| 1. |
- Molassiotis, Alexander, et al.
(author)
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Complementary and alternative medicine use in patients with haematological malignancies in Europe
- 2005
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In: Complementary Therapies in Clinical Practice. - : Elsevier. - 1744-3881 .- 1873-6947. ; 11:2, s. 105-110
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Journal article (peer-reviewed)abstract
- This study reports upon a descriptive cross-sectional survey assessing the use of complementary and alternative medicine (CAM) in patients with haematological cancers. Twelve European countries contributed data from patients with haematological cancers, as part of a larger study. Sixty-eight patients with haematological cancer participated. Among the participants, 26.5% used some form of CAM after the cancer diagnosis. The most common therapies used were homeopathy (38.9%), herbal medicine (22.2%) various psychic therapies, such as use of mediums, healers, rebirthing or past life regression therapy (22.2%). A particular profile of a CAM user was not evident in the sample. Moderate levels of satisfaction with CAM were reported. Patients commonly used CAM to increase the ability of their body to fight cancer and to improve physical and emotional well-being. Information about CAM was received mainly from friends or family. As CAM use in patients with haematological malignancies is common, clinicians should assist patients who want to use CAM to make an appropriate decision, and improve communication with them about CAM use in an open and non-judgemental dialogue. © 2005 Elsevier Ltd. All rights reserved.
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| 2. |
- Bergman, Annika, et al.
(author)
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A high frequency of germline BRCA1/2 mutations in western Sweden detected with complementary screening techniques
- 2005
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In: Familial Cancer. - : Springer. - 1389-9600 .- 1573-7292. ; 4:2, s. 89-96
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Journal article (peer-reviewed)abstract
- Dominant inheritance is presumed in 6-10% of breast and ovarian cancers. Mutations in BRCA1 and BRCA2 genes are the most commonly identified causative genes in such families. The frequency of mutation carriers with breast/ovarian cancer depends on the population studied, and display considerable variation that coincides with ethnic and geographical diversity. Mutation analyses were performed in 143 families registered at the Cancer Genetic Counseling Clinic of western Sweden. In a thorough mutation screening procedure, the entire BRCA1 and BRCA2 genes were analyzed using a combination of complementary mutation detection techniques. Mutations in either BRCA1 or BRCA2 were detected in 36% (52 out of 143) of all screened families. All families were clinically evaluated regarding age at diagnosis, type of cancer and number of cancer cases in the family. Among high-risk families, the mutation detection rate was 39% (46 out of 117). The detection rate observed among families with cases of ovarian cancer (42 out of 62, 68%), was substantially higher than in families with only breast cancer (10 out of 81, 12%). Age at ovarian cancer did not seem to have an effect on the detection rate. The analyses revealed 11 frameshift mutations, 4 nonsense mutations and 2 large deletions. Notably, the BRCA1 c.3171ins5 mutation accounted for 34 of 52 (65%) identified mutations. Seven mutations are novel: BRCA1c.409_410del; c.1912T>G; c.2228_2229del; c.3029delA; c.3433delA, a large deletion covering exons 1-3 of BRCA1and one BRCA2 mutation; BRCA2c.6287_6290del. We have shown that the founder mutation BRCA1 c.3171ins5 has a great influence on western Swedish breast/ovarian cancer families along with a high number of mutations unique for the region. In order to achieve a high mutation detection rate we suggest a combination of several detection techniques.
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| 3. |
- Ericson Lindquist, Kajsa
(author)
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Tumors associated with Hereditary Nonpolyposis Colorectal Cancer: Defective Mismatch Repair and Familial Risk of Cancer
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Inactivation of the DNA mismatch repair (MMR) system is a tumorigenic mechanism involved in 15-20% of tumor types such as colorectal and endometrial cancer and is specifically associated with the Hereditary Nonpolyposis Colorectal Cancer (HNPCC) syndrome. These MMR defective tumors are characterized by microsatellite instability (MSI), a phenomenon that reflects alterations in length of repeated sequences, and 90% of MSI tumors show loss of immunohistochemical expression for the MMR protein affected. HNPCC yields an increased risk for several tumor types; cancer of the colorectum (80-90% lifetime risk), endometrium (40-60%), ovary (5-15%), stomach (5-15%), urinary tract, small bowel, skin, and brain. The syndrome is characterized by an early age (mean 45 years) at diagnosis and one third of the patients develop metachronous tumors. The major aims of this thesis were to assess the contribution of defective MMR to the development of the more rare tumor types associated with HNPCC and to assess cancer risks in children whose parents had developed HNPCC-associated tumors. In study I, patients who developed multiple (at least 4) primary tumors, including two colorectal cancers, were assessed for MSI and immunohistochemical expression of the MMR proteins MLH1 and MSH2. MSI was identified in 63/154 (40%) tumors, 55 of which also showed immunohistochemical loss of MMR protein expression. A concordant finding of MSI and loss of the same MMR protein, which strongly suggest HNPCC, was found in 17/45 (38%) patients, which suggests that a high fraction of such multiple tumors are caused by HNPCC. In studies II and III, the frequency of defective MMR was studied in adenocarcinomas of the small intestine and in upper urinary tract cancers (UUC). MSI was detected in 16/89 (18%) of cancers of the small intestine and in 9/194 (4%) UUC. MMR protein expression loss affected 11 cancers of the small intestine and 11 UUC. Malignant fibrous histiocytoma (MFH) represents one of the largest subsets of soft tissue sarcomas, and occasional MFHs have been described in HNPCC-families. In study IV, we assessed MMR expression in a series of 209 MFH and found loss of MSH2 and MSH6 in 2 MFH. Study V is based on the national Swedish cancer registry and analyses familial risk of HNPCC-associated tumors. Cancer risks were calculated in 204 358 offspring whose 102 814 parents had developed HNPCC-associated cancer and the risks were correlated to the age of the parent, metachronous tumors in the parent, and presence of several HNPCC-associated cancers in the family. Significantly increased risks were observed for several tumor types, including colon cancer, rectal cancer, endometrial cancer, gastric cancer, and ovarian cancer. The highest offspring risks were observed in the subgroup with multiple HNPCC-associated cancers in the parent. In summary, we have demonstrated that MMR defects are common in patients who develop multiple primary tumors, occur at similar frequencies in cancers of the small intestine and the colon, contribute to development of UUC and MFH at low frequencies, and that HNPCC-associated tumor in a parent confer an increased risk of several cancer types in the offspring, especially if the parent developed more than one cancer or cancer at a young age.
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| 4. |
- Gruvberger, Sofia
(author)
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Estrogen receptor alpha and beta in breast cancer - gene expression profiles and clinical implications
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Breast cancer is the most common malignancy in women in the Western world with about 10% of women developing breast cancer during their lifetime, of which one third will eventually succumb to the metastatic form of the disease. Breast cancer arises from the epithelial cells of the breast mammary gland, but the mechanisms involved in tumor initiation, progression, and metastasis are still not fully understood. However, estrogen and its receptors are believed to play a crucial role in these events. Estrogen receptor alpha (ERalpha) has long been identified as a target for treatment and numerous studies have shown that patients expressing ERalpha are more likely to respond to endocrine therapy such as tamoxifen; however a significant fraction become resistant. Little is known of the role of the second estrogen receptor, estrogen receptor beta (ERbeta), in breast tumor biology and therapy response. This thesis is primarily concerned with investigating the global differences in gene expression between tumors that express and do not express ERalpha and/or ERbeta, and the relationship of such profiles to outcome in the setting of tamoxifen therapy. The present study shows that ERalpha status in primary breast tumor biopsies is associated with a very distinct gene expression profile, as determined by cDNA microarrays, involving a large number of genes (Papers I and III). Only a small fraction of these ERalpha-associated genes have previously been identified as estrogen-responsive in cell culture (Paper I). In addition, not only is the ERalpha status as a binary variable encoded in the gene expression profiles, but also the actual level of protein content can be predicted, as well as the percent cells in the DNA synthesis phase of the cell cycle and other prognostic markers (Paper III). However, predicting response to tamoxifen using gene expression profiles from primary breast tumors was not possible in a cohort of 44 patient with varying ERalpha status and clinical outcome (Paper II). Additionally, a previously published prognosis predictor did not have any prognostic significance in this data, suggesting that different data sets and various tumor/patient/treatment characteristics selected influence the success of an array-based predictor for prognosis (Paper II). Much less is known about the transactivating properties of ERbeta and its relationship to ERalpha and tamoxifen response. Herein, the ERbeta protein is shown to have prognostic value after adjuvant tamoxifen therapy in a large patient set (n=353; Paper IV). However, subgroup analysis shows the effect to be only significant in patients with tumors lacking ERalpha. From cDNA microarray analysis of a subset of these tumors, an ERbeta-associated gene expression profile could be generated from the ERalpha negative group of tumors but not for the ERalpha positive group, further corroborating the notion that ERbeta selectively influences the biological processes in tumors lacking ERalpha (Paper IV). These results suggest that the small subset of ERalpha negative tumors responding to tamoxifen may be explained by the presence of ERbeta, and that ERbeta is not a surrogate marker for ERalpha but is associated with its own biological processes and may respond to tamoxifen via different target genes. In conclusion, together these studies have added to our understanding of the importance of estrogen receptor status and their biological consequences in breast cancer.
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| 5. |
- Schultz, Anna
(author)
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Localisation of Protein Kinase C in Apoptosis and Neurite Outgrowth
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Protein kinase C (PKC) is a family of serine/threonine kinases, which are subgrouped into classical (a, bI, bII, g), novel (d, e, h, q) and atypical (z, i/l) isoforms. One major aim of this thesis work was to investigate if altered levels of PKC isoforms influence the apoptotic responses of malignant cell-lines. We show that overexpression of PKCd or PKCq renders SK-N-BE(2) neuroblastoma cells sensitive to apoptosis induced by phorbol esters or C2-ceramide. Moreover, overexpression of PKCa, PKCd or PKCe sensitises both androgen-dependent and androgen-independent prostate cancer cells to phorbol ester-induced cell-death. The apoptotic effects of PKCd and PKCq in neuroblastoma cells are independent on the catalytic activity of the enzymes and the isolated regulatory domain (RD) of PKCq induces apoptosis in neuroblastoma cells. Induction of apoptosis depends on the localisation of PKCqRD to the Golgi complex, which is mediated by the C1b domain of the protein. Mutation of a single amino acid residue, Met-267 in PKCqC1b, blocks both the Golgi localisation and the apoptotic effect of the PKCqRD. Previous studies have shown that PKCe induces neurites in neuroblastoma cells. Here we report that treatment with cell-permeable C2-ceramide inhibits PKCe-induced neurite formation, conceivably by relocating the protein from the cytosol to the perinuclear region. Mutation of Asp-257 and Met-278 (the latter corresponding to Met-267 in PKCq) in PKCe blocks the C2-ceramide induced translocation of PKCe. Furthermore, the mutated variant of PKCe still induces neurites after C2-ceramide treatment. Thus, the specific subcellular localisation of PKCq and PKCe are important for their biological activities.
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| 6. |
- Vallon-Christersson, Johan
(author)
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Functional and Molecular Characterization of BRCA1 and BRCA2 Associated Breast Cancer
- 2005
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Doctoral thesis (other academic/artistic)abstract
- This doctoral dissertation is based on five appended papers primarily concerned with three main topics, namely: the functional characterization of specific and clinically relevant perturbations found in BRCA1 ? one of the major breast cancer susceptibility genes; the use of microarray technologies for molecular characterization of hereditary breast tumor samples from a genomic perspective; and finally, the development of software to address some of the logistical problems of data analysis and management that arise when utilizing microarrays. Results obtained from the work presented herein demonstrate the following: that transcription az says can aid in the characterization of C-terminal missense mutations but that it may not be possible to unambiguously characterize variants with a yeast-based assay alone; that a naturally occurring C-terminal germline mutation in BRCA1 encodes a protein with apparent temperature-dependant functional properties; that open-source software can provide comprehensive solutions to meet data management needs of microarray experimenters; that BRCA1 and BRCA2 associated breast tumors exhibit markedly different copy number aberrations when compared to each other as well as to sporadic tumors; and that gene expression profiling in BRCA1 and BRCA2 associated breast tumors reveals specific gene expression patterns.
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| 7. |
- Jestin, Pia, et al.
(author)
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Emergency surgery for colonic cancer in a defined population
- 2005
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In: British Journal of Surgery. - : Oxford University Press (OUP). - 0007-1323 .- 1365-2168. ; 92:1, s. 94-100
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Journal article (peer-reviewed)abstract
- BACKGROUND: The aim of this study was to identify risk factors in emergency surgery for colonic cancer in a large population and to investigate the economic impact of such surgery. METHODS: Data from the colonic cancer registry (1997-2001) of the Uppsala/Orebro Regional Oncological Centre were analysed and classified by hospital category. Some 3259 patients were included; 806 had an emergency and 2453 an elective procedure. Data for calculating effects on health economy were derived from a national case-costing register. RESULTS: Patients who had emergency surgery had more advanced tumours and a lower survival rate than those who had an elective procedure (5-year survival rate 29.8 versus 52.4 per cent; P < 0.001). There was a stage-specific difference in survival, with poorer survival both for patients with stage I and II tumours and for those with stage III tumours after emergency compared with elective surgery (P < 0.001). Emergency surgery was associated with a longer hospital stay (mean 18.0 versus 10.0 days; P < 0.001) and higher costs (relative cost 1.5 (95 per cent confidence interval 1.4 to 1.6)) compared with elective surgery. The duration of hospital stay was the strongest determinant of cost (r(2) = 0.52, P < 0.001). CONCLUSION: Emergency surgery for colonic cancer is associated with a stage-specific increase in mortality rate.
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| 8. |
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| 9. |
- Sandgren, Staffan
(author)
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REGULATED UPTAKE OF BIOPOLYMERS Role of cell surface proteoglycans Implications for drug and gene delivery
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Cells continuously export, import, and recycle molecules over the plasma membrane. Internalization, i.e. cellular import of extracellular material, is a fundamental process, which provides cells with nutrients and enables the immune cells of higher organisms to remove debris, sample their surroundings for antigens and to fight microbes. Moreover, internalization regulates complex cellular signalling events involved in cellular division, motion, and communication with the surrounding extracellular matrix. However, the preserved routes of internalization are exploited by a large number of microbes and pathological factors such as bacterial toxins and viral proteins. The HIV-1 TAT protein was shown to enter cells and to target their nuclei, thus acting as a paracrine transcription factor, a finding that initiated the field of so called cell penetrating peptides (CPPs). Due to their ability to efficiently deliver macromolecular cargo over the plasma membrane, CPPs have proven to be useful tools in basic research. More importantly, the technology has been shown to enhance delivery of a number of macromolecular compounds in vivo, including anticancer drugs. The proteoglycan family of molecules has previously been shown to participate in the interaction with and internalization of a number of ligands, including polyamines, growth factors, morphogens, and microbes. This thesis deals with the role of proteoglycans in cellular internalization of charged biopolymers, i.e. the polyamine family of growth factors, HIV-Tat peptide, antimicrobial peptides, and nucleic acids. The presented findings bring proteoglycans into focus as a general internalization pathway for charged macromolecules, with implications for drug and gene delivery.
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| 10. |
- Stockhausen, Marie
(author)
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Notch Signaling in Human Neuroblastoma Cells
- 2005
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Doctoral thesis (other academic/artistic)abstract
- Neuroblastoma is a childhood tumor derived from the sympathetic nervous system (SNS). It is believed that the tumors arise from cells halted in their differentiation and due to their immature phenotype; they express proteins normally only detected during embryogenesis. One such protein is Hash-1, which is required for formation of the SNS. Hash-1 is a component of the Notch signaling cascade, which is involved in many cell fate decisions. In general, Notch activity maintains a pool of undifferentiated cells and dysregulated Notch signaling has been linked to development of several cancers. It has been shown that the Notch cascade is transiently induced during neuroblastoma cell differentiation in vitro and that persistent Notch expression inhibits this differentiation. These observations imply a role for Notch signaling in the blocked differentiation of neuroblastoma cells. In addition, neuroblastoma cells exposed to hypoxia, a common event of solid tumors, dedifferentiate. During this process, components of the Notch signaling cascade are up regulated. In this thesis we show that Hash-1 interacts with ubiquilin-1, a protein involved in protecting proteins from degradation. In addition, we show that valproic acid (VPA) induces differentiation of neuroblastoma cells by modulation of the Notch signaling cascade. Aberrant signaling through the EGF receptor is involved in the genesis of some human cancers. Several reports have shown cross talk between EGFR signaling and the Notch cascade. We show here that the Notch target Hes-1 can be directly regulated by Ras/MAPK signaling at both normoxia and hypoxia, without the activation of Notch receptors.
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