Diss. (sammanfattning) Umeå : Univ., 2004. / Härtill 6 uppsatser.

Indiana University-Purdue University Indianapolis (IUPUI) / Secondary gliomas are an incurable form of brain cancer that are diagnosed in people at a median age of 45 years. Next-generation sequencing has found that secondary glioblastomas have a distinct genetic profile from the more common primary glioblastomas, which are diagnosed in people typically over the age of 60. Over 80% of secondary gliomas contain an IDH1R132H mutation, resulting in neomorphic mutations, which catalyze isocitrate to the oncometabolite D-2-hydroxyglutarate (2-HG) instead of alpha-ketoglutarate (α-KG). As 2-HG accumulates, it induces a hypermethylator phenotype that prevents the cells from differentiating. Acquisition of additional mutations in tumor suppressors such as p53 and/or ATRX likely leads to tumor initiation. Work in the Wells Laboratory has found that loss of the HIPPO adaptor protein AmotL1 is also associated with increased malignancy. AmotL1 inhibits the transcriptional co-activator YAP to suppress both cell growth and migration. To understand the molecular events leading to secondary glioma development, this thesis developed a series of astrocyte cell lines that carry IDH1 and/or p53 mutations. These lines were then studied in 2D and 3D cell culture systems to identify changes that are associated with early secondary glial tumors. Work was also carried out to enable screens for small molecules that can be tested on these cell lines.

The annexin-7 (ANX7) gene is located on human chromosome 10q21, a site long been hypothesized to harbor a tumor suppressor gene (TSG) associated with brain, prostate, breast and other cancers. To test whether ANX7 might be a candidate TSG, and its role in the molecular pathogenesis of malignant glioma. We examined the ANX7 expression levels in several kinds of cell lines, 139 glioma specimens and 84 gastric cancer specimences. Consistently, analysis of ANX7 protein expression in human glioma tumor a significantly higher rate (2.14 times) of loss of ANX7 expression in glioblastoma multiformes (GBM) as compared with low grade astrocytoma (p=0.04). The striking correlation ANX7 expression and the differentiation of gastric carcinoma (p = 0.001). ANX7 may play an important role in the tumor progression. Loss or reduced expression of ANX7 is possibly a biomarker for tumor cell progression

by Yue Cheng. / "April 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 156-175). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

No description available.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2007. / Härtill 4 uppsatser.

Low-grade diffuse astrocytomas have an intrinsic tendency for malignant progression but the factors determining the kinetics of this process are still poorly understood. We report here the case of a male patient who developed a fibrillary astrocytoma at the age of 33 years and who underwent six surgical interventions over a period of 17 years without radiotherapy or chemotherapy. The first three biopsies spanned a period of 11 years and led to the diagnosis of low-grade, diffuse astrocytoma (WHO grade II), with a growth fraction (MIB-1 labeling index) of 2.3-3.7%. The fourth to sixth biopsies showed histological features of anaplastic astrocytoma (WHO grade III), with growth fractions between 5.0 and 10.5%. The fraction of gemistocytic neoplastic astrocytes also increased, from 0.3% in the first biopsy to 17.5% in the last biopsy and preceded the increase in proliferative activity and transition to anaplastic astrocytoma. The fraction of tumor cells immunoreactive to BCL-2 increased from 0.3% to 8.2%. A p53 mutation in codon 273 (CGT→TGT, Arg→Cys) was identified in the first biopsy and persisted throughout the course of the disease. However, the fraction of cells with p53 protein accumulation increased significantly during progression, from 3.2% in the first biopsy to 13.7% in the last. The absence of additional genetic alterations (PTEN mutations, loss of chromosome 10 and 19q) may be responsible for the slow progression and lack of glioblastoma features even after a 17-year disease duration.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Astrocytoma, the tumor of astrocytic origin, accounts for about 60 % of the primary brain tumors. As per World Health Organization grading system, astrocytoma is classified as circumscribed astrocytoma (Grade I; pilocytic astrocytoma) and diffusely infiltrating astrocytoma. Grade I tumor is biologically benign and can be cured by surgical resection of the tumor. The diffusely infiltrating astrocytoma is further subclassified into grade II/diffuse astrocytoma (DA), grade III/anaplastic astrocytoma (AA) and grade IV/glioblastoma (GBM). Aggressiveness of the disease increases as the tumor progresses from lower grade to higher grade. In particular, GBMs are the most malignant and aggressive human cancers. For a newly diagnosed GBM patient, the current treatment option is surgical resection of the tumor followed by radiation and temozolomide therapy. Despite the treatment is multimodal (surgery+radiation+temozolomide) the median survival of GBM patients remain very low at 14.6 months. Although numerous markers with potential utility in prognosis and treatment of GBMs have been reported, they are yet to be translated into clinical utility. Our knowledge of understanding the complete biology of GBMs needs further comprehensive studies towards the identification of markers with potential utility to prognose/treat the GBM patients efficiently. Therefore, with an immense need to develop new biomarkers/therapeutic strategies in order to improve the diagnosis, prognosis and existing treatment of the GBM, the current work is designed to study the following aspects on glioma

Chan Ching Yin. / Thesis submitted in: October 2003. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2004. / Includes bibliographical references (leaves 197-221). / Abstracts in English and Chinese. / Acknowledgement --- p.i / Abstract --- p.iii / Abstract in Chinese --- p.vi / List of abbreviations --- p.ix / List of tables --- p.xv / List of figures --- p.xvi / Contents --- p.xviii / Chapter 1. --- Introduction --- p.1 / Chapter 1.1. --- What are astrocytic tumors? --- p.1 / Chapter 1.1.1. --- Histological characteristics and classification --- p.2 / Chapter 1.1.2. --- Epidemiology --- p.2 / Chapter 1.1.3. --- Treatment and patient survival --- p.4 / Chapter 1.2. --- "Cytogenetics, molecular genetics and epigenetics of astrocytic tumors" --- p.6 / Chapter 1.2.1. --- Cytogenetics --- p.6 / Chapter 1.2.2. --- Genetic imbalances --- p.7 / Chapter 1.2.3. --- Tumor suppressor genes --- p.13 / Chapter 1.2.4. --- Oncogenes --- p.22 / Chapter 1.2.5. --- Primary and secondary GBMs --- p.26 / Chapter 1.3. --- Major pathways involved in astrocytic tumorigenesis --- p.30 / Chapter 1.3.1. --- Cell cycle dysregulation and suppression of apoptosis --- p.30 / Chapter 1.3.2. --- Promotion of proliferation and survival --- p.33 / Chapter 1.4. --- BRAF mutation in human cancers --- p.38 / Chapter 1.5. --- Other CNS tumors included in the current study --- p.52 / Chapter 2. --- Aims of study --- p.61 / Chapter 3. --- Materials and methods --- p.64 / Chapter 3.1. --- Clinical materials --- p.64 / Chapter 3.2. --- Cell lines --- p.75 / Chapter 3.3. --- Cell culture --- p.77 / Chapter 3.4. --- DNA extraction --- p.78 / Chapter 3.4.1. --- Pre-treatment of samples --- p.78 / Chapter 3.4.2. --- Cell lysis and protein removal --- p.80 / Chapter 3.4.3. --- Precipitation of DNA --- p.81 / Chapter 3.4.4. --- Determination of DNA concentration --- p.81 / Chapter 3.5. --- Mutation analysis of BRAF by cycle sequencing --- p.83 / Chapter 3.5.1. --- Amplification of BRAF exons --- p.83 / Chapter 3.5.2. --- Cycle sequencing and automated gel electrophoresis --- p.84 / Chapter 3.6. --- Immunohistochemistry of B-Raf and GFAP --- p.87 / Chapter 3.6.1. --- Pre-treatment of samples --- p.87 / Chapter 3.6.2. --- Detection of B-Raf and GFAP antigens by ABC method --- p.88 / Chapter 3.6.3. --- Controls --- p.90 / Chapter 3.7. --- Quantification of EGFR gene dosage by TaqMan based real-time PCR --- p.91 / Chapter 3.7.1. --- Preparation of gene constructs --- p.92 / Chapter 3.7.2. --- Primers and TaqMan probes --- p.93 / Chapter 3.7.3. --- Experimental condition and PCR program --- p.95 / Chapter 3.7.4. --- DNA standards --- p.95 / Chapter 3.7.5. --- Controls --- p.96 / Chapter 3.7.6. --- Experimental layout --- p.96 / Chapter 3.8. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.97 / Chapter 4. --- Results --- p.101 / Chapter 4.1. --- Mutation analysis of BRAF --- p.101 / Chapter 4.2. --- Immunohistochemistry of B-Raf protein --- p.107 / Chapter 4.3. --- Quantification of EGFR gene dosage --- p.117 / Chapter 4.4. --- Correlation between EGFR dosage and BRAF mutation --- p.128 / Chapter 4.5. --- Correlation between EGFR dosage and B-Raf expression --- p.129 / Chapter 4.6. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.131 / Chapter 5. --- Discussions --- p.149 / Chapter 5.1. --- BRAF mutations as common events in human cancers --- p.149 / Chapter 5.2. --- BRAF mutation in CNS tumor specimens --- p.150 / Chapter 5.2.1. --- Tumorigenic effect of the V599E substitution --- p.153 / Chapter 5.2.2. --- V599E B-Raf mutant activation independent of Ras activation --- p.155 / Chapter 5.2.3. --- Autocrine stimulation of Ras signaling in V599E B-Raf mutant --- p.156 / Chapter 5.3. --- BRAF expression in astrocytic tumors --- p.159 / Chapter 5.4. --- Mutually exclusive pattern between EGFR amplification and BRAF expression --- p.161 / Chapter 5.4.1. --- Similar effect of EGFR activation and B-Raf activation --- p.163 / Chapter 5.4.2. --- Mutual effects between Ras/Raf/Mek/Erk and Akt signaling --- p.164 / Chapter 5.5. --- Microsatellite analysis of chromosome 14q in human cancers --- p.167 / Chapter 5.6. --- Microsatellite analysis of chromosome 14q in astrocytic tumors --- p.170 / Chapter 5.6.1. --- Finer mapping of common regions of deletion --- p.170 / Chapter 5.6.2. --- Genes within the common regions of deletion --- p.173 / Chapter 5.6.3. --- Overlapping deletion regions in astrocytic and non-CNS tumors --- p.186 / Chapter 6. --- Further studies --- p.190 / Chapter 6.1. --- Role of BRAF alterations in astrocytic tumors --- p.190 / Chapter 6.2. --- B-Raf expression in astrocytic tumors and correlation with EGFR overexpression --- p.193 / Chapter 6.3. --- Microsatellite analysis of 14q in astrocytic tumors --- p.194 / Chapter 7. --- Conclusions --- p.195 / Chapter 8. --- References --- p.198