In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated ...events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1(high) tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E(high) tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E(high) tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1(high) and E(high) tumours. Using transfected cell lines overexpressing cyclin E, cyclin E(high) and D1(high) tumours were mimicked and the cyclin D1(high) cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E(high) cell lines obtained increased kinase activity without redirection of inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1(high) and cyclin E(high) tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer.
Telomere maintenance, important for long-term cell survival and malignant transformation, is directed by a multitude of factors, including epigenetic mechanisms, and has been implicated in outcomes ...for patients with leukemia. In the present study, the objective was to investigate the biological and clinical significance of telomere length and promoter methylation of the human telomerase reverse transcriptase gene in childhood acute lymphoblastic leukemia. A cohort of 169 childhood acute lymphoblastic leukemias was investigated for telomere length, human telomerase reverse transcriptase gene promoter methylation status, genomic aberrations, immunophenotype, and clinical outcomes. Methylation of the core promoter of the human telomerase reverse transcriptase ( hTERT ) gene was demonstrated in 24% of diagnostic samples, with a significant difference between B-cell precursor (n = 130) and T-cell acute lymphoblastic leukemia (ALL) (n = 17) cases (18% and 72%, respectively; p < 0.001). No remission sample demonstrated hTERT promoter methylation (n = 40). Within the B-cell precursor group, t(12;21)(p13;q22) ETV6/RUNX1 cases (n = 19) showed a much higher frequency of hTERT methylation than high-hyperdiploid (51−61 chromosomes) ALL (n = 44) (63% and 7%, respectively; p < 0.001). hTERT messenger RNA levels were negatively associated with methylation status and, in the t(12;21) group, methylated cases had shorter telomeres ( p = 0.017). In low-risk B-cell precursor patients (n = 101), long telomeres indicated a worse prognosis. The collected data from the present study indicate that the telomere biology in childhood ALL has clinical implications and reflects molecular differences between diverse ALL subgroups.
South Australia is a small economy that faces a fundamental need to re-shape its approach to innovation. The manufacturing sector, as the backbone of the state’s economy, has and will continue to ...change in its nature and form. This necessitates a re-think about how innovation happens and how the respective actors within an economy interact and engage with each other. In effect, innovation relies on intersections between people, knowledge, information sharing, ideas, financial and other resources. Innovation happens through regional social and economic system dynamics; innovation relies on a system view of entrepreneurship. Entrepreneurship can be taken as a study of the entrepreneur and new business creation. However, this conception of entrepreneurship misses the critical link to economic outcomes; the ebb and flow of social and economic fortunes that are underpinned by the actions, reactions and engagement of individuals in a specific social and economic system that brings about innovation and change. In this book the authors are exploring how the linkages within the system can be conceptualised and made transparent.
Telomeres are repeated sequences (the hexanucleotide TTAGGG in vertebrates) located at chromosome ends of eukaryotes, protecting DNA from end joining or degradation. Telomeres become shorter with ...each cell cycle, but telomerase, a ribonucleoprotein complex, alleviates this attrition. The telomerase RNA component (TERC) is an essential element of telomerase, serving as a template for telomere elongation. The H/ACA domain of TERC is indispensable for telomere biogenesis. Mutations in the telomerase components allow accelerated telomere loss, resulting in various disease manifestations, including bone marrow failure. To date, this is the first detailed report of an H-box mutation in TERC that is related to human disease.
A 26-year-old man with myelodysplastic syndrome (MDS) had very short telomeres. Sequencing identified a single heterozygous mutation in the H box of the patient's TERC gene. The same mutation was also present in his father and his son, demonstrating that it was germline in origin. The telomere length in the father's blood was shorter compared to age-matched healthy controls, while it was normal in the son and also in the sperm cells of the patient. In vitro experiments suggested that the mutation was responsible for the telomere shortening in the patient's leukocytes and contributed to the pathogenesis of bone marrow failure in our patient.
We analyzed a mutation (A377G) in the H box of TERC in a young MDS patient who had significantly short-for-age telomeres. As telomeres protect chromosomes from instability, it is highly plausible that this genetic lesion was responsible for the patient's hematological manifestations, including marrow failure and aneuploidy in the hematopoietic stem cell compartment.
Previous studies indicate that the inflammatory response in diffuse large B‐cell lymphomas (DLBCL) is important for the clinical outcome. Mast cells are key regulators in this response; we ...investigated whether the number of tryptase‐positive mast cells is correlated with clinical outcome. Patients with many mast cells had a significantly better event‐free survival (EFS) compared to those with few mast cells (P < 0·03 in both germinal centre (GC) and non‐GC DLBCL. This supports the idea that the infiltration of mast cells is a reflection of the host inflammatory response and is related to a favourable outcome.
Abstract Telomeres are essential structures for maintaining chromosomal stability and their length has been reported to correlate with cancer risk and clinical outcome. Single nucleotide ...polymorphisms (SNPs) in genes encoding telomere-associated proteins could affect telomere length and chromosomal stability by influencing gene expression or protein configuration in the telomeres. Here, we report the results of the first association study on genetic variation in telomere-associated genes and their effect on telomere length, breast cancer (BC) susceptibility and prognosis. We genotyped 14 potentially functional and most informative SNPs in nine telomere-associated genes ( TERT , TEP1 , TERF1 , TERF2 , TERF2IP , ACD , POT1 , TNKS and TNKS2 ) in 782 incident BC cases and 1559 matched controls. Relative telomere length (RTL) varied statistically significantly between the genotypes of the SNPs rs446977 ( TEP1 , p = 0.04), rs938886 ( TEP1 , p = 0.04) and rs6990097 ( TNKS , p = 0.04). However, none of them was associated with BC susceptibility and only rs6990097 correlated with regional lymph node metastasis (odds ratio (OR) 1.38, 95% confidence interval (CI) 1.08–1.77). The strongest association with BC susceptibility was observed for rs3785074 ( TERF2 , OR 0.51, 95% CI 0.31–0.83) and rs10509637 ( TNKS2 , OR 1.33, 95% CI 1.08–1.62). Haplotype and diplotype analysis confirmed the association of the TNKS2 gene with BC susceptibility. rs3785074 ( TERF2 ) was additionally associated with histologic grade (OR 1.44, 95% CI 1.08–1.92) and negative oestrogen receptor status (OR 2.93, 95% CI 1.13–7.58). None of the SNPs showed a significant correlation with survival of the breast cancer patients. With these results, none of the SNPs represents any valuable prognostic marker for BC.
Anaplastic Lymphoma Kinase (ALK), a receptor tyrosine kinase, was first described as the fusion product causing a subtype of non-Hodgkin's lymphoma. To date
Alk has been reported to be mainly ...expressed in CNS and other parts of the brain. Here we describe an extensive characterization of the mRNA and protein expression of ALK during mouse development. We show that mRNA and ALK protein show overlapping expressing patterns in specific regions of the central and the peripheral nervous systems. Furthermore, ALK is also expressed in the eye, nasal epithelium, olfactory nerve, tongue, skin, tissue surrounding the esophagus, stomach and midgut but not the hindgut. Expression of ALK is also found in testis and ovary.
The reasons for the positive association between skin cancer and non-Hodgkin's lymphoma are not known but may be due to common
susceptibility involving suboptimal DNA repair. Therefore, we ...investigated selected polymorphisms and haplotypes in three
DNA repair genes, previously associated with skin cancer and DNA repair capacity, in risk of follicular lymphoma, including
possible gene interaction with cigarette smoking and sun exposure. We genotyped 19 single nucleotide polymorphisms (SNP) in
the ERCC2, XRCC1 , and XRCC3 genes in 430 follicular lymphoma patients and 605 controls within a population-based case-control study in Denmark and Sweden.
Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression and haplotype
associations were assessed with a global score test. We observed no associations between variation in the ERCC2 and XRCC1 genes and follicular lymphoma risk. In XRCC3, increased risk of follicular lymphoma was suggested for rare homozygotes of
three SNPs Rs3212024: OR, 1.8 (95% CI, 1.1-2.8); Rs3212038: OR, 1.5 (95% CI, 1.0-2.4); Rs3212090: OR, 1.5 (95% CI, 1.0-2.5).
These results were strengthened in current cigarette smokers. However, evidence of differences in XRCC3 haplotype distributions between follicular lymphoma cases and controls was weak, both overall and in current smokers. We
conclude that polymorphic variation in the XRCC3 gene, but not in ERCC2 or XRCC1 , may be of importance for susceptibility to follicular lymphoma, perhaps primarily in current smokers. The link between skin
cancer and follicular lymphoma is unlikely to be mediated through common variation in the studied DNA repair gene polymorphisms.
(Cancer Epidemiol Biomarkers Prev 2006;15(2)–65)
This article uses the intellectual capital-based view of the firm, to draw conclusions about both the change in relative importance of resources and the change in relative influence of ...transformations in the firm's resource transformation system when introducing digital technologies.
The methodology is a synthesis of research conducted on the implications of digital technologies for the firm's value creation, through a review of the literature, combined with two case studies.
The findings are that when introducing digital technologies, firms will migrate towards a value network logic. There will also be an increasing value creating influence of transformations into and out of the organisational resource category, and there will be an increase in the number of possible revenue streams that can be created.
A clear practical implication for managers from this increased complexity is the need to simulate potential new resource deployment systems to verify their effectiveness before implementing them.
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