| 41. |
- Burek, C. J., et al.
(författare)
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The role of ceramide in receptor- and stress-induced apoptosis studied in acidic ceramidase-deficient Farber disease cells
- 2001
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Ingår i: Oncogene. - : Nature Publishing Group. - 0950-9232 .- 1476-5594. ; 20:45, s. 6493-6502
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Tidskriftsartikel (refereegranskat)abstract
- The activation of sphingomyelinases leading to the generation of ceramide has been implicated in various apoptotic pathways. However, the role of ceramide as an essential death mediator remains highly controversial. In the present study, we investigated the functional relevance of ceramide in a genetic model by using primary cells from a Farber disease patient. These cells accumulate ceramide as the result of an inherited deficiency of acidic ceramidase. We demonstrate that Farber disease lymphocytes and fibroblasts underwent apoptosis induced by various stress stimuli, including staurosporine, anticancer drugs and gamma -irradiation, equally as normal control cells. In addition, caspase activation by these proapoptotic agents occurred rather similarly in Farber disease and control fibroblasts. Interestingly, Farber disease lymphoid cells underwent apoptosis induced by the CD95 death receptor more rapidly than control cells. Our data therefore suggest that ceramide does not play an essential role as a second messenger in stress-induced apoptosis. However, in accordance with a role in lipid-rich microdomains, ceramide by altering membrane composition may function as an amplifier in CD95-mediated apoptosis.
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| 42. |
- Carlén, Birgitta, et al.
(författare)
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Diagnostic value of electron microscopy in a case of juvenile neuronal ceroid lipofuscinosis
- 2001
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Ingår i: Ultrastructural Pathology. - : Informa UK Limited. - 1521-0758 .- 0191-3123. ; 25:4, s. 285-288
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Tidskriftsartikel (refereegranskat)abstract
- Neuronal ceroid lipofuscinoses (NCLs) represent a large group of inherited neurodegenerative disorders characterized by an abnormal accumulation of lipopigment in neuronal and extraneuronal cells. The authors present a case of juvenile neuronal ceroid lipofuscinosis in a 7-year-old boy. Ultrastructural examination of a skin biopsy disclosed deposits of curvilinear profiles and fingerprint-like structures in epithelial cells of sweat glands, endothelial cells, peripheral nerve endings, and fibroblasts, These findings allowed specific confirmation of the assumed diagnosis of juvenile neuronal ceroid lipofuscinosis. Due to the genotypic and phenotypic variability within the group of NCLs, the clinical investigation may be long and complicated. With the NCL disorders in mind, an accurate diagnosis based on ultrastructural examination of a skin biopsy may shorten this investigation, thus benefitting the patient.
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| 43. |
- Carlsson, C., et al.
(författare)
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Voluntary associations for cancer patients in Sweden: supportive activities
- 2001
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Ingår i: Supportive Care in Cancer. - : Springer Science and Business Media LLC. - 0941-4355 .- 1433-7339. ; 9:8, s. 581-590
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Tidskriftsartikel (refereegranskat)abstract
- Our aim was to describe voluntary associations for patients with cancer in Sweden (n=108) and their activities, type and extent of member support, and the associations' collaboration with the health care system. A specially constructed questionnaire with structured and open questions was used for the investigation. The frequency of answers was 89%. The results show in the broadest sense that the associations have two missions. The direct patient-related mission concerns providing patients with support in the form of close proximity, approachability and through distribution of knowledge together with financial and practical support; the indirect patient-related mission deals with activities aimed at improving conditions for patients in general within the health care system and by influencing authorities as well as supporting family members and significant others and providing financing. The associations collaborate with the health care system, although they face difficulties in becoming 'sanctioned' and in establishing positive relationships with the health care community. The associations display a positive attitude towards their cause and the personal gratification that the voluntary work brings. In general, the findings indicate that the associations have a potential to help patients live and cope with their cancer disease.
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| 44. |
- Ceder, Jens, et al.
(författare)
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Neuroendocrine pathogenesis in adenocarcinoma of the prostate
- 2001
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Ingår i: Annals of Oncology. - 1569-8041. ; 12:Suppl. 2, s. 145-152
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In the prostate, the importance of sex hormones for its normal development and function is well known. However, it has been proposed that various neuroendocrine (NE) hormones and growth factors may be involved in the pathogenesis of prostatic carcinoma (CaP). Neuroendocrine differentiation appears to be associated with tumour progression and the androgen-independent state, for which there is currently no successful therapy. Therefore, we need to improve our understanding of NE cells, their regulatory products and influence on the prostate gland. Finally, new therapeutic protocols need to be developed. METHODS: Information is presented on prostatic NE cells and neuroendocrine differentiation (NED) in prostatic carcinoma. Neuroendocrine secretory products and interactions with epithelial prostate cells are investigated in order to understand their significance for the pathogenesis of the prostate gland, prognosis and therapy. RESULTS: Recent research suggests that NE-secreted products. such as serotonin, somatostatin and bombesin, may influence growth, invasiveness, metastatic processes and angiogenesis in CaP. During recent years. new experimental models for NED have been developed to provide evidence that NE products may promote proliferation and confer antiapoptotic capabilities on non-neuroendocrine cells in close proximity to NE cells. Cancerous epithelial cells may become more responsive to NE factors by upregulation of receptors for neuropeptides, or may induce NE cells to upregulate the secretion and synthesis of NE factors. In the androgen independent state, neuropeptides and their intracellular signals may activate the androgen receptor. Furthermore, androgen ablation may lead to downregulation of neural endopeptidase 24.11 (a zinc-dependent metalloproteinase) and PSA, which would lead to increased levels of NE products becoming available. These studies confirm that NE cells and NED may have a significant impact on prostate cancer, especially in the androgen independent state. CONCLUSIONS: Recent developments in molecular biology and pathophysiology of prostate cancer have increased our understanding of the NE regulatory mechanisms. Hopefully, this will lead to the development of entirely new therapeutic modalities. For example, somatostatin agonists may suppress angiogenesis and proliferation, and simultaneously promote apoptosis in prostate cancer cells. Somatostatin may thus have an important role in tumour biology, and in the future there may be a potential role for somatostatin analogues in the treatment of prostate cancer, but also for serotonin and bombesin receptor antagonists. However, a review of the accumulated knowledge in this field suggests that we still need to improve our understanding of NE cells and their regulatory products and influence on the prostate gland. and that clinical trials are needed, to test drugs based on neuroendocrine hormones and their agonists/antagonists.
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| 45. |
- Çiray, Ipek
(författare)
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Diagnosis and evaluation of therapeutic response of bone metastases.
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aim of this study was to investigate different aspects of different imaging modalities in the diagnosis of bone metastases and in the assessment of their response to therapy. The role of CT, with and without clinical information, was investigated as compared to CT-guided bone biopsy in the evaluation of suspected bone metastases. The diagnostic accuracy of CT alone (44%) increased to 82% when clinical information was taken into account, especially for the lesions diagnosed histopathologically as benign. In most cases, CT in combination with clinical information gave enough information about the nature (malignant or benign) of a bone lesion. In uncertain cases the diagnostic accuracy could be improved by means of CT-guided bone biopsy. Possible misinterpretation of new sclerotic lesions when judged according to the WHO criteria during treatment was studied. One hundred and thirty-nine breast cancer patients with bone metastases, who participated a the clinical trial of clodronate therapy, were studied retrospectively. In 8 of the 24 patients considered at conventional radiography to have progressive disease according to WHO criteria, 17 of 52 apparently new sclerotic lesions (33%) were detected on previous bone scintigraphy. WHO criteria may give rice to misinterpretations in patients with new sclerotic lesions. For better assessment more sensitive techniques, e.g. bone scintigraphy, can be used as a complement to conventional radiography. Eighteen breast cancer patients with known bone metastases were studied prospectively regarding evaluation of therapy response. T1-weighted spin echo (SE) and fat-suppressed long echo time inversion recovery turbo spin echo (long TE IR-TSE) MR sequences, conventional radiography, bone scintigraphy and CT-guided bone biopsy were performed before and during systemic chemotherapy. T1-weighted sequences and long TE IR-TSE sequences were compared regarding evaluation of early response of breast cancer bone metastases to chemotherapy, using a combination of clinical, radiographic and scintigraphic examinations as a reference. Therapeutic response evaluation with MR imaging was based on change in tumor size assessed quantitatively by measuring all focal metastases, and on change in pattern and signal intensity (SI) of the metastases, assessed visually. The long TE IR-TSE sequence demonstrated partial response of breast cancer bone metastases to chemotherapy more accurately than the T1-weighted sequence (58% vs. 17%). The effect of granulocyte colony-stimulating factor (G-CSF)-supported chemotherapy on MR images of normal red bone marrow was investigated. A diffuse, homogeneous SI increase was observed visually and quantitatively in initially normal bone marrow during G-CSF therapy, obscuring some focal lesions. No such SI change was visible after G-CSF therapy or in patients not receiving G-CSF. We concluded that G-CSF-supported chemotherapy might induce diffuse SI changes in normal red bone marrow on MRI, and that this might lead to misinterpretations in the evaluation of response of bone metastases. Early response of bone metastases to therapy was assessed in targeted metastatic lesions in breast cancer patients with T1-weighted and long TE IR-TSE MR sequences and CT compared with histopathological findings. The results indicated that the SI increase in the metastatic lesions following therapy on long TE IR-TSE images might be useful in indicating an early response. T1-weighted images are of limited value in assessing alterations in the amount of tumor cells. An increase in electron density on CT can be seen in both responding and progressing lesions.
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| 46. |
- Cull, A, et al.
(författare)
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Development of a European Organization for Research and Treatment of Cancer questionnaire module to assess the quality of life of ovarian cancer patients in clinical trials: a progress report.
- 2001
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Ingår i: European journal of cancer (Oxford, England : 1990). - 0959-8049. ; 37:1, s. 47-53
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Tidskriftsartikel (refereegranskat)abstract
- A questionnaire was developed, according to the European Organization for Research and Treatment of Cancer (EORTC) published guidelines, to supplement the EORTC quality of life questionnaire-core 30 (QLQ-C30) to assess the quality of life (QL) of women with ovarian cancer treated in clinical trials. The provisional 28-item module, OV28, assesses abdominal symptoms; peripheral neuropathy; other chemotherapy side-effects; hormonal symptoms; body image; attitude to disease and treatment; and sexual functioning. The first 24 items of the module (excluding sexual functioning) were included in a UK multicentre trial (SCOTROC). The trial data were used for preliminary scaling analysis. Two problematic items were identified. When these were treated as single items along with the 'other chemotherapy side-effects' the instrument showed excellent scale properties. Mean scale scores discriminated between trial patients pre- and on chemotherapy. This is a promising tool for assessing the QL of women with ovarian cancer. The EORTC international field study (Protocol 15982) to assess more fully the psychometric properties of the OV28 is well underway.
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| 47. |
- Ding, Kan, et al.
(författare)
-
Modulations of glypican-1 heparan sulfate structure by inhibition of endogenous polyamine synthesis. Mapping of spermine-binding sites and heparanase, heparin lyase, and nitric oxide/nitrite cleavage sites
- 2001
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 276:50, s. 46779-46791
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Tidskriftsartikel (refereegranskat)abstract
- Cell surface heparan sulfate proteoglycans facilitate uptake of growth-promoting polyamines (Belting, M., Persson, S., and Fransson, L.-A. (1999) Biochem. J. 338, 317-323; Belting, M., Borsig, L., Fuster, M. M., Brown, J. R., Persson, L., Fransson, L.-A., and Esko, J. D. (2001) Proc. Natl. Acad. Sci. U. S. A., in press). Here, we have analyzed the effect of polyamine deprivation on the structure and polyamine affinity of the heparan sulfate chains in various glypican-1 glycoforms synthesized by a transformed cell line (ECV 304). Heparan sulfate chains of glypican-1 were either cleaved with heparanase at sites embracing the highly modified regions or with nitrite at N-unsubstituted glucosamine residues. The products were separated and further degraded by heparin lyase to identify sulfated iduronic acid. Polyamine affinity was assessed by chromatography on agarose substituted with the polyamine spermine. In heparan sulfate made by cells with undisturbed endogenous polyamine synthesis, free amino groups were restricted to the unmodified, unsulfated segments, especially near the core protein. Spermine high affinity binding sites were located to the modified and highly sulfated segments that were released by heparanase. In cells with up-regulated polyamine uptake, heparan sulfate contained an increased number of clustered N-unsubstituted glucosamines and sulfated iduronic acid residues. This resulted in a greater number of NO/nitrite-sensitive cleavage sites near the potential spermine-binding sites. Endogenous degradation by heparanase and NO-derived nitrite in polyamine-deprived cells generated a separate pool of heparan sulfate oligosaccharides with an exceptionally high affinity for spermine. Spermine uptake in polyamine-deprived cells was reduced when NO/nitrite-generated degradation of heparan sulfate was inhibited. The results suggest a functional interplay between glypican recycling, NO/nitrite-generated heparan sulfate degradation, and polyamine uptake.
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| 48. |
- Ding, Kan, et al.
(författare)
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N-unsubstituted glucosamine in heparan sulfate of recycling glypican-1 from suramin-treated and nitrite-deprived endothelial cells. mapping of nitric oxide/nitrite-susceptible glucosamine residues to clustered sites near the core protein
- 2001
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Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 276:6, s. 3885-3894
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Tidskriftsartikel (refereegranskat)abstract
- We have analyzed the content of N-unsubstituted glucosamine in heparan sulfate from glypican-1 synthesized by endothelial cells during inhibition of (a) intracellular progression by brefeldin A, (b) heparan sulfate degradation by suramin, and/or (c) endogenous nitrite formation. Glypican-1 from brefeldin A-treated cells carried heparan sulfate chains that were extensively degraded by nitrous acid at pH 3.9, indicating the presence of glucosamines with free amino groups. Chains with such residues were rare in glypican-1 isolated from unperturbed cells and from cells treated with suramin and, surprisingly, when nitrite-deprived. However, when nitrite-deprived cells were simultaneously treated with suramin, such glucosamine residues were more prevalent. To locate these residues, chains were first cleaved at linkages to sulfated l-iduronic acid by heparin lyase and released fragments were separated from core protein carrying heparan sulfate stubs. These stubs were then cleaved off at sites linking N-substituted glucosamines to d-glucuronic acid. These fragments were extensively degraded by nitrous acid at pH 3.9. When purified proteoglycan isolated from brefeldin A-treated cells was incubated with intact cells, endoheparanase-catalyzed degradation generated a core protein with heparan sulfate stubs that were similarly sensitive to nitrous acid. We conclude that there is a concentration of N-unsubstituted glucosamines to the reducing side of the endoheparanase cleavage site in the transition region between unmodified and modified chain segments near the linkage region to the protein. Both sites as well as the heparin lyase-sensitive sites seem to be in close proximity to one another.
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| 49. |
- Domanski, Henryk, et al.
(författare)
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Distinct cytologic features of spindle cell lipoma - A cytologic-histologic study with clinical, radiologic, electron microscopic, and cytogenetic correlations
- 2001
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Ingår i: Cancer. - : Wiley. - 1097-0142 .- 0008-543X. ; 93:6, s. 381-389
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND. Spindle cell lipoma (SCL) is a relatively uncommon, benign tumor that usually presents in the subcutaneous fat of adult men. Although some studies have addressed the histologic findings of SCL, only a few descriptions of aspiration cytology findings have been published. The cytologic features are poorly defined, and aspirates from SCL may cause diagnostic problems, because SCL shares some features with other fatty/spindle cell or myxoid lesions, benign as well as malignant. METHODS. Twelve patients underwent fine-needle aspiration (FNA) cytology as the primary diagnostic modality before surgery. FNA findings were evaluated and correlated with histologic features, In addition, radiologic, electron microscopic, and cytogenetic findings were analyzed. The objective of this study was to determine cytologic criteria of SCL by reviewing cytologic specimens in 12 patients with SCL who underwent FNA cytology. RESULTS. All of the motors arose in adults, and to tumors developed in the subcutaneous tissue of the neck, back, or shoulder girdle. Two patients presented with tumors in atypical locations; one in the tongue and one in the check. Cytologically, all 12 tumors were characterized by a mixture of mature adipocytes, uniform spindle cells, and collagen bundles and/or fibers in varying proportions. The presence of a myxoid matrix and of mast cells was less specific and occurred in six aspirates. CONCLUSIONS. SCL has a characteristic cytologic appearance that, together with clinical data, helps to exclude low-grade liposarcoma as well as other spindle cell and myxoid lesions.
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| 50. |
- Edsjö, Anders, et al.
(författare)
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Differences in early and late responses between neurotrophin-stimulated trkA- and trkC-transfected SH-SY5Y neuroblastoma cells
- 2001
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Ingår i: Cell Growth & Differentiation. - 1044-9523. ; 12:1, s. 39-50
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Tidskriftsartikel (refereegranskat)abstract
- Despite their sympathetic neuroblast origin, highly malignant neuroblastoma tumors and derived cell lines have no or low expression of the neurotrophin receptor genes, trkA and trkC. Expression of exogenous trkA in neuroblastoma cells restores their ability to differentiate in response to nerve growth factor (NGF). Here we show that stable expression of trkC in SH-SY5Y neuroblastoma cells resulted in morphological and biochemical differentiation upon treatment with neurotrophin-3 (NT-3). To some extent, trkA- and trkC-transfected SH-SY5Y (SH-SY5Y/trkA and SH-SY5Y/trkC) cells resembled one another in terms of early signaling events and neuronal marker gene expression, but important differences were observed. Although induced Erk 1/2 and Akt/PKB phosphorylation was stronger in NT-3-stimulated SH-Y5Y/trkC cells, activation of the immediate-early genes tested was more prominent in NGF-treated SH-SY5Y/ trkA cells. In particular, c-fos was not induced in the SH-SY5Y/trkC cells. There were also phenotypic differences. The concentrations of norepinephrine, the major sympathetic neurotransmitter, and growth cone-located synaptophysin, a neurosecretory granule protein, were increased in NGF-treated SH-SY5Y/trkA but not in NT-3-treated SH-SY5Y/trkC cells. Our data suggest that NT-3/p145trkC and NGF/p140trkA signaling differ in some aspects in neuroblasoma cells, and that this may explain the phenotypic differences seen in the long-term neurotrophin-treated cells.
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