and Lauren, respectively. The infiltrative growth pattern was evaluated according to Kodama's classification. Only tumor-related death was considered as an end-point of interest for the survival analysis. Results. Submucosal tumors (P = 0.008), Pen A (see definition below) type disease (P = 0.0001), and lymph node-positive cancers (P = 0.0002) were significant prognostic factors on univariate analysis. Moreover, bivariate analysis showed that the worst prognosis, in terms of survival, was for patients with nodal involvment, submucosal invasion, and node-positive and Pen-A type cancer. The abbreviation Pen, penetrating, indicates a lesion with a diameter of less than 4 cm, which invades the submucosa diffusely. Pen A type EGC represents a subgroup of tumors which infiltrates the submucosa extensively, with nodular masses, causing the complete destruction of the muscularis mucosae. Conclusion. In our series, Pen A type was an important prognostic factor (hazard ratio; HR, 8.32; 95% confidence interval [CI], 3.49–19.86. For this reason, we believe it is important to evaluate the infiltration into the wall in all patients with EGC, paying particular attention to the growth pattern of the neoplasm. Moreover, submucosal Pen A type tumors had a considerably worse prognosis and this finding was reinforced when lymph node metastases coexisted. We suggest, therefore, that surgical treatment with at least a D2 lymphadenectomy is performed in all these patients, as the lesions must be considered to be advanced, no longer being EGC.
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  • 42
    ISSN: 1436-3305
    Keywords: Key words Tumor marker ; CEA ; CA19-9 ; Gastric cancer ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Background. This clinicopathological study evaluated the utility of serum carcinoembryonic antigen (CEA) and carbohydrate antigen (CA) 19-9 as predictors of locoregional recurrence and long-term disease-free survival in patients with gastric cancer. Methods. During the period January 1989 to December 1994, 485 patients with primary gastric cancer were evaluated. Gastrectomies were performed in 434 patients. Prognostic factors were analyzed by the Kaplan-Meier method and multivariate analysis, using Cox regression. Results. Elevated serum CEA and CA19-9 levels were observed in 92 of the 485 patients (19.0%), and in 95 of the 435 patients (21.8%), respectively, and both markers were elevated in 29 of these 435 patients (6.7%). Elevated serum CEA and CA19-9 levels correlated well with lymph node metastasis, lymphatic invasion, vessel invasion, stage grouping, depth of invasion, and curability. Patients with elevated serum CEA levels were at significantly higher risk of having all recurrence factors than were those with normal serum CEA levels. Patients with elevated serum CA19-9 levels were at significantly higher risk of having peritoneal metastases and distant metastases than were those with normal serum CA19-9 levels. A significant difference in the cumulative survival curves of patients was demonstrated between those with elevated and those with normal serum CEA or CA19-9 levels, even for patients at the same disease stage (stage III). Patients with elevated levels of both markers had a significantly worse prognosis than patients in whom the levels of both markers were normal. In patients who underwent gastrectomy, elevated serum CEA levels either preoperatively or within 3 weeks after gastrectomy were associated with significantly worse prognosis than were normal levels. When the cutoff level of serum CEA was increased to 10 ng/ml, serum CEA, age, lymph node metastasis, and surgical stage grouping were selected as independent prognostic factors by multivariate analysis of 14 prognostic factors, using Cox regression. Conclusion. Serum CEA and CA19-9 levels provide additional prognostic information in patients with primary gastric cancer. In particular, an elevated serum CEA level provides additional prognostic information and is a useful indicator of curability in patients who undergo gastrectomy. Serum CEA level is an independent prognostic factor in patients with primary gastric cancer.
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  • 43
    ISSN: 1436-2813
    Keywords: Key Words Adenosquamous carcinoma ; Remnant stomach ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We report herein the case of a 59-year-old man found to have adenosquamous carcinoma of the remnant stomach which demonstrated rapid progression. The patient was admitted to our hospital to undergo surgery for a papillary tumor of the remnant stomach. Total resection of the remnant stomach with lymph node dissection was performed, and pathological examination confirmed a diagnosis of adenosquamous carcinoma with invasion into the muscularis propria and lymph node metastasis around the perigastric areas. Multiple liver metastases were found 6 months after the operation, for which a right hepatectomy was performed with curative intent; however, he died 2 months later due to lymphangitis carcinomatosa of the lung.
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  • 44
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    Trauma und Berufskrankheit 2 (2000), S. S154 
    ISSN: 1436-6274
    Keywords: Schlüsselwörter ; Hinteres Kreuzband ; Isolierte Ruptur ; Therapie ; Prognose ; Key words ; Posterior cruciate ligament ; Isolated tears ; Treatment ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Abstract The treatment of injuries to the PCL is still controversial. There are still no answers to many questions on the biomechanics of PCL, the natural history of PCL injury, the surgical technique of PCL reconstruction and the biology of PCL healing. It is well established that primary repair of bony avulsions of the PCL provides good static and functional results. PCL tears should also be treated surgically in combined knee ligament injuries. For isolated midsubstance tears of the PCL, however, no prospective randomised long-term studies are available to date demonstrating that surgical treatment with current techniques leads to better results than nonoperative, functional treatment. Nonoperative management is advocated because the knee instability following isolated PCL midsubstance tear is only moderate, the natural history has been seen to end in acceptable functional stability, knee proprioception is preserved, and the incidence of late osteoarthritis is low.
    Notes: Zusammenfassung Die Behandlung von Rupturen des hinteren Kreuzbands wird international noch immer kontrovers diskutiert. Zahlreiche Fragen zur funktionellen Anatomie, zum Spontanverlauf nach Ruptur, zur chirurgischen Technik sowie zum Heilungsverlauf sind unbeantwortet. Gesichert ist, daß die primäre operative Versorgung von knöchernen Ausrissen des hinteren Kreuzbands zu guten Ergebnissen führt. Bei kombinierten Knieinstabilitäten sollte das verletzte hintere Kreuzband auch operativ versorgt werden. Für die isolierte, interligamentäre Ruptur des hinteren Kreuzbands konnte bisher jedoch mit keiner prospektiven, randomisierten Langzeitstudie bewiesen werden, daß die heutigen Operationsverfahren reproduzierbar zu besseren Ergebnissen führen als die konservativ-funktionelle Behandlung. Für die konservative Therapie sprechen die nur mäßige Instabilität nach isolierter Ruptur des hinteren Kreuzbands, der günstige Spontanverlauf und der Erhalt der Propriozeption des Kniegelenks sowie die im Verlauf nur geringe Arthroserate.
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  • 45
    ISSN: 1432-1335
    Keywords: Key words Blood group antigen ; ABH isoantigens ; Colorectal carcinoma ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The deletion of blood group ABH isoantigens on tumor tissues has been reported to be an adverse prognostic marker for patients with various solid tumors. In the present study, we evaluated the prognostic value of altered expression of ABH isoantigens in colorectal carcinomas. Using monoclonal antibodies, the expression of A, B, and H antigens was assessed by immunohistochemistry on paraffin-embedded carcinoma samples from 82 patients who had undergone surgery for colorectal cancer. ABH isoantigens were found to be deleted in 36 carcinomas (43.9%) and expressed in 46 (56.1%). Univariate and multivariate analysis using a logistic regression model revealed that N factor (lymph node metastasis) and blood group type were independently related to the expression of ABH isoantigens. In contrast to previous reports on other cancers, patients whose colorectal carcinomas express ABH isoantigens had a poorer prognosis than those whose carcinomas showed deletion of ABH isoantigens (P = 0.0008). The expression of ABH isoantigens was an independent prognostic variable, in addition to T (depth of tumor invasion), N, and M (distant metastasis) factors, as shown by means of Cox regression analysis. In conclusion, the expression of ABH isoantigens in carcinoma tissue is an important poor prognostic factor in patients with colorectal cancer. This variable needs to be considered in the design of future trials of therapy.
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  • 46
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    Journal of cancer research and clinical oncology 126 (2000), S. 280-284 
    ISSN: 1432-1335
    Keywords: Key words Thymoma ; Prognostic factors ; Prognosis ; DNA cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Purpose: The aim of this work was to evaluate the prognostic significance of DNA image cytometry in thymoma. Patients and methods: Image cytometric studies with an automatic video-based analysis system (LEYTAS) were carried out on 47 archival specimens from 36 patients with thymomas who underwent operation at a single institution from 1954 to 1992. The significance of aneuploidy DNA-content (5c-exceeding events), and nuclear size on stage and survival were evaluated. The median follow-up was 52.7 (6–164) months. Results: Masaoka's stage was predictive of aneuploidy (P 〈 0.01) and disease-free survival (P 〈 0.015). In stage I 18% of the tumors were aneuploid, in stage II 78%, in stage III 85% and in stage IV 100%. The occurrence of 5c-exceeding events was associated with both decreased disease-free survival (P 〈 0.01) and overall survival (P = 0.013). Nuclear size was not significantly correlated to stage. Under multivariate analysis, aneuploidy and DNA content failed to attain independent significance for stage, performance status, and histology. Conclusion: DNA image cytometry may provide additional information about the prognosis of resected thymoma.
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  • 47
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    Journal of neurology 247 (2000), S. 943-948 
    ISSN: 1432-1459
    Keywords: Key words Transverse myelitis ; Motor evoked potentials ; Somatosensory evoked potentials ; Electromyography ; Prognosis ; Magnetic resonance imaging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A systematic evaluation of anterior horn cell, motor and sensory pathways is possible by electromyography (EMG), motor (MEPs) and somatosensory (SEPs) evoked potentials, respectively, which may provide valuable information on acute transverse myelitis (ATM). In a prospective hospital-based study, EMG, MEP and SEP studies were carried out on admission and after 3 months in 39 patients with ATM. All the patients also underwent detailed clinical evaluation, and spinal magnetic resonance imaging (MRI) was performed in 28. Outcome was defined at the end of 3 months as poor, partial or complete recovery on the basis of functional status. Spinal MRI revealed hyperintense signal changes in T2 extending for two segments to the entire spinal cord. Central motor conduction time to tibialis anterior (CMCT-TA) was more frequently abnormal (90%), followed by tibial SEP (77%). CMCT to abductor digiti minimi (ADM) was abnormal in 30% and median SEP in 15% of patients. Evidence of denervation on EMG was present in 51% of patients. The CMCT-TA improved in 48% patients and tibial SEP in 32%. Median SEP improved in all patients, and CMCT-ADM remained prolonged in two. At 3 months 2 patients had died, and 18 had poor, 10 partial and 9 complete recovery. CMCT was correlated with miscle power, tone, reflec and MRI changes. Patients' outcome of was correlated with CMCT, SEP and EMG. These results are consistent with pronounced involvement of dorsal region of spinal cord in ATM. MEP is more frequently abnormal than SEP.
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  • 48
    ISSN: 1432-1459
    Keywords: Key words Sarcoidosis ; Spinal cord ; Magnetic resonance imaging ; Corticosteroid therapy ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Spinal cord sarcoidosis is a rare disorder whose natural history and therapeutic outcome are not fully known. We examined four patients with spinal cord sarcoidosis both clinically and radiologically, particularly in relation to corticosteroid treatment. The initial manifestation was cervical myelopathy in three and uveitis in one. All four patients progressed slowly until corticosteroid therapy was initiated. The cervial spine was involved in all patients. Magnetic resonance imaging (MRI) showed spinal cord swelling with T2-weighted high intensity and linear leptomeningeal and patchy or diffuse intramedullary enhancement with gadolinium diethylene triaminepentaacetic acid. With corticosteroid therapy, dramatic improvement was seen on MRI, including disappearance or marked reduction of swelling and enhancement. Plasma levels of angiotensin-converting enzyme (ACE) were also markedly improved. In contrast, the clinical symptoms were little improved in one patient, unchanged in two, and rather worsened in one patient. Recurrence was seen on MRI at the maintenance dose in all four patients, without any dramatic change in clinical manifestation. MRI findings and plasma ACE are well correlated with active leasion of the spinal cord sarcoidosis, providing a useful marker for recurrence, but do not parallel the clinical manifestations.
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  • 49
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    Bulletin of experimental biology and medicine 130 (2000), S. 957-960 
    ISSN: 1573-8221
    Keywords: human T lymphocytes ; staphylococcal enterotoxin B ; nitric oxide ; proliferation ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The involvement of nitric oxide (NO) in the regulation of human T cell response to bacterial superantigen (staphylococcal enterotoxin B) was studied. It was shown that stimulated T lymphocytes are the main source of NO. This superantigen markedly increased NO production and triggered the proliferative response of mononuclear cells from healthy individuals; the degree of apoptosis was low. In patients with purulent surgical diseases with high spontaneous and induced NO production, superantigen enhanced apoptosis of lymphocytes and induced anergy of T cells to enterotoxins. Increasing the concentration of NO in cultured cells from healthy individuals in the presence of NO donors also stimulated apoptosis and inhibited proliferative activity. These data suggest that NO regulates T lymphocyte response to superantigens. The increased production of NO probably contributes to the development of immunosuppression during bacterial infection.
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  • 50
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    Bulletin of experimental biology and medicine 130 (2000), S. 892-894 
    ISSN: 1573-8221
    Keywords: immune deficiency ; apoptosis ; lymphocytes ; neoplasms and autoimmune diseases
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract CD95 expression on peripheral blood lymphocytes in patients with neoplasms was higher than in patients with autoimmune disorders. Apoptosis of T cells increased during tumor growth. The data suggest that neoplasms are accompanied by more severe immune dysfunction than autoimmune disorders.
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  • 51
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    Bulletin of experimental biology and medicine 130 (2000), S. 912-916 
    ISSN: 1573-8221
    Keywords: whole-body hyperthermia ; hepatocytes ; alkaline dissociation of tissues ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract hyperthermia caused hemodynamic disorders in the liver and degenerative and necrobiotic changes in hepatocytes of CBA mice. Total hepatocyte count decreased during restitution, this decrease being most pronounced 30 min after exposure. The number of binucleated cells also markedly decreased. The absence of necrotic changes in hepatocytes during the entire restitution period indicated their apoptotic death and elimination by macrophagal resorption. Under these conditions liver regeneration at the cellular level occured mainly via division of binucleated hepatocytes. On the other hand, proliferation of oval cells in the portal zones and their differentiation into hepatocytes were observed at certain stages of reparative regeneration of the liver.
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  • 52
    ISSN: 1432-1238
    Keywords: Key words Mortality ; Oliguria ; Multiple organ failure ; Severity-of-illness ; Prognosis ; Scoring systems
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objectives: To describe risk factors for the development of acute renal failure (ARF) in a population of intensive care unit (ICU) patients, and the association of ARF with multiple organ failure (MOF) and outcome using the sequential organ failure assessment (SOFA) score. Design: Prospective, multicenter, observational cohort analysis. Setting: Forty ICUs in 16 countries. Patients: All patients admitted to one of the participating ICUs in May 1995, except those who stayed in the ICU for less than 48 h after uncomplicated surgery, were included. After the exclusion of 38 patients with a history of chronic renal failure requiring renal replacement therapy, a total of 1411 patients were studied. Measurements and results: Of the patients, 348 (24.7 %) developed ARF, as diagnosed by a serum creatinine of 300 μmol/l (3.5 mg/dl) or more and/or a urine output of less than 500 ml/day. The most important risk factors for the development of ARF present on admission were acute circulatory or respiratory failure; age more than 65 years, presence of infection, past history of chronic heart failure (CHF), lymphoma or leukemia, or cirrhosis. ARF patients developed MOF earlier than non-ARF patients (median 24 vs 48 h after ICU admission, p 〈 0.05). ARF patients older than 65 years with a past history of CHF or with any organ failure on admission were most likely to develop MOF. ICU mortality was 3 times higher in ARF than in other patients (42.8 % vs 14.0 %, p 〈 0.01). Oliguric ARF was an independent risk factor for overall mortality as determined by a multivariate regression analysis (OR = 1.59 [CI 95 %: 1.23–2.06], p 〈 0.01). Infection increased the risk of death associated with all factors. Factors that increased the ICU mortality of ARF patients were a past history of hematologic malignancy, age more than 65 years, the number of failing organs on admission and the presence of acute cardiovascular failure. Conclusion: In ICU patients, the most important risk factors for ARF or mortality from ARF are often present on admission. During the ICU stay, other organ failures (especially cardiovascular) are important risk factors. Oliguric ARF was an independent risk factor for ICU mortality, and infection increased the contribution to mortality by other factors. The severity of circulatory shock was the most important factor influencing outcome in ARF patients.
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  • 53
    ISSN: 1432-1238
    Keywords: Key words Cardiopulmonary bypass ; Coronary artery bypass graft ; Valve surgery ; Thoracic aortic surgery ; Prognosis ; Hypotension ; Systemic inflammatory response syndrome (SIRS) ; Procalcitonin ; Endotoxin
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: To investigate procalcitonin (PCT) levels in patients undergoing cardiopulmonary bypass (CPB) in order to assess the prevalence and prognostic capacity of elevated PCT levels following CPB in open heart surgery.¶Design: prospective observational study in consecutive patients.¶Setting: Twenty-four-bed ICU, department of thoracic and cardiovascular surgery, university hospital.¶Patients: Seven hundred and twenty two patients, 691 of whom underwent CPB, i. e., 476 had coronary bypass surgery (CABG), 130 valve replacement, 34 combined CABG and valve replacement, and 23 thoracic aortic surgery.¶Interventions: Standard perfusion techniques were used with cardioplegic arrest and mild hypothermia (28–32 °C). With the exception of thoracic aortic procedures, full–flow perfusion was performed.¶Measurements and results: PCT was measured prior to surgery and daily thereafter until ICU discharge or death. PCT significantly increased at day 1 postoperatively compared to baseline values (0.25 ± 1.65 vs 6.49 ± 22.0 ng/ml, p 〈 0.005). However, in 55.1 % of patients PCT was below 1.0 ng/ml. In 12.8 % of CABG patients PCT was increased to 〉 5.0 ng/ml, compared to 39 % in valve patients and 35 % of patients with aortic surgery. An elevated PCT level 〉 1.0–5.0 ng/ml at day 1 was highly predictive of mortality (P 〈 0.03, vs 〈 1.0 ng/ml), with an additional accuracy when levels 〉 5.0 ng/ml were measured (P 〈 0.002 vs 〈 1.0 ng/ml).¶Conclusions: These results provide evidence that PCT might serve as an early prognostic marker in patients undergoing CPB in open heart surgery. It may be worth considering immunomodulating approaches in patients presenting elevated PCT levels in the early phase after CPB.
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  • 54
    ISSN: 1439-0973
    Keywords: Key words Pneumonia ; Procalcitonin ; C-reactive protein ; Etiology ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Background: The diagnostic value of admission serum levels of procalcitonin (PCT) and C-reactive protein (CRP) as indicators of the etiology and prognosis was prospectively investigated. Patients: 96 patients, 50–85 years of age, treated in the hospital for community-acquired pneumonia (CAP). Results: On admission, all patients had elevated CRP levels (〉 10 mg/l), but only 60 patients (54%) had elevated PCT levels (〉 0.1 μg/l). The severity of disease measured by APACHE II score was strongly associated with admission levels of PCT (p = 0.006), but not with CRP. Eight of nine patients with pneumonia caused by atypical agents had PCT levels 〈 0.5 μg/l compared with 6/27 patients with pneumonia caused by classical bacterial pathogens, mainly Streptococcus pneumoniae (p = 0.03). No such correlation between CRP levels and etiology was found. Conclusion: Our data indicate that in patients admitted to the hospital with CAP, measurement of PCT gives information about the severity of the disease, and may aid the physician to differentiate typical bacterial etiology from atypical etiology, and thereby to choose appropriate initial antibiotic treatment.
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  • 55
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    Journal of clinical immunology 20 (2000), S. 229-239 
    ISSN: 1573-2592
    Keywords: Aging ; apoptosis ; TNF receptor ; Fas ; Fas ligand ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The cellular and molecular basis of immune senescence is unclear. A number of mechanisms have been proposed. In this issue of the Journal of Clinical Immunology, some of the mechanisms for various immunologic abnormalities in aging are presented. In this article, various molecular steps of both death receptor and mitochondrial pathways of apoptosis in general are reviewed. In particular, the role of apoptosis in T-cell immune senescence is discussed.
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  • 56
    ISSN: 1573-4919
    Keywords: tumour necrosis factor ; receptors ; subtypes ; calcium ; apoptosis ; cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Tumour necrosis factor-α (TNF) receptors mediate a variety of effects dependent on cell type. A role for Ca2+ in TNF-induced death remains uncertain. Here we investigated restricting intracellular/extracellular Ca2+ in HeLa epithelial carcinoma cells expressing low and high levels of p75TNFR receptor subtype and KYM-1 rhabdomyosarcoma cells, models of rapid TNF-induced apoptosis. Ca2+-chelators EGTA and BAPTA-AM as well as microsomal Ca2+-ATPase inhibitor thapsigargin, did not alter TNF-induced death. TNF was also unable to alter resting [Ca2+]i levels which remained 〈 200 nM even during times when these cells were undergoing apoptotic cell death. These findings indicate no role for modulated Ca2+ concentrations in TNF-induced apoptotic cell death.
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  • 57
    ISSN: 1573-4919
    Keywords: phosphatidylserine ; base exchange ; apoptosis ; thymocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The exposure of phosphatidylserine toward the external surface of the membrane is a well-established event of programmed cell death. The possibility that an apoptotic stimulus influences the metabolism of this phospholipid could be relevant not only in relation to the previously mentioned event but also in relation to the capability of membrane phosphatidylserine to influence PKC activity. The present investigation demonstrates that treatment of mouse thymocytes with the apoptotic stimulus dexamethasone, enhances the incorporation of [3H]serine into phosphatidylserine. Cell treatment with dexamethasone also enhanced the activity of serine base exchange enzyme, assayed in thymocyte lysate. Both the effects were observed at periods of treatment preceding DNA fragmentation. The addition of unlabelled ethanolamine, together with [3H]serine to the medium containing dexamethasone-treated thymocytes lowered the radioactivity into phosphatidylserine. Serine base exchange enzyme activity was influenced by the procedure used to prepare thymocyte lysate and was lowered by the addition of fluoroaluminate, that is widely used as a G-protein activator. The increase of serine base exchange enzyme activity induced by dexamethasone treatment was observed independently by the procedure used to prepare cell lysate and by the presence or absence of fluoroaluminate.
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  • 58
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    Molecular and cellular biochemistry 212 (2000), S. 35-43 
    ISSN: 1573-4919
    Keywords: cAMP ; CRE ; Cox-2 ; NO ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Previous studies revealed that expression and activation of cyclooxygenase-2 (Cox-2) conveyed a protective principle in murine macrophages, thus attenuating pro-apoptotic actions of chemotherapeutic agents or programmed cell death as a result of massive nitric oxide (NO) generation. Expression of Cox-2 was achieved by treatment of cells with lipopolysaccharide/interferon-γ or nontoxic doses of NO releasing agents. We reasoned E-type prostanoid formation, and in turn an intracellular cAMP increase as the underlying protective mechanism. To prove our hypothesis, we analyzed the effects of lipophilic cAMP-analogs on NO, cisplatin, or etoposide induced apoptosis in RAW 264.7 macrophages. Selected apoptotic parameters comprised DNA fragmentation (diphenylamine assay), annexin V staining of phosphatidylserine, caspase activity (quantitated by the cleavage of a fluorogenic caspase-3-like substrate Ac-DEVD-AMC), and mitochondrial membrane depolarisation (ΔΨ). Western blots detected accumulation of the tumor suppressor protein p53, relocation of cytochrome c to the cytosol, and expression of the anti-apoptotic protein Bcl-xL. Prestimulation with lipophilic cAMP-analogs attenuated apoptosis with the notion that cell death parameters were basically absent. To verify gene induction by cAMP in association with protection we established activation of cAMP response element binding protein (CREB) by gel-shift analysis and moreover, treated macrophages with oligonucleotides containing a cAMP-responsive element (CRE) in order to scavenge CREB. Decoy oligonucleotides, but not control oligonucleotides, attenuated cAMP-evoked protection and reestablished pro-apoptotic parameters. We conclude that gene induction by cAMP protects macrophages towards apoptosis that occurs as a result of excessive NO formation or addition of chemotherapeutica. Attenuating programmed cell death by the cAMP-signaling system may be found in association with Cox-2 expression and tumor formation.
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  • 59
    ISSN: 1573-4919
    Keywords: T-type Ca2+ channel ; polyglutamine-expanded androgen receptor ; CAG trinucleotide repeats ; spinobulbar muscular atrophy ; apoptosis ; motorneuron ; cell lines ; neuroblastoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract We have analyzed Ca2+ currents in two neuroblastoma-motor neuron hybrid cell lines that expressed normal or glutamine-expanded human androgen receptors (polyGln-expanded AR) either transiently or stably. The cell lines express a unique, low-threshold, transient type of Ca2+ current that is not affected by L-type Ca2+ channel blocker (PN 200-110), N-type Ca2+ channel blocker (ω-conotoxin GVIA) or P-type Ca2+ channel blocker (Agatoxin IVA) but is blocked by either Cd2+ or Ni2+. This pharmacological profile most closely resembles that of T-type Ca2+ channels [1-3]. Exposure to androgen had no effect on control cell lines or cells transfected with normal AR but significantly changed the steady-state activation in cells transfected with expanded AR. The observed negative shift in steady-state activation results in a large increase in the T-type Ca2+ channel window current. We suggest that Ca2+ overload due to abnormal voltage-dependence of transient Ca2+ channel activation may contribute to motor neuron toxicity in spinobulbar muscular atrophy (SBMA). This hypothesis is supported by the additional finding that, at concentrations that selectively block T-type Ca2+ channel currents, Ni2+ significantly reduced cell death in cell lines transfected with polyGln-expanded AR.
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  • 60
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    Molecular and cellular biochemistry 203 (2000), S. 59-71 
    ISSN: 1573-4919
    Keywords: PTEN tumor suppressor ; cyclin-dependent kinase inhibitors ; apoptosis ; chemosensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The recently discovered tumor suppressor gene PTEN has been found mutated in many types of advanced tumors. When introduced into tumor cells that lack the wild-type allele of the gene, PTEN was able to suppress the growth of these cells. Here, we have analyzed how PTEN might alter cell cycle-regulatory controls to achieve this growth-inhibitory effect. We found that overexpression of PTEN stimulates the synthesis of three inhibitors of cyclin-dependent kinases, p21WAF1, p27KIP1, and p57,KIP2. This effect is very specific, as the expression of other components of the cell cycle engine, various cyclins and cyclin-dependent kinases, is not affected. For p21WAF1 we show that this induction is due to the p53-independent transcriptional activation of its promoter. In addition, increased expression of PTEN rendered the cells more sensitive to apoptotic cell death. Therefore, our data suggest a two-fold mechanism of growth inhibition by PTEN: one that acts via the increased expression of CKIs such as p21WAF1, and another that augments the cellular propensity for apoptotic cell death.
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  • 61
    ISSN: 1573-4919
    Keywords: retinoic acid ; RARβ ; protein kinase A ; apoptosis ; caspase
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Both cAMP and retinoids play a role in cell differentiation and the control of cell growth. A site-selective cAMP analog, 8-Cl-cAMP and retinoic acid synergistically inhibit growth and induce apoptosis in certain cancer cells. In advanced or recurrent malignant diseases, retinoic acid (RA) is not effective even at doses that are toxic to the host. The objective of our present study was to examine the mechanism(s) of synergistic effects of retinoic acid (9-cis, 13-cis or all-trans RA) and 8-Cl-cAMP on apoptosis in human ovarian cancer NIH: OVCAR-3 and OVCAR-8 cells. RA induced growth inhibition and apoptosis in OVCAR-3 and OVCAR-8 cells. 8-Cl-cAMP acted synergistically with RA in inducing and activating retinoic acid receptor β (RARβ) which correlates with growth inhibition and apoptosis in both cell types. In addition, induction of apoptosis by RA plus 8-Cl-cAMP requires caspase-3 activation followed by cleavage of anti-poly(ADP-ribose) polymerase. Furthermore, mutations in CRE-related motif within the RARβ promoter resulted in loss of both transcriptional activation of RARβ and synergy between RA and 8-Cl-cAMP. RARβ expression appears to be associated with induction of apoptosis. Introduction of the RARβ gene into OVCAR-3 cells resulted in gain of RA sensitivity. Loss of RARβ expression, therefore, may contribute to the tumorigenicity of human ovarian cancer cells. Thus, combined treatment with RA and 8-Cl-cAMP may provide an effective means for inducing RARβ expression leading to apoptosis in ovarian cancer cells.
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  • 62
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    Molecular and cellular biochemistry 204 (2000), S. 83-88 
    ISSN: 1573-4919
    Keywords: FHIT ; cell cycle ; ecdysone ; tumor suppressor ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The mechanism of tumor suppressor action of the fragile histidine triad (FHIT) gene is unknown. Disruption of cell cycle regulation leads to the tumor formation and many tumor suppressor genes suppress tumorigenesis through their effect on cell cycle regulation. We examined the expression of FHIT during the cell cycle, and determined whether overexpression of FHIT affects cell cycle kinetics and apoptosis. The FHIT cDNA was cloned into the ecdysone-inducible expression vector in both the sense and antisense orientations. Overexpression of the sense or antisense construct did not affect cell proliferation, cell cycle distribution or apoptosis in human 293T cells. Analysis of the FHIT expression in 293T cells collected at various cell cycle phases showed that the expression of FHIT is not under cell cycle regulation. These results indicate that the tumor suppressor activity of the FHIT gene may be independent of an effect on the cell cycle and apoptosis mechanisms.
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  • 63
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    Molecular and cellular biochemistry 207 (2000), S. 19-27 
    ISSN: 1573-4919
    Keywords: PKC ; apoptosis ; bile acid ; hepatocyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The effect of GCDC-induced apoptosis on PKC activity and PKC's role in GCDC-induced hepatocyte apoptosis is unclear. The specific aims of this study were to determine if GCDC-induced apoptosis changed intracellular PKC activity and if modulation of PKC activity affected GCDC-induced hepatocyte apoptosis. Apoptosis was induced in isolated hepatocytes using GCDC. PKC activity was measured and specific PKC and calpain inhibitors were used to study the effects of PKC and calpain modulation on GCDC-induced apoptosis. After 4 h exposure, 50 μM GCDC induced apoptosis in 42% of hepatocytes. Intracellular PKC activity decreased to 44% of controls 2 h after exposure of hepatocytes to GCDC (p 〈 0.001). Pre-incubation of hepatocytes with the calpain protease inhibitor restored PKC activity in GCDC exposed hepatocytes to 91± 5% of control cells. Pre-incubation of hepatocytes with a calpain inhibitor decreased GCDC-induced apoptosis as did pre-incubation with the PKC activating phorbol ester, PMA. The combination of calpain inhibition and PMA further reduced GCDC-induced apoptosis but caused low level hepatic apoptosis. Inhibition of PKC with chelerythrine also substantially reduced GCDC-induced hepatocyte apoptosis. GCDC-induced apoptosis is associated with decreases in total cellular PKC activity, which appear to be dependent on intracellular calpain-like protease activity. The combination of protease inhibition and phorbol ester pretreatment preserved total cellular PKC activity and decreased GCDC-induced apoptosis but induced low level apoptosis in the absence of GCDC exposure. PKC inhibition also decreased GCDC-induced hepatocyte apoptosis highlighting the complex interactions of PKC and proteases during GCDC-induced apoptosis.
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  • 64
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    Molecular and cellular biochemistry 212 (2000), S. 19-28 
    ISSN: 1573-4919
    Keywords: melanoma ; transcription factors ; CREB ; invasion ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract The purpose of this study was to determine the role of CREB and its associated proteins in melanoma progression. We used MeWo human melanoma cells transfected with a dominant negative construct of CREB, KCREB. KCREB has a mutation in its DNA-binding domain and can not bind the CRE element. Expression of KCREB yields proper heterodimerization with CREB and its associated proteins, but the proteins associated with KCREB do not confer the same degree of transcriptional activity as they would in the case of wild-type CREB. Here, we demonstrate that expression of KCREB in MeWo melanoma cells leads to a decrease in their tumorigenicity and metastatic potential in nude mice. We identified two mechanisms that explain at least partially this effect of KCREB. The first, is one in which CREB and its associated proteins play an essential role in invasion. We showed that the invasive properties of KCREB-transfected MeWo cells were reduced due to the downregulation of the CRE-dependent expression of the type IV collagenase MMP-2 and the adhesion molecule MCAM/MUC18. In the second mechanism, CREB and its associated proteins act as survival factors for human melanoma cells. Here we demonstrated that expression of KCREB in MeWo cells rendered them susceptible to apoptosis induced by thapsigargin, which in turn increased the intracellular level of Ca2+. Thapsigargin induced CREB and ATF-1 phosphorylation and activated CRE-dependent transcription in MeWo cells. Collectively, our data demonstrate that CREB and its associated proteins play an important role in tumor growth and metastasis of human melanoma.
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  • 65
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    Cancer and metastasis reviews 19 (2000), S. 87-92 
    ISSN: 1573-7233
    Keywords: angiogenesis ; endothelial cell survival ; apoptosis ; thrombospondin-1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Angiogenesis is a process of capillary formation from pre-existing blood vessels. It is tightly controlled by the balance between positive and negative environmental signals – inducers and inhibitors of angiogenesis in such a way that predominance of inducers results in angiogenesis and predominance of inhibitors – in vascular quiescence. Here we discuss the ability of the angiogenic stimuli to promote survival and the pathways they may utilize. We also summarize information available on the signaling events elicited in the endothelial cells by a naturally occurring inhibitor of angiogenesis Thrombospondin-1 (TSP-1), that result in the endothelial cell apoptosis and inhibition of angiogenesis in vivo. This ability to cause programmed cell death in vascular endothelium is not unique to TSP-1. A substantial number of known angiogenesis inhibitors can also trigger apoptosis in the activated endothelial cells. This fact argues for the possibility of apoptosis to be a common denominator for a major fraction of anti-angiogenic molecules. If this is the case, it is equally possible that the ratio between environmental factors that control angiogenesis is interpreted within individual endothelial cell as a balance between pro-apoptotic and survival signals. Thus the relative strength of the death and survival signal or signals determines the fate of endothelial cell and therefore the fate of remodeling vessel.
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  • 66
    ISSN: 1573-7039
    Keywords: estrous cycle ; mammary gland ; rat ; proliferation ; differentiation ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The Sprague-Dawley rat is highly regarded for studies designed to investigate the effects of endocrine modulation on mammary carcinogenesis. In this study, we further evaluate the validity of the Sprague-Dawley rat model for the study of human breast cancer by evaluating the effects of normal 4-day estrous cycling on mammary epithelial cell proliferation, differentiation, and apoptotic death. Trends in mammary gland development with stage of 4-day estrous cycle were evident. Mammary glands isolated from follicular and early luteal stages had predominantly ductal histoarchitecture, whereas glands isolated from mid-late luteal were predominantly lobuloalveolar. Quantitation of BrdU incorporation revealed that epithelial cell proliferation was eight-fold higher in metestrus and diestrus-1 than in proestrus. Expression of β-casein and whey acidic protein (WAP)4 mRNA was also highly dependent on stage of estrous, with detection restricted to midcycle. Apoptotic cell death of mammary epithelium was found to be suppressed during the peak in cell proliferation. TRPM-2/clusterin mRNA was elevated when apoptosis was low and milk protein mRNA levels were high, consistent with putative roles for TRPM-2/clusterin in inhibiting cell death in regressing tissues and inducing mammary epithelial cell differentiation. Cell proliferation, differentiation, and death occurred only in a subset of epithelial cells per estrous cycle, and these cells appeared randomly distributed throughout multiple ductules and alveoli. These observations suggest that cellular response(s) to ovarian hormone-dependent signals is asynchronous. Cumulatively, these observations demonstrate that rat mammary epithelial cell proliferation, differentiation, and death are under the control of cycling ovarian hormones, similarly to the human mammary epithelium during the menstrual cycle.
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  • 67
    ISSN: 1573-7276
    Keywords: apoptosis ; butyrate ; cell cycle ; cholesteryl butyrate ; drug delivery ; melanoma ; solid lipid nanospheres
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Literature data show that butyric acid derivatives bear a dose-dependent differentiative anti-proliferative activity on cancer cell lines and that apoptosis induction may play a major role. Although it was recently shown that solid lipid nanospheres (SLNs) are a suitable tool for several in vivo drug administration routes, there is little available information on melanoma cell lines. This study was aimed at evaluating the anti-proliferative and apoptotic in vitro effects of cholesteryl butyrate (chol-but) SLNs on melanoma cells. Increasing concentrations of chol-but SLNs were used to test two melanoma cell lines. Both cell lines were treated with Na-butyrate (Na-but) and chol-but SLNs for viability. Those tested with chol-but SLNs were more effective than Na-butirate (3 to 72 h). The apoptotic effects of chol-but SLNs were evaluated between 3 and 72 h by annexin-V (ANX-V)/propidium iodide (PI) staining and the antiproliferative effect by PI staining. Apoptosis anti-proliferative-regulatory proteins as bcl-2, Fas/APO1 (CD95) and PCNA (PC10) were also investigated. Flow cytometric analyses evidenced a G0/1-S transition block and a `sub-G0/1' apoptotic peak from 0.5 to 1.0 mM butyric acid. In ANX-V/PI flow cytometric staining, a dose- and time-dependent increase in the apoptotic cell percentage (ANX-V+) coupled with a down-regulation of PC10 and bcl-2 and a parallel up-regulation of Fas/APO1 (CD95) were found in both lines started after 3 to 24 h of chol-but SLNs treatment. Results show that chol-but SLNs exerts a dose/time-dependent effect in melanoma cell apoptosis induction between 3 and 24 h and a dose but not time-dependent effect after 24 h of treatment.
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  • 68
    ISSN: 1573-7284
    Keywords: Epidemiology ; Meningococcal ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Study objective: To review the epidemiology of meningococcal disease in Malta over the period 1994–1998, and to identify factors at presentation and in the management of meningococcal disease which may influence mortality. Design: All admissions with meningococcal disease to a national hospital in a population-based study over the period 1994–1998 were studied retrospectively. Main results: Fifty-six cases were diagnosed over 1994–1998, the incidence rising from 0.8/100,000 to 7.2/100,000 total population (p 〈 0.0001). The median time interval from arrival at hospital to administration of parenteral antibiotic decreased over the 5-year period from 4.4 to 1.2 hours (p = 0.025), with no significant change in the case-fatality rate. There was no association between the time interval from arrival at hospital to parenteral antibiotic administration, and mortality. The following features at presentation were associated with increased mortality: older age (p = 0.03), meningococcaemia compared with meningitis (p = 0.05), shock (p 〈 0.0001), disseminated intravascular coagulation (p = 0.0001), a normal/low white blood cell count (p = 0.0003), a low platelet count (p = 0.0001) and a high serum creatinine (p = 0.003). Conclusions: The upsurge of cases in the population was accompanied by a decrease in intervention time in the general hospital, probably due to increased awareness of the disease. This study did not show a positive relationship between early in-hospital administration of antibiotics and improved survival, probably because antibiotics were given earlier to those with fulminant disease and, with therefore, an inherently worse outcome. Stratification of cases by severity on admission is recommended in future studies.
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  • 69
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    Journal of assisted reproduction and genetics 17 (2000), S. 168-173 
    ISSN: 1573-7330
    Keywords: Aging ; apoptosis ; granulosa cells ; in vitro fertilization ; oocyte quality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The objective was to determine the effects of women'sage on the ovarian fecundity as assessed by the incidenceof apoptotic granulosa cells. Methods: Twenty-eight normo-ovulatory women underwentovulation induction for standard IVF. The husbands of thesewomen showed severe male infertility factors. The womenwere divided into four groups according to their ages. Womenunderwent follicle aspiration after the administration ofhuman menopausal gonadotropin plus human chorionicgonadotropin. The nuclei of granulosa cells were examinedby using fluorescence microscopy, and the incidence of apoptotic granulosa cells was tabulated. Results: Granulosa cells in the older women revealed asignificant increase in the number of apoptotic cells. Thenumber of total oocytes and the number of mature oocytesobtained significantly decreased with age. However, endometrial thickness and follicular estradiol, progesterone, andfree testosterone levels were not significantly different amongfour different age groups. Conclusions: Age increases apoptotic changes in granulosacells and consequently decreases the ovarian fecundity.
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  • 70
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    Journal of bioenergetics and biomembranes 32 (2000), S. 15-25 
    ISSN: 1573-6881
    Keywords: Mitochondria ; endoplasmic reticulum ; Ca2+ ; IP3 ; local signaling ; energy metabolism ; apoptosis ; necrosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Many agonists bring about their effects on cellular functions through a rise incytosolic [Ca2+]([Ca2+]c) mediated by the second messenger inositol 1,4,5-trisphosphate (IP3). Imaging studiesof single cells have demonstrated that [Ca2+]c signals display cell specific spatiotemporalorganization that is established by coordinated activation of IP3 receptor Ca2+ channels.Evidence emerges that cytosolic calcium signals elicited by activation of the IP3 receptors areefficiently transmitted to the mitochondria. An important function of mitochondrial calciumsignals is to activate the Ca2+-sensitive mitochondrial dehydrogenases, and thereby to meetdemands for increased energy in stimulated cells. Activation of the permeability transitionpore (PTP) by mitochondrial calcium signals may also be involved in the control of cell death.Furthermore, mitochondrial Ca2+ transport appears to modulate the spatiotemporal organizationof [Ca2+]c responses evoked by IP3 and so mitochondria may be important in cytosolic calciumsignaling as well. This paper summarizes recent research to elucidate the mechanisms andsignificance of IP3-dependent mitochondrial calcium signaling.
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  • 71
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    Journal of bioenergetics and biomembranes 32 (2000), S. 35-46 
    ISSN: 1573-6881
    Keywords: Ca2+ signaling ; inositol 1,4,5-trisphosphate receptor ; mitochondrial Ca2+ uptake ; mitochondrial Ca2+ efflux ; permeability transition ; apoptosis ; Bcl-2 family
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Physics
    Notes: Abstract Cellular Ca2+ signals are crucial in the control of most physiological processes, cell injuryand programmed cell death; mitochondria play a pivotal role in the regulation of such cytosolicCa2+ ([Ca2+]c) signals. Mitochondria are endowed with multiple Ca2+ transport mechanismsby which they take up and release Ca2+ across their inner membrane. These transport processesfunction to regulate local and global [Ca2+]c, thereby regulating a number of Ca2+-sensitivecellular mechanisms. The permeability transition pore (PTP) forms the major Ca2+ effluxpathway from mitochondria. In addition, Ca2+ efflux from the mitochondrial matrix occursby the reversal of the uniporter and through the inner membrane Na+/Ca2+ exchanger. Duringcellular Ca2+ overload, mitochondria take up [Ca2+]c, which, in turn, induces opening of PTP,disruption of mitochondrial membrane potential (ΔΨm) and cell death. In apoptosis signaling,collapse of ΔΨ;m and cytochrome c release from mitochondria occur followed by activationof caspases, DNA fragmentation, and cell death. Translocation of Bax, an apoptotic signalingprotein from the cytosol to the mitochondrial membrane, is another step during thisapoptosis-signaling pathway. The role of permeability transition in the context of cell death in relationto Bcl-2 family of proteins is discussed.
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  • 72
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    Neurochemical research 25 (2000), S. 71-76 
    ISSN: 1573-6903
    Keywords: Arginylation ; post-translational modification ; apoptosis ; PC12 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The aim of this study was to analyze the N-terminal post-translational incorporation of arginine into cytosolic proteins from cultured cells and the in vitro incorporation of arginine into soluble proteins of PC12 cells after serum deprivation. Arginine incorporation was measured in the presence of protein synthesis inhibitors. None of the inhibitors used affected significantly the arginylation reaction while the novo synthesis of protein was reduced by 98%. Under these conditions, we found that of the total [14C]arginine incorporated into the proteins, around 20% to 40% was incorporated into the N-terminal position of soluble proteins by a post-translational mechanism. These results suggest that this post-translational aminoacylation may be a widespread reaction in neuronal and non-neuronal cells. We also found that in PC12 cells, the in vitro post-translational arginylation was 60% higher in apoptotic cells with respect to control cells. These findings suggest that the post-translational arginylation of proteins may be involved in programmed cell death.
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  • 73
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    Neurochemical research 25 (2000), S. 341-347 
    ISSN: 1573-6903
    Keywords: Neuronal survival ; apoptosis ; Heat-Shock Proteins ; HSP-70 ; NMDA
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cerebellar granule cells (CGC) die apoptotically after five days in culture (DIV) at physiological concentrations of potassium (5 mM; K5). When CGC are depolarized (K25) or treated with NMDA (150 μM) cell survival is increased. CGC changed from K25 to K5 die after 24–48 h. It is known that heat shock protein (HSP) may protect from cell death. Here, we found that cells in K5 showed an increase in HSP-70 levels after 3 DIV. Similarly, in cells changed from K25 to K5, HSP-70 levels were increased after 6 h. Neither NMDA nor K25 treatment affected HSP-70 levels from 2–7 DIV. Ethanol or thermal stress induced HSP-70, but cell survival was not affected in K5 medium. These results suggest that HSP, particularly HSP-70, are not involved in the mechanisms by which NMDA and KCl promote cell survival.
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  • 74
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    Breast cancer research and treatment 62 (2000), S. 223-235 
    ISSN: 1573-7217
    Keywords: adriamycin ; apoptosis ; DNA damage ; growth arrest ; ionizing radiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Breast tumor cells are relatively refractory to apoptosis in response to modalities which induce DNA damage such as ionizing radiation and the topoisomerase II inhibitor, adriamycin. Various factors which may modulate the apoptotic response to DNA damage include the p53 status of the cell, levels and activity of the Bax and Bcl-2 families of proteins, activation of NF-kappa B, relative levels of insulin like growth factor and insulin-like growth factor binding proteins, activation of MAP kinases and PI3/Akt kinases, (the absence of) ceramide generation and the CD95 (APO1/Fas) signaling pathway. Prolonged growth arrest associated with replicative senescence may represent an alternative and reciprocal response to DNA-damage induced apoptosis that is p53 and/or p21waf1/cip1 dependent while delayed apoptosis may occur in p53 mutant breast tumor cells which fail to maintain the growth-arrested state. Clearly, the absence of animmediate apoptotic response to DNA damage does not eliminate other avenues leading to cell death and loss of self-renewal capacity in the breast tumor cell. Nevertheless, prolonged growth arrest (even if ultimately succeeded by apoptotic or necrotic cell death) could provide an opportunity for subpopulations of breast tumor cells to recover proliferative capacity and to develop resistance to subsequent clinical intervention.
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  • 75
    ISSN: 1573-7217
    Keywords: adriamycin ; apoptosis ; breast tumor cells ; EB 1089 ; vitamin D
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Exposure of MCF-7 breast tumor cells to the vitamin D3 analog, EB 1089 enhances the response to adriamycin. Clonogenic survival studies indicate that EB 1089 shifts the dose-response curve for sensitivity to adriamycin by approximately six-fold in p53 wild-type MCF-7 cells; comparative studies in MCF-7 cells with a temperature-sensitive dominant negative p53 mutation show less than a two-fold shift in adriamycin sensitivity in the presence of EB 1089. The combination of EB 1089 with adriamycin also promotes apoptotic cell death in the p53 wild-type MCF-7 cells but not in the MCF-7 cells expressing mutant p53. EB 1089 treatment blocks the increase in p21waf1/cip1 levels induced by adriamycin and interferes with induction of MAP kinase activity by ionizing radiation, effects which could be related to the capacity of EB 1089 to promote secretion of insulin-like growth factor binding protein. Taken together with our previous findings that EB 1089 enhances breast tumor cell sensitivity to ionizing radiation, there studies further support the concept that vitamin D3 analogs could have utility in combination with conventional chemotherapy and/or radiotherapy in the treatment of breast cancer.
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  • 76
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; melatonin ; retinoic acid
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract It has been established that melatonin (Mlt) and retinoic acid, individually, inhibit the proliferation of the estrogen receptor-alpha (ERα)-positive MCF-7 breast cancer cell line. Our laboratory has previously demonstrated that Mlt and all-trans-retinoic acid (atRA) not only inhibit the proliferation, but also induce apoptosis of MCF-7 cells when used in a sequential regimen of Mlt followed 24 h later by atRA. Using this same MCF-7 breast cancer cell line, we investigated the potential pathways through which apoptosis is being induced. We found that treatment of MCF-7 cells with Mlt for 24 h before the addition of atRA decreased the protein levels of the death suppressor, Bcl-2, and increased, although with different time courses, the levels of the death promoters, Bax and Bak; however, there was no change in the levels of the tumor suppressor gene, p53. MCF-7 cells treated sequentially with Mlt and atRA also demonstrated an enhanced sensitivity to the apoptotic effects of atRA, which did not appear to be due to increased expression of the retinoic acid receptors, RARα or RXRα, but rather to enhanced transcriptional activity of the RARα. These data suggest that the sequential treatment regimen of Mlt and atRA may induce apoptosis by modulation of members of the Bcl-2 family of proteins. Thus, this combinatorial regimen, which reduces the concentration of atRA needed for clinical efficacy while enhancing its anti-tumorigenic activity, could be of great therapeutic benefit, and may, in fact, specifically induce the regression of established breast tumors due to its apoptosis-promoting effects.
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  • 77
    ISSN: 1573-7217
    Keywords: antisense oligodeoxynucleotides ; antineoplastic agents ; apoptosis ; Bcl-2 ; breast cancer ; chemosensitization
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have investigated the effects of transient Bcl-2 down-regulation induced by the Bcl-2 antisense oligodeoxynucleotide (ODN) G3139 (Genta Incorporated) in high Bcl-2 protein expressing, estrogen receptor (ER) positive MCF-7 and low Bcl-2 expressing, ER negative MDA435/LCC6 human breast cancer cells. Treatment with Bcl-2 antisense ODN in vitro caused 〉 80% reduction of Bcl-2 protein levels in a sequence specific manner for both cell lines. Maximum mRNA reduction was achieved within 24 h of the first antisense ODN exposure whereas full protein down-regulation required antisense exposure over 48 h. This Bcl-2 reduction was associated with 80–95% loss of viable cells compared to untreated cells. Similar cytotoxic effects were observed in both cell lines despite a nine-fold intrinsic difference in Bcl-2 protein expression suggesting that the relative degree of down-regulation of Bcl-2 is more important than the absolute reduction. Cell death associated with G3139 exposure exhibited properties indicative of apoptosis such as mitochondrial membrane depolarization and caspase activation. Combined treatment with G3139 and cytotoxic agents resulted in additive cytotoxicity in both cell lines. However, under most conditions studied, the direct cytotoxic activity of G3139 antisense was not synergistic with the cytotoxic agents. These results suggest that while Bcl-2 clearly constitutes an attractive therapeutic target due to its role in regulating apoptosis in breast cancer cells, additional mechanisms are important in the control of apoptosis arising from exposure to anticancer agents in vitro.
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  • 78
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; caspases ; NF-κB ; TRAIL
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Most breast cancer cell lines are resistant to TNF-related apoptosis inducing ligand (TRAIL) induced apoptosis. In sensitive breast cancer cell lines TRAIL rapidly induces the cleavage and activation of caspases leading to the subsequent cleavage of downstream caspase substrates. In contrast, there is no caspase activation in the resistant cell lines. The transcription factor NF-κB can inhibit apoptosis induced by a variety of stimuli including activation of death receptors. We investigated whether NF-κB contributes to the resistance of breast cancer cells to TRAIL induced apoptosis. All of the resistant breast cancer cell lines expressed NF-κB and had detectable NF-κB activity in nuclear extracts prior to treatment with TRAIL. Upon TRAIL treatment, a significant increase in NF-κB activity was seen in most of the cell lines. To directly test if NF-κB activity contributes to the resistance of these cell lines to TRAIL, we transiently transfected the resistant cell lines with an inhibitor of NF-κB (IκBΔN) and measured TRAIL induced apoptosis in control and transfected cells. All of the resistant cell lines tested showed an increase in TRAIL induced apoptosis when transfected with the IκBΔN. These results demonstrate that TRAIL resistant breast cancer cells fail to rapidly activate the apoptotic machinery but they do activate NF-κB. Inhibition of NF-κB activity increases the sensitivity to TRAIL mediated apoptosis in resistant cells. These results suggest that agents which inhibit NF-κB should increase the clinical efficacy of TRAIL in breast cancer cells.
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  • 79
    ISSN: 1573-7217
    Keywords: apoptosis ; breast cancer ; continuous variables statistical analysis ; cytokeratins ; multiple correspondence analysis ; prognosis ; tissue cytosol ; tissue polypeptide antigen (TPA)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apoptosis is associated with caspase-mediated proteolysis of Type I (K18 and K19) cytokeratins. We previously showed a positive association between the levels of tissue polypeptide antigen (TPA), that recognizes cytokeratins K8, K18, and K19 fragments, and induced apoptosis in breast cancer cell lines. The aim of the present study was to evaluate the interrelationships between TPA, steroid receptors, and p53, and their joint prognostic role in node-negative breast cancer patients not treated with adjuvant therapies. Age and pT were also considered since they are known prognostic factors. Five hundred and ninety-nine cases with N- breast cancer were evaluated (median follow-up: 60 months). TPA was measured by an immunoradiometric assay and p53 by an immuno-chemiluminescent assay in tumor cytosol. Multiple correspondence analysis was used to study the associations among variables. Their prognostic role (univariate analysis) and their joint effect (multivariate analysis) on RFS were investigated with Cox regression models. TPA showed a direct association with ER and PgR. Higher p53 values were weakly associated to low values of ER, PgR, and TPA. Younger age was related to low and intermediate values of ER and PgR and to low p53 values, while older age was related to high values of ER. Multivariate analysis showed a significant prognostic impact for pT, age, ER, and TPA. Among the interactions considered clinically relevant, only that between ER and age was found. RFS estimated values were poorer in cases with lower than in those with higher TPA values, both in patients expected to have a poor (pT2, young age, low ER) and a better prognosis (pT1, older age, high ER). From the findings of the present study we can draw the following conclusions: The relationship of TPA with prognosis gives an additional contribution to pT, age, and steroid receptors in N- breast cancer; TPA may be considered the first marker of apoptosis measured with a fully standardized quantitative method in tumor cytosol and could be evaluated in prognostic indexes including markers related to different biological mechanisms.
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  • 80
    ISSN: 1573-7217
    Keywords: reversal ; paclitaxel ; resistance ; P-glycoprotein ; breast cancer ; valspodar ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Paclitaxel (Taxol®) kills tumor cells by inducing both cellular necrosis and apoptosis. A major impediment to paclitaxel cytotoxicity is the establishment of multidrug resistance whereby exposure to one chemotherapeutic agent results in cross-resistance to a wide variety of other drugs. For example, selection of MCF-7 breast cancer cells for resistance to doxorubicin (MCF-7ADR cells) results in cross-resistance to paclitaxel. This appears to involve the overexpression of the drug transporter P-glycoprotein which can efflux both drugs from tumor cells. However, MCF-7ADR cells possess a deletion mutation in p53 and have considerably reduced levels of the Fas receptor, Fas ligand, caspase-2, caspase-6, and caspase-8, suggesting that paclitaxel resistance may also stem from a bona fide block in paclitaxel-induced apoptosis in these cells. To address this issue, we examined the ability of the P-glycoprotein inhibitor valspodar to restore paclitaxel accumulation, paclitaxel cytotoxicity, and paclitaxel-induced apoptosis. Compared to drug sensitive MCF-7 cells, MCF-7ADR cells accumulated 〉6-fold less paclitaxel, were approximately 100-fold more resistant to killing by the drug, and were highly resistant to paclitaxel-induced apoptosis. In contrast, MCF-7ADR cells pretreated with valspodar were indistinguishable from drug-sensitive cells in their ability to accumulate paclitaxel, in their chemosensitivity to the drug, and in their ability to undergo paclitaxel-induced apoptosis. Valspodar, by itself, did not affect these parameters. This suggests that the enhancement of paclitaxel toxicity in MCF-7ADR cells involves a restoration of apoptosis and not solely through enhanced drug-induced necrosis. Morever, it appears that changes in the levels/activity of p53, the Fas receptor, Fas ligand, caspase-2, caspase-6, or caspase-8 activity have little effect on paclitaxel-induced cytotoxicity and apoptosis in human breast cancer cells.
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  • 81
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    Pharmaceutical research 17 (2000), S. 515-520 
    ISSN: 1573-904X
    Keywords: apoptosis ; cationic liposome ; B cell ; WEHI 231 ; reactive oxygen species
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. Liposomes are of considerable interest as drug carriers andimmunoadjuvants. However, few investigators have studied thechanges exerted by liposomes in the cells with which they interact.The purpose of this study was to investigate whether liposomes induceapoptosis in B cells. Methods. The mouse immature B cell line WEHI 231 cells and mousesplenic B cells were treated with liposomes, and the induction ofapoptosis was evaluated by monitoring changes in DNA content, DNAfragmentation and chromatin condensation by flow cytometry, agarosegel electrophoresis and by morphological investigation. Results. Cationic liposomes induced apoptosis in WEHI 231 cells, butneutral and anionic liposomes did not. A contact time of 30 minbetween WEHI 231 cells and cationic liposomes was sufficient toinduce apoptosis, and 80% of the cells showed hypodiploid DNAcontent. Apoptosis induced by cationic liposomes composed ofstearylamine was inhibited by addition of the oxidant scavenger,N-acetyl-cysteine. Conclusions. Cationic liposomes induced apoptosis in WEHI 231 cells,and the production of reactive oxygen species is important in theregulation of apoptosis induced by cationic liposomes. It is well knownthat cationic liposomes show cytotoxicity, and apoptosis may be oneof the causes of this toxicity.
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  • 82
    ISSN: 1573-8469
    Keywords: apoptosis ; bacteria ; chromatin condensation ; DNA degradation analysis ; plant ; programmed cell death
    Source: Springer Online Journal Archives 1860-2000
    Topics: Agriculture, Forestry, Horticulture, Fishery, Domestic Science, Nutrition
    Notes: Abstract Ultrastructural details of the hypersensitive reaction induced by infiltration with avirulent race 2 Xanthomonas campestris pv. vesicatoria in pepper ‘Early Calwonder-10R’ leaves (incompatible interaction) are reported. Affected cells displayed plasmalemma undulations and disruption, lysis of the chloroplast membrane, degeneration of other organelles, general cytoplasm disorganisation and, often, protoplast shrinkage. The nuclei contained large masses of electron-dense material, apparently formed by chromatin aggregation. In many cases a single chromatin-like layer was deposited on the inner side of the nuclear envelope leaving a finely granular matrix in the centre of the nucleus; the nucleolus usually disappeared. The nuclear envelope was sometimes ruptured and the internal matrix leaked into the cytoplasm. The content of many affected cells eventually coagulated and became very electron-dense. The walls often collapsed. All these alterations were especially visible in spongy mesophyll cells at sites where bacteria occurred in the intercellular spaces. Although some of the nuclear and cytoplasmic alterations recall certain aspects of apoptotic cell death, molecular determinations did not reveal any DNA degradation in hypersensitively reacting tissues. The first cell alterations in leaves infected with the virulent bacterial race 1 (compatible interaction) were observed only 27 h after inoculation, when the cytoplasm of some cells showed limited internal disorganisation and plasmolysis at sites where bacterial colonies developed.
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  • 83
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    Plant molecular biology 44 (2000), S. 255-266 
    ISSN: 1573-5028
    Keywords: abscisic acid ; apoptosis ; gibberellic acid ; nuclease ; programmed cell death ; protease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Progress in understanding programmed cell death (PCD) in the cereal aleurone is described. Cereal aleurone cells are specialized endosperm cells that function to synthesize and secrete hydrolytic enzymes that break down reserves in the starchy endosperm. Unlike the cells of the starchy endosperm, aleurone cells are viable in mature grain but undergo PCD when germination is triggered or when isolated aleurone layers or protoplasts are incubated in gibberellic acid (GA). Abscisic acid (ABA) slows down the process of aleurone cell death and isolated aleurone protoplasts can be kept alive in media containing ABA for up to 6 months. Cell death in barley aleurone occurs only after cells become highly vacuolated and is manifested in an abrupt loss of plasma membrane integrity. Aleurone cell death does not follow the apoptotic pathway found in many animal cells. The hallmarks of apoptosis, including internucleosomal DNA cleavage, plasma membrane and nuclear blebbing and formation of apoptotic bodies, are not observed in dying aleurone cells. PCD in barley aleurone cells is accompanied by the accumulation of a spectrum of nuclease and protease activities and the loss of organelles as a result of cellular autolysis.
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  • 84
    ISSN: 1573-4919
    Keywords: endosulfan ; cytotoxicity ; mitochondria ; apoptosis ; Jurkat cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Several organochlorinated pesticides including DDT, PCBs and dieldrin have been reported to cause immune suppression and increase susceptibility to infection in animals. Often this manifestation is accompanied by atrophy of major lymphoid organs. It has been suggested that increased apoptotic cell death leading to altered T-B cell ratios, and loss of regulatory cells in critical numbers leads to perturbations in immune function. The major objective of our study was to define the mechanism by which endosulfan, an organochlorinated pesticide, induces human T-cell death using Jurkat, a human T-cell leukemic cell line, as an in vitro model. We exposed Jurkat cells to varying concentrations of endosulfan for 0-48 h and analyzed biochemical and molecular features characteristic of T-cell apoptosis. Endosulfan lowered cell viability and inhibited cell growth in a dose- and time-dependent manner. DAPI staining was used to enumerate apoptotic cells and we observed that endosulfan at 10-200 μM induced a significant percentage of cells to undergo apoptotic cell death. At 48 h, more than 90% cells were apoptotic with 50 μM of endosulfan. We confirmed these observations using both DNA fragmentation and annexin-V binding assays. It is now widely being accepted that mitochondria undergo major changes early during the apoptotic process. We examined mitochondrial transmembrane potential (ΔΨm) in endosulfan treated cells to understand the role of the mitochondria in T-cell apoptosis. Within 30 min of chemical exposure, a significant percentage of cells exhibited a decreased incorporation of DiOC6(3), a cationic lipophilic dye into mitochondria indicating the disruption of ΔΨm. This drop in ΔΨm was both dose- and time-dependent and correlated well with other parameters of apoptosis. We also examined whether this occurred by the down regulation of bcl-2 protein expression that is likely to increase the susceptibility of Jurkat cells to endosulfan toxicity. Paradoxically, the intracellular expression of bcl-2 protein was elevated in a dose dependent manner suggesting endosulfan-induced apoptosis occurred by a non-bcl-2 pathway. Based on these data, as well as those reported elsewhere, we propose the following sequence of events to account for T-cell apoptosis induced by endosulfan: uncoupling of oxidative phosphorylation → excess ROS production → GSH depletion → oxidative stress → disruption of ΔΨm → release of cytochrome C and other apoptosis related proteins to cytosol → apoptosis. This study reports for the first time that endosulfan can induce apoptosis in a human T-cell leukemic cell line which may have direct relevance to loss of T cells and thymocytes in vivo. Furthermore, our data strongly support a role of mitochondrial dysfunction and oxidative stress in endosulfan toxicity.
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  • 85
    ISSN: 1573-4919
    Keywords: etoposide ; Bcl-XL ; Bax ; apoptosis ; K562 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Chemistry and Pharmacology , Medicine
    Notes: Abstract Etoposide is a potent anticancer agent that is used to treat various tumors. We have investigated the dose-dependent effect of etoposide on apoptosis using chronic myeloid leukemia K562 cells treated with low (5 μM) or high (100 μM) concentrations of the drug. At a low concentration, etoposide induced little apoptosis at 24 h, while about 20% of the cells showed apoptosis morphologically at a high concentration. Processing of caspase-3 was slightly detected from 12 h and became obvious at 24 h with 100 μM etoposide. Caspase-3-like protease activity was detected at 24 h with a high concentration. Moreover, these changes were accompanied by cleavage of poly ADP ribose polymerase (PARP). Changes of the mRNA levels of most apoptosis-regulating genes were not prominent at both concentrations, except for the rapid induction of c-IAP-2/HIAP-1 and the down-regulation of Bcl-XL by 100 μM etoposide. The downregulation of Bcl-XL protein occurred from 6 h, while Bax protein conversely showed a slight increase from 6 h. Taken together, the present findings show that the dose-dependent apoptotic effect of etoposide is based on a change in the balance between Bcl-XL and Bax, which precedes the activation of caspase-3.
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  • 86
    ISSN: 1573-4978
    Keywords: apoptosis ; CD95 ; human hepatoma cell ; hydrogen peroxide ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Reactive oxygen species (ROS) play an important role in cell death induced by many different stimuli. Direct exposure of human hepatoma cell line SMMC-7221 to hydrogen peroxide (H2O2) can induce apoptosis characterized by morphological evidence and fragmentation of DNA assayed by terminal deoxynucleotidyl transferase assay (TUNEL assay). Analysis of flow cytometry indicated that H2O2 can decrease the level of CD95(APO-1/Fas), and it is confirmed that H2O2 can also activate the differential expression of some specific gene such as p53 by means of RT-PCR technique. The results indicated that CD95 signal transduction system may be involved in the H2O2-induced apoptosis, and can regulate some specific genes associated with apoptosis in transcription and translation levels such as p53.
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  • 87
    ISSN: 1434-0879
    Keywords: Key words Superficial bladder cancer ; p21WAF1/CIP1 ; Prognosis ; Cyclin D1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Immunoreactivity of p21WAF1/CIP1 and cyclin D1 proteins was assessed in a cohort of 207 patients with superficial (pTa-pT1) bladder cancer followed up for a mean of 4.9 years. The results of the immunostainings were compared with T category, WHO grade, tumor cell proliferation rate (MIB-1 score), the expressions of p53 and bcl-2 as well as survival. Sixty-eight percent and 75% of the tumors were p21WAF1/CIP1 positive (≥5% of cells positive) and cyclin D1 positive (≥10% of cells positive), respectively. The p21WAF1/CIP1 expression was related to cyclin D1 immunolabelling (P 〈 0.001) but not to the other variables studied. The expression of cyclin D1 was inversely associated with T category (P=0.001), WHO grade (P=0.006), MIB-1 score (P=0.014), p53 expression (P=0.001), and bcl-2 (P=0.011) immunoreactivity. In univariate analysis, T category (P=0.0001), WHO grade (P 〈 0.0001), MIB-1 score (P 〈 0.0001), bcl-2 (P=0.0092), p53 (P=0.0016) and p21WAF1/CIP1 (P=0.009) expressions were significant prognostic factors with regard to tumor progression, whereas cyclin D1 was without any prognostic significance (P=0.1). Out of 123 p21 positive tumors 21 progressed, whereas only 2 out of 58 p21 negative tumors progressed. In multivariate analysis, the MIB-1 score was the only independent predictor of cancer-specific survival (P=0.03), whereas tumor grade (P=0.002) and cyclin D1 expression (P=0.04) were independent predictors of tumor recurrence. Only the WHO grade (P=0.04) retained its prognostic value indicating the risk of progression. We suggest that in superficial bladder cancer p21WAF1/CIP1 and cyclin D1 immunohistochemistry provide no additional prognostic information compared with already established prognostic factors for predicting the risk of progressive disease.
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  • 88
    ISSN: 1432-2307
    Keywords: Key words Endometrium ; Endometrial carcinoma ; Lectins ; Con A ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Lectins are proteins and glycoproteins of non-immune origin which bind specifically to carbohydrate residues, agglutinate cells and/or precipitate complex carbohydrates. Lectin-binding patterns in normal, hyperplastic and neoplastic endometria were studied using four biotinylated lectins (Con A, LCA, e-PHA, l-PHA) and the avidin-biotin-peroxidase technique. Canavalia ensiformis agglutinin (ConA) and Lens culinaris agglutinin (LCA) reacted strongly with the luminal borders and the cytoplasm of epithelial cells but, whilst in normal and benign endometrial tissues the cytoplasmic staining was confined to the apical and the basal aspect of the cells, in endometrial carcinomas and in some atypical hyperplasias lectin binding also occurred in the lateral cytoplasm (Con-A-lat), although in differing proportions of cells. Interestingly, extensive Con-A-lat in the tumour cells was much more frequent in non-endometrioid carcinomas (P〈0.05) and was significantly associated with poor histological differentiation (P〈0.0001), low oestrogen and progesterone receptor content (P〈0.01 and P=0.0001, respectively) and an unfavourable long-term survival (P〈0.05). With Phaseolus vulgaris erythroagglutinin (e-PHA) and leucoagglutinin (l-PHA) a linear, rather inconsistent, staining at the level of the basement membranes was observed in the glands: this, also noted with LCA, appeared intact in normal and hyperplastic glands without cytological atypia, and fragmented or absent in malignant glandular structures and in most hyperplastic glands showing cytological atypia. It is concluded that changes in the distribution of lectin-binding molecules in the endometrial cells are associated with the malignant state, whilst the extent of Con-A-lat reflects the biological behaviour of the tumours.
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  • 89
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    Child's nervous system 16 (2000), S. 21-24 
    ISSN: 1433-0350
    Keywords: Key words Children ; Glasgow Coma Scale ; Glasgow Outcome Scale ; Prognosis ; Traumatic brain stem lesions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Glasgow Coma Scale (GCS) scores on admission may be predictors of outcome in patients with brain injuries. This study correlated the outcomes of children with traumatic brain stem lesions with their initial GCS scores and morphological patterns of injury as shown on computed tomography (CT) or magnetic resonance (MR) imaging. During the last 16 years, we have treated 1,108 children with brain injuries. The entire series included only 21 (1.9%) children who had clinical signs of brain stem lesions with morphological correlates on CT or MR imaging. Clinical findings were assessed according to the GCS and compared with scores on the Glasgow Outcome Scale (GOS). Of these 21 children, 16 (76%) had morphological lesions seen on CT scans. In 5 (24%) of the children only the MR images revealed brain stem lesions and their CT scans were negative. Generalized severe brain swelling was present in 6 cases (28%). There was a significant difference in GOS scores between patients with initial GCS scores of 3 and 4 and those with GCS scores between 5 and 7 (P〈0.02). Children with intracranial pressure higher than 40 mmHg had poorer outcomes than patients whose intracranial pressure was lower, but the differences were not significant. Outcome did not correlate significantly with morphological patterns of injury or the presence of extracranial injuries. The GCS is a reliable indicator of severity of injury and of outcome in children with brain stem injuries. MR imaging was more sensitive than CT in detecting brain stem lesions.
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  • 90
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    European archives of oto-rhino-laryngology and head & neck 257 (2000), S. 154-157 
    ISSN: 1434-4726
    Keywords: Key words Basaloid squamous cell carcinoma ; Laryngeal neoplasms ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Basaloid squamous cell carcinoma (BSC) is regarded as a variant of squamous cell carcinoma, but displays distinct morphological and biological features as well as a different clinical course. The tumor is frequently seen in the head and neck and is preferentially located in the larynx, especially in supraglottic sites. Ten patients with BSC of the supraglottic larynx were treated from 1991 to 1995 at the Medical Faculty of the University of Istanbul. Results of treatment were compared retrospectively with a control group consisting of 44 patients with well-differentiated squamous cell carcinomas. Ages, ¶localizations, stages and treatment procedures were similar. In both groups mean survival, nodal involvement and distant metastases were comparable although the local ¶(laryngeal) recurrence rate in patients with early supraglottic (T2) disease in the BSC group after conservative partial surgery was distinct compared to the control group (P 〈 0.05). These results indicate that conservative surgery should be assessed with caution in patients with BSC, and postoperative irradiation be taken into consideration.
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  • 91
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    European archives of oto-rhino-laryngology and head & neck 257 (2000), S. 517-520 
    ISSN: 1434-4726
    Keywords: Key words Nucleolar organizer region ; Nasopharyngeal carcinoma ; Silver-staining ; Prognosis ; Outcome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Increased expression of argyrophilic nucleolar organizer regions (AgNORs) has been identified in certain malignant tumors including nasopharyngeal carcinoma (NPC). However, its prognostic significance in NPC is uncertain and remains to be evaluated. To address this we silver-stained 63 paraffin sections of NPC cases, and examined the correlation between AgNOR count and area, calculated by the CAS 200 image analysis system, and tumor behavior, locoregional control, and survival of patients. The mean AgNOR count and area were 1.62 ± 0.31 and 3.98 ± 11.4 μm2, respectively. The AgNOR area was positively associated with T stage (r = 0.26, P = 0.04). The Mann-Whitney test confirmed no significant difference in AgNOR area and count between patients with different outcomes. Multivariate analysis using the Cox proportional hazard model showed neither AgNOR count nor area to be significant predictors of actuarial survival or disease-free survival. It is concluded that AgNOR does not have an independent and significant prognostic value in NPC. AgNOR expression may be merely a reflection of malignant phenotype as well as cellular activity but not necessarily the ultimate behavior of the tumor.
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  • 92
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    Digestive diseases and sciences 45 (2000), S. 291-297 
    ISSN: 1573-2568
    Keywords: apoptosis ; pit cell lineage ; caspase ; gastric mucosal cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to elucidate the mechanism of spontaneous and rapid cell death of cultured gastric pit cells. Gastric pit cells have a rapid cell turnover rate in vivo. We here show that guinea pig gastric pit cells in culture undergo spontaneous and rapid apoptotic DNA fragmentation, which may represent the rapid cell turnover cycle of gastric pit cells in vivo. This spontaneous apoptotic DNA fragmentation required the presence of fetal calf serum in the culture media. Furthermore, the spontaneous apoptotic DNA fragmentation was prevented by protein synthesis and caspase inhibitors.
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  • 93
    ISSN: 1573-2568
    Keywords: Helicobacter pylori ; chronic gastritis ; Fas receptor ; Fas ligand ; immune privilege ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract H. pylori infection almost invariably results in chronic gastritis, but only a proportion of patients develops severe destruction of epithelial glandular structure or peptic ulcer. To confirm the recent data obtained in testis and eye, showing that Fas ligand is involved in the phenomenon of “immune privilege,” expression of Fas receptor and its ligand of the stomach was investigated in a panel of gastric biopsies obtained from patients H. pylori-positive (N = 42) and with H. pylori-negative (N = 18) by two-color flow cytometry. The results show that membrane-bound Fas ligand protein is constitutively expressed on freshly isolated human gastric mucosal epithelium coupled with infiltrating lymphocytes. There was significant overexpression of Fas receptor and its ligand, and a higher frequency of apoptotic cell death detected by TUNEL in epithelium and infiltrating lymphocytes in H. pylori-infected patients. These findings suggest that involvement of Fas receptor and its ligand system contributes to some extent to mucosal damage in H. pylori-associated gastritis. However, the more specific findings are apoptotic depletion of invading mucosal lymphocytes associated with Fas ligand expression by gastric epithelium. These provide the first direct quantitative evidence to support Fas receptor counterattack and/or paracrine fratricide as a mechanism of immune privilege in vivo in the H. pylori-infected glandular stomach.
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  • 94
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    Reviews in endocrine & metabolic disorders 1 (2000), S. 183-196 
    ISSN: 1573-2606
    Keywords: thyroid cancer ; gene mutations ; oncogenes ; tumor suppressor genes ; cell cycle control ; apoptosis ; growth factors ; differentiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
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  • 95
    ISSN: 1573-2568
    Keywords: cholangiocellular carcinoma ; p53 ; proliferation markers ; apoptosis ; histopathological parameters ; prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract This study was performed to examine the correlation between mutations of the p53 tumor suppressor gene, the occurrence of apoptosis, and proliferation in cholangiocellular carcinoma of the liver. The results obtained were compared with pathohistological stage (according to UICC) and grade and with disease related survival rate. In 41 curatively (R0−) resected intrahepatic cholangiocellular carcinomas, the status of the p53 gene was determined by direct sequencing of exons 4–9 and immunohistochemically. Apoptosis was assessed using the in situ end labeling (ISEL) technique in combination with morphological criteria. Proliferation was analyzed by immunohistochemistry of MIB-1 (Ki-67), Proliferating cell nuclear antigen (PCNA), and silver-stained nucleolar organizer regions (AgNOR). The results obtained were compared with pathohistological stage (according to UICC), grade, several other histopathological factors, and survival rate. Mutations of p53 were detected in 15/41 carcinomas examined (37%). The most common change was a G→C and C→T transition, changing the hot spot amino acid determined by exons 4–8. Of these 15 tumors, 14 were also p53-positive by immunohistochemistry. In each carcinoma examined, we could demonstrate MIB-1, PCNA, and AgNOR dots and also apoptotic cells in variable proportions. The proliferation markers showed a significant correlation among themselves. In univariate survival analysis, the extent of the primary tumor, lymph node status, grade, and p53 were significant factors influencing patient survival. Performing multivariate Cox regression survival analysis, however, only the extent of primary tumor and lymph node status had an independent prognostic impact. Apoptosis was not related to patient prognosis or to other parameters examined. In conclusion, these results indicated that p53 could serve as an additional prognostic parameter that could provide auxiliary information for patient outcome. However, tumor stage and lymph node involvement were the strongest prognostic factors. We failed to establish apoptosis or other pathological parameters as factors predicting the prognosis of patients with cholangiocellular carcinoma.
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  • 96
    ISSN: 1573-2568
    Keywords: burns ; starvation ; gut ; apoptosis ; proliferation ; rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Maintenance of gut mucosal homeostasis depends on a balance between cell proliferation and cell death. Gut mucosal integrity is impaired after severe burn and during starvation. We determined the effect of burn, starvation, and the combination of both on small bowel epithelial apoptosis and proliferation. Fifty adult male Fischer 344 rats (260–300 g) received a 60% full-thickness scald burn and were randomly divided into fed and starved groups. Small intestine was taken at 12, 24, and 48 hr after injury. All animals in the 12-hr group were starved while recovering from anesthesia. Apoptosis was quantified by immunohistochemical staining (TUNEL) and mucosal proliferation was determined by bromodeoxyuridine (BrdU) incorporation. The apoptotic index was higher in burned rats compared to controls at 12 hr after burn; both these groups were starved (P 〈 0.05). At 24 and 48 hr after burn, apoptosis was highest in the starved groups, with no additional effects of burn (P 〈 0.05). Mucosal epithelial cell proliferation was not different between groups at any time point. In conclusion, burn and starvation both increase apoptosis in the small bowel mucosa; however, these effects are not additive. Apoptosis could be attenuated by enteral feeding, which delineates the importance of early enteral feeding initiation after injury to maintain mucosal integrity.
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  • 97
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    International urology and nephrology 32 (2000), S. 59-62 
    ISSN: 1573-2584
    Keywords: Bladder neoplasms ; Chemotherapy ; Prognosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Of 50 patients with pT3b, pT4 and/or pN+ disease after cystectomy, 27 were administered adjuvant four cycles of cisplatin, methotrexate and vinblastine (CMV) and 23 were followed expectantly (no-treatment group).Median follow-up was 14 months in CMV group and 11 months in no-treatment group. Median recurrence-free survival was 21 months in CMV group and 17 months in no-treatment group (p = 0.573). Median overallsurvival was 41+ months in CMV group and 84+ months in no-treatmentgroup, respectively (p = 0.501). In our experience, adjuvant chemotherapy after cystectomy seemed not to provide a survival advantage.
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  • 98
    ISSN: 1573-2568
    Keywords: apoptosis ; cyclooxygenase-2 ; gastric epithelial cells ; Helicobacter pylori ; prostaglandin E2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Helicobacter pylori induces apoptosis and alters the proliferation of gastric mucosal epithelial cells. Cyclooxygenase-2 (COX-2), the inducible form of prostaglandin (PG) synthesis, is known to cause alteration in epithelial cell growth. The goal of this study was to determine whether COX-2 gene expression by H. pylori infection could influence gastric epithelial cell apoptosis. Expression of COX-2 mRNA and proteins was up-regulated in Hs746T gastric epithelial cell lines infected with H. pylori, when assessed by quantitative RT-PCR and western blot. Inhibition of COX-2 expression using NS-398, a specific COX-2 inhibitor, showed a significant increase of gastric epithelial cell apoptosis and caspase-3 activation in Hs746T cells infected with H. pylori. Moreover, the effect of NS-398 on H. pylori-induced apoptosis was reversed by the addition of PGE2. These results suggest that up-regulated COX-2 expression by H. pylori infection can inhibit apoptosis of gastric epithelial cells.
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  • 99
    ISSN: 1573-2568
    Keywords: chemoprevention ; colorectal cancer ; 5-aminosalicylic acid ; olsalazine ; apoptosis ; bromdeoxyuridine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The ability of 5-aminosalicylic acid and olsalazine to inhibit colonic aberrant crypts and tumors was investigated in 1,2-dimethylhydrazine-treated rats. The effect of these drugs on the rates of tumor apoptosis and proliferation was studied as potential mechanisms for their action. 5-Aminosalicylic acid reduced the number of aberrant crypt foci by over one third, while olsalazine had no effect on this parameter. However, both agents effectively reduced tumor number and load, increased the rate of tumor apoptosis, and reduced the rate of tumor cell proliferation. In conclusion, 5-aminosalicylic acid and olsalazine are both ultimately effective chemopreventive agents in this model; however, only 5-aminosalicylic acid inhibited the formation of aberrant crypt foci. The inhibitory effect of these agents in tumors is related to the inhibition of proliferation and the induction of apoptosis.
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  • 100
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    Cancer and metastasis reviews 19 (2000), S. 19-27 
    ISSN: 1573-7233
    Keywords: angiogenesis ; apoptosis ; cyclooxygenase-2 ; prostaglandins ; vascular endothelial growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cyclooxygenase-2 (COX-2) is an immediate early response gene that can be induced by a variety of tumor promoters, cytokines, growth factors and hypoxia. COX-2 overexpression is linked to all stages of carcinogenesis with the enzyme localized to the neoplastic cells, microvascular endothelial cells, and stromal fibroblasts. The contributions of COX-2 in tumor angiogenesis include: (a) the increased expression of the proangiogenic growth factor VEGF; (b) the production of the eicosanoid products thromboxane A2, PGE2 and PGI2 that can directly stimulate endothelial cell migration and growth factor-induced angiogenesis; and potentially, (c) the inhibition of endothelial cell apoptosis by stimulation of Bcl-2 or Akt activation. Selective pharmacological inhibitors of COX-2 as angiosuppressive agents could have therapeutic benefit in the treatment of neoplastic disease from prevention through treatment of advanced metastatic disease. These agents are safe and well tolerated and can be added to chemotherapy and radiation therapy where angiogenesis inhibitors appear to provide at least additive therapeutic benefit.
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