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19 ungesichtete Fragmente: Plagiat

[1.] Src/Fragment 009 02 - Diskussion
Bearbeitet: 27. September 2014, 20:21 (Kybot)
Erstellt: 23. September 2014, 00:37 Hindemith
Fragment, SMWFragment, Schutzlevel, Src, Verschleierung, Waelzlein 2007, ZuSichten

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Quelle: Waelzlein 2007
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1.1. Brain tumors and their classification

Glia cells are the most common cell type in the brain and make up 90 % of the total cell number (Kettenmann, H et al, 1995) depending on species. They were discovered by Virchow (1856), who described them as Nervenkitt, a kind of glue for neurons (gr. glia: glue). Initially, they were considered as merely supporting cells for neurons, yet recently they were shown to fulfill a range of far more complex functions. The group of glia cells consists of astrocytes, oligodendrocytes and Schwann cells (Kettenmann, H et al, 1995). Historically, brain tumors were thought to consist of transformed glia cells and are therefore called gliomas. Different types of gliomas are astrocytomas, oligodendrogliomas and schwannomas, depending on the preferential type of differentiation of these tumors. Schwannomas often correspond to benign tumors. It is still unknown how these transformations occur and what triggers them. One theory claims that disruptions in the glial cell cycle lead to glioma formation. However, recent research provided more and more evidence that gliomas emerge from neural precursor cells.

Gliomas are the most common group of primary tumors in the brain and make up 30 – 40 % of all brain tumors (Kleihues, P et al, 1993). The World Health Organisation (WHO) introduced a classification in 1993, which divides astrocytomas into four malignancy grades:

1.3. Brain tumours and their classification

Glia cells are the most common cell type in the brain and make up 90 % of the total cell number (37). They were discovered by Virchow (1856), who described them as Nervenkitt, a kind of glue for neurons (gr. glia: glue). Initially, they were considered as merely supporting cells for neurons, yet recently they were shown to fulfill a range of far more complex functions. The group of glia cells consists of astrocytes, oligodendrocytes and Schwann cells (37).

Historically, brain tumours were thought to consist of transformed glia cells and are therefore called gliomas. Different types of gliomas are astrocytomas, oligodendrogliomas and schwannomas, depending on the relevant cell type. Schwannomas often correspond to benign tumours. It is still unknown how these transformations occur and what triggers them. One theory claims that disruptions in the glial cell cycle lead to glioma formation. However, recent research provided more and more evidence that gliomas emerge from neural precursor cells (1.2.).

Gliomas are the most common group of primary tumours in the brain and make up 30 – 40 % of all brain tumours (40). The World Health Organisation (WHO) introduced a classification in 1993, which divides astrocytomas into four malignancy grades:


37. Kettenmann,H. and Ransom,B. 1995. Neuroglia. Oxford University Press.

40. Kleihues,P., Burger,P.C., and Scheithauer,B.W. 1993. The new WHO classification of brain tumours. Brain Pathol. 3:255-268.

Anmerkungen

Ein Verweis auf die Quelle fehlt.

Sichter
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[2.] Src/Fragment 010 01 - Diskussion
Bearbeitet: 27. September 2014, 20:21 (Kybot)
Erstellt: 23. September 2014, 00:48 Hindemith
Fragment, SMWFragment, Schutzlevel, Src, Verschleierung, Waelzlein 2007, ZuSichten

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Seite(n): 12, Zeilen: 1ff
Tab. 1.1. The World Health Organization (WHO) grading system for astrocytomas

Scr 010a diss.png

In the present work research and conclusions will be restricted to cells representing glioblastoma multiforme (GBM) or glioma, i.e. a grade IV brain tumor.

1.2. Epidemiology of gliomas

Gliomas or glioblastomas occur with an incidence of 5 in 100,000 (Friese, M.A.et al, 2004). The peak of onset of glioblastomas is around 50 - 55 years, which makes them a strongly age-related pathology. Men are slightly more prone to these neoplasms. Furthermore, the incidence is 2 - 3 times higher in white than in black people. Prognosis is poor and the median survival has remained at 9 to 12 months for decades (Stupp, R et al, 2005), only few patients survive for three or more years. Main risk factors are high dose radiation, hereditary syndromes and increasing age. Although the last years have revealed some major approaches to develop new surgical and radiation techniques as well as multiple antineoplastic drugs, a cure for glioblastoma remains elusive (DeAngelis, L.M. et al, 2001).

Tab. 1.2. The World Health Organization (WHO) grading system for astrocytomas

Scr 010a source.png

In the present work research and conclusions will be restricted to cells representing glioblastoma multiforme (GBM), i.e. a grade IV brain tumour.

1.3.1. Epidemiology of gliomas

Gliomas occur with an incidence of 5 in 100,000 (19). They make up 44 % of all primary brain tumours and 52 % of these are represented by the glioblastoma multiforme. The peak of onset of glioblastomas is around 50 - 55 years, which makes them a strongly age-related pathology. Men are slightly more prone to these neoplasms. Furthermore, the incidence is 2 - 3 times higher in white than in black people. Prognosis is poor and the median survival is 14.6 months (67); only few patients survive for three or more years. Main risk factors are high dose radiation, hereditary syndromes and increasing age. Although the last years have revealed some major approaches to develop new surgical and radiation techniques as well as multiple antineoplastic drugs, a cure for glioblastoma remains elusive (11).


11. DeAngelis,L.M. 2001. Brain tumors. N.Engl.J.Med. 344:114-123.

19. Friese,M.A., Steinle,A., and Weller,M. 2004. The innate immune response in the central nervous system and its role in glioma immune surveillance. Onkologie. 27:487-491.

67. Stupp,R., Mason,W.P., van den Bent,M.J., Weller,M., Fisher,B., Taphoorn,M.J., Belanger,K., Brandes,A.A., Marosi,C., Bogdahn,U. et al. 2005. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N.Engl.J.Med. 352:987- 996.

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[3.] Src/Fragment 014 07 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 01:02 Hindemith
BauernOpfer, Bjerkvig 2005, Fragment, SMWFragment, Schutzlevel, Src, ZuSichten

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Seite(n): 900, Zeilen: Figure 1
Scr 014a diss.png

Fig. 1.5: Mutations in stem cells and/or progenitor cells might give rise to glioma stem cells. The cancer stem cell might appear after mutations in specific stem cells or early stem cell progenitors. It is also possible that cancer stem cells can be derived from differentiated cells. There might be numerous factors in the host microenvironment that trigger the initial steps of tumor formation. (Modified from Bjerkvig R, et al, 2005).

FIGURE 1 Mutations in stem cells and/or progenitor cells might give rise to cancer stem cells.

Scr 014a source.png

The cancer stem cell might appear after mutations in specific stem cells or early stem cell progenitors. It is also possible that cancer stem cells can be derived from differentiated cells. There might be numerous factors in the host microenvironment that trigger the initial steps of tumour formation.

Anmerkungen

Die hier dokumentierte Abbildung ist online frei zugänglich: [1]

Die Quelle ist zwar angegeben, aber zum einen ist die Abbildung in keiner Weise modifiziert, und zum anderen ist auch die Bildunterschrift unverändert übernommen.

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[4.] Src/Fragment 024 03 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 11:31 Hindemith
Fragment, Lok and Loh 1998, SMWFragment, Schutzlevel, Src, Verschleierung, ZuSichten

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Seite: 24, Zeilen: 3-9, 12-22, 24-28
Quelle: Lok and Loh 1998
Seite(n): 163, 164, Zeilen: 163: 2. Spalte: 30ff; 164: 1. Spalte: 6ff
[...] oligodendrocytes are believed to be the predominant iron-containing cells in the brain and have a special requirement of iron for myelin production, and immature oligodendrocytes express TfR for iron acquisition (Connor, J.R., Menzies, S.L.et al, 1996). In normal brain, TfR immunostaining is detected primarily in endothelial and glial cells, whereas neoplastic cells from nearly all brain tumors are found to be TfR-positive (Recht, L., C.O.et al, 1990, Prior, R. et al, 1990) [...]

[...]

Most malignant and proliferating cells express high numbers of TfRs as compared to their normal and quiescent counterparts and the first direct evidence of the proliferation-associated expression of TfR was demonstrated in several lymphoblastoid cell lines and activated peripheral blood lymphocytes which have high numbers of transferrin binding sites (Larrick, J.W. et al, 1979). Subsequently, numerous reports (Kuhn, L.C. et al, 1990, Neckers, L.M. et al, 1991) confirmed that virtually all cell lines and normal proliferating cells possess high numbers of TfRs, TfR expression increases upon mitogenic stimulation and diminishes upon terminal differentiation and growth arrest and furthermore anti-TfR antibodies that can block transferrin binding and hence iron uptake inhibit cell proliferation (Trowbridge, I.S. et al, 1982). In some tumors like in breast cancers TfR has been discussed to have growth factor like functions (Cavanaugh et al 1999) which will support the notion that the TfR is a proliferation-associated marker. The explanation for the proliferation-associated expression of TfR is attributed in part to an increased requirement of iron for synthesis and functioning of numerous iron-containing proteins, in particular ribonucleotide reductase, which is a rate-limiting enzyme in DNA synthesis (Chitambar, C.R. et al, 1995).

The oligodendrocytes are believed to be the predominant iron-containing cells in the brain and have a special requirement of iron for myelin production, and immature oligodendrocytes express TfR for iron acquisition [82].

[Seite 164]

In normal brain, TfR immunostaining is detected primarily in endothelial and glial cells, whereas neoplastic cells from nearly all brain tumors are found to be TfR-positive [84, 85].

[...]

Not only tissues such as reticulocytes and placenta, but also most malignant and proliferating cells express high numbers of TfRs as compared to their normal and quiescent counterparts. The first direct evidence of the proliferation-associated expression of TfR was demonstrated in several lymphoblastoid cell lines and activated peripheral blood lymphocytes which have high numbers of transferrin binding sites [92]. Subsequently, numerous reports [93, 94] confirmed that (1) virtually all cell lines and most normal proliferating cells examined possess high numbers of TfRs, (2) TfR expression increases upon mitogenic stimulation and diminishes upon terminal differentiation and growth arrest, (3) the proliferation-associated antigens (cluster of differentiation, CD 71) present on lymphocytes are the TfR [5] and (4) anti-TfR antibodies that can block transferrin binding and hence iron uptake inhibit cell proliferation [95]. These observations, together with studies showing that iron deprivation prevents DNA synthesis [96, 97] and that transferrin is essential for in vitro cell growth in serum-free systems [98], support the notion that the TfR is a proliferation-associated marker. The explanation for the proliferation-associated expression of TfR is attributed in part to an increased requirement of iron for synthesis and functioning of numerous iron-containing proteins, in particular ribonucleotide reductase, which is a rate-limiting enzyme in DNA synthesis [99, 100].


82 Connor JR, Menzies SL: Relationship of iron to oligodendrocytes and myelination. Glia 1996;17:83–93.

84 Recht L, Torres CO, Smith TW, Raso V, Griffin TW: Transferrin receptor in normal and neoplastic brain tissue: Implications for braintumor immunotherapy. J Neurosurg 1990;72:941–945.

85 Prior R, Reifenberger G, Wechsler W: Transferrin receptor expression in tumour of the human nervous system: Relation to tumour type, grading and tumour growth fraction. Virchows Arch A Pathol Anat Histopathol 1990;416:491–496.

92 Larrick JW, Cresswell P: Modulation of cell surface iron transferrin receptors by cellular density and state of activation. J Supermol Struct 1979;11:579–586.

93 Kuhn LC, Schulman HM, Ponka P: Iron-transferrin requirements and transferrin receptor expression in proliferating cells; in Ponka, Schulman, Woodworth (eds): Iron Transport and Storage. Boca Raton, CRC Press, 1990, pp 149–191.

94 Neckers LM: Regulation of transferrin receptor expression and control of cell growth. Pathobiology 1991; 59:11–18.

95 Trowbridge IS, Lopez F: Monoclonal antibody to transferrin receptor blocks transferrin binding and inhibits human tumor cell growth in vitro. Proc Natl Acad Sci USA 1982; 79:1175–1179.

96 Hoffbrand AV, Graneshaguru K, Hooton JWL, Tattersall MHN: Effect of iron deficiency and desferrioxamine on DNA synthesis in human cells. Br J Haematol 1976;33: 517–526.

97 Fernandez-Pol JA, Bono VH Jr, Johnson GS: Control of growth by picolinic acid: Differential response of normal and transformed cells. Proc Natl Acad Sci USA 1977;74:2889–2893.

98 Barnes D, Sato G: Serum-free cell culture: A unifying approach. Cell 1980;22:649–655.

99 Eriksson S, Graslund A, Skog S, Thelander L, Tribukait B: Cell cycle- dependent regulation of mammalian ribonucleotide reductase. J Biol Chem 1984;259:11695– 11700.

100 Chitambar CR, Wereley JP: Effect of hydroxyurea on cellular iron metabolism in human leukemic CCRF-CEM cells: Changes in iron uptake and the regulation of transferrin receptor and ferritin gene expression following inhibition of DNA synthesis. Cancer Res 1995; 55:4361–4366.

Anmerkungen

Ein Verweis auf die Quelle fehlt.

Auch die meisten Literaturverweise sind übernommen.

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[5.] Src/Fragment 025 02 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 11:49 Hindemith
Fragment, Lok and Loh 1998, SMWFragment, Schutzlevel, Src, Verschleierung, ZuSichten

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Kuhn and coworkers reported the first genomic clone for the transferrin receptor by expression and cloning techniques (Kuhn, L.C. et al, 1984). The human TfR gene was found to contain at least 19 exons distributed over 31 kb of DNA and contains a translated region of 2,280 nucleotides in their respective cDNA clones.

TfR gene transcription is activated during cell proliferation (Seiser, C. et al, 1993), cell transformation (Beard, P. et al, 1991) and differentiation of immature erythroid cells to hemoglobin synthesizing cells (Chan, R.Y.Y. et al, 1994, Chan, L.N. et al, 1992). On the other hand, gene transcription is comparatively inactive in the quiescent state of the cells, that is during growth arrest and terminal differentiation in the nonerythroid cells (Lok, C.N. et al, 1996). TfR gene transcription is believed to be controlled by cellular signals involved in the cell growth and differentiation, resulting in the expression of TfR for iron demand during cell proliferation or heme synthesis. The TfR gene promoter region (fig. 1.10) is GC-rich and contains a TATA box about 30 bp upstream from the known transcriptional start site. A consensus SP-1/GC-rich sequence is located near the TATA box and a sequence as short as 47 bp upstream of the transcriptional start site has been found to be sufficient for driving the basal transcription of the reporter gene as shown by reporter gene assays (Owen, D. et al, 1987).

Scr 025a diss.png

Fig. 2.5. TfR gene promoter region. Part of the TfR promoter region that is critical for its expression. The underlined sequences represent elements similar to certain consensus cisacting elements. Sequence similarity to consensus regulatory cis-elements and putative binding factors are indicated (see text for explanation). Bold typeface identifies bases identical to the TfR gene elements (Sieweke, M.H. et al, 1996, Ouyang, Q. et al, 1993, Roberts, M.R. et al, 1994). CRE = cAMP-responsive element; CREB = CREbinding protein; PSE = proximal sequence element.

By expression cloning techniques, Schneider and coworkers first isolated cDNA clones of TfR in MOLT-4 cells, and later Kuhn and coworkers [8] reported the first genomic clone for the receptor. The human TfR gene was found to contain at least 19 exons distributed over 31 kb of DNA. Both groups reported a translated region of 2,280 nucleotides in their respective cDNA clones.

[Seite 167]

In general, the gene transcription is activated during cell proliferation [120, 130, 131, 146], cell transformation [147] and differentiation of immature erythroid cells to hemoglobinsynthesizing cells [41, 45]. On the other hand, gene transcription is comparatively inactive in the quiescent state of the cells, that is during growth arrest and terminal differentiation in the nonerythroid cells [148–150]. TfR gene transcription is believed to be controlled by cellular signals involved in the cell growth and differentiation, resulting in the expression of TfR for iron demand during cell proliferation or heme synthesis.

[...] The TfR gene promoter region (fig. 3) is GC-rich and contains a TATA box about 30 bp upstream from the known transcriptional start site. A consensus SP-1/GC-rich seqence is located near the TATA box. [...] By reporter gene assays, a sequence as short as 47 bp upstream of the transcriptional start site has been found to be sufficient for driving the basal transcription of the reporter gene [121].

[Seite 168]

Scr 025a source.png

Fig. 3. TfR gene promoter region. Part of the TfR promoter region that is critical for its expression. The underlined sequences represent elements similar to certain consensus cisacting elements. Sequence similarity to consensus regulatory cis-elements and putative binding factors are indicated (see text for explanation). Bold typeface identifies bases identical to the TfR gene elements [46, 151, 154]. CRE = cAMP-responsive element; CREB = CREbinding protein; PSE = proximal sequence element.


8 Kuhn LC, McClelland A, Ruddle FH: Gene transfer, expression and molecular cloning of the human transferrin receptor gene. Cell 1984; 37:95–103.

41 Chan RYY, Seiser C, Schulman HM, Kuhn LC, Ponka P: Regulation of transferrin receptor mRNA expression: Distinct regulatory features in erythroid cells. Eur J Biochem 1994;220:683–692.

45 Chan LN, Gerhardt EM: Transferrin receptor gene is hyperexpressed and transcriptionally regulated in differentiating erythroid cells. J Biol Chem 1992;267:8254–8259.

121 Owen D, Kuhn LC: Noncoding 3) sequences of the transferrin receptor gene are required for mRNA regulation by iron. EMBO J 1987; 6:1287–1293.

130 Seiser C, Teixeira S, Kuhn LC: Interleukin-2-dependent transcriptional and post-transcriptional regulation of transferrin receptor mRNA. J Biol Chem 1993;268: 13074–13080.

131 Casey JL, Di Jeso B, Rao K, Klausner RD, Harford JB: Two genetic loci participate in the regulation by iron of the gene for the human transferrin receptor. Proc Natl Acad Sci USA 1988;85:1787– 1791.

146 Kronke M, Leonard W, Depper JM, Greene WC: Sequential expression of genes involved in human T lymphocyte growth and differentiation. J Exp Med 1985;161: 1593–1598.

147 Beard P, Offord E, Paduwat N, Bruggmann H: SV40 activates transcription from the transferrin receptor promoter by inducing a factor which binds to the CRE/AP- 1 recognition sequence. Nucleic Acids Res 1991;25:7117–7123.

148 Alcantara O, Denham CA, Phillips JL, Boldt DH: Transcriptional regulation of transferrin receptor expression by cultured lymphoblastoid T cells treated with phorbol esters. J Immunol 1989;142:1719– 1725.

149 Trepel JB, Colamonici OR, Kelly K, Schwab G, Watt RA, Sauville EA, Jaffe ES, Neckers LM: Transcriptional inactivation of c-myc and the transferrin receptor in dibutyryl cyclic AMP-treated HL-60 cells. Mol Cell Biol 1987;7:2644– 2648.

150 Lok CN, Chan KF, Loh TT: Transcriptional regulation of transferrin receptor gene expression during phorbol ester-induced HL-60 cell differentiation: Evidence for a negative regulatory role of the phorbol ester-responsive elementlike sequence. Eur J Biochem 1996;236:614–619.

151 Ouyang Q, Bommakanti M, Miskimins WK: A mitogen-responsive promoter region that is synergistically activated through multiple signalling pathways. Mol Cell Biol 1993;13:1796–1804.

154 Roberts MR, Han Y, Fienberg A, Hunihan L, Ruddle FH: A DNAbinding activity, TRAC, specific for the TRA element of the transferrin receptor gene copurifies with the KU autoantigen. Proc Natl Acad Sci USA 1994;91:6354–6358.

Anmerkungen

Ein Verweis auf die Quelle fehlt.

Auch die meisten Literaturverweis sind übernommen.

"fig. 1.10" existiert in der untersuchten Arbeit nicht. Gemeint ist wohl Abbildung 2.5., denn diese entspricht der Abbildung 3 der Quelle.

Sichter
(Hindemith)

[6.] Src/Fragment 026 01 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 11:55 Hindemith
Fragment, KomplettPlagiat, Lok and Loh 1998, SMWFragment, Schutzlevel, Src, ZuSichten

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One of the most important transcriptional control mechanisms of the TfR is the upregulation of the receptor expression in developing erythroid cells. In an avian erythroblastic cell line, the transcription factor Ets-1 could stimulate the erythroid differentiation and was also found to enhance the TfR promoter activity by 2- to 3-fold via an Ets binding site close to the TRE-like sequence (Sieweke, M.H. et al, 1996). Interestingly, overexpression of Maf B, a direct repressor of Ets-1, downregulated the TfR expression and inhibited the erythroid differentiation, without affecting cell growth (Sieweke, M.H. et al, 1996). Therefore, an erythroid-specific transcriptional control of the TfR seems to operate. One of the most important transcriptional control mechanisms of the TfR is the upregulation of the receptor expression in developing erythroid cells. In an avian erythroblastic cell line, the transcription factor Ets-1 could stimulate the erythroid differentiation and was also found to enhance the TfR promoter activity by 2- to 3-fold via an Ets binding site close to the TRE-like sequence [46]. Interestingly, overexpression of Maf B, a direct repressor of Ets-1, downregulated the TfR expression and inhibited the erythroid differentiation, without affecting cell growth [46]. Therefore, an erythroid-specific transcriptional control of the TfR seems to operate.

46 Sieweke MH, Tekotte H, Frampton J, Graf T: MafB is an interaction partner and repressor of Ets-1 that inhibits erythroid differentiation. Cell 1996;85:49–60.

Anmerkungen

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[7.] Src/Fragment 023 02 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 13:52 Hindemith
Fragment, KomplettPlagiat, SMWFragment, Schutzlevel, Src, Visser 2005, ZuSichten

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The expression level of the TfR depends on the level of iron supply and rate of cell proliferation. The iron concentration determines TfR synthesis and expression via an iron-responsive element (IRE) in the mRNA of the TfR (Kuhn, L. C. et al, 1991, Casey, J. L. et al, 1989). This IRE is also found in the mRNA of ferritin, a protein that can store iron (Kuhn, L. C. et al, 1991). In cases of low iron concentrations, a so called IRE binding protein stabilises the mRNA of the TfR, which can therefore be translated. The mRNA of ferritin is in low-iron situations less stable and is therefore translated to a lesser extent. Recently, a second TfR (TfR-2) has been identified (Trinder, D. and Baker, E. et al, 2003), which does not contain an IRE in its mRNA. TfR-2 is differentially distributed from TfR and has a 25-fold lower affinity for Tf.

The TfR is expressed mainly on hepatocytes, erythrocytes, intestinal cells, monocytes, as well as on endothelial cells of the BBB [...] (Morgan, E. [H. et al, 1996, Ponka, P. and Lok, C. N. et al, 1999).]

The TfR is expressed mainly on hepatocytes, erythrocytes, intestinal cells, monocytes, as well as on endothelial cells of the BBB (34, 35).

[Seite 22]


The expression level of the TfR depends on the level of iron supply and rate of cell proliferation. [...] The iron concentration determines TfR synthesis and expression via an iron-responsive element (IRE) in the mRNA of the TfR (37, 38). This IRE is also found in the mRNA of ferritin, a protein that can store iron (37). In cases of low iron concentrations, a so-called IRE binding protein stabilises the mRNA of the TfR, which can therefore be translated. The mRNA of ferritin is in low-iron situations less stable and is therefore translated to a lesser extent.

Recently, a second TfR (TfR-2) has been identified (39), which does not contain an IRE in its mRNA. TfR-2 is differentially distributed from TfR and has a 25-fold lower affinity for Tf.


34. Morgan, E. H. (1996) Iron metabolism and transport. In Hepatology. A textbook of liver disease, Vol. 1 (D. Zakin and T. D. Boyer, eds.), Saunders, Philadelphia, pp. 526-554

35. Ponka, P. and Lok, C. N. (1999) The transferrin receptor: role in health and disease. Int J Biochem Cell Biol 31 (10): 1111-1137

37. Kuhn, L. C. (1991) mRNA-protein interactions regulate critical pathways in cellular iron metabolism. Br J Haematol 79 (1): 1-5

38. Casey, J. L., Koeller, D. M., Ramin, V. C., Klausner, R. D. and Harford, J. B. (1989) Iron regulation of transferrin receptor mRNA levels requires iron- responsive elements and a rapid turnover determinant in the 3' untranslated region of the mRNA. Embo J 8 (12): 3693-3699

39. Trinder, D. and Baker, E. (2003) Transferrin receptor 2: a new molecule in iron metabolism. Int J Biochem Cell Biol 35 (3): 292-296

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[8.] Src/Fragment 026 15 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 19:00 Hindemith
Fragment, Pervaiz and Clement 2007, SMWFragment, Schutzlevel, Src, Verschleierung, ZuSichten

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Untersuchte Arbeit:
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Quelle: Pervaiz and Clement 2007
Seite(n): 1297, 1298, Zeilen: 1297: l. Spalte: 4ff; 1298: r. Spalte: 13ff
The major reactive oxygen species (ROS) include oxygen radicals such as superoxide (O2−) and hydroxyl (OH), as well as non-radical derivatives of molecular oxygen (O2), such as hydrogen peroxide (H2O2). Whereas O2− and H2O2 do not exhibit strong reactivity with other bio-molecules, their reaction generates the highly reactive OH radical, which probably accounts for most of the oxidative damage attributed to ROS (Halliwell & Gutteridge, 1999).

In healthy living cells, one or more of redox regulatory mechanisms are activated in response to a transient increase in intracellular ROS to prevent oxidative stress. A disturbance in the tight balance between ROS production and elimination, either via augmentation of ROS generation or defective/deficient anti-oxidant defenses for their elimination, results in a build up of intracellular ROS and may lead to persistent changes in signal transduction and gene expression (Sauer et al., 2001), thereby giving rise to oxidative stress-related pathological states (Burdon, 1995 and Burdon, 1996).

Leaving aside the reactive nitrogen species, the major reactive oxygen species (ROS) include oxygen radicals such as superoxide (O2 −) and hydroxyl (•OH), as well as non-radical derivatives of molecular oxygen (O2), such as hydrogen peroxide (H2O2) (Fridovich, 1978). Whereas O2 − and H2O2 do not exhibit strong reactivity with other bio-molecules, their reaction generates the highly reactive •OH radical, which probably accounts for most of the oxidative damage attributed to ROS (Halliwell & Gutteridge, 1999).

[Seite 1298]

In healthy living cells, one or more of these redox regulatory mechanisms are activated in response to a transient increase in intracellular ROS to prevent oxidative stress. A disturbance in the tight balance between ROS production and elimination, either via augmentation of ROS generation or defective/deficient anti-oxidant defenses for their elimination, results in a build up of intracellular ROS and may lead to persistent changes in signal transduction and gene expression, thereby giving rise to oxidative stress-related pathological states.

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[9.] Src/Fragment 018 12 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 23. September 2014, 19:23 Hindemith
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Promotion of tumor stem-cell differentiation may be an important strategy for treatment of brain tumor stem cells. Bone morphogenic proteins (BMPs), which normally induce astrocyte differentiation from normal neural precursors, have been shown to promote glioblastoma cell differentiation in vitro and in vivo. Most importantly, recombinant BMPs induce the suppression of glioblastoma tumorigenicity in vivo, possibly though promotion of the differentiation cancer stem cells in the tumor (Piccirillo, S.G., et al 2006). Promotion of tumor stem-cell differentiation may be an important strategy for treatment of brain tumor stem cells. Vescovi et al26 have shown that bone morphogenic proteins (BMPs), which normally induce astrocyte differentiation from normal neural precursors, have been shown to promote glioblastoma cell differentiation in vitro and in vivo. Most importantly, BMPs induce the suppression of glioblastoma tumorigenicity in vivo, possibly though promotion of the differentiation of restricted tumor progenitors or by direct action on the most primitive cell (the cancer stem cell) in the tumor.

26. Piccirillo SG, Reynolds BA, Zanetti N, et al: Bone morphogenetic proteins inhibit the tumorigenic potential of human brain tumour-initiating cells. Nature 444:761-765, 2006

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[10.] Src/Fragment 016 01 - Diskussion
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CD133 positive human glioblastoma cells were shown to be resistant to radiation therapy, retaining a clonogenic and tumorigenic potential. CD133 positive cells increase in number after irradiation of glioblastoma cells in culture and in tumors growing in vivo. The CD133 positive cells undergo similar DNA damage to those of their CD133 negative counterparts, but they show a better ability to repair strand breaks, through a more potent activation of DNA damage checkpoint mechanisms (Bao, S. et al, 2006). In work by the Rich group,24 CD133+ humanglioblastoma cells were shown to be resistant to radiation therapy, retaining a clonogenic and tumorigenic potential. CD133+ cells increase in number after irradiation of glioblastomas cells in culture and in tumors growing in vivo. The CD133+ cells undergo similar DNA damage to those of their CD133– counterparts, but they show a better ability to repair strand breaks, through a more potent activation of DNA-damage checkpoint mechanisms.

24. Bao S, Wu Q, McLendon RE, et al: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature 444:756-760, 2006

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[11.] Src/Fragment 015 11 - Diskussion
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Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases, these therapies may miss the rare, self-renewing population that truly gives rise to the malignancy (GSCs) and which is usually non-responsive to standard chemotherapy (Lu C et al, 2008) Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may allow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating tumors. Current chemotherapeutic strategies involve using non-specific cytotoxic agents that target rapidly cycling cells. Although this may reduce disease burden in many cases, these therapies may miss the rare, self-renewing population that truly gives rise to the malignancy (the CSC).

[...] Dissecting the molecular mechanisms that underlie the ability of these cells to self-renew and maintain quiescence may allow the development of novel therapeutic strategies that will allow for more efficacious and less toxic therapies for these devastating malignancies.

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[12.] Src/Fragment 019 10 - Diskussion
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Fragment, SMWFragment, Schutzlevel, Seth and Watson 2005, Src, Verschleierung, ZuSichten

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In general cancer can be defined as a genetic disease and as a consequence of multiple events associated with initiation, promotion and metastatic growth. Cancer also results from the loss of control of cellular homeostasis. Cell homeostasis is the result of the balance between proliferation and cell death, while cellular transformation can be viewed as a loss of relationship between these events. Oncogenes and tumor suppressor genes act as modulators of cell proliferation, while the balance of apoptotic and anti-apoptotic genes controls cell death. All cancer cells acquire similar sets of functional capacities: (1) independence from mitogenic/growth signals; (2) loss of sensitivity to “anti-growth” signals; (3) evade apoptosis; (4) Neo-angiogenic conversion; (5) release from senescence; and (6) invasiveness and metastasis (Hanahan D and Weinberg RA., 2000). One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection as well as better diagnosis and staging of disease with detection of minimal residual disease recurrences and evaluation of response to therapy; (2) prevention; and (3) novel treatment strategies and the increased understanding of ETS-regulated biological pathways will directly impact these areas. Cancer can be defined as a genetic disease, resulting as a consequence of multiple events associated with initiation, promotion and metastatic growth. Cancer results from the loss of control of cellular homeostasis. Cell homeostasis is the result of the balance between proliferation and cell death, while cellular transformation can be viewed as a loss of relationship between these events. Oncogenes and tumour suppressor genes act as modulators of cell proliferation, while the balance of apoptotic and anti-apoptotic genes controls cell death. All cancer cells acquire similar sets of functional capacities: (1) independence from mitogenic/growth signals; (2) loss of sensitivity to “anti-growth” signals; (3) evade apoptosis; (4) Neo-angiogenic conversion; (5) release from senescence; and (6) invasiveness and metastasis [Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000, 100, 57–70]. One of the goals of molecular biology is to elucidate the mechanisms that contribute to the development and progression of cancer. Such understanding of the molecular basis of cancer will provide new possibilities for: (1) earlier detection as well as better diagnosis and staging of disease with detection of minimal residual disease recurrences and evaluation of response to therapy; (2) prevention; and (3) novel treatment strategies. We feel that increased understanding of ETS-regulated biological pathways will directly impact these areas.
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[13.] Src/Fragment 020 01 - Diskussion
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As shown in Fig. 2.1. ETS proteins are transcription factors that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis (Oikawa T et al, 20004). Identification of target genes that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth, and differentiation, as well as provide information critical to understanding cancer development. ETS proteins are transcription factors that activate or repress the expression of genes that are involved in various biological processes, including cellular proliferation, differentiation, development, transformation and apoptosis. Identification of target genes that are regulated by a specific transcription factor is one of the most critical areas in understanding the molecular mechanisms that control transcription. Furthermore, identification of target gene promoters for normal and oncogenic transcription factors provides insight into the regulation of genes that are involved in control of normal cell growth, and differentiation, as well as provide information critical to understanding cancer development.
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[14.] Src/Fragment 021 01 - Diskussion
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[Ets] family of transcription factors comprising more than 30 different members sharing a highly conserved DNA binding motif termed the ETS domain and through this domain they bind to specific purine-rich DNA sequence containing a conserved motif of GGAA/T in the middle of ten base pairs of DNA and depending on which Ets transcription proteins are binding these flanking sequences are variable (Wasylyk et al, 1993).

These flanking sequences are variable and there is evidence that they help to determine which Ets proteins will bind (reviewed in Wasylyk et al., 1993; Wasylyk and Nordheim, 1997; Watson and Seth, 2000). Ets-1 is the founding member of the Ets family and was initially identified as the protooncogene corresponding to the v-Ets oncogene of the E26 leukemia virus. In humans, Ets-1 is expressed at high levels in proliferating vascular endothelial cells of the embryo and in blood vessels of the adult during angiogenesis (Wernert et al., 1992). In the hematopoietic system the analysis of targeted mutants has revealed an essential role for Ets-1 in the differentiation of all lymphoid cells; it was found to be essential for the development of functional NK cells (Barton et al., 1998) and for survival and maturation of B and T cell lineages (Bories et al., 1995; Muthusamy et al., 1995).

The Ets family of transcription factors, comprising more than 30 different members is characterized by the presence of an 85-aminoacid sequence termed the `Ets domain' that is highly conserved from lower metazoans to humans. Through this domain the Ets proteins bind to specific purine-rich DNA sequence containing a conserved core motif of GGAA/T in the middle of 10 base pairs (bp) of DNA. These flanking sequences are variable and there is evidence that they help to determine which Ets proteins will bind (reviewed in Wasylyk et al., 1993; Wasylyk and Nordheim, 1997; Watson and Seth, 2000). Ets-1 is the founding member of the Ets family and was initially identified as the protooncogene corresponding to the v-Ets oncogene of the E26 leukemia virus. In humans, Ets-1 is expressed at high levels in proliferating vascular endothelial cells of the embryo and in blood vessels of the adult during angiogenesis (Wernert et al., 1992). In the hematopoietic system the analysis of targeted mutants has revealed an essential role for Ets-1 in the differentiation of all lymphoid cells; it was found to be essential for the development of functional NK cells (Barton et al., 1998) and for survival and maturation of B and T cell lineages (Bories et al., 1995; Muthusamy et al., 1995).
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[15.] Src/Fragment 017 07 - Diskussion
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Scr 017a diss.png

Fig. 1.8. BMP signalling: The BMPs bind to type I and II receptors and facilitate their association. The constitutively active kinase domains of type II receptors phosphorylate type I receptors, and this in turn activates the SMAD signaling pathway through phosphorylation of receptor SMADs (SMAD1, SMAD5 and SMAD8). These associate with co-SMADs (SMAD4) to form a heteromeric complex that translocates to the nucleus and stimulates the expression of a wide range of target genes. BMPs can also signal through SMAD-independent pathways, notably via MAP kinases. Dorsomorphin inhibits BMP signaling through the SMAD pathway, likely by affecting BMPR-I kinase activity. Many of the previously known inhibitors of BMP signaling (such as noggin and chordin) act upstream to sequester BMPs and cannot differentiate SMAD-dependent from SMAD-independent signaling. (Modified from Anderson and Darshan et al 2008).

Scr 017a source.png

Figure 1 The BMPs bind to type I and II receptors and facilitate their association. The constitutively active kinase domains of type II receptors phosphorylate type I receptors, and this in turn activates the SMAD signaling pathway through phosphorylation of receptor SMADs (SMAD1, SMAD5 and SMAD8). These associate with co-SMADs (SMAD4) to form a heteromeric complex that translocates to the nucleus and stimulates the expression of a wide range of target genes, including the gene encoding the iron regulatory peptide hepcidin. BMPs can also signal through SMAD-independent pathways, notably via MAP kinases. Dorsomorphin inhibits BMP signaling through the SMAD pathway, likely by affecting BMPR-I kinase activity. Many of the previously known inhibitors of BMP signaling (such as noggin and chordin) act upstream to sequester BMPs and cannot differentiate SMAD-dependent from SMAD-independent signaling. The activation of the hepcidin gene by IL-6 requires both the JAK-STAT and BMP-SMAD pathways, but how the pathways interact is unclear. Similarly, TfR2 and the HFE–TfR1 complex can alter hepcidin expression, but it is not known whether their functions require the BMPSMAD system. Modified from ref. 10.

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[16.] Src/Fragment 011 01 - Diskussion
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1.3. Diagnosis and treatment of gliomas

Scr 011a diss.png

Fig. 1.3. MRT of a human brain, revealing a glioblastoma multiforme

(rad.usuhs.mil/rad/who/zs224248)

If a neurological examination points to a brain tumor, additional testings will be made. These mainly include scans like magnetic resonance imaging (MRI, Fig. 1.3.), computer tomography (CT) or positron emission tomography (PET). In most cases therapy starts with surgical removal of the tumor. Since for the tumor patient gliomas may be located in brain areas which are of vital importance and the surgical removal of these neoplasms can be much more difficult than removing a tumor in other parts of the body. Even if the surgery is successful it has to be assumed that tumor cells have already spread throughout the brain and may be the source for tumor relapses.

One of the main properties of glioma cells is their invasive behaviour, which also signifies the biggest challenge regarding therapy (Holland, E.C. et al, 2001; Kleihues, P et al, 1995). Therefore combined radiochemotherapy typically follows surgery. Conventional radiation therapy uses X- or gamma-rays but also other types of radiation are available. At present, the standard chemotherapeutic is temozolomide (Temodal®). Its cytotoxicity is due to alcylation of the nucleobase guanine.

1.3.3. Diagnosis and treatment of glioblastoma

Scr 011a source.png

Fig. 1.4. MRT of a human brain, revealing a glioblastoma multiforme

(rad.usuhs.mil/rad/who/zs224248)

If a neurological examination points to a brain tumour, additional tests will be made. These mainly include scans like magnetic resonance imaging (MRI, fig. 1.4.), computer tomography (CT) or positron emission tomography (PET). In most cases therapy starts with surgical removal of the tumour. Due to the limited space in the brain this is much more difficult than removing a tumour in other parts of the body. Even if the surgery is

[Seite 15]

successful it has to be assumed that tumour cells have already spread throughout the brain and may be the source for tumour relapses.

One of the main properties of glioma cells is their invasive behaviour, which also signifies the biggest challenge regarding therapy (31;41). Therefore combined radiochemotherapy typically follows surgery. At present, the standard chemotherapeutic is temozolomide (Temodal®); its cytotoxicity is due to alcylation of the nucleobase guanine.


31. Holland,E.C. 2001. Gliomagenesis: genetic alterations and mouse models. Nat.Rev.Genet. 2:120-129.

41. Kleihues,P., Soylemezoglu,F., Schauble,B., Scheithauer,B.W., and Burger,P.C. 1995. Histopathology, classification, and grading of gliomas. Glia 15:211-221.

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[17.] Src/Fragment 012 01 - Diskussion
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[Although many efforts have been made during the last years to improve] the existing therapies, the biggest problem is still the extreme invasive nature of glioblastomas. It is virtually impossible to prevent migration of tumor cells into the adjacent brain tissue, which may be the primary cause for relapses.

1.4. Pathophysiology of gliomas

Glioma or Glioblastoma multiforme (GBM) consist of a heterogenous mixture of poorly differentiated neoplastic astrocytes (Holland, E.C.et al, 2001). They can occur as primary, which means de novo tumors but can also, although less frequent, develop from lower grade astrocytomas and thus are defined as secondary tumors. The latter typically develop in younger patients (< 45 years) whereas de novo tumors arise almost solely in elderly patients (around 65 years). The tumor as such forms a solid mass from which neoplastic cells are disseminating into the adjacent brain tissue. The tumor itself can reach a considerable size and squeeze out larger amounts of brain mass (Fig. 1.4.), which usually leads to diverse neurological defects.

Scr 012a diss.png

Fig. 1.4. Macroscopic view of glioblastoma multiforme in a human brain

(www.neuropat.dote.hu/jpeg/tumor/3gliobl1).

Although primary and secondary tumors differ on the genetic level in many ways, there are some common genetic abnormalities, which are considered as hallmarks of glioblastomas. One of them is the loss of heterozygosity (LOH) on chromosome 10, which seems to be specific for grade IV brain tumors.

1.3.2. The pathophysiology of glioblastoma

Glioblastoma multiforme (GBM) consist of a heterogenous mixture of poorly differentiated neoplastic astrocytes (31). They can occur as primary, which means de novo tumours but can also, although less frequent, develop from lower grade astrocytomas and thus are defined as secondary tumours. The latter typically develop in younger patients


[Seite 13]

(< 45 years) whereas de novo tumours arise almost solely in elderly patients (around 65 years).

The tumour as such forms a solid mass from which neoplastic cells are disseminating into the adjacent brain tissue. The tumour itself can reach a considerable size and squeeze out larger amounts of brain mass (fig. 1.3.), which usually leads to diverse neurological defects.

Scr 012a source.png

Fig. 1.3. Macroscopic view of glioblastoma multiforme in a human brain

(www.neuropat.dote.hu/jpeg/tumor/3gliobl1).

Although primary and secondary tumours differ on the genetic level in many ways, there are some common genetic abnormalities, which are considered as hallmarks of glioblastomas. One of them is the loss of heterozygosity (LOH) on chromosome 10, which seems to be specific for grade IV brain tumours.

[Seite 15]

Although many efforts have been made during the last years to improve the existing therapies, the biggest problem is still the extreme invasive nature of glioblastomas. It is virtually impossible to prevent migration of tumour cells into the adjacent brain tissue, which is the cause of relapses in most cases.


31. Holland,E.C. 2001. Gliomagenesis: genetic alterations and mouse models. Nat.Rev.Genet. 2:120-129.

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[18.] Src/Fragment 013 01 - Diskussion
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[Very well known are] mutations in the tumor suppressor gene p53 on chromosome 9, which also plays a pivotal role in other types of cancer. In fact, only about a third of glioblastomas carries this mutation, which corresponds to the percentage in lower grade gliomas. [...] This suggests that the p53 gene is involved rather early in neoplastic transformation (Kleihues, P., et al, 1993). In about one third of all GBMs one can find amplification and mutation of the endothelial growth factor receptor gene (EGFR) like EGFRvIII which is the mutant version of EGFR in Glioblastoma multiforme mutation which leads to increased cell proliferation. Furthermore platelet-derived growth factor alpha (PDGF-α) and phosphatase and tensin homolog deleted on chromosome ten (PTEN) are two more genes, of which the expression is altered in GBMs (Knobbe,C.B. et al, 2002; Nakamura, J.L. et al, 2007). PDGF-α belongs to the family of growth factors and is involved in the regulation of cell growth and cell division. It plays a particular role in angiogenesis, which is characteristically increased in cancer to provide sufficient nutrition supply for the tumor. The phosphatase PTEN is a tumor suppressor, which is related to a variety of biological functions like apoptosis, inflammation and immunity. These genetic defects have an effect on other cell proteins and finally result in tumor formation. Very well known are mutations in the tumour suppressor gene p53 on chromosome 9, which also plays a pivotal role in other types of cancer. In fact, only about one third of glioblastomas carries this mutation, which corresponds to the percentage in lower grade gliomas. This suggests that the p53 gene is involved rather early in neoplastic transformation (40). In about one third of all GBMs one can find amplification of the endothelial growth factor receptor gene (EGFR), which leads to increased cell proliferation. Furthermore platelet-derived growth factor alpha (PDGF-α) and phosphatase and tensin homolog (PTEN) are two more genes, of which the expression is altered in GBMs (42;52). PDGF-α belongs to the family of growth factors and is

[Seite 14]

involved in the regulation of cell growth and cell division. It plays a particular role in angiogenesis, which is characteristically increased in cancer to provide sufficient nutrition supply for the tumour. The phosphatase PTEN is a tumour suppressor, which is related to a variety of biological functions like apoptosis, inflammation and immunity. These genetic defects have an effect on other cell proteins and finally result in tumour formation.


40. Kleihues,P., Burger,P.C., and Scheithauer,B.W. 1993. The new WHO classification of brain tumours. Brain Pathol. 3:255-268.

42. Knobbe,C.B., Merlo,A., and Reifenberger,G. 2002. Pten signaling in gliomas. Neuro.-oncol. 4:196-211.

52. Nakamura,J.L. 2007. The epidermal growth factor receptor in malignant gliomas: pathogenesis and therapeutic implications. Expert.Opin.Ther.Targets. 11:463-472.

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[19.] Src/Fragment 026 12 - Diskussion
Bearbeitet: 27. September 2014, 20:22 (Kybot)
Erstellt: 24. September 2014, 21:56 Hindemith
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Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metalion in our body, may work as a catalyst for the generation of ROS in pathological conditions Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metal ion in our body, may work as a catalyst for the generation of ROS in pathological conditions.
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