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| 5. |
- Wang, Zhaoming, et al.
(författare)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 12. |
- Cerrato, Carmine P. P., et al.
(författare)
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Monitoring Disassembly and Cargo Release of Phase-Separated Peptide Coacervates with Native Mass Spectrometry
- 2023
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Ingår i: Analytical Chemistry. - : American Chemical Society (ACS). - 0003-2700 .- 1520-6882. ; 95:29, s. 10869-10872
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Tidskriftsartikel (refereegranskat)abstract
- Engineering liquid-liquid phase separation (LLPS)of proteinsand peptides holds great promise for the development of therapeuticcarriers with intracellular delivery capability but requires accuratedetermination of their assembly properties in vitro, usually with fluorescently labeled cargo. Here, we use mass spectrometry(MS) to investigate redox-sensitive coacervate microdroplets (thedense phase formed during LLPS) assembled from a short His- and Tyr-richpeptide. We can monitor the enrichment of a reduced peptide in dilutephase as the microdroplets dissolve triggered by their redox-sensitiveside chain, thus providing a quantitative readout for disassembly.Furthermore, MS can detect the release of a short peptide from coacervatesunder reducing conditions. In summary, with MS, we can monitor thedisassembly and cargo release of engineered coacervates used as therapeuticcarriers without the need for additional labels.
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| 13. |
- Hedlund, P. O., et al.
(författare)
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Parenteral estrogen versus combined androgen deprivation in the treatment of metastatic prostatic cancer : Part 2. Final evaluation of the Scandinavian Prostatic Cancer Group (SPCG) Study No. 5
- 2008
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Ingår i: Scandinavian Journal of Urology and Nephrology. - : Informa UK Limited. - 0036-5599 .- 1651-2065. ; 42:3, s. 220-229
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Tidskriftsartikel (refereegranskat)abstract
- Objective. To compare parenteral estrogen therapy in the form of high-dose polyestradiol phosphate (PEP, Estradurin®) with combined androgen deprivation (CAD) in the treatment of prostate cancer patients with skeletal metastases. The aim of the study was to compare anticancer efficacy and adverse events, especially cardiovascular events. Material and methods. In total, 910 eligible patients with T0-4, NX, M1, G1-3 prostate cancer with an Eastern Cooperative Oncology Group performance status of 0-2 were randomized to treatment with either PEP 240mg i.m. twice a month for 2months and thereafter monthly, or flutamide (Eulexin®) 250mg t.i.d. per os in combination with either triptorelin (Decapeptyl®) 3.75mg i.m. per month or on an optional basis bilateral orchidectomy. Results. At this final evaluation of the trial 855 of the 910 patients were dead. There was no difference between the treatment groups in terms of biochemical or clinical progression-free survival or in overall or disease-specific survival. There was no difference in cardiovascular mortality, but a significant increase in non-fatal cardiovascular events in the PEP arm (p<0.05) predominantly caused by an increase in ischemic heart and heart decompensation events. There were 18 grave skeletal events in the CAD group but none in the PEP group (p=0.001). Conclusions. PEP has an anticancer efficacy equal to CAD and does not increase cardiovascular mortality in metastasized patients, but carries a significant risk of non-fatal cardiovascular events, which should be balanced against the skeletal complications in the CAD group. It is feasible to use Estradurin in the primary or secondary endocrine treatment of metastasized patients without prominent cardiac risk factors and especially those with osteoporosis. © 2008 Taylor & Francis.
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| 14. |
- Kehoe, Laura, et al.
(författare)
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Make EU trade with Brazil sustainable
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 16. |
- Machiela, Mitchell J, et al.
(författare)
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Female chromosome X mosaicism is age-related and preferentially affects the inactivated X chromosome
- 2016
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Ingår i: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- To investigate large structural clonal mosaicism of chromosome X, we analysed the SNP microarray intensity data of 38,303 women from cancer genome-wide association studies (20,878 cases and 17,425 controls) and detected 124 mosaic X events >2 Mb in 97 (0.25%) women. Here we show rates for X-chromosome mosaicism are four times higher than mean autosomal rates; X mosaic events more often include the entire chromosome and participants with X events more likely harbour autosomal mosaic events. X mosaicism frequency increases with age (0.11% in 50-year olds; 0.45% in 75-year olds), as reported for Y and autosomes. Methylation array analyses of 33 women with X mosaicism indicate events preferentially involve the inactive X chromosome. Our results provide further evidence that the sex chromosomes undergo mosaic events more frequently than autosomes, which could have implications for understanding the underlying mechanisms of mosaic events and their possible contribution to risk for chronic diseases.
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| 18. |
- Moussas, X., et al.
(författare)
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The gears of the Antikythera Mechanism : an educational pathfinder to the solar system
- 2011
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Ingår i: IAU Symposium.
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Konferensbidrag (refereegranskat)abstract
- The Antikythera Mechanism is the most sophisticated extant ancient astronomical instrument and analogue computer known and was assembled sometime between 150 and 100 BCE, almost a century after the death of Archimedes. The mechanism has a great educational potential as it appeals to inquiring minds as an astonishing artefact of science and technology. The latest research findings reveal significant cultural and social functions in its operations. This astonishing astronomical instrument has a clear interdisciplinary valueand it has that it may be used as an educational medium, to engage the general public, and especially to attract students both to/from exact sciences and to/from the humanities. The astronomical and technical knowledge embedded in the mechanism can also be used to introduce some aspects of modern science through the unknown technological achievements of Hellenic antiquity.
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| 21. |
- Baev, A., et al.
(författare)
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A quantum mechanical - Electrodynamical approach to nonlinear properties : Application to optical power limiting with platinum-organic compounds
- 2007
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Ingår i: Journal of nonlinear optical physics and materials. - 0218-8635. ; 16:2, s. 157-169
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Tidskriftsartikel (refereegranskat)abstract
- Light propagation in a medium is sensitively dependent on the shape and intensity of the optical pulse as well as on the electronic and vibrational structure of the basic molecular units. We review in this paper the results of systematic studies of this problem for isotropic media. Our theoretical approach - the quantum mechanical-electrodynamical (QMED) approach - is based on a quantum mechanical account of the many-level electron-nuclear medium coupled to a numerical solution of the density matrix and Maxwell's equations. This allows us to accommodate a variety of nonlinear effects which accomplish the propagation of strong light pulses. Particular attention is paid to the understanding of the role of coherent and sequential excitations of electron-nuclear degrees of freedom. The QMED combination of quantum chemistry with classical pulse propagation enables us to estimate the optical transmission from cross sections of multi-photon absorption processes and from considerations of propagation effects, saturation and pulse effects. Results of the theory suggest that in the nonlinear regime, it is often necessary to simultaneously account for coherent one-step and incoherent step-wise multi-photon absorption, as well as for off-resonant excitations even when resonance conditions prevail. The dynamic theory of nonlinear propagation of a few interacting intense light pulses is highlighted here in a study of the optical power limiting with platinum-organic molecular compounds. © World Scientific Publishing Company.
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| 22. |
- Baev, A., et al.
(författare)
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Light-matter interaction of strong laser pulses in the micro-, nano-, and picosecond regimes
- 2007
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Ingår i: Materials Research Society Symposium Proceedings. - 9781605604206 ; , s. 12-29
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Konferensbidrag (refereegranskat)abstract
- Light propagation in a medium is sensitively dependent on the shape and intensity of the optical pulse as well as on the electronic and vibrational structure of the basic molecular units. We review in this paper results of systematic studies of this problem for isotropic media. Our theoretical approach-the quantum mechanical-electrodynamical (QMED) approach-is based on a quantum mechanical account of the many-level electron-nuclear medium coupled to a numerical solution of the density matrix and Maxwell s equations. This allows to accommodate a variety of nonlinear effects which accomplish the propagation of strong light pulses. Particular attention is paid to the understanding of the role of coherent and sequential excitations of electron-nuclear degrees of freedom. The QMED combination of quantum chemistry with classical pulse propagation allows to estimate the optical transmission from cross sections of multi-photon absorption processes and from considerations of propagation effects, saturation and pulse effects. Results of the theory suggest that in the nonlinear regime it is often necessary to account simultaneously for coherent one-step and incoherent step-wise multi-photon absorption, as well as for off-resonant excitations even when resonance conditions prevail. The dynamic theory of nonlinear propagation of a few interacting intense light pulses is here highlighted in a study of the optical power limiting with platinum-organic molecular compounds. © 2007 Materials Research Society.
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| 23. |
- Berglund, U. W., et al.
(författare)
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Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
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Ingår i: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
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| 26. |
- Carville, S F, et al.
(författare)
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EULAR evidence-based recommendations for the management of fibromyalgia syndrome
- 2008
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 67:4, s. 536-541
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To develop evidence-based recommendations for the management of fibromyalgia syndrome. Methods: A multidisciplinary task force was formed representing 11 European countries. The design of the study, including search strategy, participants, interventions, outcome measures, data collection and analytical method, was defined at the outset. A systematic review was undertaken with the keywords "fibromyalgia", "treatment or management" and "trial". Studies were excluded if they did not utilise the American College of Rheumatology classification criteria, were not clinical trials, or included patients with chronic fatigue syndrome or myalgic encephalomyelitis. Primary outcome measures were change in pain assessed by visual analogue scale and fibromyalgia impact questionnaire. The quality of the studies was categorised based on randomisation, blinding and allocation concealment. Only the highest quality studies were used to base recommendations on. When there was insufficient evidence from the literature, a Delphi process was used to provide basis for recommendation. Results: 146 studies were eligible for the review. 39 pharmacological intervention studies and 59 non-pharmacological were included in the final recommendation summary tables once those of a lower quality or with insufficient data were separated. The categories of treatment identified were antidepressants, analgesics, and "other pharmacological" and exercise, cognitive behavioural therapy, education, dietary interventions and "other non-pharmacological". In many studies sample size was small and the quality of the study was insufficient for strong recommendations to be made. Conclusions: Nine recommendations for the management of fibromyalgia syndrome were developed using a systematic review and expert consensus.
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| 29. |
- Ek, M., et al.
(författare)
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Microsatellite markers for powdery mildew resistance in pea (Pisum sativum L.)
- 2005
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Ingår i: Hereditas. - : Springer Science and Business Media LLC. - 1601-5223 .- 0018-0661. ; 142, s. 86-91
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Tidskriftsartikel (refereegranskat)abstract
- Powdery mildew is a common disease of field pea, Pisum sativum L., and is caused by the ascomycete fungus Erysiphe pisi. It can cause severe damage in areas where pea is cultivated. Today breeders want to develop new pea lines that are resistant to the disease. To make the breeding process more efficient, it is desirable to find genetic markers for use in a marker-assisted selection (MAS) strategy. In this study, microsatellites (SSR) were used to find markers linked to powdery mildew resistance. The resistant pea cultivar '955180' and the susceptible pea cultivar 'Majoret' were crossed and F-2 plants were screened with SSR markers, using bulked segregant analysis. A total of 315 SSR markers were screened out of which five showed linkage to the powdery mildew resistance gene. No single marker was considered optimal for inclusion in a MAS program. Instead, two of the markers can be used in combination, which would result in only 1.6% incorrectly identified plants. Thus SSR markers can be successfully used in marker-assisted selection for powdery mildew resistance breeding in pea.
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| 33. |
- Falkmer, Torbjörn, 1958-, et al.
(författare)
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Driver education for persons with cerebral palsy - a retrospective study of educational problems.
- 2000
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Ingår i: Transportation Research Part F,2000. - New York, USA : Elsevier Science. ; , s. 15-27
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Konferensbidrag (refereegranskat)abstract
- In many countries, the community has a legal obligation to help persons with disabilities to participate in society on the same level as other groups. One aspect of such participation is access to unlimited and spontaneous transportation through the ability to drive a car. In the case of persons with cerebral palsy (CP), the possibility of becoming a driver is related to several factors such as the severity of the impairment, the individual’s financial situation and the quality of driver education. One of the aims of this study was to analyse the education process among learner drivers with CP, in order to understand where and why problems are encountered. A further aim was to enhance the development of test methods for predicting the ability of a person with CP to become a licensed driver. In the analysis of the learning process, logbooks from one of the two national Swedish centres for educating disabled learner drivers were analysed. The analysis showed that certain key tasks in the education process were critical for the outcome in terms of becoming a licensed driver or not. The results suggest that it may be possible to develop a test battery, which, in combination with an analysis of the performance of these key tasks, will assist prediction of the outcome of driving education for persons with CP.
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| 41. |
- Jacobs, Kevin B, et al.
(författare)
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Detectable clonal mosaicism and its relationship to aging and cancer.
- 2012
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Ingår i: Nature Genetics. - New York : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 44:6, s. 651-658
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Tidskriftsartikel (refereegranskat)abstract
- In an analysis of 31,717 cancer cases and 26,136 cancer-free controls from 13 genome-wide association studies, we observed large chromosomal abnormalities in a subset of clones in DNA obtained from blood or buccal samples. We observed mosaic abnormalities, either aneuploidy or copy-neutral loss of heterozygosity, of >2 Mb in size in autosomes of 517 individuals (0.89%), with abnormal cell proportions of between 7% and 95%. In cancer-free individuals, frequency increased with age, from 0.23% under 50 years to 1.91% between 75 and 79 years (P = 4.8 × 10(-8)). Mosaic abnormalities were more frequent in individuals with solid tumors (0.97% versus 0.74% in cancer-free individuals; odds ratio (OR) = 1.25; P = 0.016), with stronger association with cases who had DNA collected before diagnosis or treatment (OR = 1.45; P = 0.0005). Detectable mosaicism was also more common in individuals for whom DNA was collected at least 1 year before diagnosis with leukemia compared to cancer-free individuals (OR = 35.4; P = 3.8 × 10(-11)). These findings underscore the time-dependent nature of somatic events in the etiology of cancer and potentially other late-onset diseases.
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| 43. |
- Juslin, N., et al.
(författare)
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Analytical interatomic potential for modeling nonequilibrium processes in the W-C-H system
- 2005
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Ingår i: Journal of Applied Physics. - : AIP Publishing. - 0021-8979 .- 1089-7550. ; 98:12
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Tidskriftsartikel (refereegranskat)abstract
- A reactive interatomic potential based on an analytical bond-order scheme is developed for the ternary system W-C-H. The model combines Brenner's hydrocarbon potential with parameter sets for W-W, W-C, and W-H interactions and is adjusted to materials properties of reference structures with different local atomic coordinations including tungsten carbide, W-H molecules, as well as H dissolved in bulk W. The potential has been tested in various scenarios, such as surface, defect, and melting properties, none of which were considered in the fitting. The intended area of application is simulations of hydrogen and hydrocarbon interactions with tungsten, which have a crucial role in fusion reactor plasma-wall interactions. Furthermore, this study shows that the angular-dependent bond-order scheme can be extended to second nearest-neighbor interactions, which are relevant in body-centered-cubic metals. Moreover, it provides a possibly general route for modeling metal carbides.
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| 45. |
- Lama, Dilraj, et al.
(författare)
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A druggable conformational switch in the c-MYC transactivation domain
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- The c-MYC oncogene is activated in over 70% of all human cancers. The intrinsic disorder of the c-MYC transcription factor facilitates molecular interactions that regulate numerous biological pathways, but severely limits efforts to target its function for cancer therapy. Here, we use a reductionist strategy to characterize the dynamic and structural heterogeneity of the c-MYC protein. Using probe-based Molecular Dynamics (MD) simulations and machine learning, we identify a conformational switch in the c-MYC amino-terminal transactivation domain (termed coreMYC) that cycles between a closed, inactive, and an open, active conformation. Using the polyphenol epigallocatechin gallate (EGCG) to modulate the conformational landscape of coreMYC, we show through biophysical and cellular assays that the induction of a closed conformation impedes its interactions with the transformation/transcription domain-associated protein (TRRAP) and the TATA-box binding protein (TBP) which are essential for the transcriptional and oncogenic activities of c-MYC. Together, these findings provide insights into structure-activity relationships of c-MYC, which open avenues towards the development of shape-shifting compounds to target c-MYC as well as other disordered transcription factors for cancer treatment. Here, the authors identify a conformational switch in the amino-terminal transactivation domain of c-MYC, termed coreMYC, which cycles between a closed, inactive state and an open, active conformation. Polyphenol epigallocatechin gallate (EGCG) is used to modulate the conformational landscape of coreMYC, stabilizing the closed and inactive conformation.
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| 46. |
- Larsson, K., et al.
(författare)
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COX/mPGES-1/PGE2 pathway depicts an inflammatory-dependent high-risk neuroblastoma subset
- 2015
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Ingår i: Proceedings of the National Academy of Science of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 112:26, s. 8070-8075
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Tidskriftsartikel (refereegranskat)abstract
- The majority of solid tumors are presented with an inflammatory microenvironment. Proinflammatory lipid mediators including prostaglandin E2 (PGE2) contribute to the establishment of inflammation and have been linked to tumor growth and aggressiveness. Here we show that high-risk neuroblastoma with deletion of chromosome 11q represents an inflammatory subset of neuroblastomas. Analysis of enzymes involved in the production of proinflammatory lipid mediators showed that 11q-deleted neuroblastoma tumors express high levels of microsomal prostaglandin E synthase-1 (mPGES-1) and elevated levels of PGE2. High mPGES-1 expression also corresponded to poor survival of neuroblastoma patients. Investigation of the tumor microenvironment showed high infiltration of tumor-promoting macrophages with high expression of the M2-polarization markers CD163 and CD206. mPGES-1-expressing cells in tumors from different subtypes of neuroblastoma showed differential expression of one or several cancer-associated fibroblast markers such as vimentin, fibroblast activation protein alpha, alpha smooth muscle actin, and PDGF receptor beta. Importantly, inhibition of PGE2 production with diclofenac, a nonselective COX inhibitor, resulted in reduced tumor growth in an in vivo model of 11q-deleted neuroblastoma. Collectively, these results suggest that PGE2 is involved in the tumor microenvironment of specific neuroblastoma subgroups and indicate that therapeutic strategies using existing anti-inflammatory drugs in combination with current treatment should be considered for certain neuroblastomas.
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