| 71. |
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| 72. |
- Gruvberger, Sofia, et al.
(författare)
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Estrogen receptor status in breast cancer is associated with remarkably distinct gene expression patterns
- 2001
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Ingår i: Cancer Research. - 1538-7445. ; 61:16, s. 5979-5984
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Tidskriftsartikel (refereegranskat)abstract
- To investigate the phenotype associated with estrogen receptor alpha (ER) expression in breast carcinoma, gene expression profiles of 58 node-negative breast carcinomas discordant for ER status were determined using DNA microarray technology. Using artificial neural networks as well as standard hierarchical clustering techniques, the tumors could be classified according to ER status, and a list of genes which discriminate tumors according to ER status was generated. The artificial neural networks could accurately predict ER status even when excluding top discriminator genes, including ER itself. By reference to the serial analysis of gene expression database, we found that only a small proportion of the 100 most important ER discriminator genes were also regulated by estradiol in MCF-7 cells. The results provide evidence that ER+ and ER- tumors display remarkably different gene-expression phenotypes not solely explained by differences in estrogen responsiveness.
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| 73. |
- Grynfeld, Anna
(författare)
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bHLH transcription factors in differentiating neuroblastoma cells
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Neuroblastoma is a tumor of the sympathetic nervous system, and arises during early childhood. The tumor is highly heterogeneous and evidence, such as expression of genes normally only expressed during embryonic and fetal stages, suggests that the tumor is of embryonic origin and that the tumor arises as a consequence of perturbed differentiation during the development of the sympathetic nervous system. Transcription factors implicated in this differentiation program are therefore of potential interest in order to understand the genesis of neuroblastoma. Based on findings in Drosophila, several transcription factors playing vital roles in the development of the vertebrate peripheral nervous system have been identified, some of them belonging to the basic helix-loop-helix (bHLH) family. Amplification of the protooncogene N-Myc is one of the most important genetic aberrations in neuroblastoma. There is a high positive correlation between N-Myc amplification and malignancy, but the molecular consequences of this phenomenon have only been partly investigated. The work presented here describes the roles of the bHLH transcription factors HASH-1, HES-1, and the bHLHZip transcription factors N-Myc, Mad proteins, Mnt/Rox, and Max during neuroblastoma cell differentiation. It suggests that a controlled temporal expression patterns of some of these genes are important in order to allow neuronal differentiation to proceed.
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| 74. |
- Grönberg, Henrik, et al.
(författare)
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BRCA2 mutation in a family with hereditary prostate cancer
- 2001
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Ingår i: Genes, Chromosomes and Cancer. - 1045-2257. ; 30:3, s. 299-301
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary prostate cancer is a genetically heterogeneous disease, and so far four different susceptibility loci have been identified. Reports of associated cancers are few, and it is generally considered a sire-specific disease. However, some reports have shown an elevated risk for prostate cancer among BRCA2 mutation carriers. In this report, we present a family in which the father and four of his sons were diagnosed with prostate cancer at exceptionally early ages (51, 52, 56, 58, and 63 years, respectively). In addition, three daughters were diagnosed with breast cancer between the ages of 47 and 61. In this family, a truncating mutation in exon 11, 6051delA of the BRCA2 gene, leading to an early termination of the protein (codon 1962), was identified. Although BRCA2 is probably responsible only for a very small fraction of hereditary prostate cancers, this finding supports previous reports of an increased risk of prostate cancer in BRCA2 mutation carriers.
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| 75. |
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| 76. |
- Guzhova, Irina, et al.
(författare)
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Interferon-gamma cooperates with retinoic acid and phorbol ester to induce differentiation and growth inhibition of human neuroblastoma cells
- 2001
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 94:1, s. 97-108
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Tidskriftsartikel (refereegranskat)abstract
- The prognosis of patients with advanced stages of neuroblastoma with N-myc amplification remains poor despite escalated therapy, a situation that has called for alternative therapeutic approaches. Neuroblastoma cells, which represent immature peripheral neuronal cells, treated with certain physiologic and nonphysiologic agents such as retinoic acid (RA), phorbol esters and interferons (IFN) in vitro undergo cellular differentiation and stop to divide, a process that mimics normal neuronal development. Such "differentiation therapy" using RA after autologous bone marrow transplantation has recently given encouraging results in neuroblastoma patients with advanced disease. Considering approaches for improved differentiation therapy, we investigated possible synergistic effects of combining agents known to influence neuroblastoma growth and differentiation in vitro. Our results show that combined treatment with IFN-gamma and RA or the phorbol ester 12-O-tetradecanoyl-phorbol acetate (TPA) had synergistic or enhancing effects on morphologic differentiation and neurite outgrowth in 5 of 5 neuroblastoma cell lines, 3 of which expressed very high levels of N-myc mRNA due to N-myc amplification. The combinations RA+IFN-gamma or TPA+IFN-gamma also enhanced induced growth inhibition in all 5 cell lines, in several cases resulting in complete growth arrest under conditions where cells stimulated with either agent alone continued to grow. The phenotypic effects of the combined RA+IFN-gamma or TPA+IFN-gamma treatments were in most, but not all, investigated cases accompanied by moderate reductions in N-myc expression, suggesting that the cooperative signals may counteract N-Myc activity at several levels. The cooperativity between IFN-gamma and other differentiation signals may be relevant for approaches to improve the therapy for high-risk neuroblastoma with N-myc-amplification.
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| 77. |
- Hammerlid, Eva, 1957, et al.
(författare)
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Health-related quality of life three years after diagnosis of head and neck cancer : A longitudinal study
- 2001
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Ingår i: Head and Neck-Journal for the Sciences and Specialties of the Head and Neck. - 1043-3074. ; 23:2, s. 113-125
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Tidskriftsartikel (refereegranskat)abstract
- Purpose. To examine health-related quality of life (HRQL) of all head and neck cancer patients from diagnosis until 3 years later and to analyze its dependence on tumor site and other patient characteristics. Subjects and Methods. Two hundred thirty-two patients (mean age 61 years; 70% men) were included and followed with clinical measures and mailed standardized HRQL questionnaires (The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core-80 (EORTC QLQ-C30), the EORTC QLQ-Head and Neck Cancer module (QLQ-H&N35), and the Hospital Anxiety and Depression Scale (HADS). Results. After 3 years 66 % of the patients were alive and 88 % of these completed the study. The HRQL was worse during treatment and returned slowly thereafter to pretreatment values with few exceptions. After 3 years the best improvement was found for mental distress, followed by a significant global quality of life improvement and reduced pain compared with diagnosis. A significant deterioration was found for problems with dry mouth, senses, and teeth, as well as for opening the mouth wide tie, they seemed to be related to the treatment given). There were few significant improvements between the 1- and 3-year follow-ups. Depression and physical functioning at diagnosis were independent predictors for global quality of life at 3 years. Patients who died during the study had a worse HRQL at diagnosis compared with patients completing the study. Patients with advanced disease (stage III + IV) scored worse than patients with small tumors for most of the HRQL domains. These differences increased over time. Few differences were found relating to gender and age. The pharyngeal cancer group scored worse compared with the other tumor sites, and these patients would probably benefit from a rehabilitation program right from diagnosis, including treatment for malnutrition and pain. Conclusions. The largest HRQL changes for head and neck cancer patients are seen within the first year after diagnosis, with a significant deterioration just after finishing treatment. Thereafter, most of the variables return to pretreatment values. The significant problems with dry mouth, senses, and teeth after treatment are constant over time. (C) 2001 John Wiley & Sons, Inc.
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| 78. |
- Hashemi, J, et al.
(författare)
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Haplotype analysis and age estimation of the 113insR CDKN2A founder mutation in Swedish melanoma families.
- 2001
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Ingår i: Genes, chromosomes & cancer. - : Wiley. - 1045-2257 .- 1098-2264. ; 31:2, s. 107-16
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in the CDKN2A tumor suppressor gene located on 9p21 have been linked to development of melanomas in some families. A germline 3-bp insertion in exon 2 of CDKN2A, leading to an extra arginine at codon 113 (113insR), has been identified in 17 Swedish melanoma families. Analysis of 10 microsatellite markers, spanning approximately 1 Mbp in the 9p21 region, showed that all families share a common allele for at least one of the markers closest to the CDKN2A gene, suggesting that the 113insR mutation is an ancestral founder mutation. Differences in the segregating haplotypes, due to meiotic recombinations and/or mutations in the short-tandem-repeat markers, were analyzed further to estimate the age of the mutation. Statistical analysis using a maximum likelihood approach indicated that the mutation arose 98 generations (90% confidence interval: 52-167 generations), or approximately 2,000 years, ago. Thus, 113insR would be expected to have a more widespread geographic distribution in European and North American regions with ancestral connections to Sweden. Alternatively, CDKN2A may lie in a recombination hot spot region, as suggested by the many meiotic recombinations in this narrow approximately 1-cM region on 9p21.
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| 79. |
- Hedenfalk, I, et al.
(författare)
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Gene-expression profiles in hereditary breast cancer
- 2001
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Ingår i: New England Journal of Medicine. - 0028-4793. ; 344:8, s. 48-539
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Many cases of hereditary breast cancer are due to mutations in either the BRCA1 or the BRCA2 gene. The histopathological changes in these cancers are often characteristic of the mutant gene. We hypothesized that the genes expressed by these two types of tumors are also distinctive, perhaps allowing us to identify cases of hereditary breast cancer on the basis of gene-expression profiles.METHODS: RNA from samples of primary tumor from seven carriers of the BRCA1 mutation, seven carriers of the BRCA2 mutation, and seven patients with sporadic cases of breast cancer was compared with a microarray of 6512 complementary DNA clones of 5361 genes. Statistical analyses were used to identify a set of genes that could distinguish the BRCA1 genotype from the BRCA2 genotype.RESULTS: Permutation analysis of multivariate classification functions established that the gene-expression profiles of tumors with BRCA1 mutations, tumors with BRCA2 mutations, and sporadic tumors differed significantly from each other. An analysis of variance between the levels of gene expression and the genotype of the samples identified 176 genes that were differentially expressed in tumors with BRCA1 mutations and tumors with BRCA2 mutations. Given the known properties of some of the genes in this panel, our findings indicate that there are functional differences between breast tumors with BRCA1 mutations and those with BRCA2 mutations.CONCLUSIONS: Significantly different groups of genes are expressed by breast cancers with BRCA1 mutations and breast cancers with BRCA2 mutations. Our results suggest that a heritable mutation influences the gene-expression profile of the cancer.
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| 80. |
- Hegardt, Cecilia, et al.
(författare)
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Different roles of spermine in glucocorticoid- and Fas-induced apoptosis
- 2001
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 1090-2422 .- 0014-4827. ; 266:2, s. 333-341
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Tidskriftsartikel (refereegranskat)abstract
- Two experimental systems representative of the mitochondrial and death receptor apoptotic pathways are the dexamethasone-induced programmed cell death in mouse thymocytes and the antibody-mediated cross-ligation of the Fas receptor in the human leukemic T-cell line Jurkat, respectively. In both cell systems, caspase-9, -8, and -3 were activated upon induction of apoptosis and a sub-G(1) peak appeared as a sign of ongoing DNA fragmentation. Addition of 1 mM spermine together with dexamethasone inhibited caspase activation and the appearance of the sub-G(1) peak in mouse thymocytes. In contrast, Fas-induced cell death was totally unaffected by spermine addition. Spermine addition significantly elevated the spermine concentration in both thymocytes and Jurkat cells. Thus, spermine per se did not inhibit the caspases but rather their activation. The fact that spermine inhibited caspase activation only in the thymocytes implies that spermine inhibited dexamethasone-induced apoptosis upstream of caspase-9 activation.
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