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  • 2000-2004  (217)
  • 1920-1924
  • apoptosis  (117)
  • Immunohistochemistry  (100)
  • 101
    Electronic Resource
    Electronic Resource
    Quantitative measurement of soluble cytokeratin fragments in tissue cytosol of 599 node negative breast cancer patients: a prognostic marker possibly associated with apoptosis (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 211-221 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006318112776
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  • 102
    Electronic Resource
    Electronic Resource
    Role of specific apoptotic pathways in the restoration of paclitaxel-induced apoptosis by valspodar in doxorubicin-resistant MCF-7 breast cancer cells (2000)
    Springer
    Breast cancer research and treatment 59 (2000), S. 231-244 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006344200094
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  • 103
    Electronic Resource
    Electronic Resource
    Induction of Apoptosis in WEHI 231 Cells by Cationic Liposomes (2000)
    Springer
    Pharmaceutical research 17 (2000), S. 515-520 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007552529280
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  • 104
    Electronic Resource
    Electronic Resource
    Ultrastructural Observations and DNA Degradation Analysis of Pepper Leaves Undergoing a Hypersensitive Reaction to Xanthomonas campestris pv. Vesicatoria (2000)
    Springer
    European journal of plant pathology 106 (2000), S. 423-431 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008773321809
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  • 105
    Electronic Resource
    Electronic Resource
    Programmed cell death in cereal aleurone (2000)
    Springer
    Plant molecular biology 44 (2000), S. 255-266 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026584207243
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  • 106
    Electronic Resource
    Electronic Resource
    Evidence for the induction of apoptosis by endosulfan in a human T-cell leukemic line (2000)
    Springer
    Molecular and cellular biochemistry 205 (2000), S. 53-66 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007080910396
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  • 107
    Electronic Resource
    Electronic Resource
    Differential responses to Bcl-2 family genes to etoposide in chronic myeloid leukemia K562 cells (2000)
    Springer
    Molecular and cellular biochemistry 206 (2000), S. 43-50 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007056727876
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  • 108
    Electronic Resource
    Electronic Resource
    Hydrogen peroxide-induced apoptosis in human hepatoma cells is mediated by CD95(APO-1/Fas) receptor/ligand system and may involve activation of wild-type p53 (2000)
    Springer
    Molecular biology reports 27 (2000), S. 1-11 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007003229171
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  • 109
    Electronic Resource
    Electronic Resource
    Increased interleukin-8 (IL-8) expression is related to aseptic loosening of total hip replacement (2000)
    Springer
    Archives of orthopaedic and trauma surgery 120 (2000), S. 328-332 
    Details
    ISSN: 1434-3916
    Keywords: Key words Interleukin-8 ; Aseptic loosening ; Total hip replacement ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Aseptic loosening is an increasing problem in total hip replacement (THR). Chronic inflammatory reaction against implant wear particle results in collageno- and osteolysis, leading to loosening of the implant. Cytokines are known to play a major role in this particular inflammatory process [10]. The aim of the present study was to examine interleukin-8 (IL-8) in the synovial-like interface membrane (SLIM) and pseudocapsular tissue of THRs and to compare it to normal knee synovial membrane. Eleven patients suffering from aseptically loosened THRs were included. All the SLIM and pseudocapsular tissue samples were obtained during revision operations. Ten control samples of normal synovium were collected per arthroscopy from the superior recessus of the knee. For immunohistochemical IL-8 detection, polyclonal mouse anti-human immunoglobulin (Ig)G1 IL-8-primary antibody was used with the alkaline phosphatase anti-alkaline phosphatase (APAAP) method. Results were quantitated using the Vidas image analysis system. The highest count levels (mean ± SEM) were detected in SLIM tissue (386 ± 82 cells/mm2). The difference was statistically significant compared with pseudocapsular tissue (193 ± 36 cells/mm2) and control samples (18 ± 5 cells/mm2). Count levels in control tissue were on average 5% of the SLIM tissues values. The present study determines for the first time the cellular origin of IL-8 in aseptically loosened THRs and also quantitates the IL-8-producing cells in the periprosthetic tissue. The results reveal a high rise in IL-8 concentration in SLIM and in synovial tissues. This finding moves us one step forward in solving the complex network of multiple factors affecting loosening of hip implants.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004020050475
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  • 110
    Electronic Resource
    Electronic Resource
    Immunolocalization of types I, II, and X collagen in the tibial insertion sites of the medial meniscus (2000)
    Springer
    Knee surgery, sports traumatology, arthroscopy 8 (2000), S. 61-65 
    Details
    ISSN: 1433-7347
    Keywords: Key words Collagen ; Meniscal ¶insertions ; Knee joint ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine , Sports Science
    Notes: Abstract The medial meniscus of the rabbit knee joint attaches to the tibial plateau via anterior and posterior insertions. Intact meniscal tibial insertions are essential for meniscal function. In the present study the distributions of types I, II, and X collagen in meniscal tibial insertions were investigated by indirect immunohistochemistry in a rabbit model. Four tissue zones were histologically identified in the anterior insertion site, including the ligamentous zone, uncalcified and calcified fibrocartilaginous zones and bone; the ligamentous zone was not observed in the posterior insertion site. Labeling for type I collagen was found to be strong in the ligament tissue and bone, and weak in the fibrocartilages which were also labeled for type II collagen. Tissues positive for different types of collagen overlapped and formed an irregular interface with various angles and depths, especially at the interface between the calcified fibrocartilage and bone. Positive labeling for type X collagen was identified only in the calcified fibrocartilage zone. The coexistence of types I and II collagen in the meniscal tibial insertions may indicate that this structural unit is subjected to both compressive and tensile loads. Type X collagen may play a role in maintaining the calcifying status of this tissue zone, so that its mechanical stiffness is kept between that of uncalcified fibrocartilage and hard bone. Restoration of the insertional structure including the distinct collagen distribution should be considered for a functional meniscal substitution.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s001670050013
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  • 111
    Electronic Resource
    Electronic Resource
    PE-35-related antigen expression and CD1a-positive lymphocytes in thymoma subtypes based on Müller-Hermelink classification (2000)
    Springer
    Virchows Archiv 436 (2000), S. 20-27 
    Details
    ISSN: 1432-2307
    Keywords: Key words PE-35 ; CD1a ; Immunohistochemistry ; Catalyzed signal amplification (CSA) ; Thymoma ; Thymic carcinoma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  PE-35 monoclonal antibody, detecting a cell-surface antigen of various types of carcinoma and normal epithelium, reacts exclusively with the medullary epithelium in the thymus; therefore, the antigen has been considered as a marker of medullary differentiation in thymomas. Using the catalyzed signal amplification method, which made it possible to apply PE-35 to routinely processed, archival tissues, we examined expression of this antigen, together with CD1a reactivity of lymphocytes, in 40 thymic epithelial tumors subclassified using the Mü1ler-Hermelink system. Medullary thymomas infiltrated with a small number of CD1a-negative lymphocytes were PE-35 positive, although many of the long spindle tumor cells were PE-35 negative. Mixed thymomas and predominantly cortical thymomas, both with prominent CD1a-positive lymphocytes, were also PE-35 positive, although some areas of the latter type were PE-35 negative. Cortical thymomas with decreased numbers of CD1a-positive lymphocytes were largely PE-35 negative. In well-differentiated thymic carcinomas with a few CD1a-positive lymphocytes, two cases were negative, but four cases were at least focally positive with PE-35. All high-grade thymic carcinomas infiltrated with some CD1a-negative lymphocytes were PE-35 positive. These results suggested that medullary thymoma generally possesses the medullary nature, although the latter tends to be lost in the long spindle tumor cells. Mixed and predominantly cortical thymomas may have mixed medullary phenotype and cortical function. Cortical thymoma and many well-differentiated thymic carcinomas may possess the cortical nature, while the large polygonal tumor cells tend to lose immature T-lymphocyte-retaining function.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008194
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  • 112
    Electronic Resource
    Electronic Resource
    Peripheral primitive neuroectodermal tumour of the cervix (2000)
    Springer
    Virchows Archiv 436 (2000), S. 68-73 
    Details
    ISSN: 1432-2307
    Keywords: Key words Cervix ; Peripheral primitive neuroectodermal tumour ; Ewing’s tumour pathology ; Immunohistochemistry ; Cytogenetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Peripheral primitive neuro-ectodermal tumours (PNET) of the cervix are very rare. Here, we report the clinical, pathological, immunohistochemical and genetic features of a case of a PNET located in the cervix. Hysterectomy revealed a cervical tumour. On microscopic examination, a vaguely lobular arrangement of uniformly appearing neoplastic cells, with round to oval nuclei, distinct nuclear membranes and a clear, moderately glycogen-rich cytoplasm was seen. Cells stained positive for LEU 7, S 100, monoclonal NSE and particularly for MIC2. Neurogenic differentiation was also seen by electron microscopic examination. The genetic hallmark of PNET, a 22q12 rearrangement was demonstrated by fluorescence in situ hybridisation experiments, supporting the diagnosis. Awareness of the existence of primary PNET of the cervix is important to avoid confusion with other tumours of the cervix.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00008201
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  • 113
    Electronic Resource
    Electronic Resource
    Vesicular monoamine transporter 2 as a marker of gastric enterochromaffin-like cell tumors (2000)
    Springer
    Virchows Archiv 436 (2000), S. 217-223 
    Details
    ISSN: 1432-2307
    Keywords: Key words VMAT2 ; Stomach ; ECL cell ; Tumors ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  The vesicular monoamine transporter 2 (VMAT2) facilitates the ATP-dependent accumulation of biogenic amine inside the secretory granules of endocrine cells and neurons and was demonstrated in the histamine-producing enterochromaffin-like (ECL) cells of the stomach. In the present investigation, VMAT2 immunohistochemistry was tested in 85 endocrine tumors, of which 60 were well differentiated gastrointestinal and pancreatic growths, 5 poorly differentiated (neuro)endocrine carcinomas (PDEC) and 1 mixed PDEC/ECL cell carcinoma of the stomach, 12 pheochromocytomas/paragangliomas, 3 adrenocortical lesions, 2 parathyroid and 2 lung neuroendocrine tumors. Extensive and intense VMAT2 immunoreactivity was observed in 16 of 16 gastric ECL cell tumors, 6 of 6 adrenal pheochromocytomas, 2 of 2 chromaffin paragangliomas and in 3 of the 4 carotid body paragangliomas investigated. Rare VMAT2-positive cells were observed in 12 of 21 intestinal enterochromaffin (EC) cell tumors, in 9 of 11 pancreatic neuroendocrine tumors, and in the mixed PDEC/ ECL cell carcinoma of the stomach (differentiated cells only). No VMAT2 immunoreactivity was observed in five gastrin, four somatostatin and three enteroglucagon/peptideYY tumors of the gastrointestinal tract, in six gastric PDECs, in three adrenocortical growths, and two parathyroid and two lung neuroendocrine tumors. These data support VMAT2 immunohistochemistry as being a useful tool for the diagnosis of gastric ECL cell tumors, separating them from all other endocrine tumors arising in the gastroduodenal area i.e., gastrin, somatostatin, EC cell and PDEC tumors, all of which proved essentially negative.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280050033
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  • 114
    Electronic Resource
    Electronic Resource
    Protein expression of p53, p21 (WAF1/CIP1), bcl-2, Bax, cyclin D1 and pRb in human colon carcinomas (2000)
    Springer
    Virchows Archiv 436 (2000), S. 224-228 
    Details
    ISSN: 1432-2307
    Keywords: Key words Apoptosis ; bax ; bcl-2 ; Colon carcinoma ; CyclinD1 ; Immunohistochemistry ; p21 ; p53 ; pRb
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Tumour growth is regulated by a balance between proliferation, growth arrest and programmed cell death (apoptosis). Until recently, the majority of the studies dealing with oncogenesis has been focused on the regulation of cell proliferation. There is now growing understanding that control of growth arrest and apoptosis play key roles in the development of human cancer and in cancer treatment. Some of the more heavily studied proteins of importance for the control of growth arrest and apoptosis are p53, p21, bcl-2 and bax. Alterations in the p53 protein may lead to malignant transformation and defect therapy response, most likely as a result of defective p53-dependent apoptosis. In addition, p21 (WAF1/CIP1) is involved in cell-cycle arrest and probably in induction of p53-dependent apoptosis. Proteins belonging to the bcl-2 family are also important for normal apoptosis. Overexpression of bcl-2 protein is thought to reduce the apoptotic capacity, while bax protein seems to be necessary for induction of apoptosis. In this study, we have immunostained tissues from 93 primary colon carcinomas and have examined the expression of p53, p21 (WAF1/CIP1), bcl-2 bax, pRb and cyclin D1 for evaluation of their roles in colon-cancer progression. A highly significant association between p53 accumulation and downregulation of p21 (WAF1/CIP1) was seen. We also found a strong association between reduced/absent p21 and the development of metastases and death due to cancer disease. Cyclin D1, bcl-2 and bax protein failed to have independent prognostic impacts. Bcl-2 and bax protein levels showed an inverse relationship. The results of the present study indicate that reduced p21 protein levels play an important role in progression of colon cancer. We concluded that evaluation of p21 expression in primary colon carcinomas at the time of surgery might be a valuable tool in defining patients with a high risk of developing metastases.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280050034
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  • 115
    Electronic Resource
    Electronic Resource
    Peripheral papillary tumor of type-II pneumocytes: a rare neoplasm of undetermined malignant potential (2000)
    Springer
    Virchows Archiv 436 (2000), S. 289-295 
    Details
    ISSN: 1432-2307
    Keywords: Key words Unusual lung tumors ; Papillary adenoma ; Surfactant proteins ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Peripheral papillary adenomas of the lung are uncommon neoplasms (only ten cases have been described so far in the English literature) composed predominantly of type-II pneumocytes and generally considered benign. We describe here two additional cases of this lung tumor. In both cases histological examination revealed an encapsulated papillary neoplasm with invasion of the capsule and, in one case, invasion of the adjacent alveoli and visceral pleura too. The proliferative index (Ki67) was less than 2% and the epithelial cells were positive for cytokeratins, surfactant apoproteins (SP), and nuclear thyroid transcription factor-1 (TTF-1). Ultrastructurally, the epithelial cells showed the characteristic surface microvilli and cytoplasmic lamellar inclusions of type-II cells. Review of the literature has revealed two other cases of peripheral papillary adenoma of type-II pneumocytes with infiltrative features. Thus, we propose replacing the term peripheral papillary adenoma with peripheral papillary tumor of undetermined malignant potential.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280050043
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  • 116
    Electronic Resource
    Electronic Resource
    Sclerosing, pseudovascular rhabdomyosarcoma in adults (2000)
    Springer
    Virchows Archiv 436 (2000), S. 305-311 
    Details
    ISSN: 1432-2307
    Keywords: Key words Rhabdomyosarcoma ; Soft tissue tumours ; Adults ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Rhabdomyosarcoma in adults represents a rare soft tissue neoplasm which is seen most frequently in its pleomorphic subtype in this age group. Very rarely, clear cell and spindle-cell variants have been reported. In this study we describe three cases of rhabdomyosarcoma in adult patients, characterised by prominent hyaline sclerosis and a pseudovascular growth pattern. All cases were identified in the consultation files of one of the authors and routinely processed. Immunohistochemical studies were performed on paraffin sections with the alkaline phosphatase–antialkaline phophatase method. The patients, two women and one man, were 40, 41, and 56 years old. One developed a deep-seated soft tissue mass in the left lower leg, and one, a tumour of the left upper jaw. In one patient a bone tumour in the proximal body of the sacrum without extension into soft tissues was seen. The patients were treated by wide excision, piecemeal excision and incomplete excision in one case each; additional radiotherapy was performed in all three cases, and chemotherapy in two patients. In one patient multiple pulmonary metastases were noted, which showed progression despite systemic chemotherapy. Histologically, the neoplasms were composed of round/polygonal and spindle-shaped tumour cells including typical rhabdomyoblasts. In all cases a pseudovascular pattern and prominent hyaline sclerosis of the intercellular matrix was seen. Immunohistochemically, tumour cells stained positively for desmin and muscle actin (HHF35) and also for markers of striated muscle differentiation (myogenin, MyoD1, fast myosin). In this paper an unusual morphological variant of rhabdomyosarcoma arising in adult patients is described, which should be added to the morphological spectrum of these neoplasms.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280050451
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    Immunoexpression of transforming growth factor β in desmoplastic ameloblastoma (2000)
    Springer
    Virchows Archiv 436 (2000), S. 319-323 
    Details
    ISSN: 1432-2307
    Keywords: Key words Ameloblastoma ; Transforming growth factor-beta ; Desmoplasia ; Type-IV collagen ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  Desmoplastic ameloblastoma (DA) is an unusual subtype of ameloblastoma histologically characterized by the pronounced collagenized stroma. In the present study, the immunolocalization of transforming growth factor beta (TGF-β), one of the most potent local factors for modulating extracellular matrix formation, was observed in DA in order to study its participation in the stromal desmoplasia. Seven cases of DA, including a ”hybrid” lesion, were studied together with ten cases of ordinary follicular and plexiform ameloblastomas as the control. In contrast to ordinary ameloblastomas, marked immunoexpression was observed in all DAs but one. In the ”hybrid” lesion, TGF-β was not expressed in the area of follicular ameloblastoma but in that of DA. These results show that TGF-β produced by tumor cells of DA plays a part in the desmoplastic matrix formation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004280050453
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  • 118
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    Congenital oral gastrointestinal cyst: an immunohistochemical analysis (2000)
    Springer
    European archives of oto-rhino-laryngology and head & neck 257 (2000), S. 459-461 
    Details
    ISSN: 1434-4726
    Keywords: Key words Oral cyst ; Heterotopic gastrintestinal ¶epithelium ; Morphology ; Histochemistry ; Immunohistochemistry ; Clinico-pathological correlation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Cystic lesions of the oral cavity are quite common. Mostly their morphology is that of simple cystic lesions lined by squamous epithelium. Rarely the epithelium may be of another type, e.g. that of gastrointestinal tract. In the English literature in English about 30 cases of oral cysts with gastrointestinal epithelium lining have been reported. This developmental lesion is very rare and is found more frequently in young males. The majority of lesions were reported to occur in the ventral surface of the anterior tongue and extend to the floor of the mouth. Heterotopic gastrointestinal epithelium has been more commonly described in the duodenum, gallbladder, jejunum, Meckel’s diverticulum, ileum, appendix, colon and rectum. We report an oral heterotopic gastrointestinal cyst in a child. A healthy 2-month-old boy had an asymptomatic swelling in the sublingual area that had been present since birth. Under general anesthesia, the patient underwent conservative excision of the cyst. Gross examination of the excised tissue showed a monolocular cystic lesion in the bottom of the oral cavity. Microscopically, the cystic lining mostly resembled intestinal mucosa; in some places, stratified squamous and columnar epithelium was also present. The pathogenesis of this lesion remains uncertain. Several theories have been postulated; the most commonly held suggests that these cysts may be derived from misplacement of embryonic rests.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/s004050000255
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    Spontaneous Apoptotic DNA Fragmentation in Cultured Guinea Pig Gastric Mucosal Cells (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 291-297 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005404424698
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    Apoptotic Depletion of Infiltrating Mucosal Lymphocytes Associated with Fas Ligand Expression by Helicobactor pylori-Infected Gastric Mucosal Epithelium: Human Glandular Stomach as a Site of Immune Privilege (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 773-780 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005408113467
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    Expression Patterns of Cellular Growth-Controlling Genes in Non-Medullary Thyroid Cancer: Basic Aspects (2000)
    Springer
    Reviews in endocrine & metabolic disorders 1 (2000), S. 183-196 
    Details
    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
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1010079031162
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    Mutations of p53 Tumor Suppressor Gene, Apoptosis, and Proliferation in Intrahepatic Cholangiocellular Carcinoma of the Liver (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 317-324 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005412626515
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    Burn and Starvation Increase Programmed Cell Death in Small Bowel Epithelial Cells (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 415-420 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005445501016
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    The distribution of S-100 protein in hyperplastic and neoplastic prostatic epithelium (2000)
    Springer
    International urology and nephrology 32 (2000), S. 259-261 
    Details
    ISSN: 1573-2584
    Keywords: Benign prostatic hyperplasia ; Immunohistochemistry ; Prostatic adenocarcinoma ; S-100 protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Specimens from 30 cases of benign prostatichyperplasia and 75 cases of prostatic carcinomaobtained during suprapubic prostatectomy, transurethalresection of the prostate and radical prostatectomy,were stained immunohistochemically for S-100 protein,prostatic acid phosphatase (PAP), prostatic specificantigen (PSA), neuron specific enolase (NSE) andpolyclonal keratin. S-100 protein was positive in9.3% of prostatic carcinomas and negative in allcases of prostatic hyperplasia. PAP and PSA werepositive in all cases, while NSE was positive in 16%of the carcinoma cases. Polyclonal keratin waspositive in both cell layers of the double layeredhyperplastic prostatic epithelium with a more intensestaining pattern in the outer cell layer. The authorsbelieve that the S-100 protein immunoreactivityobserved in some prostatic carcinomas, reflecting thechange in the functional status of the neoplasticcells, might be of prognostic significance. They alsoemphasize the non-myoepithelial nature of the outercell layer of the double layered prostaticepithelium.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007118210759
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    Upregulated Cyclooxygenase-2 Inhibits Apoptosis of Human Gastric Epithelial Cells Infected with Helicobacter pylori (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 2436-2443 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005611613542
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    5-Aminosalicylic Acid and Olsalazine Inhibit Tumor Growth in a Rodent Model of Colorectal Cancer (2000)
    Springer
    Digestive diseases and sciences 45 (2000), S. 1578-1584 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1005517112039
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    Immunohistochemical detection of retinoic acid receptorα in prostate carcinoma: Correlation with proliferative activity and tumor grade (2000)
    Springer
    International urology and nephrology 32 (2000), S. 263-269 
    Details
    ISSN: 1573-2584
    Keywords: Immunohistochemistry ; Ki67 ; Prostate carcinoma ; Retinoic acid receptor-α
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Background: The use of retinoids as differentiation therapy is a novel approach to prostate cancer. Retinoids act via their own nuclear receptors, RARs and RXRs, modulating gene activity, cell growth and differentiation. This study provides new data on the content and cellular distribution of RARα protein in prostate cancer specimens, in correlation to tumor grade and proliferative activity. Material and methods: A total of 84 cases of primary prostate carcinoma, divided into 3 subgroups according to tumor grade, were immunohistochemically evaluated for retinoic acid receptor-α (RARα) and Ki67 using the streptavidin/peroxidase method on formalin fixed, paraffin embedded tissues. Results: RARα positivity was detected in all cases of prostatic carcinoma, with a more profound expression in well differentiated cancers. A statistically significant correlation between RARα staining and tumor grade was found (ANOVA, p 〈 0.031). Ki67 immunoreactivity was present in 35.7% of cases, but no correlation with tumor grade was found. When RARα staining was correlated with Ki67 positivity, a statistically significant correlation was present (unpaired t-test, p 〈 0.003). Conclusions: These findings indicate that RARα expression is correlated to some extent with tumor grade and its presence is more profound in highly proliferative tumors. Further studies are needed to establish the possible clinical value of the immunohistochemical evaluation of RARα content in tumor specimens.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007126332651
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    The Contributions of Cyclooxygenase-2 to Tumor Angiogenesis (2000)
    Springer
    Cancer and metastasis reviews 19 (2000), S. 19-27 
    Details
    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.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026575610124
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    The Controls of Microvascular Survival (2000)
    Springer
    Cancer and metastasis reviews 19 (2000), S. 75-81 
    Details
    ISSN: 1573-7233
    Keywords: endothelial cell ; angiogenesis ; survival ; apoptosis ; VEGF-A ; pericyte
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The regulation of microvascular survival impacts both developmental remodeling of the vasculature, and various microvascular pathologies. In pathological settings of vascular insufficiency, molecular targets to affect stabilization of neovascularization are needed. Conversely, an important part of anti-tumor angiogenesis is the de-stabilization of the tumor vasculature. In the study of vascular remodeling, one difficult challenge is to understand the molecular controls that allow regression of one entire vessel segment and not another. This phenomenon requires coordination of the survival signaling pathways to successfully impact vascular structure. This review describes the known mechanisms and molecules involved in microvascular and endothelial cell survival. In particular the mechanisms of molecular signaling for survival in vitro are discussed in light of what is known about microvascular survival in vivo. Possible ways to bring these data together to explain the complex regulation of vessel survival are discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026552415576
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    Angiostatin and Angiostatin-related Proteins (2000)
    Springer
    Cancer and metastasis reviews 19 (2000), S. 97-107 
    Details
    ISSN: 1573-7233
    Keywords: angiogenesis ; angiostatin ; cancer biology ; cancer therapy ; proteolysis ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The study of angiogenesis, and the promise of angiogenesis inhibition as a means of cancer therapy, has dramatically accelerated in the last several years. The discovery and publication of angiostatin by O'Reilly and colleagues in Judah Folkman's lab in 1994 has greatly contributed to this progress. Angiostatin is a kringle-containing fragment of plasminogen, which is a potent inhibitor of angiogenesis in-vivo, and selectively inhibits endothelial cell proliferation and migration in-vitro. There have been a number of proposed proteolytic mechanisms by which plasminogen is cleaved to form angiostatin, and the resulting cleavage products contain different NH2 and COOH termini of the angiostatin. Therefore, it is possible that there are more than one angiostatin isoforms (or angiostatin-related proteins) which occur in one or more normal or pathophysiological situations. It is also possible that some of the proteolytic processes which can convert plasminogen to angiostatin-like proteins are simply laboratory artifacts. Angiostatin-related proteins exert potent endothelial cell inhibitory activity, including the induction of apoptosis, and inhibition of migration, and the intact kringle structures are believed to be necessary for the antiangiogenic activity. Efforts are now underway to translate the understanding of the biology of angiostatin to clinical practice, which includes phase 1 clinical trials with recombinant angiostatin K1–3 (kringles 1–3) as well as phase 1 trials of an Angiostatin Cocktail, which induces the direct in vivo conversion of plasminogen to angiostatin 4.5 (kringles 1–4, plus most of kringle 5). The translation of the basic science of angiostatin and angiostatin-related proteins to clinical trial promises to provide an important new tool in the treatment of cancer by inhibition of angiogenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026525121027
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    Altered Nuclear Localization of Bax Protein in BCNU-resistant Glioma Cells (2000)
    Springer
    Journal of neuro-oncology 49 (2000), S. 117-129 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; chemotherapy resistance ; bcl-2 ; bax ; glioma ; nucleolus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To investigate the role of apoptosis suppression in glioma chemotherapy resistance, protein levels and subcellular localization of bcl-2 family members were investigated in 2 pairs of sensitive cell lines and their in vitro generated resistant derivatives. The alkylating agent, 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), induced apoptosis in both sensitive cell strains and apoptosis was suppressed in both resistant derivatives. Both resistant cell lines contained altered regulation of a bcl-2 related protein consistent with the suppression of apoptosis. Independent of which bcl-2 family member was dysregulated, resistance was associated with altered regulation in the subcellular localization of bax protein. Following BCNU treatment, bax accumulated in nucleoli and a nuclei containing fraction of sensitive cells but not their resistant derivatives. Nuclear accumulation was an early event in apotosis induction. These data indicates altered subcellular localization of bax may play a role in resistance. In addition, the association between an early, nucleolar localization of bax and the induction of apoptosis suggests that localization of bax to nucleoli may play a role in apoptosis-induction of glioma cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026574123273
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    Selenium Causes Growth Inhibition and Apoptosis in Human Brain Tumor Cell Lines (2000)
    Springer
    Journal of neuro-oncology 46 (2000), S. 125-133 
    Details
    ISSN: 1573-7373
    Keywords: selenium ; human glioma cells ; mitochondria ; apoptosis ; fibroblasts ; ultrastructure ; MTT
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We examined the effect of the trace element selenium on human glioma cell lines: T98G, U373MG, and U87MG, in addition to dermal fibroblast cells. Cultures were incubated with sodium selenite, and the following parameters were studied: cell growth, mitochondrial function, and ultrastructure. Cell growth was assayed by counting the number of viable cells after treatment with selenium. Mitochondrial function was analyzed using the MTT (tetrazolium salt reduction) assay. Apoptosis was determined by evaluating nuclear chromatin condensation by electron microscopy. The results indicated that selenium had a significant inhibitory effect on the growth of the tumor cells but had little effect upon dermal fibroblasts which had been passaged numerous times. Selenium also induced mitochondrial damage as shown by MTT assay in two brain tumor cell lines and in minimally passaged fibroblasts, but it had little effect upon the high-passage fibroblasts. Ultrastructurally, mitochondria had electron-dense inclusions resulting from selenium treatment. High rates of apoptosis were induced by selenium in the tumor cell lines and in the minimally passaged fibroblasts, whereas the fibroblasts with a high number of passages had some resistance to selenium treatment. This study correlates the adverse effects of selenium on mitochondrial function, inhibition of cell growth, and apoptosis and shows that selenium similarly affects three different brain tumor cell lines and minimally passaged fibroblasts. Further, the results with fibroblasts show that some types of cells after repeated passages can develop resistance to selenium damage.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006436326003
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    Drug-induced Apoptosis by Anti-microtubule Agent, Estramustine Phosphate on Human Malignant Glioma Cell Line, U87MG; in vitro Study (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 133-140 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; DNA ; glioma ; estramustine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The drug effect of estramustine phosphate (EMP), an anti-microtubule agent on human glioma cells has been studied with the focus being mainly its cytotoxity or its targeting of organelles. However, the pharmacological knowledge of estramustine with respect to its cytotoxity and mechanism is limited. To acquire such knowledge, the present study investigates the ability of EMP to induce apoptosis in a human malignant glioma cell line. Transmission electron microscope (TEM) images were examined to monitor periodic changes. Agarose gel electrophoresis was also examined. Cellular DNA fragmentation ELISA was performed to investigate the DNA fragmentation rates and an MTT assay was studied to evaluate the ID50. A TEM study revealed condensing and fragmentation of the chromatin. Laddering of the bands was observed in all EMP exposure groups in agarose gel electrophoresis. DNA fragmentation in all EMP groups began at 0.5 h following an exposure with EMP and increased in a dose- and time-dependent manner as revealed by DNA ELISA fragmentation. ID50 at 24 h was 5.0 µM according to the MTT assay, a value close to 4.8 µM of ID50 was revealed by the DNA fragmentation assay. None of the above mentioned changes was observed in the control group. These results indicated that EMP caused a drug-induced apoptosis in the human malignant glioma cell line, U87MG.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006393705560
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    Induction of apoptosis in cultured cells by extracts from shiitake (Lentinula edodes) mycelial culture broth (2000)
    Springer
    Mycoscience 41 (2000), S. 623-631 
    Details
    ISSN: 1618-2545
    Keywords: apoptosis ; caspase-3 ; E2F factor ; Lentinula edodes ; mycelial culture broth
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Extracts fromshiitake (Lentinula edodes) mycelial culture broth, by an organic solvent ethyl acetate, inhibited the proliferation of cultured cells. At lower concentrations (1.25–15 μg/ml), this inhibition, measured by the MTT assay, was dose- and cell line-dependent. Inhibition of tumor cells, such as Caski, SiHa, HeLa, HP-1 and A375, byL. edodes-436 extracts was stronger than inhibition of normal cells (3T3). At 20 μg/ml, the extracts induced changes in cell shape, DNA-fragmentation and the activation of caspase-3. The extracts also inhibited the binding of E2F protein to its promoter. The results suggest that extracts ofL. edodes culture broth contain substances that have the ability to induce apoptosis in the cultured cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02460929
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    Vascular abnormalities in surgical specimens obtained from the resected focus of intractable epilepsy (2000)
    Springer
    Brain tumor pathology 17 (2000), S. 121-131 
    Details
    ISSN: 1861-387X
    Keywords: Intractable epilepsy ; Cerebral malformation ; Pathology ; Hypervascularity ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The histopathological features, particularly hypervascularity, were examined in specimens resected from 21 patients, 15 with intractable epilepsy accompanying cortical dysplasia or dysembryoplastic neuroepithelial tumor (DNT), and 6 with benign brain tumors, such as ganglioglioma and low-grade glioma. Hypervascularity was found in resected specimens from 15 of the 21 patients (71.4%) and in 10 of the 12 patients (83.3%) who had double pathology. Counting of numbers of vessels by CD31 immunohistochemistry revealed that hypervascularity was prominent, especially in cases of vascular malformation or cortical dysplasia. However, almost all cases were negative for vascular endothelial growth factor (VEGF) staining, except for some cases of benign brain tumors. Moreover, all cases showed low or no proliferative potential in MIB-1 immunohistochemistry. These results suggest that the etiology of hypervascularity in the dysplastic lesions is one of a variety of cerebral malformations, as is the case with abnormal maturation and differentiation in neuroglial elements.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02484283
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  • 136
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    Immunohistochemical study of tight junction-related protein in neovasculature in astrocytic tumor (2000)
    Springer
    Brain tumor pathology 17 (2000), S. 1-6 
    Details
    ISSN: 1861-387X
    Keywords: Blood-brain barrier ; Brain tumor ; Immunohistochemistry ; Neovasculature tight junction
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract To clarify whether the neovasculature of brain tumors preserves blood-brain barrier (BBB) functions, we studied the expression of a tight junction—related protein, Zo-1, using immunohistochemistry. Twenty-six astrocytic tumors were examined using an anti-Zo-1 Mab, and Zo-1 expression was compared with the expression of vasicular endothelial growth factor (VEGF), vascular endothelial growth factor receptor (VEGFR) (flt-1), and antiproliferative cell nuclear antigen (PCNA). A positive reaction for Zo-1 was seen in the endothelial cells in micro-blood vessels in all astrocytic tumors. The reactions for Zo-1 in the endothelial cells forming glomeruloid proliferations in newly formed micro-blood vessels in high-grade tumors were weaker than those in the endothelial cells of normal cerebral capillaries. Although there is a negative correlation between positive immunoreactions for BBB-related proteins and the expression of VEGF of the endothelial cells in micro-blood vessels, the proliferative activity of tumor cells, and histological grades, the present findings suggest that the endothelial cells of the neovasculature of high-grade tumors preserve partial BBB function at the cellular level. Because of the ease of immunohistochemical procedures compared with electron microscopic examination, the immunohistochemical detection of Zo-1 should provide a useful marker for tight junctions.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02478911
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  • 137
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    A cellular variant of supratentorial hemangioblastoma (2000)
    Springer
    Brain tumor pathology 17 (2000), S. 15-19 
    Details
    ISSN: 1861-387X
    Keywords: Hemangioblastoma ; Supratentorial tumor ; Immunohistochemistry ; Ultrastructure
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Supratentorial hemangioblastomas are rarely seen, especially in children and adolescents. We report the case of a 17-year-old male with supratentorial hemangioblastoma. Neuroimaging demonstrated a cystic lesion within the right parietal lobe. Systemic examination revealed no abnormality. The lesion was not attached to the dura and was not associated with von Hippel-Lindau disease. It was very difficult to confirm the final diagnosis of this case, in spite of extensive examination by light microscopy, immunohistochemical studies, and electron microscopy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02478913
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  • 138
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    Chordoid meningioma (2000)
    Springer
    Brain tumor pathology 17 (2000), S. 153-157 
    Details
    ISSN: 1861-387X
    Keywords: Chordoid meningioma ; Castleman syndrome ; Electron microscopy ; Immunohistochemistry ; Magnetic resonance image
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Chordoid meningioma is a relatively rare variant that is often associated with peritumoral lymphoplasmacellular infiltration causing Castleman syndrome (CS). We present a 44-year-old woman with chordoid meningioma not associated with CS. The patient presented with epilepsy and right hemiparesis (Todd's palsy) on admission. The radiological findings revealed an extraaxial mass lesion in the premotor cortex. They were compatible with a preoperative diagnosis of meningioma. No physical abnormalities related to CS were detected. A left frontal craniotomy was performed. The tumor surface was gelatinous, and it was totally resected with the attached dura mater (Simpson grade I). The patient had an uneventful recovery, and her seizures subsided. The pathological findings of the specimens revealed nests and cords of spindle and epithelioid cells with abundant myxoid matrix, mimicking the features of chordoma. On the basis of radiological, immunohistochemical, and electron microscopic findings, chordoid meningioma was verified, and a review of the literature was performed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02484287
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  • 139
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    Establishment of an apoptosis-suppressible,cell-cycle arrestable cell line and its applicationfor enhancing protein production of serum-free or-supplemented culture (2000)
    Springer
    Cytotechnology 32 (2000), S. 125-134 
    Details
    ISSN: 1573-0778
    Keywords: antisense ; apoptosis ; cell cycle ; c-jun ; protein production
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Expression of c-jun gene induces apoptosis ofcells cultured in serum-free medium. It also promotescell-cycling in serum-containing medium, leading cellsto die by overgrowth. Previously, we established anapoptosis-suppressible, cell-cycle arrestable cellline, c-jun AS, by transfecting Friend murineerythroleukemia (F-MEL) cells with adexamethasone-inducible antisense c-jun gene.Induction of the antisense c-jun transcriptionwith dexamethasone suppressed c-jun expression.As a result, c-jun AS cells survived inserum-free medium containing dexamethasone for a longtime, while F-MEL cells died quickly in the presenceor absence of dexamethasone. In serum-containingmedium, the growth of c-jun AS cells was viablyblocked by inducing antisense c-juntranscription, and the cells survived at thenon-growth state avoiding overgrowth. In the presentstudy, protein productivity of c-jun AS cellswas examined in comparison with that of wild typeF-MEL cells. C-jun AS and F-MEL cells werefurther transfected with a vector for expressingalkaline phosphatase as a protein to be produced, andnamed c-jun AS-SEAP and F-MEL-SEAP cells,respectively. In the serum-free medium withdexamethasone, c-jun AS-SEAP cells produced theprotein for up to 6 days, while F-MEL-SEAP cellsstopped production on day 3 due to cell death causedby serum deprivation. In the serum-containing mediumwith dexamethasone, c-jun AS-SEAP cells wereviably arrested in the cell cycle, and cell death dueto overgrowth was avoided. As the result, they couldproduce the protein for up to 18 days, whileF-MEL-SEAP cells stopped production within 7 days dueto cell death caused by overgrowth.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008149218360
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  • 140
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    Treatment of mouse melanoma cells with phorbol 12-myristate 13-acetate counteracts mannosylerythritol lipid-induced growth arrest and apoptosis (2000)
    Springer
    Cytotechnology 33 (2000), S. 123-130 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; mannosylerythritol lipid ; melanoma ; protein kinase C
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Mannosylerythritol lipid (MEL), an extracellularglycolipid from yeast, induces the differentiation ofHL-60 promyelocytic leukemia cells towardsgranulocytes. We show here that MEL is also a potentinhibitor of the proliferation of mouse melanoma B16cells. Flow-cytometric analysis of the cell cycle ofMEL-treated B16 cells revealed the accumulation ofcells in the sub-G0/G1 phase, which is a hallmark ofcells undergoing apoptosis. Treatment of B16 cellsfor 24 h with phorbol 12-myristate 13-acetate (PMA),an activator of protein kinase C (PKC), did notinterfere with the growth and survival of the cells,but it effectively counteracted the MEL-induced growtharrest and apoptosis. The activity of PKC was reducedin B16 cells treated with MEL at a concentration atwhich MEL induced apoptosis. However, incubation withPMA in addition to MEL reversed this reduction in theactivity of PKC. These results suggest thatconverging signaling pathways are triggeredindependently by MEL and PMA and that the signalsmight both be mediated by PKC.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008129616127
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  • 141
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    Antisense Downregulation of the Apoptosis-related Bcl-2 and Bcl-xL Proteins: A New Approach to Cancer Therapy (2000)
    Springer
    Molecular biology 34 (2000), S. 875-887 
    Details
    ISSN: 1608-3245
    Keywords: antisense oligonucleotides ; oncogenesis ; therapy of cancer ; apoptosis ; bcl family
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Members of the bcl-2 family genes are thought to be central regulators of apoptosis. Overexpression of antiapoptotic proteins, such as Bcl-2 and Bcl-xL, contributes not only to the development of cancer but also to its resistance against a wide variety of anticancer agents. Thus, downregulation of Bcl-2 and Bcl-xL can potentially be used to improve therapeutic approaches to advanced cancer. The use of antisense biotechnology to downregulate antiapoptotic bcl family members in diverse cancers in vitro and in vivo is reviewed. The effects and potential limitations of antisense strategies are also discussed in the context of a critical view of recent research in the field.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026679826610
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  • 142
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    Decrease in cell surface sialic acid in etoposide-treated Jurkat cells and the role of cell surface sialidase (2000)
    Springer
    Glycoconjugate journal 17 (2000), S. 301-306 
    Details
    ISSN: 1573-4986
    Keywords: sialidase ; sialyltransferase ; apoptosis ; Jurkat cells ; etoposide
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The present study investigated the mechanism underlying alterations of cell surface sugar chains of Jurkat cells by inducing apoptosis with etoposide, an inhibitor of topoisomerase II. Within 3[emsp4 ]h of etoposide treatment, flowcytometric analysis revealed a decrease in Maackia amurensis agglutinin recognized α2,3-linked sialic acid moieties and an increase in Ricinus communis agglutinin recognized galactose. The results suggested that asialo-sugar chains on glycoconjugates were rapidly induced on the etoposide-treated cell surface. To clarify the desialylation mechanism, we studied α2,3-sialyltransferase mRNA expression and the activity of sialidase on the cell surface during etoposide-induced apoptosis. The expression of hST3Gal III and hST3Gal IV mRNAs were down-regulated and sialidase activity on the cell surface increased threefold within 2[emsp4 ]h of etoposide treatment. Moreover, the decrease in α2,3-linked sialic acid levels was significantly suppressed in the presence of 2,3-dehydro-2-deoxy-N-acetylneuraminic acid, an inhibitor of sialidase. These results suggested that activation or exposure of sialidase on the cell surface was induced by etoposide treatment and was the main cause of the decrease in sialic acids.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007165403771
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  • 143
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    Regulated overexpression of the survival factor bcl-2 in CHO cells increases viable cell density in batch culture and decreases DNA release in extended fixed-bed cultivation (2000)
    Springer
    Cytotechnology 32 (2000), S. 45-61 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; Bcl-2 ; fixed-bed reactor ; regulated gene expression
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Using multicistronic expression technology we generated a stable Chinese hamster ovary (CHO) cell line (MG12) expressing a model secreted heterologous glycoprotein, the secreted form of the human placental alkaline phosphatase (SEAP), and bcl-2, best known as an apoptosis inhibitor, in a tetracycline-repressible dicistronic configuration. In batch cultivations in serum-containing medium, MG12 cells reached twice the final viable cell density when Bcl-2 was overexpressed (in the absence oftetracycline) compared to MG12 populations culturedunder tetracycline-containing conditions (bcl-2repressed). However, bcl-2-expressing MG12 cellsshowed no significant retardation of the decline phasecompared to batch cultures in which the dicistronicexpression unit was repressed.Genetic linkage of bcl-2 expression with the reporter protein SEAP in our multicistronic construct allowed online monitoring of Bcl-2 expression over an extended, multistage fixed-bed bioreactor cultivation. The cloned multicistronic expression unit proved to be stable over a 100 day bioreactor run. CHO MG12 cells in the fixed-bed reactor showed a drastic decrease in the release of DNA into the culture supernatant under conditions of reduced tetracycline (and hencederepressed SEAP and bcl-2 overexpression). This observation indicated enhanced robustness associated with bcl-2 overexpression, similar to recent findings for constitutive Bcl-2-overexpressing hybridoma cells under the same bioprocess conditions. These findings indicate, in these serum-containing CHO cell cultures, that overexpression of Bcl-2 results in desirable modifications in culture physiology.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008168522385
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  • 144
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    Immunochemical characteristics of a novel cell death receptor and a decoy receptor on granulosa cells of porcine ovarian follicles (2000)
    Springer
    Cytotechnology 33 (2000), S. 189-201 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; cell death receptor ; decoyreceptor ; granulosa cell ; porcine ovary
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract Previously, we prepared an IgM monoclonal antibody(PFG-1) which specifically recognized a cell-membraneglycoprotein (PFG-1 antigen; 55 kD, pI 5.9),immunohistochemically reacted with granulosa cells ofhealthy follicles but not of atretic follicles, andinduced granulosa cell apoptosis. In the presentstudy, an IgM monoclonal antibody (PFG-3) capable ofinducing granulosa cell apoptosis and an IgGmonoclonal antibody (PFG-4) not capable of inducingapoptosis were produced against granulosa cellsprepared from healthy antral follicles of porcineovaries. Two-dimensional Western blotting analysisrevealed that PFG-3 specifically recognized twocell-membrane proteins (named PFG-3-1 andPFG-3-2/PFG-1 antigens; 42 kD, pI 5.2 and 55 kD, pI5.9, respectively) of healthy granulosa cells, andthat PFG-4 recognized the same two cell-membraneproteins. In atretic granulosa cells, PFG-3-2/PFG-1antigen disappeared. Immunochemical reactions of theseantibodies were only detected in follicular granulosacells but not any other ovarian tissues or organs.PFG-3 and PFG-4 immunohistochemically reacted withgranulosa cells of healthy and atretic follicles. Whenthe isolated granulosa cells prepared from healthyfollicles were cultured in medium containing PFG-3,the cells underwent apoptosis, and co-incubation withPFG-4 inhibited PFG-3-inducible apoptosis. Theseobservations suggested that PFG-3-2/PFG-1 antigen isa novel cell death receptor which is different fromthe apoptosis-mediating receptors (Fas/Apo-1/CD95 orTNF receptor), and that PFG-3-1 antigen may act as adecoy receptor and inhibit apoptotic signal transmission.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008146119761
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  • 145
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    Prolongation of murine hybridoma cell survival in stationary batch culture by Bcl-xL expression (2000)
    Springer
    Cytotechnology 34 (2000), S. 131-139 
    Details
    ISSN: 1573-0778
    Keywords: apoptosis ; bcl-xL ; cell growth ; cell viability ; hybridoma ; myeloma
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine , Process Engineering, Biotechnology, Nutrition Technology
    Notes: Abstract While the ectopic expression of the anti-apoptoticprotein Bcl-2 has been shown to significantly increaseboth cell viability and antibody production in batchculture, some cell lines are refractory to thesemanipulations. For example, the NS/O and theP3x63Ag8.653 murine myelomas, which express highendogenous levels of the Bcl-2 homologue Bcl-xL, areboth resistant to the anti-apoptotic effect of Bcl-2.This indicates that, in these cells, Bcl-2 and Bcl-xLmay be functionally redundant. In order to define therole which Bcl-xL plays in hybridoma cultures, we usedthe Sp2/0-Ag14 cell line. This murine hybridomaexpresses low levels of Bcl-xL and is highly sensitiveto apoptosis induction by cycloheximide (CHX) and byamino acid depletion. Bcl-xL-transfected Sp2/0-Ag14cells were more resistant than the wild type and theplasmid-containing cells to apoptosis induced by CHXand by glutamine depletion. Moreover, when compared tothe vector-transfected control, Bcl-xL-Sp2/0 cellsexhibited a substantial increase in viability instationary batch culture. Interestingly, Sp2/0-Ag14cells overexpressing Bcl-xL showed a growth behaviourthat was similar to the parent myeloma cell lineP3x63Ag8.653. Our results suggest that Bcl-xLexpression levels are sufficient to account for therelative robustness of some hybridoma cell lines instationary batch cultures.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1008186302600
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    Critical Temporal Modulation of Neuronal Programmed Cell Injury (2000)
    Springer
    Cellular and molecular neurobiology 20 (2000), S. 383-400 
    Details
    ISSN: 1573-6830
    Keywords: apoptosis ; annexin ; DNA fragmentation ; ischemia ; nitric oxide ; primary hippocampal neurons
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract 1. As a free radical, nitric oxide (NO) may be toxic to neurons through mechanisms that directly involve DNA damage. Lubeluzole, a novel benzothiazole compound, has recently been demonstrated to be neuroprotective through the signal transduction pathways of NO. We therefore examined whether neuroprotection by lubeluzole was dependent upon the molecular pathways of programmed cell death (PCD). 2. In primary hippocampal neurons, evidence of PCD was determined by hematoxylin and eosin (H&E) stain, transmission electron microscopy, and annexin-V binding. NO administration with the NO generators sodium nitroprusside (300 μM) or SIN-1 (300 μM) directly induced PCD. 3. Neurons positive for PCD increased from 22 ± 3% (untreated) to 72 ± 3% (NO) over a 24-hr period. Coadministration of NO and lubeluzole (750 nM), a neuroprotective concentration, actively decreased PCD expression on H&E stain from 72 ± 3% (NO only) to 25 ± 3% (NO and lubeluzole). Significant reduction in DNA fragmentation by lubeluzole also was evident on electron microscopy. Application of lubeluzole in concentrations that were not neuroprotective or administration of the biologically inactive R-isomer did not significantly alter NO-induced PCD, suggesting that neuroprotection by lubeluzole was intimately linked to the modulation of PCD. Lubeluzole also was able to prevent the initial stages of cellular membrane inversion labeled with annexin-V binding, an early and sensitive indicator of PCD. Interestingly, the critical period for lubeluzole to reverse PCD induction appeared to be within the first 4 hr following NO exposure. 4. Further investigation into the neuroprotective pathways that alter PCD may provide greater insight into the molecular mechanisms that ultimately determine neuronal injury.
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    URL: http://dx.doi.org/10.1023/A:1007070311203
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  • 147
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    A short peptide derived from the antisense homology box of Fas ligand induces apoptosis in anti-Fas antibody-insensitive human ovarian cancer cells (2000)
    Springer
    Apoptosis 5 (2000), S. 37-41 
    Details
    ISSN: 1573-675X
    Keywords: Anti-Fas antibody ; antisense homology box-derived peptide ; apoptosis ; Fas ligand ; ovarian cancer.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract We found that a short synthetic peptide corresponding to the “antisense homology box” of Fas ligand induced apoptotic cell death of Fas-expressing human ovarian cancer cell lines. The peptide was deduced from residues 256–265 of human Fas ligand, based on the hypothesis that it should contain a specific binding site to the corresponding Fas. Interestingly, the ovarian cancer cell line NOS4, which was sensitive to anti-Fas antibody induced apoptosis, was not affected by the peptide, whereas another cell line, SKOV-3, which was insensitive to anti-Fas antibody, was killed by the peptide. Thus, this short peptide was shown to have a unique activity to induce apoptosis in human ovarian cancer cells in a manner different from anti-Fas antibody.
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    URL: http://dx.doi.org/10.1023/A:1009633525205
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  • 148
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    The Daxx enigma (2000)
    Springer
    Apoptosis 5 (2000), S. 217-220 
    Details
    ISSN: 1573-675X
    Keywords: Daxx ; apoptosis ; Fas ; PML ; ND10
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Several reports describing Daxx and its putative role have emerged without a unifying theme. While Daxx has been implicated in apoptosis, it remains unclear whether Daxx is pro- or anti-apoptotic, and whether its role in apoptosis is direct or indirect. Moreover, whether Daxx plays alternative or additional roles in regulating transcription, centromere binding or any number of other activities within the cell, is uncertain. The ability of Daxx to interact with a wide variety of molecules in yeast-interaction trap systems (Table 1) has allowed for this range of speculation. The fact that Daxx contains no significant homology to other known proteins has rendered its study all the more challenging.
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    URL: http://dx.doi.org/10.1023/A:1009696227420
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  • 149
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    Suicidal differential housekeeping gene activity in apoptosis induced by DCNP (2000)
    Springer
    Apoptosis 5 (2000), S. 379-388 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; ATP depletion ; cell acidification and shrinkage ; CpG-specific megabase fragmentations ; DCNP (2,6-dichloro-4-nitrophenol) ; housekeeping genes ; microarray (genechip) ; zVAD-fmk
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Previous suggestions of CpG-specific apoptotic commitment implied critical epigenetic modulation of house-keeping genes which have canonical CpG islands at 5′ promoter regions. Differential housekeeping gene activity however has not been shown. Using a focussed microarray (genechip) of 22 housekeeping genes we show this in apoptosis induced in human Chang liver cells by DCNP (2,6-dichloro-4-nitrophenol), a non-genotoxic inhibitor of sulfate detoxification. 3–7 folds downregulation of 9 genes in glycolysis, tricarboxylic acid cycle and the respiratory electron transport chain suggested gene-directed energy depletion which was correlated with observed ATP depletion. 4 folds downregulation of the pyruvate dehydrogenease gene suggested gene-directed metabolic acidosis which was correlated with observed cell acidification. Other differential housekeeping gene activity, including 4 folds upregulation of microtubular alpha-tubulin gene, and 2 folds upregulation of ubiquitin, also had a bearing on apoptosis. Broadspectrum zVAD-fmk caspase inhibition abolished 200 bp DNA ladder fragmentations but not the CpG-specific megabase fragmentations and other hallmarks of cell destruction, suggesting a caspase-independent cell death. Death appeared committed at gene-level.
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    URL: http://dx.doi.org/10.1023/A:1009695811147
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  • 150
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    Concanavalin A induced apoptosis in murine macrophage PU5-1.8 cells through clustering of mitochondria and release of cytochrome c (2000)
    Springer
    Apoptosis 5 (2000), S. 369-377 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; concanavalin A ; cytochrome c release ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Concanavalin A (ConA), normally a mitogen of T-lymphocytes, was found to be a cell cycle-independent apoptosis-inducing agent in cultured murine macrophage PU5-1.8 cells. This assertion is based on the following observations: (1) ConA increased the number of cells with hypo-diploid DNA in a dose dependent manner as revealed by flow cytometry; (2) ConA elicited DNA fragmentation and the cytotoxicity of ConA was suppressed by α-D-methylmannoside which blocks the lectin site of ConA; (3) ConA was able to release cytochrome c (cyto c) into the cytosol of PU5-1.8 cells. When isolated mitochondria were incubated with ConA, release of cyto c was observed too. Interestingly, clustering of mitochondria was found in the cytosol under a confocal microscope after ConA treatment. When cells were incubated with ConA-FITC and subsequently with mitotracker red (a probe for mitochondria), co-localization of fluorescence signals was observed. These results suggest that ConA was delivered to the mitochondria, induced mitochondrial clustering and released cyto c. Our results also show that introduction of exogenous cyto c electroporationally into ConA-untreated cells elicited DNA fragmentation. On the other hand, introduction of specific antibody against cyto c into PU5-1.8 cells suppressed the ConA-mediated cell death. Taken together, our results indicate that ConA induced apoptosis in PU5-1.8 cells through mitochondrial clustering and release of cyto c and the release of cyto c was sufficient to elicit apoptosis in PU5-1.8 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009691727077
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    Apoptosis and airway inflammation in asthma (2000)
    Springer
    Apoptosis 5 (2000), S. 473-485 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; asthma ; inflammation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Asthma is a disease characterized by a chronic inflammation of the airways and by structural alterations of bron-chial tissues, often referred to as airway remodelling. The development of chronic airway inflammation in asthma depends upon the continuous recruitment of inflammatory cells from the bloodstream towards the bronchial mucosa and by their subsequent activation. It is however increasingly accepted that mechanisms involved in the regulation of the survival and apoptosis of inflammatory cells may play a central role in the persistent inflammatory process characterizing this disease. Increased cellular recruitment and activation, enhanced cell survival and cell:cell interactions are therefore the key steps in the development of chronic airway inflammation in asthma, and represent the major causes for tissue damge, repair and remodelling.
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    URL: http://dx.doi.org/10.1023/A:1009661406440
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    Apoptosis, cross-presentation, and the fate of the antigen specific immune response (2000)
    Springer
    Apoptosis 5 (2000), S. 307-314 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; cancer ; cross-priming ; cross-tolerance ; dendritic cells ; T lymphocytes
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Induction of cell death by apoptosis, also called programmed cell death, and clearance of apoptotic bodies by scavenger cells has long thought to be an efficient means to dispose of unwanted cells without causing inflammatory responses able to mediate specific reactions. However, a number of evidences have been accumulated suggesting that apoptotic cell death is implicated in the pathogenesis of systemic and organ specific autoimmune diseases. In addition, recognition and engulfement of apoptotic cells by professional antigen presenting cells, such as dendritic cells, and their interaction with effector immune cells have been recently described to result in apoptotic cell-derived antigen specific tolerance. This review will summarise the most recent findings on the immunogenic potential of cells undergoing programmed death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009671105696
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  • 153
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    Endothelial cell survival and apoptosis in the tumor vasculature (2000)
    Springer
    Apoptosis 5 (2000), S. 323-328 
    Details
    ISSN: 1573-675X
    Keywords: Angiogenesis ; angiopoietins ; apoptosis ; integrins ; vascular endothelial growth factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Angiogenesis is essential for the growth and metastasis of solid tumors. The balance of endothelial cell (EC) proliferation and apoptosis is a major determinant in tumor angiogenesis. Recently, several studies demonstrated that numerous angiogenic factors not only induce angiogenesis but also function as EC survival factors. Vascular endothelial growth factor (VEGF), a potent angiogenic factor, is also an EC survival factor in embryonic vasculogenesis and tumor angiogenesis. VEGF activates specific intracellular survival pathways in ECs including Bcl-2, A1, IAP, Akt, and Erk. Integrins may function as EC survival factors by preventing anoikis by enhancing binding to the extracellular matrix. In addition, integrins may function in concert with VEGF to promote EC survival. Angiopoietin-1 (Ang-1) has recently been shown to stabilize EC networks by binding to the EC-specific tyrosine kinase receptor Tie-2. Pericytes also function as EC survival factors, by cell-cell contact, secretion of survival factors, or both. Targeting any of the above mechanisms for EC survival may provide novel antineoplastic strategies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009679307513
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  • 154
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    Induction of apoptosis in human cancer cells by TZT-1027, an antimicrotubule agent (2000)
    Springer
    Apoptosis 5 (2000), S. 345-353 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; antimicrotubule agent ; cell cycle ; dolastatin 10 ; TZT-1027
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract TZT-1027, a newly synthesized dolastatin 10 derivative, is a potent antitumor agent which inhibits microtubule polymerization and perturbs microtubule dynamics. In this report, we investigated whether TZT-1027 inhibited the growth of various human cancer cells, and the cell death caused by TZT-1027 was due to apoptosis. In addition, we elucidated the apoptosis machinery induced by treatment with TZT-1027. The 50% growth-inhibitory concentrations (IC50 values) of TZT-1027 on cancer cells derived from various sources were not more than 5.9 ng/ml. TZT-1027 showed superior cytotoxicity than any other antitumor agents. Next, we evaluated morphological nuclear change, namely, chromatin condensation and DNA fragmentation. We used three cancer cell lines derived from different types in view of having apoptosis related protein, human leukemia HL-60 (in the presence of both Caspase-3 and Bcl-2), human breast cancer MCF-7 (in the absence of Caspase-3), and human prostate cancer DU145 (in the absence of Bcl-2). TZT-1027 induced DNA fragmentation in the presence but not absence of Caspase-3. Nevertheless, apoptic chromatin condensation was observed in all cancer cells even if there was no Caspase-3. Furthermore, we examined whether TZT-1027, microtubule-disrupting agent, influenced cell cycle progression. Flow cytometric analysis revealed the cells treated with TZT-1027, and with the other antimicrotubule agents, to be arrested at the G2/M phase and subsequently to show fragmented DNA smaller than that of G1 phase cells. Moreover, we tested TZT-1027 for its ability to induce Bcl-2 phosphorylation in human cancer cell lines. TZT-1027 and other agents which interacted with microtubules induced Bcl-2 phosphorylation, whereas DNA-damaging agents did not. The present results suggested an association of the growth-inhibitory effect of TZT-1027 with the induction of apoptosis and indicated that the apoptosis induced by TZT-1027 was followed by G2/M arrest even if there was no Caspase-3 or Bcl-2.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009687609330
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  • 155
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    Increased apoptosis and increased clonogenic survival of 12V-H-ras transformed rat fibroblasts in response to cisplatin (2000)
    Springer
    Apoptosis 5 (2000), S. 355-367 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; chemotherapy resistance ; clonogenicity ; ras
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Mutationally activated Ras is involved in tumor progression and likely also in drug resistance. Using survival, viability and apoptosis assays, we have here compared the cisplatin sensitivities of FR3T3 rat fibroblasts and a 12V-H-ras transformed subline (Ras2:3). Around 24 h after cisplatin treatment Ras2:3 cells showed higher apoptosis levels and lower viability than FR3T3. This increased sensitivity correlated with weaker cisplatin-induced activation of Jun N-terminal kinase (JNK). In contrast to apoptosis assays, colony formation assays showed that Ras2:3 were more resistant to cisplatin than were FR3T3. This was partly due to the increased cisplatin sensitivity of FR3T3 seeded at low densities, as required in colony formation assays. In addition, Ras2:3 cisplatin survivors had a higher relative proliferative capacity. Cell cycle analyses showed that FR3T3 cells initially responded with a dose-dependent G2 arrest, while Ras2:3 accumulated in S-phase. Experiments with an anti-apoptotic mutant of MEKK1 suggested that the apoptotic response of Ras2:3 cells is not specific to the S-phase fraction. In summary, the cisplatin response of ras-transformed fibroblasts is distinct from that of parental cells, in that they show increased apoptosis, a different cell cycle response and increased post-treatment proliferative capacity. The results illustrate the need to carefully consider methods and protocols for in vitro studies on chemotherapy sensitivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009639726168
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  • 156
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    Role of reactive oxygen species (ROS) in apoptosis induction (2000)
    Springer
    Apoptosis 5 (2000), S. 415-418 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; death receptors ; inflammation ; reactive oxygen species (ROS)
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Reactive oxygen species (ROS) and mitochondria play an important role in apoptosis induction under both physiologic and pathologic conditions. Interestingly, mitochondria are both source and target of ROS. Cytochrome c release from mitochondria, that triggers caspase activation, appears to be largely mediated by direct or indirect ROS action. On the other hand, ROS have also anti-apoptotic effects. This review focuses on the role of ROS in the regulation of apoptosis, especially in inflammatory cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009616228304
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  • 157
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    Ethanol-induced apoptotic neurodegeneration in the developing brain (2000)
    Springer
    Apoptosis 5 (2000), S. 515-521 
    Details
    ISSN: 1573-675X
    Keywords: anesthetics ; apoptosis ; barbiturates ; benzodiazepines ; ethanol ; GABAA receptors ; ketamine ; NMDA receptors ; phencyclidine ; synaptogenesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract It has been known for three decades that ethanol, the most widely abused drug in the world, has deleterious effects on the developing human brain, but progress has been slow in developing animal models for studying this problem, and the underlying mechanisms have remained elusive. Recently, we have shown that during the synaptogenesis period, also known as the brain growth spurt period, ethanol has the potential to trigger massive neuronal suicide in the in vivo mammalian brain. The brain growth spurt period in humans spans the last trimester of pregnancy and first several years after birth. The NMDA antagonist and GABAmimetic properties of ethanol may be responsible for its apoptogenic action, in that other drugs with either NMDA antagonist or GABAmimetic actions also trigger apoptotic neurodegeneration in the developing brain. Our findings provide a likely explanation for the reduced brain mass and neurobehavioral disturbances associated with the human fetal alcohol syndrome. Furthermore, since NMDA antagonist and GABAmimetic drugs are sometimes abused by pregnant women and also are used as anticonvulsants, sedatives or anesthetics in pediatric medicine, our findings raise several complex drug safety issues. In addition, the observation that ethanol and several other drugs trigger massive neuronal apoptosis in the developing brain provides an unprecedented opportunity to study both neuropathological aspects and molecular mechanisms of apoptotic neurodegeneration in the in vivo mammalian brain.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009685428847
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  • 158
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    Hidden Effects of Cryopreservation on Quality of Human Spermatozoa (2000)
    Springer
    Cell and tissue banking 1 (2000), S. 133-142 
    Details
    ISSN: 1573-6814
    Keywords: human spermatozoa ; cryopreservation ; plasma membrane ; fluorogenic enzyme substrates ; Annexin V-binding ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The effects of cryopreservation on two characteristics of human spermatozoa were investigated: the early phases of disturbed plasma membrane function and the activity of enzymes in intact spermatozoa. The membrane function was detected by means of the calcium-dependent binding of fluorescein isothiocyanate (FITC)-conjugated Annexin V to sperm plasma membranes. Annexin V monitors the translocation of phosphatidylserine from the inner to the outer leaflet of the plasma membrane, which is one of the earliest features of membrane disintegration. For the second aim synthetic fluorogenic substrates for peptidases, proteinases, esterases, elastases and collagenases were applied. These substrates, CellProbe™ reagents consist of different peptide sequences, specific for the enzymes, and a fluorescein- or rhodamine 110-dye moiety. They enter the cells without previous membrane permeabilisation and exhibit fluorescence after cleavage depending on enzyme activity. The number of positive cells and the intensity of the fluorescence were determined by flow cytometric analysis comparing fresh spermatozoa with cryopreserved ones. Thirty-five semen samples collected from 35 donors were cryopreserved using the freezing medium TEST yolk buffer. All specimens showed normal spermiogram parameters. Twenty-five of the samples were used for detection of Annexin V-FITC binding and 10 semen samples for investigations of the intracellular enzymes. The Annexin V-assay applied two fluorescent dyes (Annexin V, AN and propidium iodide, PI) which led to three groups of spermatozoa (a) viable spermatozoa (AN V-negative and PI-negative), (b) dead spermatozoa (AN V-positive and PI-positive) and (c) cells with impaired but integer plasma membrane (AN V-positive and PI-negative). The percentage of vital Annexin V-negative spermatozoa (x ± SEM) decreased significantly (p 〈 0.001) from fresh spermatozoa (51.6 ± 3.1) to cryopreserved spermatozoa (26.6 ± 2.2%) and was associated with their motility (57.9 ± 1.9% motile fresh spermatozoa vs. 22.6 ± 3.9% motile sperm after cryopreservation). Of the spermatozoa 28.2% were Annexin V-positive before and 44.4% after cryostorage even though they did not bind to PI. Thus, vital spermatozoa showed a disturbed membrane function indicating viability before as well as after cryostorage. Moreover, after cryopreservation the spermatozoal fluorescence increased applying substrates for butyryl esterase (p 〈 0.05), prolyl-aminopeptidase (p 〈 0.001) and val-lys-(VK)-cathepsin (p 〈 0.001). In contrast, the activities of fluorescein diacetate (FDA)- and FDA/sodium fluoride (NAF)-esterase (p 〈 0.05), ala-ala-pro-val-(AAPV)-elastase (p 〈 0.001), gly-pro-leu-gly-pro-(GPLGP)-collagenase (p 〈 0.05) and gly-gly-leu-(GGL)-subtilisin (p 〈 0.001) decreased after cryopreservation. The substrates for arg-gly-glut-ser-(RGES)-elastase, gly-phenyl-gly-ala-(GFGA)-collagenase and threo-pro-(TP)-cathepsin were not cleaved before as well as after cryostorage. In addition to the known effects of sperm cryopreservation our results showed two further alterations of human ejaculated spermatozoa: (a) disturbed plasma membrane function, which is not detectable by supravital staining and (b) a changed pattern of intracellular enzyme activities.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1010122800157
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  • 159
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    RGD peptide-induced apoptosis in human leukemia HL-60 cells requires caspase-3 activation (2000)
    Springer
    Cell biology and toxicology 16 (2000), S. 275-283 
    Details
    ISSN: 1573-6822
    Keywords: apoptosis ; RGD ; HL-60 ; caspase-3
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract RGD motif-containing peptides have been used in various studies of cell adhesion and growth. We report that RGD triggered apoptosis at a concentration of 1 mmol/L, whereas RAD-containing peptides failed to induce apoptosis in HL-60 cells. RGD-treated cells revealed internucleosomal DNA fragmentation. Western blot reveals caspase-3 activation in RGD peptide-treated cells. A caspase-3 inhibitor z-VAD-FMK completely blocked the apoptosis, but a caspase-1 inhibitor (Ac-YVAD-CMK) and caspase-2 inhibitor (z-VDVAD-FMK) did not block the apoptosis, suggesting that caspase-3 might have a critical role in the execution process of apoptosis induced by RGD. RGD peptides have been used extensively to inhibit tumor metastasis. Our results should help in further understanding the RGD peptide-induced apoptosis, which is important since RGD peptides have a potential role in therapies of the future.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026758429238
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  • 160
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    (−)1-(Benzofuran-2-yl)-2-propylaminopentane Shows Survival Effect on Cortical Neurons Under Serum-Free Condition Through Sigma Receptors (2000)
    Springer
    Cellular and molecular neurobiology 20 (2000), S. 695-702 
    Details
    ISSN: 1573-6830
    Keywords: apoptosis ; impulse enhancer ; sigma receptor ; neuroprotection ; (+)-pentazocine
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract SUMMARY 1. The rapid cell death of cortical neurons in serum-free culture was rescued by the condition medium from the high-density culture, but not by brain-derived neurotrophic factor or basic fibroblast growth factor. 2. Similar rescue was observed by the addition of (−)BPAP, an impulse enhancer, and (+)-pentazocine, a sigma receptor agonist. These actions were blocked by BD1063, a sigma receptor antagonist. 3. (−)BPAP showed a weak displacement activity in the [3H]pentazocine binding to synaptic membranes from rat cerebral cortex. 4. These findings suggest that (−)BPAP and (+)-pentazocine have unique survival activity on cortical neurons through sigma receptors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007050808754
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  • 161
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    Apoptosis in Alzheimer's disease—an update (2000)
    Springer
    Apoptosis 5 (2000), S. 9-16 
    Details
    ISSN: 1573-675X
    Keywords: Aging ; Alzheimer's disease ; amyloid precursor protein ; apoptosis ; Bcl-2 ; caspase ; presenilin ; transcription factor ; β amyloid.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Alzheimer's disease (AD) is the most common human neurodegenerative disorder characterized by the progressive deterioration of cognition and memory in association with the presence of senile plaques, neurofibrillary tangles, and massive loss of neurons. Most cases of AD are late-onset and sporadic, but in some cases the disease is inherited as an autosomal dominant trait. Four different genes, the amyloid precursor protein, apolipoprotein E, and presenilins 1 and 2 have been implicated in the etiology of familial AD. It is now generally accepted that massive neuronal death due to apoptosis is a commmon characteristic in the brains of patients suffering from neurodegenerative diseases, and apoptotic cell death has been found in neurons and glial cells in AD. This review summarizes the current findings regarding the evidence for apoptosis in AD and discusses the possible involvement of apoptosis-regulating factors in the pathology of AD. Modification of the apoptotic cascade could be considered as a primary therapeutic strategy for the disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009625323388
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  • 162
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    Caspase-dependent and -independent death pathways in cancer therapy (2000)
    Springer
    Apoptosis 5 (2000), S. 17-20 
    Details
    ISSN: 1573-675X
    Keywords: Anti-tumor drugs ; apoptosis ; cancer ; caspases ; necrosis.
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The majority of current anticancer therapies induce tumor cell death through the induction of apoptosis. Alterations in the apoptotic pathways may determine tumor resistance to these therapies. Activation of the proteolytic cascade involving caspase family members is a critical component of the execution of cell death in apoptotic cells. However, recent studies suggest that cell death can proceed in the absence of caspases. In this review we describe the role of caspase-dependent and -independent pathways as targets for anticancer treatment; better understanding of diverse modes of tumor cell death will help to avoid ineffective treatment and provide a molecular basis for the new strategies targeting caspase-independent death pathways in apoptosis-resistant forms of cancer.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009677307458
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  • 163
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    Activation of MAD 2 checkprotein and persistence of cyclin B1/CDC 2 activity associate with paclitaxel-induced apoptosis in human nasopharyngeal carcinoma cells (2000)
    Springer
    Apoptosis 5 (2000), S. 235-241 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; cyclin B1/CDC 2 ; G2/M arrest ; MAD 2 ; paclitaxel
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Paclitaxel (Taxol™) is a microtubule-interfering agent that induced persistent and transient G2/M arrest before apoptosis in human nasopharyngeal carcinoma (NPC) cells at high and low concentrations, respectively. In this study, we intended to explore the underlying molecular events and found that cellular cyclin B1/CDC 2 kinase activity was increased and persisted for 〉6 h upon paclitaxel treatment both at high and low concentrations. Furthermore, activation of MAD 2 checkprotein could account for the loss of cyclin B1 ubiquitination and the persistence of cyclin B1/CDC 2 activation in the cases. To investigate the involvement of cyclin B1 and MAD 2 activation in paclitaxel-induced apoptosis, we introduced affinity-purified anti-cyclin B1 and MAD 2 antibodies into NPC cells by electroporation before the further paclitaxel treatment. The antibodies against cyclin B1 and MAD 2 indeed attenuated paclitaxel-induced cytotoxicity and DNA fragmentation. Our study suggests that activation of cyclin B1/CDC 2 and MAD 2 were the M-phase events required for paclitaxel-induced apoptosis in NPC cells. The dys-regulated cyclin B1/CDC 2 activation could enhance the prometaphase progression, but activation of MAD 2 rendered cells inable to exit from the metaphase. Under this circumstance, cells were probably going to “mitotic catastrophe” and ultimately, destined to apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009652412399
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  • 164
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    Regulation of apoptosis in mast cells (2000)
    Springer
    Apoptosis 5 (2000), S. 435-441 
    Details
    ISSN: 1573-675X
    Keywords: activation ; apoptosis ; death receptors ; glucocorticosteroids ; mast cells ; survival factors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Apoptosis is a physiological process of cell death that occurs in all multicellular organisms. Its dysregulation has been postulated as one of the main causes in the development of diseases such as cancer, AIDS, autoimmune diseases and allergy. Apoptosis has been mainly studied in the inflammatory cells that participate in the late and chronic stages of allergy (eosinophils, neutrophils, lymphocytes and macrophages) as a new way to elucidate the pathogenesis of this disease. Nevertheless, much less it is known about the regulation of apoptosis in the “initiators” of the allergic process: The Mast Cells. In normal conditions, mast cells are described as long-living cells that keep a constant number of cells in tissues. However, increased numbers of mast cells are observed in the late phase of asthma and in both the inflammatory and in the repair/remodeling stage of various inflammatory/fibrotic disorders. In this report, we discuss the possible mechanisms that regulate the apoptotic process in normal conditions and disease, such as survival factors and death receptors. A link between mast cell activation, during the early stages of the allergic process, and triggering of anti-apoptotic signaling pathways is also suggested as an important contributor to the extended life of mast cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009680500988
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  • 165
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    The molecular control of DNA damage-induced cell death (2000)
    Springer
    Apoptosis 5 (2000), S. 491-507 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; Bcl-2 ; caspases ; death receptors ; DNA damage ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Because of the singular importance of DNA for genetic inheritance, all organisms have evolved mechanisms to recognize and respond to DNA damage. In metazoans, cells can respond to DNA damage either by undergoing cell cycle arrest, to facilitate DNA repair, or by undergoing cell suicide. Cell death can either occur by activation of the apoptotic machinery or simply be a consequence of irreparable damage that prevents further cell division. In germ cells, mechanisms for limiting alterations to the genome are required for faithful propagation of the species whereas in somatic cells, responses to DNA damage prevent the accumulation of mutations that might lead to aberrant cell proliferation or behavior. Several of the genes that regulate cellular responses to DNA damage function as tumor suppressors. The clinical use of DNA damaging agents in the treatment of cancer can activate these tumor suppressors and exploits the cellular suicide and growth arrest mechanisms that they regulate. It appears that in some but not all types of tumors the propensity to undergo apoptosis is a critical determinant of their sensitivity to anti-cancer therapy. This review describes current understanding of the molecular control of DNA damage-induced apoptosis with particular attention to its role in tumor suppression and cancer therapy.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009617727938
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  • 166
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    Protection of apoptotic cell death by protein A (2000)
    Springer
    Apoptosis 5 (2000), S. 509-514 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; protection ; protein A ; pro- and anti-apoptotic factor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The word “Apoptosis” or pragrammed cell death is described as the ultimate end of multiple cellular events converging from numerous initiating events to the ultimate death of a cell or organism. Several processes, such as initiation of death signals at the plasma membrane, expression of pro-apoptotic oncoproteins, activation of death proteases, endonucleases etc., that ultimately coalesce to a common irreversible execution phase, lead to cell demise. Counteracting the death signals are cell survival factors. A balance between the cell death and cell survival factors plays a major role in the decision making process as to whether a cell should die or must live. It is, therefore, hypothesized that if the balance can be shifted in favor of cell survival, one might be able to arrest the aging process, save the injured cells or else if the balance is shifted toward cell-kill it might help destroy tumors and other undesirable cells. Protein A (PA) of Staphylococcus aureus has been found to have multifarious biological response modifying properties. It has been shown to possess anti-tumor, anti-toxic, anti-parasitic and antifungal activities. It also acts as a potent immunostimulator. PA can protect bone marrow progenitor cells from zidovudin(AZT)-induced apoptosis and can stimulate immunocyte proliferation, thereby helping to replenish/restore the depleted hematopoietic cell pool. Such ability to replenish hematopoietic cells is a common property of PA observed against a number of toxic drugs/chemicals, such as cyclophosphamide, benzene, aflatoxin, salmonella endotoxin, etc. Interestingly, it was further demonstrated in our laboratory that PA can selectively kill tumor cells without affecting normal cells of the host. A search for the mechanisms of PA action revealed that this bacterial protein could shift the balance between pro- and anti-apoptotic proteins in favor of survival in normal cells, but in favor of cell death in tumor cells at a particular dose level. This unique property of PA suggests that controlled use of such type of Biological Response Modifier might help in controlling both cell growth and death phenomena.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009633412009
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  • 167
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    ATM dependent apoptosis in the nervous system (2000)
    Springer
    Apoptosis 5 (2000), S. 523-529 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; ATM ; DNA damage ; ionizing radiation ; p53
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Ataxia-telangiectasia is a human syndrome resulting from mutations of the ATM protein kinase that is characterized by radiation sensitivity and neurodegeneration. Although neuroprotective, the molecular details of ATM function in the nervous system are uncertain. However, in the mouse, Atm is essential for ionizing radiation-induced apoptosis in select postmitotic populations of the developing nervous system. Atm-dependent apoptosis in the nervous system also requires p53, consistent with the well-established link of p53 as a major substrate of ATM. Furthermore, the proapoptotic effector Bax is also required for most, but not all, Atm-dependent apoptosis. Therefore, after DNA damage in the developing nervous system, Atm initiates a p53-dependent apoptotic cascade in differentiating neural cells. Together, these data suggest ATM-dependent apoptosis may be important for elimination of neural cells that have accumulated genomic damage during development, thus preventing dysfunction of these cells later in life.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009637512917
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  • 168
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    Early transitory rise in intracellular pH leads to Bax conformation change during ceramide-induced apoptosis (2000)
    Springer
    Apoptosis 5 (2000), S. 551-560 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; Bax ; ceramide ; mitochondria ; pH
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Ceramide can induce apoptosis through a caspase independent pathway. Bax has been described as able to kill cells in the absence of caspase activity, therefore we measured Bax in situ during ceramide-induced apoptosis using anti-Bax antibodies and flow cytometry analysis. An early (〈30 min) increase in Bax labeling was observed after the addition of several ceramide species to several hemopoietic-related cell types. On U937, this increase was not due to antigens synthesis or processing, but rather an increased accessibility or reactivity of Bax antigens for antibodies. This increased immuno-reactivity of Bax was not inhibited by Z-VAD-fmk nor leupeptin, and preceded nuclear fragmentation by several hours. Such an increase in immuno-reactivity was also observed after Fas ligation, but it occurred later (〉2 h) accompanying nuclear apoptosis, and was inhibited by Z-VAD-fmk. Bax immuno-reactivity was found to be related to intracellular pH (pHi), and C2-Ceramide (C2-Cer) induced a very early (〈10 min) transitory increase in pHi. Both Bax immuno-reactivity and pHi increases were dependent on the mitochondrial permeability transition pore (PTP) status. It was concluded from these results that C2-Cer induced a transitory increase in pHi in relation to the PTP. This rise in pHi led to conformational changes in Bax which could be responsible for further apoptosis in the C2-Cer pathway while it was a consequence of caspase activation in the Fas pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009693630664
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    Minireview: Apoptosis as seen through a lens (2000)
    Springer
    Apoptosis 5 (2000), S. 203-209 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; lens development ; organelle loss ; denucleation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The lens represents an ideal model system for studying many of the cellular and molecular events of differentiation. It is composed of two ectodermally-derived cell types: the lens epithelial cells and the lens fibre cells, which are derived from the lens epithelial cells by differentiation. Programmed removal of nuclei and other organelles from the lens fibre cells ensures that an optically clear structure is created, while the morphology of the degenerating nuclei is similar to that observed during apoptosis and is accompanied by DNA fragmentation. These observations suggest the existence of biochemical parallels between the process of lens fibre cell organelle loss and classical apoptosis. For example, proteins encoded by the bcl-2 and caspase gene families are expressed in developing lenses and nuclear degeneration in lens fibre cells can be inhibited in vivo by overexpression of bcl-2 and in vitro by incubation of differentiating lens epithelial cell cultures with caspase inhibitors. Thus, the developing lens may represent a particularly useful model system for researchers interested in apoptosis. In this review, the recent literature pertaining to lens fibre cell organelle loss and its relationship to apoptosis is reviewed and possible future research directions are suggested.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009653326511
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    Induction of apoptosis by adenovirus E4orf4 protein (2000)
    Springer
    Apoptosis 5 (2000), S. 211-215 
    Details
    ISSN: 1573-675X
    Keywords: adenovirus ; E4orf4 ; apoptosis ; protein phosphatase 2A (PP2A) ; caspases ; cancer ; gene therapy
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Adenovirus E4orf4 protein is a multifunctional viral regulator that induces p53-independent apoptosis in transformed cells, but not in normal cells. E4orf4-induced apoptosis can occur without activation of known caspases, although E4orf4 induces caspase activity in some cell lines. The interaction of E4orf4 with a specific subpopulation of protein phosphatase 2A (PP2A) molecules that contain B subunits, but not with those that contain B′ subunits, is required for induction of apoptosis. This review suggests the potential use of E4orf4 in cancer therapy, and discusses whether E4orf4-induced apoptosis plays a role in the viral life cycle. Future research directions are also highlighted.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009644210581
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  • 171
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    Apoptosis and the cell cycle in Xenopus: PMA and MPMA exposure of splenocytes (2000)
    Springer
    Apoptosis 5 (2000), S. 225-233 
    Details
    ISSN: 1573-675X
    Keywords: Amphibia ; apoptosis ; cancer ; cell cycle
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Spontaneous and induced cancers are rare in non-isogeneic or inbred amphibians. Neoplastic cells become immortalized through loss of a normal capacity to die by apoptosis. Mature lymphocytes of mammals require activation and entry into the cell cycle in order to become susceptible to apoptosis. Whether Xenopus lymphocytes differ from mammalian lymphocytes in this regard is examined. In vitro exposure of PMA, or its analogue, MPMA, to adult splenocytes of Xenopus laevis was used to affect apoptosis. Flow cytometric analysis of FITC-Annexin V/propidium iodide (PI) fluorescence (apoptosis) and BrdU uptake (DNA synthesis) were assayed concurrently in the same lymphocyte population over time. Significant increases in apoptotic levels were induced throughout a 72 hour period in PMA-treated cells only. Lymphocytes were also separated by size for analysis. Several sub-populations of lymphocytes were identified, the most interesting of which was small and apoptotic within 4 hours, after PMA exposure. PMA-induced DNA synthesis did not become elevated until after 24 hours. “Direct” apoptosis, i.e. without cell cycle entry, was found only in these small, mature lymphocytes. Since small lymphocytes make up the vast majority of those being analyzed, “direct” apoptosis may be a determining mechanism in the resistance to neoplasia observed in Amphibia. Cells that die more readily are less likely to transform into neoplastic cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009600428328
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  • 172
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    Regulation of neutrophil apoptosis: A role for protein kinase C and phosphatidylinositol-3-kinase (2000)
    Springer
    Apoptosis 5 (2000), S. 451-458 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; inflammation ; neutrophil ; PI-3-kinase ; PKC ; T-cell
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Neutrophils play a central role in host defense and are recruited in vast numbers to sites of infection where they phagocytose and kill invading bacterial pathogens. Neutrophils have a short half-life that is extended at the inflamed site by pro-inflammatory cytokines and contact with bacterial cell walls. Normal resolution of inflammation involves the removal of neutrophils and other inflammatory cells by the induction of apoptosis. Spontaneous neutrophil apoptosis does not require Fas ligation, but is mediated by caspases 3, 8 and possibly caspase 9 and also involves activation of protein kinase C-δ. With chronic inflammatory disease, neutrophil apoptosis is delayed by pro-inflammatory cytokines, leading to persistence of neutrophils at the inflamed site and non-specific tissue damage. Here we discuss the evidence for inhibition of neutrophil apoptosis via signaling though PI-3-kinase and downstream pathways, including PDK-1 and PKB. Therapeutic strategies to resolve chronic inflammation could therefore usefully target neutrophil apoptosis and the PI-3-kinase or PKC-δ signaling pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009601220552
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  • 173
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    GnRH-Bik/Bax/Bak chimeric proteins target and kill adenocarcinoma cells; the general use of pro-apoptotic proteins of the Bcl-2 family as novel killing components of targeting chimeric proteins (2000)
    Springer
    Apoptosis 5 (2000), S. 531-542 
    Details
    ISSN: 1573-675X
    Keywords: adenocarcinoma cells ; apoptosis ; Bcl-2 family proteins ; chimeric proteins ; GnRH-binding site ; targeting
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract In recent years chimeric proteins carrying bacterial toxins as their killing moiety, have been developed to selectively recognize and kill cell populations expressing speciific receptors. The involvement of Gonadotropin releasing hormone (GnRH) has been demonstrated in several adenocarcinomas and a GnRH-bacterial toxin chimeric protein (GnRH-PE66) was thus developed and found to specifically target and kill adenocarcinoma cells both in vitro and in vivo. Because of the immunogenicity and the non-specific toxicity of the bacterial toxins, we have developed new chimeric proteins, introducing apoptosis inducing proteins of the Bcl-2 family as novel killing components. Sequences encoding the human Bik, Bak or Bax proteins were fused to the GnRH coding sequence at the DNA level and were expressed in E. coli. GnRH-Bik, GnRH-Bak and GnRH-Bax new chimeric proteins efficiently and specifically inhibited the cell growth of adenocarcinoma cell lines and eventually led to cell death. All three Bcl2-proteins-based chimeric proteins seem to induce apoptosis within the target cells, without any additional cell death stimulus. Apoptosis-inducing-proteins of the Bcl-2 family targeted by the GnRH are novel potential therapeutic reagents for adenocarcinoma treatment in humans. This novel approach could be widely applied, using any molecule that binds a specific cell type, fused to an apoptosis-inducing protein.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009689529756
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  • 174
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    Caspase-3 activates endo-exonuclease: Further evidence for a role of the nuclease in apoptosis (2000)
    Springer
    Apoptosis 5 (2000), S. 243-254 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; caspase-3 ; nuclease ; endo-exonuclease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Single-strand DNase and poly rAase, activities characteristic of endo-exonuclease, were co-activated in nuclear fractions of HL-60 cells by caspase-3. Activation was accompanied by cleavages of large soluble polypeptides (130–185 kDa) and a 65 kDa inactive chromatin-associated polypeptide related to the endo-exonuclease of Neurospora crassa as detected on immunoblots. The major products seen in vitro were a 77 kDa soluble polypeptide and an active chromatin-associated 34 kDa polypeptide. When HL-60 cells were induced to undergo apoptosis by treating with 50 μM etoposide (VP-16) for 4 hours, 77 kDa and 40 kDa polypeptides accumulated in nuclear fractions. Chromatin DNA fragmentation activity was also activated in cytosol and nuclear extract either by pre-treating the cells in vivo with VP-16 or by treating the cytosol in vitro with caspase-3 or dATP and cytochrome c. Endo-exonuclease activated by caspase-3 in cytosol-derived fractions augmented chromatin DNA fragmentation activity in vitro. Endo-exonuclease is proposed to act in vivo in conjunction with the caspase-activated DNase (CAD) to degrade chromatin DNA during apoptosis of HL-60 cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009604529237
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  • 175
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    CD95/CD95L interactions and their role in autoimmunity (2000)
    Springer
    Apoptosis 5 (2000), S. 419-424 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; diabetes ; Fas ; organ-specific auto-immunity ; thyroiditis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract CD95 (Fas/Apo-1) is a broadly expressed death receptor involved in a variety of physiological and pathological apoptotic processes. Since its discovery, defects in CD95/CD95L system have been proposed as major pathogenic factors responsible for impaired immunological tolerance to self antigens and autoimmunity. Later, analysis of altered sensitivity to CD95-induced apoptosis in cells targeted by the immune response has revealed an unexpected role for CD95 and CD95L in organ-specific autoimmunity. CD95 has been shown to be expressed and functional in virtually all cell types that are target of the organ-specific autoimmune response. Here we review some of the major findings concerning the role of CD95 in autoimmunity, in dysfunctions due to increased or decreased CD95-induced apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009668212375
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  • 176
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    Role of apoptosis in autoimmunity (2000)
    Springer
    Apoptosis 5 (2000), S. 443-449 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; autoimmunity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Apoptosis is a physiological form of cell death required to ensure that the rate of cell division is balanced by the rate of cell death in multicellular organisms. Dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases: cancer, neurodegeneration, autoimmunity, heart disease and others. In this review we collect arguments supporting a hypothesis of a dysregulated apoptosis leading to development of autoimmunity like systemic lupus erythematosus (SLE). This notion is supported by occurence of known autoantigens in apoptotic blebs, in vitro findings of an increased rate of apoptotic lymphoblasts despite optimal cytokine stimulation combined with a defective in vitro clearance of apoptotic bodies by SLE phagocytes. Moreover, we and others could generate histone-specific lymphocytic cell lines from cells after activation with autologous apoptotic material. These lymphocytes could stimulate autologous B-lymphocytes to produce of anti-dsDNA antibodies, a diagnostic hallmark for SLE. Finally, antibodies against phospholipids like phosphatidylserine are often associated with systemic autoimmunopathies like SLE and others. Phosphatidylserine is exposed on apoptotic cells as early sign of programmed cell death and serves as phagocyte recognition molecule for apoptotic cells. Formation of immune complexes and deposition in tissues might lead to organ damage and disease. This scenario will be discussed in this review in detail.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009692902805
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  • 177
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    Caspase-dependent and independent cell death in rat hepatoma 5123tc cells (2000)
    Springer
    Apoptosis 5 (2000), S. 265-275 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; DNA fragmentation ; necrosis ; phosphorylation ; protease inhibitors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The objective of this study was to establish whether apoptosis in 5123tc rat hepatoma cells required the caspase-3 dependent pathway. Apoptosis was induced by either growth factor deprivation or treatment with a topoisomerase II inhibitor, VM26, in the absence or presence of caspase inhibitors (DEVD-fmk, z-VAD-fmk and BAF). The results indicated that, although these inhibitors at 10 μM concentration completely blocked caspase-3 activity, they had no effect on either the rate of cell death or on any other apoptotic features, e.g., chromatin condensation, DNA fragmentation, protein cleavage, suggesting that caspase-3 was not required to mediate nuclear destruction in these hepatoma cells. At higher concentrations, up to 100 μM, z-VAD-fmk and BAF, but not DEVD-fmk, did block apoptosis, however, they also caused cell swelling and membrane permeabilization, which are the hallmarks of necrotic cell death. Clearly, high concentrations of these inhibitors must have interfered non-specifically with other metabolic pathways, e.g., z-VAD-fmk at a high concentration blocked protein phosphorylation, and caused cell death by a different mechanism.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009608630145
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  • 178
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    Homocysteine-thiolactone induces caspase-independent vascular endothelial cell death with apoptotic features (2000)
    Springer
    Apoptosis 5 (2000), S. 403-411 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; atherosclerosis ; cell culture ; endothelial function ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Objective. Cell death is generally classified into two large categories: apoptosis, which represents active, physiological programmed cell death, and necrosis, which represents passive cell death without underlying regulatory mechanisms. Apoptosis plays an important role in tissue homeostasis and its role in endothelium integrity can be influenced by the functional status of endothelial cells. Homocysteine, a sulfated amino-acid product of methionine demethylation, is an independent risk factor for vascular disease (arterial and venous thombosis). Our goal was to investigate the thiol-derivatives effect on the endothelial cell apoptosis. Methods. Three parameters were measured: mitochondrial membrane potential using DiOC6(3) as the probe, DEVDase activation, and phosphatidylserine exposure on the cell surface with fluorosceinated annexin V labeling which allows apoptosis to be distinguished from necrosis. Results. Homocysteine-thiolactone induced endothelial cell apoptosis in a concentration-dependent manner (range: 50–200 μ M), independently of the caspase pathway. Only homocysteine-thiolactone, among the thiol derivatives tested, induced apoptosis. Apoptosis was not influenced by the serum concentration in culture medium, suggesting that the observed apoptotic process could occur in vivo. None of the inhibitors used (e.g., leupeptin, fumosinin Bl, catalase, or z-VAD-fmk) was able to prevent homocysteine-induced apoptosis of vascular endothelial cells. Conclusion. The apoptosis of vascular endothelial cells induced by high concentration of homocysteine-thiolactone might be one step atherosclerotic cardiovascular disease, and contribute to its complication.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009652011466
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  • 179
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    Experimental Chagas disease: Phagocytosis of apoptotic lymphocytes deactivates macrophages and fuels parasite growth (2000)
    Springer
    Apoptosis 5 (2000), S. 221-224 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; macrophages ; Chagas disease ; Trypanosoma cruzi ; T lymphocytes ; vitronectin receptor ; transforming growth factor-beta ; prostaglandins
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009648311490
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  • 180
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    CDK inhibitors suppress apoptosis induced by chemicals and by excessive expression of a cell death gene, reaper, in Drosophila cells (2000)
    Springer
    Apoptosis 5 (2000), S. 543-550 
    Details
    ISSN: 1573-675X
    Keywords: apoptosis ; CDK ; cell cycle ; cell death gene ; drosophila ; reaper
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The present study was aimed to investigate whether or not cyclin-dependent kinases (CDKs) participate in different cascades leading to apoptosis. We examined the effects of two CDK inhibitors, olomoucine (OLM) and buty-rolactone-I (BL-I), on apoptosis induced in two kinds of Drosophila cell lines. Increases of caspase activity induced by actinomycin D, cycloheximide, H-7 or A23187 in a Drosophila neuronal cell line, ML-DmBG2-c2, and induced by excessive expression of a Drosophila cell death gene, reaper, in Drosophila S2 cells were suppressed by 24-h pretreatment of each CDK inhibitor. Concomitant with the suppression of the caspase activity, fragmentations of cells and DNA, representatives of apoptosis, were also inhibited. These results suggest that CDK(s) participates in progression of apoptosis. However, these effects of the CDK inhibitors were also observed even at lower doses which did not affect cell proliferation. Therefore, it was shown that apoptosis is not always related to cell cycle in Drosophila cells. It was also suggested that the target(s) of the CDK inhibitors locates upstream of caspase in the cascade(s) of apoptosis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1009641613826
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  • 181
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    Apoptosis evaluation in epithelial cells exposed to different chemicals: relevance of floating cells (2000)
    Springer
    Cell biology and toxicology 16 (2000), S. 53-62 
    Details
    ISSN: 1573-6822
    Keywords: apoptosis ; cell adhesion ; cytotoxicity tests ; epithelial cells ; morphology
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The recent increase in understanding of cell death has promoted new approaches in toxicological studies, mainly those dealing within vitro systems where the evaluation of cell death has been the most widely adopted end-point in measuring the effects of chemical toxicants. The aim of this study was to investigate the possibility of improving the traditional cytotoxicity test protocols in order to produce more specific information on the type of cell death induced by exposure to toxicants. In particular, we characterized the mode of cell death in an established epithelial cell line, HEp-2 cells, which is frequently used in cytotoxicity testing owing to its easy handling and standardization of culture conditions. Reference chemicals for apoptosis and necrosis were selected as controls, together with other molecules that have been shown, in preliminary studies, to induce various morphological and structural modifications in relation to cell death. The results obtained show that: (a) the floating fraction of treated cells gives the clearest picture of the necrotic/apoptotic distribution; (b) morphological analysis is crucial for characterization of apoptosis; (c) more than one cytotoxic end-point is necessary to clearly identify the type of cell death.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007696604725
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    Induction of apoptosis in normal cultured rat hepatocytes and in Hep3B, a human hepatoma cell line (2000)
    Springer
    Cell biology and toxicology 16 (2000), S. 185-200 
    Details
    ISSN: 1573-6822
    Keywords: apoptosis ; hepatic cells ; culture conditions
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The in vitro occurrence of apoptosis in hepatic cells has not been well characterized because it depends on apoptosis inducing-agents and culture conditions. Furthermore, for a given hepatic cell and the same agent, discrepant results have been reported depending on the technique used to evaluate the proportion of apoptotic cells. In this study, we compared the effects of several apoptosis-inducing agents – transforming growth factor β1 (TGF-β1), retinoic acid (RA), okadaic acid (OA), and cycloheximide (CY) – on two types of hepatic cells, the human hepatoma cell line Hep3B and normal rat hepatocytes, maintained either plated for 24 to 48 h or in suspension for 20 h. Chromatin condensation and/or nucleus fragmentation were investigated morphologically by DAPI staining. DNA fragmentation was investigated biochemically by agarose gel electrophoresis and poly(ADP-ribose) polymerase (PARP) cleavage was studied by western blot. Apoptotic cells were quantified either by counting cells on UV microscopy after DAPI staining or by flow cytometry. Nuclear changes, the ladder pattern on DNA electrophoresis and PARP cleavage were observed in plated cells, hepatoma cells and normal rat hepatocytes, with all inducers but especially with OA. Semiquantification confirmed that OA was a strong inducer in plated cells under the present conditions, since about 14% and 30% of Hep3B cells (with DAPI staining and flow cytometry, respectively) were apoptotic after 48 h treatment, while, with the other inducers, apoptosis was weaker and discrepancies were also observed between the two counting methods (TGF-β1; 4% and 12%; RA, 7% and 12%; CY, 4% and 16%, with DAPI staining and flow cytometry, respectively). OA induced a moderate apoptosis in cultured hepatocytes (13% with DAPI staining), while TGF-β1, RA and CY were found to be weakly apoptotic (respectively 4% for the first two and 6% for the last ) after 48 h. In contrast, in suspension cells, apoptosis was observed neither in Hep3B cells nor in normal hepatocytes, whatever the apoptotic inducer and whatever the techniques used to detect apoptosis. In conclusion, our results show that induction of apoptosis in hepatic cells depends not only on the apoptosis-inducing agent but also on the culture conditions.
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    URL: http://dx.doi.org/10.1023/A:1007611022477
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  • 183
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    Successful separation of apoptosis and necrosis pathways in HaCaT keratinocyte cells induced by UVB irradiation (2000)
    Springer
    Cell biology and toxicology 16 (2000), S. 293-302 
    Details
    ISSN: 1573-6822
    Keywords: apoptosis ; differentiation ; keratinocytes ; UVB radiation
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract UVB irradiation can induce apoptotic, necrotic, and differentiation pathways in normal human keratinocytes. The present study was undertaken to determine at what dose of UVB each of these pathways is induced and whether these pathways are distinct or overlapping. We have observed that UVB induces fragmentation of DNA in human HaCaT keratinocytes, in a bimodal manner. Low doses of UVB, 5–20 mJ/cm2, increase the levels of apoptosis as shown by increased levels of fragmented DNA, Fas, PARP, and FasL protein, and the number of apoptotic cells as assessed by FACS analysis. At higher doses of UVB (20 and 30 mJ/cm2) the number of apoptotic cells becomes reduced, as does the amount of Fas, PARP, and FasL protein. At these higher doses, cell viability is decreased as measured by DNA synthesis (BrdU labeling) neutral red uptake, which represents an increasing necrotic phenotype. Expression of markers of keratinocyte differentiation, involucrin, keratin K1, and keratin K10, are also observed to decrease with increasing UVB dose. These changes are accompanied by a further increase in DNA fragmentation. We conclude that low doses of UVB (5–20 mJ/cm2) induced an apoptotic pathway, whereas increasing doses (greater than 20 mJ/cm2) of UVB produce a direct necrotic effect and inhibit terminal differentiation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026746330146
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  • 184
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    The Endosomal-Lysosomal System of Neurons in Alzheimer's Disease Pathogenesis: A Review (2000)
    Springer
    Neurochemical research 25 (2000), S. 1161-1172 
    Details
    ISSN: 1573-6903
    Keywords: Proteases ; cathepsin D ; apoptosis ; β-amyloid ; amyloid precursor protein
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A prominent feature of brain pathology in Alzheimer's disease is a robust activation of the neuronal lysosomal system and major cellular pathways converging on the lysosome, namely, endocytosis and autophagy. Recent studies that identify a disturbance of the endocytic pathway as one of the earliest known manifestation of Alzheimer's disease provide insight into how β-amyloidogenesis might be promoted in sporadic Alzheimer's disease, the most prevalent and least well understood form of the disease. Primary lysosomal dysfunction has historically been linked to neurodegeneration. New data now directly implicate cathepsins as proteases capable of initiating, as well as executing, cell death programs in certain pathologic states. These and other studies support the view that the progressive alterations of lysosomal function observed during aging and Alzheimer's disease contribute importantly to the neurodegenerative process in Alzheimer's disease.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1007675508413
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    Relationship Between the Ubiquitin-Dependent Pathway and Apoptosis in Different Cells of the Central Nervous System: Effect of Thyroid Hormones (2000)
    Springer
    Neurochemical research 25 (2000), S. 627-635 
    Details
    ISSN: 1573-6903
    Keywords: Granule cells ; oligodendrocytes ; thyroid hormones ; apoptosis ; ubiquitin ; proteasome
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have recently shown that sustained neonatal hyperthyroidism in the rat activates apoptosis of oligodendroglial cells (OLGc) and that inhibition of the proteasome-ubiquitin (Ub) pathway by lactacystin produces increased apoptosis in cerebellar granule cells (CGC). In the present study we have analyzed the relationship between the activation of the Ub-dependent pathway, the expression of the Ub genes and programmed cell death in neurons of the rat cerebellum and cerebral cortex and in OLGc. This study was carried out in normal animals, in rats submitted to sustained neonatal hyperthyroidism and in cell cultures treated with an excess of thyroid hormones. In neurons of the cerebral cortex, thyroid hormone produces an increase of Ub-protein conjugates, an enhancement in the expression of the Ub genes and an increase in apoptosis, while the opposite results are obtained in CGC. These results indicate that in neurons, the changes in the cell death program produced by thyroid hormone run in parallel with those occurring in the Ub-dependent pathway. In OLGc, thyroid hormone increases apoptosis but does not produce changes in the Ub pathway. Preliminary studies indicate that in coincidence with what occurs in optic nerves, the sciatic nerves both in controls and in hyperthyroid animals are unable to form Ub-protein conjugates. These results indicate that in cells of the CNS such as neurons, in which the Ub-dependent pathway is actively expressed, it appears to be closely correlated with apoptosis.
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    URL: http://dx.doi.org/10.1023/A:1007554902352
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  • 186
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    Cytotoxic Effect through Fas/APO-1 Expression due to Vitamin K in Human Glioma Cells (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 31-38 
    Details
    ISSN: 1573-7373
    Keywords: glioma ; apoptosis ; vitamin K ; reactive oxygen intermediates ; Fas/APO-1 ; flow cytometry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Congeners of vitamin K have been found to inhibit growth in various rodent and human tumor cells, but the mechanisms of the inhibitory action are still not well understood. To investigate the modes of actions of vitamin K, we used several vitamin K analogs and examined their cytotoxic effect for human glioma cell lines RBR17T and U251. The analogs included vitamin K1 (VK1), vitamin K2 (VK2), vitamin K3 (VK3), and geranylgeraniol (GGO) which form an unsaturated side chain of VK2. Cell viability was estimated by MTT assay. DNA fragmentation was demonstrated by gel electrophoresis and flow cytometry. In order to study the mechanism of apoptosis, we measured the changes of intracellular reactive oxygen intermediates (ROI) and Fas/APO-1 expression by flow cytometry. The results showed: (1) VK2, VK3, and GGO inhibited cell growth; (2) VK3 had a more potent cytotoxic effect than VK2, and VK3 enhanced the cytotoxic effect of antitumor agents (ACNU and IFN-beta) in RBR17T cells; (3) VK2, VK3, and GGO induce apoptosis; (4) VK3 increased the expression of Fas/APO-1 although VK2 and GGO did not increase its expression in glioma cells; (5) VK3 increased the production of intracellular ROI. Catalase and reduced glutathione (GSH) inhibited production of intracellular ROI and antagonized inhibition of cell-growth induced by VK2, but failed to antagonize that of VK2 and GGO. We hypothesize that VK3 induces apoptosis by promoting the generation of intracellular ROI and Fas/APO-1 expression. On the other hand, VK2 and GGO induce apoptosis but most likely by some other unknown pathway.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006443422488
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    Meningiomas in Singapore: Demographic and Biological Characteristics (2000)
    Springer
    Journal of neuro-oncology 47 (2000), S. 153-160 
    Details
    ISSN: 1573-7373
    Keywords: tumour ; apoptosis ; incidence ; p53 ; bax ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We sought to determine the relative incidence of meningiomas compared to other central nervous system tumours in an Asian surgical series, as well as the demographic and biological characteristics of these meningiomas. A review of 655 consecutive cases of central nervous system tumours from 583 patients representing the last five years admissions to one hospital in Singapore was undertaken. A total of 33 malignant/atypical tumours from 19 patients and 196 benign meningiomas from 187 patients were identified. Twenty malignant/atypical and 20 benign tumours were selected at random and subjected to histochemical and immunohistochemical analysis using antibodies directed against p53, bax and 3′-DNA hydroxy groups (TUNEL). Meningiomas comprised some 35.2% of all central nervous system tumours with malignant/atypical meningiomas representing 9.2% of meningiomas. Histochemically, necrosis was the predominant finding. However, peri-necrotic areas displayed p53 positivity in 10% of cases and bax positivity in 25% of cases. Apoptotic cells were detected in the peri-necrotic areas in 90% of benign and 75% of malignant/atypical meningiomas. Meningiomas represent the predominant form of central nervous system tumour in the Singaporean population, and aberration of p53 expression is not associated with tumour formation or progression. There was a slight but non-significant reduction in apoptosis in the progression from benign to malignant meningioma, suggesting that in contrast to many other tumour types disruption of cellular apoptosis is not a predominant driving force in Asian meningioma tumourigenesis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006484829159
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  • 188
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    Electronic Resource
    Glucose Transporters and Glucose Utilization in Rat Brain after Acute Ethanol Administration (2000)
    Springer
    Metabolic brain disease 15 (2000), S. 211-222 
    Details
    ISSN: 1573-7365
    Keywords: Ethanol ; GLUT1 ; GLUT3 ; Glucose ; Cerebral Metabolism ; Immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract In the normal adult brain, glucose provides 90% of the energy requirements as well as substrate for nucleic acid and lipid synthesis. In the present study, effects of ethanol on glucose transporters (GLUT) and glucose utilization were examined in rat brain. Male Sprague-Dawley rats weighing 250-300 gms were given either ethanol 3 gm/kg BW or saline IP 4 hrs prior to the animal sacrifice and removal of the cerebral cortical tissue. The cortical plasma membranes analyzed by cytochalasin B binding assay showed a decrease in GLUT number but not in GLUT affinity in the ethanol treated rats as compared to the control rats. The estimated Ro values were 70 ± 8.9 Vs 91 ± 8.9 pmoles/mg protein (p 〈 0.05 N=4) and the estimated Kd values were 0.37 ± 0.03 and 0.28 ± 0.05 μM (p: NS) in ethanol and control experiments respectively. Immunoblots of purified cerebral plasma membranes and low density microsomal fraction showed 17% and 71% decrease for GLUT1 and 54% and 21% (p〈0.05 or less; n=6) for GLUT3 respectively in ethanol treated rats than in control animals. Immunofluoresence studies also showed reduction of GLUT1 immunoreactively in choroid plexus and cortical microvessels of ethanol treated rats as compared to control rats. The effect of ethanol on regional cerebral metabolic rates for glucose (CMRGle) was studied using [6-14C] glucose and showed statistically insignificant decrease in brain glucose utilization. These data suggest that ethanol invivo decrease GLUT number and protein content in rat cerebral cortex
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1011115809810
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  • 189
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    Electronic Resource
    Human Malignant Glioma Therapy Using Anti-αVβ3 Integrin Agents (2000)
    Springer
    Journal of neuro-oncology 46 (2000), S. 135-144 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; cRGDfV ; human gliomas ; integrin αVβ3 ; mouse glioma model
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Glioblastoma multiforme (GBM) is the most frequent malignant brain tumor in adults and is invariably fatal. We have investigated the effect of cyclo-(Arg-Gly-Asp-D-Phe-Val) (cRGDfV) peptide on survival of human malignant glioma cells in vitro and in vivo. Immunofluorescent analyses revealed the presence of αVβ3 integrin on U-87MG and U-373MG cells, but minimal expression on U-251MG cells. Treatment of U-87MG and U-373MG cells in vitro with cRGDfV (20 µg/ml), but not the linear peptide, resulted in the appearance of rounded and loosely attached cells with subsequent cell death. By comparison, neither this cyclic peptide nor its linear homolog had any significant effect on growth and morphology of U-251MG cells. The death of cRGDfV-treated (20 µg/ml) glioma cells was blocked by pretreatment (10 µM) of cells with DEVD-FMK and LEHD-FMK, inhibitors of caspase-3 and caspase-9, respectively. Moreover, when glioma cells grown as spheroids were treated with cRGDfV (50 µg/ml), spheroid formation was markedly reduced. Further, treatment of intracranial U-87MG tumors in scid mice with cyclic peptide significantly (p〈0.001) prolonged their survival. These results indicated (i) that cRGDfV induced apoptosis of human glioma cells by binding αVβ3 integrin expressed on their cell surfaces and (ii) that cRGDfV may be an effective and non-toxic direct anti-tumor therapy for αVβ3-expressing GBMs.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006444300504
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  • 190
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    Electronic Resource
    Distinct Radiochemotherapy Protocols Differentially Influence Cellular Proliferation and Expression of p53 and Bcl-2 in Glioblastoma Multiforme Relapses In Vivo (2000)
    Springer
    Journal of neuro-oncology 48 (2000), S. 121-129 
    Details
    ISSN: 1573-7373
    Keywords: apoptosis ; proliferation ; p53 ; Bcl-2 ; transglutaminase ; immunohistochemistry
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Several protocols for the adjuvant treatment of glioblastoma multiforme (GBM) are currently being evaluated. In this context, little is known about the influence of radiochemotherapy on apoptosis and the expression of apoptosis-related proteins in vivo. We have analyzed the incidence of apoptosis using in situ nick translation (ISNT) and expression of Ki-67 (MIB-1), p53 (DO-1 and DO-7), Bcl-2 and transglutaminase II (TGase II) by immunohistochemistry in 41 patients with GBM and their matched relapses. Sixteen patients received radiochemotherapy, 18 irradiation and 7 no treatment. Radiochemotherapy resulted in an increase in Bcl-2+ cells (p=0.013). Irradiation caused the reduction of MIB-1+ (p=0.0015), DO-7+ (p=0.0043) and the increase of Bcl-2+ cells (p=0.016). We calculated a positive correlation between high TGase II scores in patients preceding radiochemotherapy (p=0.0186) and no treatment (p=0.0158), low ISNT scores (p=0.0018) and high DO-1 scores (p=0.0233) in patients preceding irradiation and short time to progression. These data show that distinct postsurgical radiochemotherapy protocols differentially alter cellular proliferation and expression of p53 and Bcl-2 in GBM relapses. Furthermore, we show that ISNT, DO-1 and TGase II labeling scores are therapy-specific predictors of time to progression in GBM patients.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006462618800
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  • 191
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    Electronic Resource
    Quercetin inhibits the invasion and mobility of murine melanoma B16-BL6 cells through inducing apoptosis via decreasing Bcl-2 expression (2000)
    Springer
    Clinical & experimental metastasis 18 (2000), S. 415-421 
    Details
    ISSN: 1573-7276
    Keywords: apoptosis ; Bcl-2 ; cell cycle ; invasion ; metastasis ; mobility ; melanoma B16-BL6 cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Quercetin has been known to have anti-tumor and anti-oxidation activities. In the present study, we have investigated its in vitro anti-metastatic activity. Quercetin inhibited the invasion and mobility of murine melanoma B16-BL6 cells in a dose-dependent manner but did not affect their adhesion to either laminin, fibronectin, or type VI collagen. Moreover, quercetin significantly inhibited the proliferation of B16-BL6 cells only in the case of time incubation longer than 48 h. Quercetin dose-dependently decreased the cell rates in S and G2–M phases of cell cycle. The effect of quercetin to cause a remarkable apoptosis of B16-BL6 cells was also demonstrated by flow cytometric assay as well as DNA fragmentation with a typical 180-bp ladder band in agarose electrophoresis and a quantitative analysis. Furthermore, quercetin markedly inhibited the expression of anti-apoptotic protein Bcl-2 but hardly influenced Bcl-XL. These results suggest that the inhibition of quercetin on invasiveness and migration of B16-BL6 cells are closely associated with the arrest of cell cycle as well as the induction of apoptosis by decreasing the Bcl-2 expression.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1010960615370
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  • 192
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    Effects of Controlled Ovarian Hyperstimulation on Oocyte Quality in Terms of the Incidence of Apoptotic Granulosa Cells (2000)
    Springer
    Journal of assisted reproduction and genetics 17 (2000), S. 580-585 
    Details
    ISSN: 1573-7330
    Keywords: apoptosis ; controlled ovarian hyperstimulation ; granulosa cells ; in vitro fertilization ; oocyte quality
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Purpose: The aim was to investigate which ovarian hyperstimulation protocol performed in the same patients causes development of oocytes of good quality. Methods: Twenty normo-ovulatory women underwent three different controlled ovarian hyperstimulation protocols for in vitro fertilization–embryo transfer. Patients underwent follicle aspiration after administration of human chorionic gonadotropin (hCG). The total number of retrieved oocytes, the number of mature oocytes, and the rate of mature oocytes were examined. Recovered granulosa cells were stained with Hoechst 33258 and examined by fluorescence microscopy to estimate the incidence of apoptotic cells. Results: The total number of oocytes and the number of mature oocytes in gonadotropin-releasing hormone agonist (GnRHa) + human menopausal gonadotropin (hMG) + hCG and hMG + hCG cycles were higher than those in the natural cycle (P 〈 0.0001). The rate of mature oocytes in hMG + hCG cycle was the highest among the three protocols (P 〈 0.04). In the mural granulosa cells, the incidence of apoptotic cells in the GnRHa + hMG + hCG cycle was significantly higher than those of the natural (P 〈 0.002) and hMG + hCG cycles (P = 0.0002). The incidence of apoptotic cumulus granulosa cells in the GnRHa + hMG + hCG cycle was significantly higher than those of natural and hMG + hCG cycles (P 〈 0.002). Moreover, the incidence of apoptotic cumulus granulosa cells in the hMG + hCG cycle was significantly lower than that in the natural cycle (P 〈 0.01). Conclusions: These results indicated that hMG + hCG is the most appropriate controlled ovarian hyperstimulation protocol among the three examined with regard to oocyte quality.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026439409584
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  • 193
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    Electronic Resource
    Cellular responses of mammary carcinomas to aromatase inhibitors: Effects of vorozole (2000)
    Springer
    Breast cancer research and treatment 60 (2000), S. 117-128 
    Details
    ISSN: 1573-7217
    Keywords: vorozole ; aromatase inhibitors ; mammary tumors ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Vorozole (Vz) is a competitive non-steroidal inhibitor of aromatase, which has been used to treat breast cancer in postmenopausal women and in various chemoprevention pre-clinical studies. Recently, we assessed the inhibitory effect of Vz on Mnu-induced mammary carcinogenesis (Lubet et al., 1994), as well as on the progression of mammary tumors (Lubet et al., 1998). In this study we evaluated the effects of Vz on tumor growth, serum estradiol, cell proliferation, apoptotic and non-apoptotic cell death to determine whether any of these 'surrogate’ markers might reflect the efficacy of various doses of Vz. Vz at doses of 2.5 (Hi), 0.32 (Md), and 0.08 (Lo) mg/kg body weight induced complete (100%), 60%, and 20% regression of mammary tumors, respectively. Vz at Hi and Md doses caused a decrease in serum estradiol within the first two days of treatment, and the estradiol values remained low with additional treatment for 4 and 10 days. When Vz was administered to animals bearing palpable tumors a time and dose-dependent decrease in the proliferating cells (BrdU-LI) was observed. The percentage of apoptotic cells (Al) sharply increased 2 days after initiation of Vz treatment and then decreased followed by an increase in non-apoptotic dead cells. Interestingly even the Lo dose of Vz, which was only moderately effective in suppressing tumor growth, decreased cell proliferation and increased cell death in the peripheral tumor areas at 4 and 10 days after initiation of treatment. The time- and dose-dependent alterations in various cell parameters suggest two different phases of Vz-induced cellular responses: (1) an early phase (2–4 days of treatment) with a sharp increase in apoptotic cells and decrease in proliferating cells, and (2) a later phase (10 days) with disintegration of tumor parenchyma, increase in non-apoptotic dead cells, and decrease in apoptotic cells. The dose-dependent decrease in proliferating cells and increase in apoptotic and non-apoptotic cell death in Vz-treated animals suggest that these biomarkers might be used as potential surrogate endpoints for efficacy in breast cancer chemoprevention and therapy studies with aromatase inhibitors.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006384026252
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  • 194
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    Treatment with the pure antiestrogen faslodex (ICI 182780) induces tumor necrosis factor receptor 1 (TNFR1) expression in MCF-7 breast cancer cells (2000)
    Springer
    Breast cancer research and treatment 63 (2000), S. 249-259 
    Details
    ISSN: 1573-7217
    Keywords: antiestrogens ; apoptosis ; breast ; cancer ; faslodex ; ICI 182780 ; MCF-7 ; tamoxifen ; TNFR1
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Apoptosis induction by the pure antiestrogen faslodex, also known as ICI 182780 (ICI), is associated with an effective down-regulation of Bcl-2 expression in the human breast cancer cell line MCF-7. Recent observations point out that beside members of the Bcl-2 family also the TNFR1 signaling pathway may be involved in apoptosis induction by antiestrogens. In this report we have analyzed the expression of members of the TNFR1 signaling pathway during the apoptotic process induced by the pure antiestrogen faslodex and by tamoxifen (Tam) in MCF-7 breast cancer cells. Treatment with 10−7 M ICI or 10−7 M Tam leads to a time dependent increase of TNFR1 and TRADD steady-state mRNA levels in MCF-7 cells. In contrast, Bcl-2 expression was strongly decreased following administration of ICI but only weakly after administration of Tam. Western blot analysis and studies by the use of fluorescence microscopy and flow cytometry revealed a time dependent induction of TNFR1 protein and cell surface expression in MCF-7 cells in response to treatment with ICI. To investigate if TNFR1 is functionally involved in apoptosis induction by antiestrogens, we tested whether TNFR1 blocking antibodies can counteract the growth inhibitory action of Tam and ICI. Coincubation of MCF-7 cells with antiestrogens (ICI or Tam) and blocking TNFR1 antibodies lead to an increase in cell viability. Our results provide evidence for a cross talk between the TNFR1 signaling pathway and antiestrogens during the process of apoptosis induction in MCF-7 breast cancer cells. The superiority of the pure antiestrogen ICI to induce apoptosis in MCF-7 cells may result from its capability to modulate the induction of apoptosis via Bcl-2 as well as TNF-associated signal transduction pathways.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006490416408
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  • 195
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    Electronic Resource
    Sex hormone-induced mammary carcinogenesis in the female Noble rats: Expression of Bcl-2 and Bax in hormonal mammary carcinogenesis (2000)
    Springer
    Breast cancer research and treatment 61 (2000), S. 45-57 
    Details
    ISSN: 1573-7217
    Keywords: androgen receptor ; apoptosis ; Bax ; Bcl-2 ; breast cancer ; estrogen receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract We have established a Noble rat model to explore the mechanisms of hormonal mammary carcinogenesis, in which the role of androgen in promoting mammary carcinogenesis was highlighted. We have also established that stromal-epithelial interactions may be responsible for the promotional effects of testosterone in mammary carcinogenesis. Based on these understandings, in the present study we examined the expression of Bcl-2 and Bax in pre-malignant mammary glands from rats treated with different protocols of sex hormones for 7 weeks as well as sex hormone induced mammary tumours. We observed that Bcl-2 was strongly expressed in most of mammary tumour cells, whereas weak or negative in adjacent normal or hyperplastic ductal structures. On the contrary, Bax immunoreactivity was weak in mammary tumour cells while strongly expressed in adjacent normal or hyperplastic ductal structures. More importantly, the results from comparative study of ‘pre-malignant’ glands further showed that when animals were treated with 17β-oestradiol, the mammary epithelial cells expressed high levels of Bcl-2. The results from rats treated with testosterone, either alone or in combination with oestrogen, give rise to high levels of Bax expression in ‘pre-malignant’ mammary glands. These observations indicate that in ‘pre-malignant’ mammary glands, treatment with testosterone, either alone or in combination with 17β-oestradiol, may induce high apoptotic activities. However, in fully developed mammary tumours, the apoptotic activities apparently decrease in tumour cells. TUNEL assay provides further data to support this conclusion. Our study, thus, suggests that androgens may play a promoting role in mammary carcinogenesis by upregulation of Bax expression and induction of high apoptotic activities in ‘pre-malignant’ stage, which would provide a selective pressure favouring the expansion of the initiated cells.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1006400732154
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  • 196
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    Electronic Resource
    Caspase-like protease involvement in the control of plant cell death (2000)
    Springer
    Plant molecular biology 44 (2000), S. 417-428 
    Details
    ISSN: 1573-5028
    Keywords: apoptosis ; baculovirus p35 ; Bcl-2-like proteins ; caspases ; cell death ; hypersensitive response ; mitochondria
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Abstract Cell death as a highly regulated process has now been recognized to be an important, if not essential, pathway that is ubiquitous in all multicellular eukaryotes. In addition to playing key roles in the morphogenesis and sculpting of the organs to give rise to highly specialized forms and shapes, cell death also participates in the programmed creation of specialized cell types for essential functions such as the selection of B cells in the immune system of mammals and the formation of tracheids in the xylem of vascular plants. Studies of apoptosis, the most well-characterized form of animal programmed cell death, have culminated in the identification of a central tripartite death switch the enzymatic component of which is a conserved family of cysteine proteases called caspases. Studies in invertebrates and other animal models suggest that caspases are conserved regulators of apoptotic cell death in all metazoans. In plant systems, the identities of the main executioners that orchestrate cell death remain elusive. Recent evidence from inhibitor studies and biochemical approaches suggests that caspase-like proteases may also be involved in cell death control in higher plants. Furthermore, the mitochondrion and reactive oxygen species may well constitute a common pathway for cell death activation in both animal and plant cells. Cloning of plant caspase-like proteases and elucidation of the mechanisms through which mitochondria may regulate cell death in both systems should shed light on the evolution of cell death control in eukaryotes and may help to identify essential components that are highly conserved in eukaryotes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1026509012695
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  • 197
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    Electronic Resource
    Peptide Bioregulators Inhibit Apoptosis (2000)
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 1175-1176 
    Details
    ISSN: 1573-8221
    Keywords: peptide bioregulators ; apoptosis ; aging
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract The effects of peptide bioregulators epithalon and vilon on the dynamics of irradiation-induced apoptotic death of spleen lymphocytes in rats indicate that these agents inhibit physiologically programmed cell death. The antiapoptotic effect of vilon was more pronounced, which corroborates the concept on tissue-specific effect of peptide bioregulators.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1017584018746
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  • 198
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    The Use of Large-Scale cDNA Analysis to Profile Differential Gene Expression in KYSE 410 Human Esophageal Cancer Cells after Irradiation (2000)
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 882-885 
    Details
    ISSN: 1573-8221
    Keywords: cDNA analysis ; irradiation ; transcription ; carcinogenesis ; genes ; regulation of cell cycle ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Atlas Human cDNA Expression Array, which includes 588 genes divided into functional classes, was used to study gene expression profiles in KYSE 410 human esophageal cancer cells irradiated in doses of 6 and 18 Gy. Considerable changes in the expression of a number of genes was found, including down-regulation of 3 cell cycle regulators and up-regulation of an apoptosis-related gene. Comparison of the expression profiles and identification of genes were performed with Atlas Vision 3.0 software.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015374530823
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  • 199
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    Apoptosis of Cardiomyocytes as Extreme Manifestation of Regeneration and Plastic Insufficiency of Myocardium (2000)
    Springer
    Bulletin of experimental biology and medicine 130 (2000), S. 903-907 
    Details
    ISSN: 1573-8221
    Keywords: anthracycline cardiomyopathy ; regeneration and plastic myocardium insufficiency ; cardiomyocytes ; absolute number of cardiomyocytes ; apoptosis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Alkaline dissociation of the myocardium from rats with modeled anthracycline cardiomyopathy revealed decreased absolute number of cardiomyocytes, disturbances in their intracellular regeneration, although no sings of necrosis were observed. Regeneration and plastic insufficiency of the myocardium due to structural changes in the nuclei and disturbances in myofibril reproduction resulting from selective suppression of synthesis of contractile proteins in the cardiomyocytes leads to the death of up to 30% cardiomyocytes.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1015386800781
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  • 200
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    Electronic Resource
    Oxidative stress in keratinocytes as an etiopathogenetic factor of psoriasis (2000)
    Springer
    Bulletin of experimental biology and medicine 129 (2000), S. 309-313 
    Details
    ISSN: 1573-8221
    Keywords: psoriasis ; apoptosis ; inflammation ; proliferation ; oxidative stress ; lipid peroxidation ; reactive oxygen species ; redox potential
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract A new etiopathogenetic concept of psoriasis is proposed, which considers psoriasis as a typical inflammatory process characterized by increased antioxidant activity and overexpression of apoptotic receptors. Under these conditions, hyperstimulation of germinative layer cells proliferation dramatically accelerates kerationcyte passage towards apoptotic effect of atmospheric oxygen and its reactive species dooming to death cells with enhanced expression of apoptotic receptors. Oxidative stress of nondifferentiated kerationcytes triggers the formation of defective horny layer, the key mechanism of psoriasis.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02439252
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