| 1. |
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| 2. |
- Jiang, Hai, et al.
(författare)
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The combined status of ATM and p53 link tumor development with therapeutic response
- 2009
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 23:16, s. 1895-1909
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Tidskriftsartikel (refereegranskat)abstract
- While the contribution of specific tumor suppressor networks to cancer development has been the subject of considerable recent study, it remains unclear how alterations in these networks are integrated to influence the response of tumors to anti-cancer treatments. Here, we show that mechanisms commonly used by tumors to bypass early neoplastic checkpoints ultimately determine chemotherapeutic response and generate tumor-specific vulnerabilities that can be exploited with targeted therapies. Specifically, evaluation of the combined status of ATM and p53, two commonly mutated tumor suppressor genes, can help to predict the clinical response to genotoxic chemotherapies. We show that in p53-deficient settings, suppression of ATM dramatically sensitizes tumors to DNA-damaging chemotherapy, whereas, conversely, in the presence of functional p53, suppression of ATM or its downstream target Chk2 actually protects tumors from being killed by genotoxic agents. Furthermore, ATM-deficient cancer cells display strong nononcogene addiction to DNA-PKcs for survival after DNA damage, such that suppression of DNA-PKcs in vivo resensitizes inherently chemoresistant ATM-deficient tumors to genotoxic chemotherapy. Thus, the specific set of alterations induced during tumor development plays a dominant role in determining both the tumor response to conventional chemotherapy and specific susceptibilities to targeted therapies in a given malignancy.
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| 3. |
- Blomqvist, Michael, et al.
(författare)
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Probing dark energy inhomogeneities with supernovae
- 2008
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Ingår i: Journal of Cosmology and Astroparticle Physics. - : IOP Publishing. - 1475-7516. ; 06, s. 027-
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Tidskriftsartikel (refereegranskat)abstract
- We discuss the possibility of identifying anisotropic and/or inhomogeneous cosmological models using type Ia supernova data. A search for correlations in current type Ia peak magnitudes over a large range of angular scales yields a null result. However, the same analysis limited to supernovae at low redshift shows a feeble anticorrelation at the 2σ level at angular scales θ≈40°. Upcoming data from, e.g., the SNLS (Supernova Legacy Survey) and the SDSS-II (SDSS: Sloan Digital Sky Survey) supernova searches will improve our limits on the size of—or possibly detect—possible correlations also at high redshift at the per cent level in the near future. With data from the proposed SNAP (SuperNova Acceleration Probe) satellite, we will be able to detect the induced correlations from gravitational lensing on type Ia peak magnitudes on scales less than a degree.
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| 4. |
- Blomqvist, Ulf, et al.
(författare)
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DRM – Intrusion or Solution?
- 2005
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Ingår i: Innovation and the knowledge economy. - Amsterdam : IOS Press. ; , s. 925-933
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Konferensbidrag (refereegranskat)abstract
- DRM could be the solution to the content industry’s P2P dilemma, but content owners’ desire to monitor and control the consumer’s use of content can be perceived as an intrusion of privacy. High control makes consumers less active and low control invites them to experiment and to gain experience. Digital music files can easily be spread. Therefore legal services prefer keeping control over the music. This study reveals that consumers are one step ahead of the content industry, finding ways to circumvent protection and laws, and that the music industry is awaiting the "right" DRM business model. Online Music sellers basically rely on B2C DRM business models, but attempts have been made with C2C models, using consumers as distributors, and ISP models, where ISPs pay to collecting societies for all file trans-fers of copyrighted material in their networks. Future models include licensing mod-els, micro models, and no copyright at all.
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| 5. |
- Cox, Angela, et al.
(författare)
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A common coding variant in CASP8 is associated with breast cancer risk
- 2007
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 39:3, s. 352-358
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Tidskriftsartikel (refereegranskat)abstract
- The Breast Cancer Association Consortium (BCAC) has been established to conduct combined case-control analyses with augmented statistical power to try to confirm putative genetic associations with breast cancer. We genotyped nine SNPs for which there was some prior evidence of an association with breast cancer: CASP8 D302H (rs1045485), IGFBP3 -202 C --> A (rs2854744), SOD2 V16A (rs1799725), TGFB1 L10P (rs1982073), ATM S49C (rs1800054), ADH1B 3' UTR A --> G (rs1042026), CDKN1A S31R (rs1801270), ICAM5 V301I (rs1056538) and NUMA1 A794G (rs3750913). We included data from 9-15 studies, comprising 11,391-18,290 cases and 14,753-22,670 controls. We found evidence of an association with breast cancer for CASP8 D302H (with odds ratios (OR) of 0.89 (95% confidence interval (c.i.): 0.85-0.94) and 0.74 (95% c.i.: 0.62-0.87) for heterozygotes and rare homozygotes, respectively, compared with common homozygotes; P(trend) = 1.1 x 10(-7)) and weaker evidence for TGFB1 L10P (OR = 1.07 (95% c.i.: 1.02-1.13) and 1.16 (95% c.i.: 1.08-1.25), respectively; P(trend) = 2.8 x 10(-5)). These results demonstrate that common breast cancer susceptibility alleles with small effects on risk can be identified, given sufficiently powerful studies.
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| 6. |
- Fletcher, Olivia, et al.
(författare)
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Family history, genetic testing, and clinical risk prediction : pooled analysis of CHEK2 1100delC in 1,828 bilateral breast cancers and 7,030 controls
- 2009
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - 1055-9965 .- 1538-7755. ; 18:1, s. 230-4
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Tidskriftsartikel (refereegranskat)abstract
- If breast cancers arise independently in each breast the odds ratio (OR) for bilateral breast cancer for carriers of CHEK2 1100delC should be approximately 5.5, the square of the reported OR for a first primary (OR, 2.34). In the subset of bilateral cases with one or more affected relatives, the predicted carrier OR should be approximately 9. We have tested these predictions in a pooled set of 1,828 cases with 2 primaries and 7,030 controls from 8 studies. The second primary OR for CHEK2 1100delC carriers was 6.43 (95% confidence interval, 4.33-9.56; P < 0.0001), significantly greater than the published estimate for a first primary (P < 0.001) but consistent with its square. The predicted increase in carrier OR with increasing numbers of affected relatives was seen using bilateral cases from the UK (P(trend) = 0.0003) and Finland (P(trend) = 0.37), although not using those from the Netherlands and Russia (P = 0.001 for heterogeneity between countries). Based on a standard genetic model, we predict lifetime risks for CHEK2 1100delC carrier and noncarrier daughters of bilateral breast cancer cases of 37% and 18%, respectively. Our results imply that clinical management of the daughter of a woman with bilateral breast cancer should depend on her CHEK2 1100delC carrier status. This and other moderate penetrance breast cancer susceptibility alleles, together with family history data, will thus identify increasing numbers of women at potentially very high risk. Before such predictions are accepted by clinical geneticists, however, further population-based evidence is needed on the effect of CHEK2 1100delC and other moderate penetrance alleles in women with a family history of breast cancer.
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| 7. |
- Garcia-Closas, Montserrat, et al.
(författare)
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Heterogeneity of breast cancer associations with five susceptibility loci by clinical and pathological characteristics
- 2008
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 4:4, s. e1000054-
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Tidskriftsartikel (refereegranskat)abstract
- A three-stage genome-wide association study recently identified single nucleotide polymorphisms (SNPs) in five loci (fibroblast growth receptor 2 (FGFR2), trinucleotide repeat containing 9 (TNRC9), mitogen-activated protein kinase 3 K1 (MAP3K1), 8q24, and lymphocyte-specific protein 1 (LSP1)) associated with breast cancer risk. We investigated whether the associations between these SNPs and breast cancer risk varied by clinically important tumor characteristics in up to 23,039 invasive breast cancer cases and 26,273 controls from 20 studies. We also evaluated their influence on overall survival in 13,527 cases from 13 studies. All participants were of European or Asian origin. rs2981582 in FGFR2 was more strongly related to ER-positive (per-allele OR (95%CI) = 1.31 (1.27-1.36)) than ER-negative (1.08 (1.03-1.14)) disease (P for heterogeneity = 10(-13)). This SNP was also more strongly related to PR-positive, low grade and node positive tumors (P = 10(-5), 10(-8), 0.013, respectively). The association for rs13281615 in 8q24 was stronger for ER-positive, PR-positive, and low grade tumors (P = 0.001, 0.011 and 10(-4), respectively). The differences in the associations between SNPs in FGFR2 and 8q24 and risk by ER and grade remained significant after permutation adjustment for multiple comparisons and after adjustment for other tumor characteristics. Three SNPs (rs2981582, rs3803662, and rs889312) showed weak but significant associations with ER-negative disease, the strongest association being for rs3803662 in TNRC9 (1.14 (1.09-1.21)). rs13281615 in 8q24 was associated with an improvement in survival after diagnosis (per-allele HR = 0.90 (0.83-0.97). The association was attenuated and non-significant after adjusting for known prognostic factors. Our findings show that common genetic variants influence the pathological subtype of breast cancer and provide further support for the hypothesis that ER-positive and ER-negative disease are biologically distinct. Understanding the etiologic heterogeneity of breast cancer may ultimately result in improvements in prevention, early detection, and treatment.
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| 8. |
- Monazzam, Azita, et al.
(författare)
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Evaluation of the Hsp90 inhibitor NVP-AUY922 in multicellular tumour spheroids with respect to effects on growth and PET tracer uptake
- 2009
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Ingår i: Nuclear Medicine and Biology. - : Elsevier BV. - 0969-8051 .- 1872-9614. ; 36:3, s. 335-342
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Molecular targeting has become a prominent concept in cancer treatment and heat shock protein 90 (Hsp90) inhibitors are suggested as promising anticancer drugs. The Hsp90 complex is one of the chaperones that facilitate the refolding of unfolded or misfolded proteins and plays a role for key oncogenic proteins such as Her2, Raf-1, Akt/PKB, and mutant p53. NVP-AUY922 is a novel low-molecular Hsp90 inhibitor, currently under clinical development as an anticancer drug. Disruption of the Hsp90-client protein complexes leads to proteasome-mediated degradation of client proteins and cell death. The aim of the current study was to use a combination of the multicellular tumour spheroid (MTS) model and positron emission tomography (PET) to investigate the effects of NVP-AUY922 on tumour growth and its relation to PET tracer uptake for the selection of appropriate PET tracer. A further aim was to evaluate the concentration and time dependence in the relation between growth inhibition and PET tracer uptake as part of translational imaging activities. METHODS: MTS of two breast cancer cell lines (MCF-7 and BT474), one glioblastoma cell line (U87MG) and one colon carcinoma cell line (HCT116) were prepared. Initially, we investigated MTS growth pattern and (3)H-thymidine incorporation in MTS after continuous exposure to NVP-AUY922 in order to determine dose response. Then the short-term effect of the drug on the four PET tracers 2-[(18)F] fluoro-2-deoxyglucose (FDG), 3'-deoxy-3'-fluorothymidine (FLT), methionine and choline was correlated to the long-term effect (changes in growth pattern) to determine the adequate PET tracer with high predictability. Next, the growth inhibitory effect of different dose schedules was evaluated to determine the optimal dose and time. Finally, the effect of a 2-h exposure to the drug on growth pattern and FDG/FLT uptake was evaluated. RESULTS: A dose-dependent inhibition of growth and decrease of (3)H-thymidine uptake was observed with 100% growth cessation in the dose range 7-52 nM and 50% (3)H-thymidine reduction in the range of 10-23 nM, with the most pronounced effect on BT474 cells. The effect of the drug was best detected by FLT. The results suggested that a complete cessation of growth of the viable cell volume was achieved with about 50% inhibition of FLT uptake 3 days after continuous treatment. Significant growth inhibition was observed at all doses and all exposure time spans. Two-hour exposure to NVP-AUY922 generated a growth inhibition which persisted dose dependently up to 10 days. The uptake of FDG per viable tumour volume was reduced by just 25% with 300 nM treatment of the drug, whereas the FLT uptake decreased up to 75% in correlation with the growth inhibition and recovery. CONCLUSIONS: Our results indicate a prolonged action of NVP-AUY922 in this cell culture, FLT is a suitable tracer for the monitoring of the effect and a FLT PET study within 3 days after treatment can predict the treatment outcome in this model. If relevant in vivo, this information can be used for efficient planning of animal PET studies and later human PET trial.
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| 9. |
- Ricklefs, Michael, 1979-, et al.
(författare)
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Ontology-based relevance assessment : An evaluation of different semantic similarity measures
- 2008
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Ingår i: Proceedings of OTM 2008 - OTM Confederated International Conferences, CoopIS, DOA, GADA, IS, and ODBASE 2008. - Berlin : Springer. - 9783540888727 ; , s. 1235-1252
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Konferensbidrag (refereegranskat)abstract
- Ontology-based relevance assessment of documents is an importanttask. When viewing this in a business context, approaches arecommonly based on the use of one ontology describing the enterprise. Amore specific problem is then how to assess the relevance of a set of ontologyconcepts with respect to a user profile expressed within the sameontology. Semantic similarity measures have been widely used and describedin literature, but few experiments have been performed to showthe benefits and drawbacks of certain measures. In this paper we describehow a set of measures have been combined, tested, and evaluated. Theevaluation was performed through a rank correlation coefficient comparingthe measured results with a manually constructed “gold standard”.Conclusions are that certain combinations of measures seem less suitablefor solving this type of problem. On the other hand a set of combinationsperform quite well, although the detailed performance of most combinedmeasures seem to depend heavily on the structure of the ontology used.
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| 10. |
- Suzuki, Chikako, et al.
(författare)
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Radiologic measurements of tumor response to treatment : practical approaches and limitations
- 2008
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Ingår i: Radiographics. - : Radiological Society of North America (RSNA). - 0271-5333 .- 1527-1323. ; 28:2, s. 329-44
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Tidskriftsartikel (refereegranskat)abstract
- Objective response assessment is important to describe the treatment effect of anticancer drugs. Standardization by using a "common language" is also important for comparison of results from different trials. In contrast to clinical results, which can be subjective, diagnostic imaging provides a greater opportunity for objectivity and standardization. It was generally accepted that a decrease in tumor size correlated with treatment effect; as a result, imaging was adopted for lesion measurement in the World Health Organization (WHO) criteria in 1979. However, because of some limitations of the WHO criteria, the Response Evaluation Criteria in Solid Tumors (RECIST) were introduced in 2000. In RECIST, imaging was recognized as indispensable for response evaluation of solid tumors. Nevertheless, the widespread use of multidetector computed tomography and other imaging innovations have made RECIST outdated, with a concomitant need for modifications. Meanwhile, newer anticancer agents with targeted mechanisms of action have demonstrated an inherent limitation and unsuitability of anatomic tumor evaluation that assesses only lesion size. In addition, the effect of these new drugs changes the paradigm according to which tumor response or response rate is measured. Complete and partial responses cannot be the end points in all clinical trials; in some cases, disease control or progression-free survival may be the more relevant end point.
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