| 1. |
- Fernandez-Rozadilla, Ceres, et al.
(författare)
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Deciphering colorectal cancer genetics through multi-omic analysis of 100,204 cases and 154,587 controls of European and east Asian ancestries
- 2023
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 55, s. 89-99
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer (CRC) is a leading cause of mortality worldwide. We conducted a genome-wide association study meta-analysis of 100,204 CRC cases and 154,587 controls of European and east Asian ancestry, identifying 205 independent risk associations, of which 50 were unreported. We performed integrative genomic, transcriptomic and methylomic analyses across large bowel mucosa and other tissues. Transcriptome- and methylome-wide association studies revealed an additional 53 risk associations. We identified 155 high-confidence effector genes functionally linked to CRC risk, many of which had no previously established role in CRC. These have multiple different functions and specifically indicate that variation in normal colorectal homeostasis, proliferation, cell adhesion, migration, immunity and microbial interactions determines CRC risk. Crosstissue analyses indicated that over a third of effector genes most probably act outside the colonic mucosa. Our findings provide insights into colorectal oncogenesis and highlight potential targets across tissues for new CRC treatment and chemoprevention strategies.
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| 2. |
- Chen, Zhishan, et al.
(författare)
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Fine-mapping analysis including over 254 000 East Asian and European descendants identifies 136 putative colorectal cancer susceptibility genes
- 2024
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 15:1
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Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have identified more than 200 common genetic variants independently associated with colorectal cancer (CRC) risk, but the causal variants and target genes are mostly unknown. We sought to fine-map all known CRC risk loci using GWAS data from 100,204 cases and 154,587 controls of East Asian and European ancestry. Our stepwise conditional analyses revealed 238 independent association signals of CRC risk, each with a set of credible causal variants (CCVs), of which 28 signals had a single CCV. Our cis-eQTL/mQTL and colocalization analyses using colorectal tissue-specific transcriptome and methylome data separately from 1299 and 321 individuals, along with functional genomic investigation, uncovered 136 putative CRC susceptibility genes, including 56 genes not previously reported. Analyses of single-cell RNA-seq data from colorectal tissues revealed 17 putative CRC susceptibility genes with distinct expression patterns in specific cell types. Analyses of whole exome sequencing data provided additional support for several target genes identified in this study as CRC susceptibility genes. Enrichment analyses of the 136 genes uncover pathways not previously linked to CRC risk. Our study substantially expanded association signals for CRC and provided additional insight into the biological mechanisms underlying CRC development.
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| 3. |
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| 4. |
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| 5. |
- Huyghe, Jeroen R., et al.
(författare)
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Discovery of common and rare genetic risk variants for colorectal cancer
- 2019
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:1, s. 76-
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Tidskriftsartikel (refereegranskat)abstract
- To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 x 10(-8), bringing the number of known independent signals for CRC to similar to 100. New signals implicate lower-frequency variants, Kruppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
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| 6. |
- Schmit, Stephanie L, et al.
(författare)
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Novel Common Genetic Susceptibility Loci for Colorectal Cancer.
- 2019
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 111:2, s. 146-157
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous genome-wide association studies (GWAS) have identified 42 loci (P < 5 × 10-8) associated with risk of colorectal cancer (CRC). Expanded consortium efforts facilitating the discovery of additional susceptibility loci may capture unexplained familial risk.Methods: We conducted a GWAS in European descent CRC cases and control subjects using a discovery-replication design, followed by examination of novel findings in a multiethnic sample (cumulative n = 163 315). In the discovery stage (36 948 case subjects/30 864 control subjects), we identified genetic variants with a minor allele frequency of 1% or greater associated with risk of CRC using logistic regression followed by a fixed-effects inverse variance weighted meta-analysis. All novel independent variants reaching genome-wide statistical significance (two-sided P < 5 × 10-8) were tested for replication in separate European ancestry samples (12 952 case subjects/48 383 control subjects). Next, we examined the generalizability of discovered variants in East Asians, African Americans, and Hispanics (12 085 case subjects/22 083 control subjects). Finally, we examined the contributions of novel risk variants to familial relative risk and examined the prediction capabilities of a polygenic risk score. All statistical tests were two-sided.Results: The discovery GWAS identified 11 variants associated with CRC at P < 5 × 10-8, of which nine (at 4q22.2/5p15.33/5p13.1/6p21.31/6p12.1/10q11.23/12q24.21/16q24.1/20q13.13) independently replicated at a P value of less than .05. Multiethnic follow-up supported the generalizability of discovery findings. These results demonstrated a 14.7% increase in familial relative risk explained by common risk alleles from 10.3% (95% confidence interval [CI] = 7.9% to 13.7%; known variants) to 11.9% (95% CI = 9.2% to 15.5%; known and novel variants). A polygenic risk score identified 4.3% of the population at an odds ratio for developing CRC of at least 2.0.Conclusions: This study provides insight into the architecture of common genetic variation contributing to CRC etiology and improves risk prediction for individualized screening.
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| 7. |
- Archambault, Alexi N., et al.
(författare)
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Cumulative Burden of Colorectal Cancer Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer
- 2020
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Ingår i: Gastroenterology. - : Elsevier BV. - 0016-5085 .- 1528-0012. ; 158:5, s. 1274-1286.e12
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC.METHODS: We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants.RESULTS: Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (P for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28-4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80-3.04). This association was strongest for participants without a first-degree family history of CRC (P for interaction = 5.61 x 10(-5)). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61-5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70-3.00). Sensitivity analyses were consistent with these findings.CONCLUSIONS: In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.
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| 8. |
- Ebersole, Charles R., et al.
(författare)
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Many Labs 5: Testing Pre-Data-Collection Peer Review as an Intervention to Increase Replicability
- 2020
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Ingår i: Advances in Methods and Practices in Psychological Science. - : Sage. - 2515-2467 .- 2515-2459. ; 3:3, s. 309-331
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Tidskriftsartikel (refereegranskat)abstract
- Replication studies in psychological science sometimes fail to reproduce prior findings. If these studies use methods that are unfaithful to the original study or ineffective in eliciting the phenomenon of interest, then a failure to replicate may be a failure of the protocol rather than a challenge to the original finding. Formal pre-data-collection peer review by experts may address shortcomings and increase replicability rates. We selected 10 replication studies from the Reproducibility Project: Psychology (RP:P; Open Science Collaboration, 2015) for which the original authors had expressed concerns about the replication designs before data collection; only one of these studies had yielded a statistically significant effect (p < .05). Commenters suggested that lack of adherence to expert review and low-powered tests were the reasons that most of these RP:P studies failed to replicate the original effects. We revised the replication protocols and received formal peer review prior to conducting new replication studies. We administered the RP:P and revised protocols in multiple laboratories (median number of laboratories per original study = 6.5, range = 3-9; median total sample = 1,279.5, range = 276-3,512) for high-powered tests of each original finding with both protocols. Overall, following the preregistered analysis plan, we found that the revised protocols produced effect sizes similar to those of the RP:P protocols (Delta r = .002 or .014, depending on analytic approach). The median effect size for the revised protocols (r = .05) was similar to that of the RP:P protocols (r = .04) and the original RP:P replications (r = .11), and smaller than that of the original studies (r = .37). Analysis of the cumulative evidence across the original studies and the corresponding three replication attempts provided very precise estimates of the 10 tested effects and indicated that their effect sizes (median r = .07, range = .00-.15) were 78% smaller, on average, than the original effect sizes (median r = .37, range = .19-.50).
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| 9. |
- Gunhaga, Lena, et al.
(författare)
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Specification of dorsal telencephalic character by sequential Wnt and FGF signaling.
- 2003
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Ingår i: Nature Neuroscience. - : Springer Science and Business Media LLC. - 1097-6256 .- 1546-1726. ; 6:7, s. 701-707
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Tidskriftsartikel (refereegranskat)abstract
- Dorsoventral patterning of the telencephalon is established early in forebrain development and underlies many of the regional subdivisions that are critical to the later organization of neural circuits in the cerebral cortex and basal ganglia. Sonic hedgehog (Shh) is involved in the generation of the ventral-most telencephalic cells, but the identity of the extrinsic signal(s) that induce dorsal character in telencephalic cells is not known. Here we show in chick embryos that sequential Wnt and fibroblast growth factor (FGF) signaling specifies cells of dorsal telencephalic character.
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| 10. |
- Haiman, Christopher A., et al.
(författare)
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A common variant at the TERT-CLPTM1L locus is associated with estrogen receptor-negative breast cancer
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 43:12, s. 61-1210
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Tidskriftsartikel (refereegranskat)abstract
- Estrogen receptor (ER)-negative breast cancer shows a higher incidence in women of African ancestry compared to women of European ancestry. In search of common risk alleles for ER-negative breast cancer, we combined genome-wide association study (GWAS) data from women of African ancestry (1,004 ER-negative cases and 2,745 controls) and European ancestry (1,718 ER-negative cases and 3,670 controls), with replication testing conducted in an additional 2,292 ER-negative cases and 16,901 controls of European ancestry. We identified a common risk variant for ER-negative breast cancer at the TERT-CLPTM1L locus on chromosome 5p15 (rs10069690: per-allele odds ratio (OR) = 1.18 per allele, P = 1.0 x 10(-10)). The variant was also significantly associated with triple-negative (ER-negative, progesterone receptor (PR)-negative and human epidermal growth factor-2 (HER2)-negative) breast cancer (OR = 1.25, P = 1.1 x 10(-9)), particularly in younger women (<50 years of age) (OR = 1.48, P = 1.9 x 10(-9)). Our results identify a genetic locus associated with estrogen receptor negative breast cancer subtypes in multiple populations.
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| 11. |
- Marklund, Matthew, et al.
(författare)
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Retinoic acid signalling specifies intermediate character in the developing telencephalon.
- 2004
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 131:17, s. 4323-4332
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Tidskriftsartikel (refereegranskat)abstract
- The organisation of the telencephalon into its major structures depends on its early regionalisation along the dorsoventral axis. Previous studies have provided evidence that sonic hedgehog (SHH) is required for the generation of telencephalic cells of ventral character, and that sequential WNT and fibroblast growth factor (FGF) signalling specifies cells of dorsal telencephalic character. However, the signalling mechanisms that specify telencephalic cells of an intermediate character remain to be defined. We provide evidence here that retinoic acid has a crucial role in specifying telencephalic progenitor cells of intermediate character.
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| 12. |
- Nordström, Ulrika, 1971-, et al.
(författare)
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An early role for WNT signaling in specifying neural patterns of Cdx and Hox gene expression and motor neuron subtype identity
- 2006
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Ingår i: PLoS biology. - : Public library of science. - 1544-9173 .- 1545-7885. ; 4:8, s. 1438-1452
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Tidskriftsartikel (refereegranskat)abstract
- The link between extrinsic signaling, progenitor cell specification and neuronal subtype identity is central to the developmental organization of the vertebrate central nervous system. In the hindbrain and spinal cord, distinctions in the rostrocaudal identity of progenitor cells are associated with the generation of different motor neuron subtypes. Two fundamental classes of motor neurons, those with dorsal (dMN) and ventral (vMN) exit points, are generated over largely non-overlapping rostrocaudal domains of the caudal neural tube. Cdx and Hox genes are important determinants of the rostrocaudal identity of neural progenitor cells, but the link between early patterning signals, neural Cdx and Hox gene expression, and the generation of dMN and vMN subtypes, is unclear. Using an in vitro assay of neural differentiation, we provide evidence that an early Wnt-based program is required to interact with a later retinoic acid- and fibroblast growth factor–mediated mechanism to generate a pattern of Cdx and Hox profiles characteristic of hindbrain and spinal cord progenitor cells that prefigure the generation of vMNs and dMNs.
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| 13. |
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| 14. |
- Steneberg, Pär, et al.
(författare)
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PAN-AMPK activator O304 improves glucose homeostasis and microvascular perfusion in mice and type 2 diabetes patients
- 2018
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Ingår i: JCI INSIGHT. - : American Society for Clinical Investigation. - 2379-3708. ; 3:12
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Tidskriftsartikel (refereegranskat)abstract
- AMPK activated protein kinase (AMPK), a master regulator of energy homeostasis, is activated in response to an energy shortage imposed by physical activity and caloric restriction. We here report on the identification of PAN-AMPK activator O304, which - in diet-induced obese mice - increased glucose uptake in skeletal muscle, reduced beta cell stress, and promoted beta cell rest. Accordingly, O304 reduced fasting plasma glucose levels and homeostasis model assessment of insulin resistance (HOMA-IR) in a proof-of-concept phase IIa clinical trial in type 2 diabetes (T2D) patients on Metformin. T2D is associated with devastating micro-and macrovascular complications, and O304 improved peripheral microvascular perfusion and reduced blood pressure both in animals and T2D patients. Moreover, like exercise, O304 activated AMPK in the heart, increased cardiac glucose uptake, reduced cardiac glycogen levels, and improved left ventricular stroke volume in mice, but it did not increase heart weight in mice or rats. Thus, O304 exhibits a great potential as a novel drug to treat T2D and associated cardiovascular complications.
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| 15. |
- Sundqvist, Bertil, et al.
(författare)
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Physical properties of pressure polymerized C60
- 1996
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Ingår i: Fullerenes: Recent Advances in the Chemistry and Physics of Fullerenes and Related Materials, volume 3. - Pennington, NJ : The Electrochemical Society. - 1566771625 ; , s. 1014-1028
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Konferensbidrag (refereegranskat)abstract
- We present in this paper an overview of the physical properties of the high pressure polymerized C60 phase commonly known as "soft fcc". This phase has been studied by several methods over wide ranges in temperature T and/or pressure, p. We present here experimental information about the specific heat capacity, the thermal expansion coefficient, the lattice structure, and the thermal conductivity, and we also show results obtained by NMR and Raman spectroscopy. All data presented agree with the accepted model that the individual molecules in this phase are covalently bound to form linear molecular chains. In particular, the NMR data show clearly the presence of covalent bonds, and the Raman data exhibit several new lines at very low energies connected with chain vibrations. Thermal conductivity data obtained during polymerization show both the time dependence of the process and that polymerization occurs at lower p and T than observed previously for this phase.
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| 16. |
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| 17. |
- Berg, Jan-Erik, 1957-, et al.
(författare)
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Refining gentleness - a key to bulky CTMP
- 2022
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Ingår i: Nordic Pulp & Paper Research Journal. - : Walter de Gruyter GmbH. - 0283-2631 .- 2000-0669. ; 37:2, s. 349-355
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Tidskriftsartikel (refereegranskat)abstract
- Chemithermomechanical pulp (CTMP) is often used in middle layers of multiply paperboards due to its high bulk at specified strength. Such a CTMP should consist of well-separated undamaged fibres with sufficient bonding capacity. The basic objective of this work is to examine the effect of refining on bulk, taking into account conditions such as temperature, sulphonation, refining gap and refiner size. First stage CTMP made from Norway spruce (Picea abies) were produced in pilot and mill scale trials. Two new parameters, Equivalent temperature related to softness and Refining gentleness are introduced that take into account refining conditions as actual temperature, softening temperature, bound sulphonate content, refining gap and refiner diameter. The results show that bulk increases linearly with refining gentleness.
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| 18. |
- Berndt, Sonja, I, et al.
(författare)
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Distinct germline genetic susceptibility profiles identified for common non-Hodgkin lymphoma subtypes
- 2022
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Ingår i: Leukemia. - : Springer Nature. - 0887-6924 .- 1476-5551. ; 36:12, s. 2835-2844
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Tidskriftsartikel (refereegranskat)abstract
- Lymphoma risk is elevated for relatives with common non-Hodgkin lymphoma (NHL) subtypes, suggesting shared genetic susceptibility across subtypes. To evaluate the extent of mutual heritability among NHL subtypes and discover novel loci shared among subtypes, we analyzed data from eight genome-wide association studies within the InterLymph Consortium, including 10,629 cases and 9505 controls. We utilized Association analysis based on SubSETs (ASSET) to discover loci for subsets of NHL subtypes and evaluated shared heritability across the genome using Genome-wide Complex Trait Analysis (GCTA) and polygenic risk scores. We discovered 17 genome-wide significant loci (P < 5 × 10−8) for subsets of NHL subtypes, including a novel locus at 10q23.33 (HHEX) (P = 3.27 × 10−9). Most subset associations were driven primarily by only one subtype. Genome-wide genetic correlations between pairs of subtypes varied broadly from 0.20 to 0.86, suggesting substantial heterogeneity in the extent of shared heritability among subtypes. Polygenic risk score analyses of established loci for different lymphoid malignancies identified strong associations with some NHL subtypes (P < 5 × 10−8), but weak or null associations with others. Although our analyses suggest partially shared heritability and biological pathways, they reveal substantial heterogeneity among NHL subtypes with each having its own distinct germline genetic architecture.
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| 19. |
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| 20. |
- Crabtree, Judy S, et al.
(författare)
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Of mice and MEN1 : Insulinomas in a conditional mouse knockout.
- 2003
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Ingår i: Molecular and Cellular Biology. - 0270-7306 .- 1098-5549. ; 23:17, s. 6075-6085
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Tidskriftsartikel (refereegranskat)abstract
- Patients with multiple endocrine neoplasia type 1 (MEN1) develop multiple endocrine tumors, primarily affecting the parathyroid, pituitary, and endocrine pancreas, due to the inactivation of the MEN1 gene. A conditional mouse model was developed to evaluate the loss of the mouse homolog, Men1, in the pancreatic beta cell. Men1 in these mice contains exons 3 to 8 flanked by loxP sites, such that, when the mice are crossed to transgenic mice expressing cre from the rat insulin promoter (RIP-cre), exons 3 to 8 are deleted in beta cells. By 60 weeks of age, >80% of mice homozygous for the floxed Men1 gene and expressing RIP-cre develop multiple pancreatic islet adenomas. The formation of adenomas results in elevated serum insulin levels and decreased blood glucose levels. The delay in tumor appearance, even with early loss of both copies of Men1, implies that additional somatic events are required for adenoma formation in beta cells. Comparative genomic hybridization of beta cell tumor DNA from these mice reveals duplication of chromosome 11, potentially revealing regions of interest with respect to tumorigenesis.
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| 21. |
- Edlund, Thomas
(författare)
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On Vertex Operator Algebras of Affine Type at Admissible Levels
- 2013
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The main purpose of this thesis is the study of the structure and representation theory of simple vertex operator algebras (VOAs) of affine type at admissible levels. To do this, it is crucial to obtain knowledge of the singular vectors which generate the maximal submodules, with respect to which these VOAs appear as irreducible quotients, and therefore a substantial part of the text is devoted to this matter. We study in particular the simple VOAs associated to affine sl(3, C) with half-integer admissible levels, and especially the one with the minimal admissible level -3/2. We tackle the problem of describing singular vectors in Verma modules for affine Lie algebras by providing a novel way of realizing the ideas presented in an article by F. G. Malikov, B. L. Feigin and D. B. Fuchs. Our approach is based on the rigorous construction of a broader algebraic framework by means of Ore localization in the universal enveloping algebra and via the introduction of certain conjugation automorphisms. We are able to express operators corresponding to those of Malikov et al. and to partially extend to our setting their main result regarding whether or not these operators represent elements of the enveloping algebra. Using this knowledge about singular vectors we deal with the problem of finding the irreducible modules in the category O for VOAs of affine type, when the level is admissible. Applying the theory of Zhu's algebra, the highest weights of these modules are characterized as the zeros of a polynomial ideal determined by the single singular vector generating the maximal proper submodule of the generalized Verma module. For the VOA associated to affine sl(3, C) at level -3/2, we prove that these highest weights are precisely the four admissible weights of level -3/2, and moreover that any module in the category O for this VOA is completely reducible. We also show that there are no nontrivial intertwining operators between these irreducible modules, except those deriving from the module structures. Furthermore, we demonstrate how the Sapovalov form can be employed to gain insight into the polynomial ideal, if merely the weight of the corresponding singular vector is known.
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| 22. |
- Godoy, Patricio, et al.
(författare)
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Gene networks and transcription factor motifs defining the differentiation of stem cells into hepatocyte-like cells
- 2015
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Ingår i: Journal of Hepatology. - : Elsevier. - 0168-8278 .- 1600-0641. ; 63:4, s. 934-942
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: The differentiation of stem cells to hepatocyte-like cells (HLC) offers the perspective of unlimited supply of human hepatocytes. However, the degree of differentiation of HLC remains controversial. To obtain an unbiased characterization, we performed a transcriptomic study with HLC derived from human embryonic and induced stem cells (ESC, hiPSC) from three different laboratories.METHODS: Genome-wide gene expression profiles of ESC and HLC were compared to freshly isolated and up to 14days cultivated primary human hepatocytes. Gene networks representing successful and failed hepatocyte differentiation, and the transcription factors involved in their regulation were identified.RESULTS: Gene regulatory network analysis demonstrated that HLC represent a mixed cell type with features of liver, intestine, fibroblast and stem cells. The "unwanted" intestinal features were associated with KLF5 and CDX2 transcriptional networks. Cluster analysis identified highly correlated groups of genes associated with mature liver functions (n=1057) and downregulated proliferation associated genes (n=1562) that approach levels of primary hepatocytes. However, three further clusters containing 447, 101, and 505 genes failed to reach levels of hepatocytes. Key TF of two of these clusters include SOX11, FOXQ1, and YBX3. The third unsuccessful cluster, controlled by HNF1, CAR, FXR, and PXR, strongly overlaps with genes repressed in cultivated hepatocytes compared to freshly isolated hepatocytes, suggesting that current in vitro conditions lack stimuli required to maintain gene expression in hepatocytes, which consequently also explains a corresponding deficiency of HLC.CONCLUSIONS: The present gene regulatory network approach identifies key transcription factors which require modulation to improve HLC differentiation.
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| 23. |
- Grinberg, Marianna, et al.
(författare)
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Toxicogenomics directory of chemically exposed human hepatocytes
- 2014
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Ingår i: Archives of Toxicology. - : Springer Science and Business Media LLC. - 1432-0738 .- 0340-5761. ; 88:12, s. 2261-2287
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Tidskriftsartikel (refereegranskat)abstract
- A long-term goal of numerous research projects is to identify biomarkers for in vitro systems predicting toxicity in vivo. Often, transcriptomics data are used to identify candidates for further evaluation. However, a systematic directory summarizing key features of chemically influenced genes in human hepatocytes is not yet available. To bridge this gap, we used the Open TG-GATES database with Affymetrix files of cultivated human hepatocytes incubated with chemicals, further sets of gene array data with hepatocytes from human donors generated in this study, and publicly available genome-wide datasets of human liver tissue from patients with non-alcoholic steatohepatitis (NASH), cirrhosis, and hepatocellular cancer (HCC). After a curation procedure, expression data of 143 chemicals were included into a comprehensive biostatistical analysis. The results are summarized in the publicly available toxicotranscriptomics directory (http://wiki.toxbank.net/toxicogenomics-map/) which provides information for all genes whether they are up- or downregulated by chemicals and, if yes, by which compounds. The directory also informs about the following key features of chemically influenced genes: (1) Stereotypical stress response. When chemicals induce strong expression alterations, this usually includes a complex but highly reproducible pattern named 'stereotypical response.' On the other hand, more specific expression responses exist that are induced only by individual compounds or small numbers of compounds. The directory differentiates if the gene is part of the stereotypical stress response or if it represents a more specific reaction. (2) Liver disease-associated genes. Approximately 20 % of the genes influenced by chemicals are up- or downregulated, also in liver disease. Liver disease genes deregulated in cirrhosis, HCC, and NASH that overlap with genes of the aforementioned stereotypical chemical stress response include CYP3A7, normally expressed in fetal liver; the phase II metabolizing enzyme SULT1C2; ALDH8A1, known to generate the ligand of RXR, one of the master regulators of gene expression in the liver; and several genes involved in normal liver functions: CPS1, PCK1, SLC2A2, CYP8B1, CYP4A11, ABCA8, and ADH4. (3) Unstable baseline genes. The process of isolating and the cultivation of hepatocytes was sufficient to induce some stress leading to alterations in the expression of genes, the so-called unstable baseline genes. (4) Biological function. Although more than 2,000 genes are transcriptionally influenced by chemicals, they can be assigned to a relatively small group of biological functions, including energy and lipid metabolism, inflammation and immune response, protein modification, endogenous and xenobiotic metabolism, cytoskeletal organization, stress response, and DNA repair. In conclusion, the introduced toxicotranscriptomics directory offers a basis for a rationale choice of candidate genes for biomarker evaluation studies and represents an easy to use source of background information on chemically influenced genes.
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| 24. |
- Grönlund, Anne, 1962-
(författare)
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Flexibilitetens gränser : Förändring och friktion i arbetsliv och familj
- 2004
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- THE TERM FLEXIBILITY has come to be a symbol for a number of grand hopes. An increased flexibility is seen as a key issue for modern organisations and is assumed to pave the way for a more gender equal and family friendly working life. The aim of the thesis has been to confront a number of assumptions about the “flexibilization” of working life with quantitative data from the Swedish labour market. An important goal has been to discuss the effects of flexibility on gender segregation in work and family life. The study focuses on three branches with different gender composition of the work force: manufacturing, health care and finance. The main data consists of a questionnaire that was sent to a representative sample of employees in the three branches (n=1.836) and another that was sent to their workplaces (n=625). Addional data comes from interviews with representatives of labour unions and employer organisations, and reviews of collective agreements and of- ficial statistics. The results provide a picture of flexibility in working life that differs from the one depicted in the ongoing debate, both regarding the strategies of organisations and the significance of flexibility to employees. The debate has focused on expanding employers’ room to manoeuvre, especially the possibilities to hire and fire personnel according to shifts in demand. The thesis shows, however, that efforts to create flexibility within the existing work force, through for instance overtime and work rotation, are equally important as the numerical flexibility obtained through termination of personnel, temporary jobs and sub-contracting. The results also challenge the idea that labour market regulation constitutes a decisive obstacle for flexibility. Workplaces that regard regulation as a problem do not adapt staffing to demand any less than others do and in all three branches competence issues pose a greater problem. The analyses point to a somewhat ambiguous relationship between gender and flexibility. Women have less employeroriented flexible work hours than men, which could be a result of their greater responsibility for home and children, but despite this responsibility they have less of a possibility to set their own working hours. This is explained by the fact that influence over work hours is an organisational perk associated with a high position and an adaptation to employer needs, rather than a right for the employee. Demands on time from the family in the form of children or a greater responsibility for housework do not affect the possibilities for flexible work schedules. The thesis also gives cause to question the idea that flexible work hours make it easier to combine paid work and family. Flexibility does not seem to lessen the conflict between these two spheres, nor does it lead to a more egalitarian division of housework. Functional flexibility in the form of work rotation and other forms of varying work tasks leads to job enrichment, but also to an intensification of work This kind of flexibility is not more common among men than women and there is no gender difference regarding its effects on work.
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| 25. |
- Gunhaga, Lena, et al.
(författare)
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Sonic hedgehog signaling at gastrula stages specifies ventral telencephalic cells in the chick embryo
- 2000
-
Ingår i: Development. - 0950-1991 .- 1477-9129. ; 127:15, s. 3283-3293
-
Tidskriftsartikel (refereegranskat)abstract
- A secreted signaling factor, Sonic hedgehog (Shh), has a crucial role in the generation of ventral cell types along the entire rostrocaudal axis of the neural tube. At caudal levels of the neuraxis, Shh is secreted by the notochord and floor plate during the period that ventral cell fates are specified. At anterior prosencephalic levels that give rise to the telencephalon, however, neither the prechordal mesoderm nor the ventral neural tube expresses Shh at the time that the overt ventral character of the telencephalon becomes evident. Thus, the precise role and timing of Shh signaling relevant to the specification of ventral telencephalic identity remains unclear. By analysing neural cell differentiation in chick neural plate explants we provide evidence that neural cells acquire molecular properties characteristic of the ventral telencephalon in response to Shh signals derived from the anterior primitive streak/Hensen's node region at gastrula stages. Exposure of prospective anterior prosencephalic cells to Shh at this early stage is sufficient to initiate a temporal program of differentiation that parallels that of neurons generated normally in the medial ganglionic eminence subdivision of the ventral telencephalon.
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| 26. |
- Göransson, Hanna, et al.
(författare)
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Quantification of normal cell fraction and copy number neutral LOH in clinical lung cancer samples using SNP array data
- 2009
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 4:6, s. e6057-
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Technologies based on DNA microarrays have the potential to provide detailed information on genomic aberrations in tumor cells. In practice a major obstacle for quantitative detection of aberrations is the heterogeneity of clinical tumor tissue. Since tumor tissue invariably contains genetically normal stromal cells, this may lead to a failure to detect aberrations in the tumor cells. PRINCIPAL FINDING: Using SNP array data from 44 non-small cell lung cancer samples we have developed a bioinformatic algorithm that accurately models the fractions of normal and tumor cells in clinical tumor samples. The proportion of normal cells in combination with SNP array data can be used to detect and quantify copy number neutral loss-of-heterozygosity (CNNLOH) in the tumor cells both in crude tumor tissue and in samples enriched for tumor cells by laser capture microdissection. CONCLUSION: Genome-wide quantitative analysis of CNNLOH using the CNNLOH Quantifier method can help to identify recurrent aberrations contributing to tumor development in clinical tumor samples. In addition, SNP-array based analysis of CNNLOH may become important for detection of aberrations that can be used for diagnostic and prognostic purposes.
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| 27. |
- Halvarsson, Sören, 1956-
(författare)
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Manufacture of straw MDF and fibreboards
- 2010
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The purpose of this thesis was to develop an economical, sustainable, and environmentally friendly straw Medium Density Fibreboard (MDF) process, capable of full-scale manufacturing and to produce MDF of requested quality. The investigated straw was based on wheat (Triticum aestivum L.) and rice (Oryzae sativa L.). In this thesis three different methods were taken for manufacture of straw MDF; (A) wheat-straw fibre was blowline blended with melamine-modified urea-formaldehyde (MUF), (B) rice-straw fibre was mixed with methylene diphenyl diisocyanate (MDI) in a resin drum-blender, and (C) wheat-straw fibre was activated in the blowline by the addition of Fenton’s reagent (H2O2/Fe2+) for production of non-resin MDF panels. The MUF/wheat straw MDF panels were approved according to the requirements of the EN standard for MDF (EN 622-5, 2006). The MDI/rice-straw MDF panels were approved according to requirements of the standard for MDF of the American National Standard Institute (ANSI A208.2-2002). The non-resin wheat-straw panels showed mediocre MDF panel properties and were not approved according to the requirements in the MDF standard. The dry process for wood-based MDF was modified for production of straw MDF. The straw MDF process was divided into seven main process steps. 1. Size-reduction (hammer-milling) and screening of straw 2. Wetting and heating of straw 3. Defibration 4. Resination of straw fibre 5. Mat forming 6. Pre-pressing 7. Hot-pressing The primary results were that the straw MDF process was capable of providing satisfactory straw MDF panels based on different types of straw species and adhesives. Moreover, the straw MDF process was performed in pilot-plant scale and demonstrated as a suitable method for producing straw MDF from straw bales to finished straw MDF panels. In the environmental perspective the agricultural straw-waste is a suitable source for producing MDF to avoid open field burning and to capture carbon dioxide (CO2), the biological sink for extended time into MDF panels, instead of converting straw directly into bio energy or applying straw fibre a few times as recycled paper. Additionally, the straw MDF panels can be recycled or converted to energy after utilization. A relationship between water retention value (WRV) of resinated straw fibres, the thickness swelling of corresponding straw MDF panels, and the amount of applied adhesive was determined. WRV of the straw fibre increased and the TS of straw MDF declined as a function of the resin content. The empirical models developed were of acceptable significance and the R2 values were 0.69 (WRV) and 0.75 (TS), respectively. Reduced thickness swelling of MDF as the resin content is increased is well-known. The increase of WRV as a function of added polymers is not completely established within the science of fibre swelling. Fortunately, more fundamental research can be initiated and likely a simple method for prediction of thickness swelling of MDF by analysis of the dried and resinated MDF fibres is possible.
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| 28. |
- Holgersson, Georg, et al.
(författare)
-
Effect of Increased Radiotoxicity on Survival of Patients with Non-small Cell Lung Cancer Treated with Curatively Intended Radiotherapy
- 2015
-
Ingår i: Anticancer Research. - 0250-7005 .- 1791-7530. ; 35:10, s. 5491-5497
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To elucidate the impact of different forms of radiation toxicities (esophagitis, radiation pneumonitis, mucositis and hoarseness), on the survival of patients treated with curatively intended radiotherapy for non-small cell lung cancer (NSCLC).Patients and Methods: Data were individually collected retrospectively for all patients diagnosed with NSCLC subjected to curatively intended radiotherapy (>= 50 Gy) in Sweden during the time period 1990 to 2000.Results: Esophagitis was the only radiation-induced toxicity with an impact on survival (hazard ratio=0.83, p=0.016). However, in a multivariate model, with clinical-and treatment-related factors taken into consideration, the impact of esophagitis on survival was no longer statistically significant (hazard ratio=0.88, p=0.17).Conclusion: The effect on survival seen in univariate analysis may be related to higher radiation dose and to the higher prevalence of chemotherapy in this group. The results do not suggest that the toxicities examined have any detrimental effect on overall survival.
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| 29. |
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| 30. |
- Jiang, X., et al.
(författare)
-
Shared heritability and functional enrichment across six solid cancers
- 2019
-
Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10
-
Tidskriftsartikel (refereegranskat)abstract
- Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer (r(g) = 0.57, p = 4.6 x 10(-8)), breast and ovarian cancer (r(g) = 0.24, p = 7 x 10(-5)), breast and lung cancer (r(g) = 0.18, p = 1.5 x 10(-6)) and breast and colorectal cancer (r(g) = 0.15, p = 1.1 x 10(-4)). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
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| 31. |
- Johansson, Pernilla, et al.
(författare)
-
Mould growth on kiln-dried and air-dried timber
- 2013
-
Ingår i: European Journal of Wood & Wood Products. - : Springer Science and Business Media LLC. - 0018-3768 .- 1436-736X. ; 71:4, s. 473-481
-
Tidskriftsartikel (refereegranskat)abstract
- The problem with discoloration, due to fungal growth, of wooden outdoor constructions seems to have increased in recent years. One reason for this increase might be an impact of new drying methods of timber. Modern kiln drying methods use high temperatures in an effort to shorten the drying process, which leads to fast capillary water transport and subsequently redistribution and accumulation of dissolved substances at the surface. These can then be used as nutrients by fungi. In this study, wood was dried according to different simulated drying schedules. The mould resistance of the timber was then tested. Wood dried at room temperature was used as a reference. No differences could be confirmed at the end of the test; mould growth was extensive on all the samples. However, mould growth started earlier on the kiln-dried samples than on air-dried timber. As for the discolouring fungus, there was a clear difference between wood dried at room temperature and kiln-dried wood, though no difference could be established between the two artificial methods.
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| 32. |
- Kronholm, Thomas, et al.
(författare)
-
Implementering av skyddsbågar på fyrhjulingar : en utvärdering av användares erfarenheter av ett vältskydd
- 2023
-
Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Intresset för fyrhjulingar har ökat under de senaste åren och fyrhjulingen är idag ett frekvent använt arbets- och nöjesfordon i Sverige. Enbart under år 2021 registrerades 12 000 nya fyrhjulingar i Sverige. Med en mer utbredd användning av fyrhjulingar så har också antalet allvarliga olyckor och dödsfall i samband med fyrhjulingskörning ökat. Trafikverket, försäkringsbolag, skogsföretag, forskare och en del branschorganisationer har under de senaste åren därför initierat flera projekt och insatser i syfte att öka säkerheten och minska antalet omkomna och skadade fyrhjulingsanvändare. En säkerhetshöjande åtgärd som återkommande lyfts fram i forskningen är att utrusta fyrhjulingen med ett vältskydd, en så kallad skyddsbåge, som skyddar föraren vid vältningsolyckor. Vid en vältningsolycka riskerar föraren att hamna i kläm under maskinen, men med ett vältskydd som hindrar maskinen från att rulla runt så minskar denna risk betydligt. I vissa länder, t.ex. Australien, finns idag krav på att fyrhjulingar skall vara utrustade med någon typ av vältskydd. I Sverige har intresset för att utrusta fyrhjulingen med vältskydd hittills varit begränsat. En del studier har pekat på att det både bland förare och tillverkare har funnits ett motstånd mot implementering av vältskydd, bl.a. på grund av en oro för att det skulle vara hindrande för normal användning.Det övergripande syftet med detta projekt har varit att kartlägga och beskriva erfarenheterna från en stor grupp med användare av fyrhjuling med vältskydd och därigenom öka säkerheten och det allmänna medvetandet om nyttan med vältskydd på fyrhjulingar. En målsättning är att detta arbete kan skynda på utvecklingen av säkerheten för fyrhjulingar och på sikt leda till en storskalig implementering av vältskydd i Sverige, i likhet med den utveckling som redan skett i andra länder.För kunna samla in erfarenheter från fyrhjulingsanvändare med vältskydd så importerades vältskydd av märket Quadbar från Australien och distribuerades till ca 50 personer som hade anmält intresse att montera ett vältskydd på sin fyrhjuling och därefter dela med sig av sina synpunkter och erfarenheter. Dessa synpunkter samlades in vid tre olika enkättillfällen. Den första enkäten gjordes inför monteringen av vältskyddet, den andra efter en kortare tids användning och den sista drygt ett år efter att vältskyddet hade monterats. Den första enkäten besvarades av 50 deltagare, den andra av 38, och den sista enkäten besvarades av 37 deltagare.De vanligaste farhågorna inför projektet var att vältskyddet skulle påverka körningen och framkomligheten, eller att det skulle vara hindrande för transporter. Exempelvis att det kan fastna i låg hängande grenar eller liknande och därmed orsaka en olycka. Andra farhågor var att det skulle vara hindrande för användningen av vissa redskap, så som vinsch eller släp. Ur ett säkerhetsperspektiv var deltagarna generellt positivt inställda till vältskyddet.En stor majoritet av deltagarna använde normalt sin fyrhjuling till transporter av material, person och utrustning i skogsbruket, eller till transporter på gården. Färre än hälften använde den normalt till nöjesåkning. De vanligaste terrängtyperna som fyrhjulingen framfördes i var skogsmark, enskild väg, traktorväg och jordbruksmark. En mindre andel av deltagarna framförde i normala fall fyrhjulingen på allmän väg. Det var mycket vanligt att fyrhjulingen kördes tillsammans med ett tillkopplat släp som saknade bromsar. Drygt hälften av deltagarna transporterade även last på fyrhjulingens bakre eller främre lastbåge.Under testperioden var ca 20 % av deltagarna med om en olycka eller incident med sin fyrhjuling. Totalt inrapporterades tio olyckor eller incidenter. Vid de vältningsolyckor som inträffat hade vältskyddet fungerat som det var tänkt och haft en positiv inverkan på utfallet, enligt de beskrivningar som deltagarna har lämnat. Vid några av de mindre allvarliga incidenterna hade förarna av ovana eller oaktsamhet missbedömt den nya höjden på ekipaget eller glömt bort att de Sammanfattning hade vältskyddet bakom ryggen, vilket hade lett till att vältskyddet hade tagit i när de kört under låga passager (t.ex. en klädlina). Inga personskador har inrapporterats i samband med incidenterna.Deltagarna var generellt nöjda med den vältskydd de hade haft, vilket framgår av att en stor andel uttryckte att det var troligt eller mycket troligt att de skulle rekommendera Quadbar till sina bekanta. Resultaten visar också att deltagarnas säkerhetskänsla ökade med vältskyddet monterad på fyrhjulingen. Detta gällde både för deras egen och för andra förares säkerhet. Deras trygghetskänsla ökade över tid.De mest vanliga bekymren som en del deltagare hade upplevt var att det aktuella vältskyddets infästning försämrade möjligheten att koppla till släpp på fyrhjulingen, samt att det försvårade användningen av vinsch. Den medföljande dragkroksförlängaren ansågs i vissa fall ha för dålig hållfasthet. Några deltagare hade därför gjort modifieringar på vältskyddet, dess infästning, eller något tillbehör till denna för att kunna nyttja fyrhjulingen enligt sina egna behov. Att vältskyddet gjorde ekipaget högre försvårade också transport av fyrhjulingen på släp med kåpa. Flera deltagare efterlyste därför en smidigare lösning för att tillfälligt kunna plocka av eller vika ner vältskyddet. Liknande önskemål hade de som ville kunna använda vinsch eller för att komma åt förvaringsutrymmen som annars blockerades av vältskyddet.En av studiens slutsatser är att vältskyddet generellt verkar ha fungerat bra för de flesta av deltagarna, och användningen av vältskydd kan öka både den upplevda och den faktiska säkerheten vid fyrhjulingsanvändning. Deltagarnas positiva inställning till att rekommendera vältskyddet till bekanta kan antas bidra till ett ökat intresse hos fler att införskaffa denna eller liknande vältskydd. Projektet har också synliggjort vad som särskilt behöver utvecklas för att just Quadbar ska bli ännu bättre lämpad för fyrhjulingsanvändare som främst nyttjar den i skogsbruket.
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| 33. |
- Lee, Man K.S., et al.
(författare)
-
Defective AMPK regulation of cholesterol metabolism accelerates atherosclerosis by promoting HSPC mobilization and myelopoiesis
- 2022
-
Ingår i: Molecular Metabolism. - : Elsevier. - 2212-8778. ; 61
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: Dysregulation of cholesterol metabolism in the liver and hematopoietic stem and progenitor cells (HSPCs) promotes atherosclerosis development. Previously, it has been shown that HMG-CoA-Reductase (HMGCR), the rate-limiting enzyme in the mevalonate pathway, can be phosphorylated and inactivated by the metabolic stress sensor AMP-activated protein kinase (AMPK). However, the physiological significance of AMPK regulation of HMGCR to atherogenesis has yet to be elucidated. The aim of this study was to determine the role of AMPK/HMGCR axis in the development of atherosclerosis.Methods: We have generated a novel atherosclerotic-prone mouse model with defects in the AMPK regulation of HMGCR (Apoe−/−/Hmgcr KI mice). Atherosclerotic lesion size, plaque composition, immune cell and lipid profiles were assessed in Apoe−/− and Apoe−/−/Hmgcr KI mice.Results: In this study, we showed that both male and female atherosclerotic-prone mice with a disruption of HMGCR regulation by AMPK (Apoe−/−/Hmgcr KI mice) display increased aortic lesion size concomitant with an increase in plaque-associated macrophages and lipid accumulation. Consistent with this, Apoe−/−/Hmgcr KI mice exhibited an increase in total circulating cholesterol and atherogenic monocytes, Ly6-Chi subset. Mechanistically, increased circulating atherogenic monocytes in Apoe−/−/Hmgcr KI mice was associated with enhanced egress of bone marrow HSPCs and extramedullary myelopoiesis, driven by a combination of elevated circulating 27-hydroxycholesterol and intracellular cholesterol in HSPCs.Conclusions: Our results uncovered a novel signalling pathway involving AMPK-HMGCR axis in the regulation of cholesterol homeostasis in HSPCs, and that inhibition of this regulatory mechanism accelerates the development and progression of atherosclerosis. These findings provide a molecular basis to support the use of AMPK activators that currently undergoing Phase II clinical trial such as O–3O4 and PXL 770 for reducing atherosclerotic cardiovascular disease risks.
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| 34. |
- Micke, Patrick, et al.
(författare)
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Gene Copy Number Aberrations Are Associated with Survival in Histologic Subgroups of Non-small Cell Lung Cancer
- 2011
-
Ingår i: Journal of Thoracic Oncology. - 1556-0864 .- 1556-1380. ; 6:11, s. 1833-1840
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Non-small cell lung cancer (NSCLC) is characterized by a multitude of genetic aberrations with unknown clinical impact. In this study, we aimed to identify gene copy number changes that correlate with clinical outcome in NSCLC. To maximize the chance to identify clinically relevant events, we applied a strategy involving two prognostically extreme patient groups. Methods: Short-term (<20 month; n = 53) and long-term survivors (>58 month; n = 47) were selected from a clinically well-characterized NSCLC patient cohort with available fresh frozen tumor specimens. The samples were analyzed using high-resolution single-nucleotide polymorphism array technology to assess gene copy number variations and array-based gene expression profiling. The molecular data were combined with information on clinical parameters. Results: Genetic aberrations were strongly associated with tumor histology. In adenocarcinoma (n = 50), gene copy number gains on chromosome 8q21-q24.3 (177 genes) were more frequent in long-term than in short-term survivors. In squamous cell carcinoma (n = 28), gains on chromosome 14q23.1-24.3 (133 genes) were associated with shorter survival, whereas losses in a neighboring region, 14q31.1-32.33 (110 genes), correlated with favorable outcome. In accordance with copy number gains and losses, messenger RNA expression levels of corresponding genes were increased or decreased, respectively. Conclusion: Comprehensive tumor profiling permits the integration of genomic, histologic, and clinical data. We identified gene copy number gains and losses, with corresponding changes in messenger RNA levels that were associated with prognosis in adenocarcinoma and squamous cell carcinoma of the lung.
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| 35. |
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| 36. |
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| 37. |
- Mthembu, Yolanda H., et al.
(författare)
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Recombinant mucin-type proteins carrying LacdiNAc on differentO-glycan core chains fail to supportH. pyloribinding
- 2020
-
Ingår i: Molecular Omics. - : Royal Society of Chemistry (RSC). - 1742-206X .- 1742-2051 .- 2515-4184. ; 16:3, s. 243-257
-
Tidskriftsartikel (refereegranskat)abstract
- The beta 4-N-acetylgalactosaminyltransferase 3 (B4GALNT3) transfers GalNAc in a beta 1,4-linkage to GlcNAc forming the LacdiNAc (LDN) determinant on oligosaccharides. The LacdiNAc-binding adhesin (LabA) has been suggested to mediate attachment ofHelicobacter pylorito the gastric mucosaviabinding to the LDN determinant. TheO-glycan core chain specificity of B4GALNT3 is poorly defined. We investigated the specificity of B4GALNT3 on GlcNAc residues carried byO-glycan core 2, core 3 and extended core 1 precursors using transient transfection of CHO-K1 cells and a mucin-type immunoglobulin fusion protein as reporter protein. Binding of the LabA-positiveH. pyloriJ99 and 26695 strains to mucin fusion proteins carrying the LDN determinant on differentO-glycan core chains and human gastric mucins with and without LDN was assessed in a microtiter well-based binding assay, while the binding of(125)I-LDN-BSA to various clinicalH. pyloriisolates was assessed in solution. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and western blotting confirmed the requirement of a terminal GlcNAc for B4GALNT3 activity. B4GALNT3 added a beta 1,4-linked GalNAc to GlcNAc irrespective of whether the latter was carried by a core 2, core 3 or extended core 1 chain. No LDN-mediated adhesion ofH. pyloristrains 26 695 and J99 to LDN determinants on gastric mucins or a mucin-type fusion protein carrying core 2, 3 and extended core 1O-glycans were detected in a microtiter well-based adhesion assay and no binding of a(125)I-labelled LDN-BSA neoglycoconjugate to clinicalH. pyloriisolates was identified.
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| 38. |
- Nordström, Ulrika, 1971-
(författare)
-
Early Rostrocaudal Patterning of the CNS
- 2005
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The transformation of an initially uniform population of epiblast cells into an intricately complex central nervous system (CNS) is one of the most fascinating processes during embryonic development. Presumptive neural cells are initially specified as cells of forebrain character. Studies in various vertebrates have indicated that cells of more caudal neural character, that will generate the brain stem and spinal cord, are generated through the reprogramming of these initial rostral cells. The initial regionalization of these neural progenitor cells is central to all further diversification of neuronal cell types and the subsequent formation of functional euronal circuits. The aim of this thesis has been to enhance our understanding of which stages of embryonic development that are critical for the initial rostrocaudal regionalization of neural precursor cells, and which signaling mechanisms that orchestrate this early diversification.Both human and chick embryos have the shape of a flat disc during gastrulation. At this early stage, the chick neural plate is already regionalized and cells positioned at distinct rostrocaudal levels are specified to generate cells exhibiting a gene expression profile characteristic of the forebrain, midbrain, rostral hindbrain and caudal spinal cord, respectively. In addition, the Isthmic organizer (IsO), a secondary signaling centre at the midbrain–hindbrain border that is required for the further development of this region, is also specified already at the gastrula stage. Caudal neural character is induced by signals from adjacent tissues - the primitive streak and the paraxial mesoderm. Wingless/Wnts, Fibroblastic growth factors (FGFs) and retinoids (RA) are signaling molecules that have been proposed to promote caudal embryonic development, and exhibit spatio- emporal expression patterns that coincide with early caudalizing activities. The caudalizing activity that emanates from the gastrula stage paraxial mesoderm is mediated by Wnt signals, and the induction of caudal neural character by Wnts results from a direct action on neural precursor cells. In the presence of FGF activity, graded Wnt signaling is sufficient to induce cells exhibiting caudal forebrain, midbrain and rostral hindbrain character. The discrimination between rostral hindbrain and caudal spinal cord character appear to depend on a gradient of both Wnt and FGF signals.At hindbrain and spinal cord levels the patterned generation of neural progenitor cells along the rostrocaudal axis controls the generation of different classes of motor neurons in response to diffusible Sonic hedgehog (Shh) signals. Gastrula stage Wnt signaling is also required for this subsequent generation of motor neuron subtypes characteristic of the hindbrain and spinal cord.Later, at the early somite stage, cells characteristic of the caudal hindbrain and rostral spinal cord are specified adjacent to RA producing paraxial mesoderm. Opponent RA and FGF signals appear to act on, and refine the rostrocaudal identity of the initial hindbrain and spinal cord cells induced by gastrula stage Wnt based signals. Consistently, combinatorial Wnt, FGF and/or RA signals are sufficient to reconstruct neural progenitor cells that differentiate into motor neurons characteristic of the caudal hindbrain, rostral spinal cord and caudal spinal cord, respectively, in response to Shh.
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| 39. |
- Nordström, Ulrika, et al.
(författare)
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Progressive induction of caudal neural character by graded Wnt signaling
- 2002
-
Ingår i: Nature Neuroscience. - : Nature Publishing Group. - 1097-6256 .- 1546-1726. ; 5:6, s. 525-532
-
Tidskriftsartikel (refereegranskat)abstract
- Early in differentiation, all neural cells have a rostral character. Only later do posteriorly positioned neural cells acquire characteristics of caudal forebrain, midbrain and hindbrain cells. Caudalization of neural tissue in the chick embryo apparently involves the convergent actions of (i) fibroblast growth factor (FGF) signaling and (ii) signaling from the caudal paraxial mesoderm, or 'PMC activity', which has not yet been defined molecularly. Here we report evidence that Wnt signaling underlies PMC activity, and show that Wnt signals act directly and in a graded manner on anterior neural cells to induce their progressive differentiation into caudal forebrain, midbrain and hindbrain cells.
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| 40. |
- ODonnell, Michael, et al.
(författare)
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Registered Replication Report: Dijksterhuis and van Knippenberg (1998)
- 2018
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Ingår i: Perspectives on Psychological Science. - : SAGE PUBLICATIONS LTD. - 1745-6916 .- 1745-6924. ; 13:2, s. 268-294
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Tidskriftsartikel (refereegranskat)abstract
- Dijksterhuis and van Knippenberg (1998) reported that participants primed with a category associated with intelligence (professor) subsequently performed 13% better on a trivia test than participants primed with a category associated with a lack of intelligence (soccer hooligans). In two unpublished replications of this study designed to verify the appropriate testing procedures, Dijksterhuis, van Knippenberg, and Holland observed a smaller difference between conditions (2%-3%) as well as a gender difference: Men showed the effect (9.3% and 7.6%), but women did not (0.3% and -0.3%). The procedure used in those replications served as the basis for this multilab Registered Replication Report. A total of 40 laboratories collected data for this project, and 23 of these laboratories met all inclusion criteria. Here we report the meta-analytic results for those 23 direct replications (total N = 4,493), which tested whether performance on a 30-item general-knowledge trivia task differed between these two priming conditions (results of supplementary analyses of the data from all 40 labs, N = 6,454, are also reported). We observed no overall difference in trivia performance between participants primed with the professor category and those primed with the hooligan category (0.14%) and no moderation by gender.
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| 41. |
- Olander, Susanne, et al.
(författare)
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Convergent Wnt and FGF signaling at the gastrula stage induce the formation of the isthmic organizer.
- 2006
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Ingår i: Mechanisms of Development. - : Elsevier BV. - 0925-4773 .- 1872-6356. ; 123:2, s. 166-176
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Tidskriftsartikel (refereegranskat)abstract
- The development of the vertebrate brain depends on the formation of local organizing centres within the neural tube that express secreted signals that refine local neural progenitor identity. The isthmic organizer (IsO) forms at the isthmic constriction and is required for the growth and ordered development of mesencephalic and metencephalic structures. The formation of the IsO, which is characterized by the generation of a complex pattern of cells at the midbrain-hindbrain boundary, has been described in detail. However, when neural plate cells are initially instructed to form the IsO, the molecular nature of the inductive signals remain poorly defined. We now provide evidence that convergent Wnt and FGF signaling at the gastrula stage are required to generate the complex polarized pattern of cells characteristic of the IsO, and that Wnt and FGF signals in combination are sufficient to reconstruct, in naïve forebrain cells, an IsO-like structure that exhibits an organizing activity that mimics the endogenous IsO when transplanted into the diencephalon of chick embryos.
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| 42. |
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| 43. |
- Patthey, Cédric, et al.
(författare)
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Wnt-regulated temporal control of BMP exposure directs the choice between neural plate border and epidermal fate
- 2009
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Ingår i: Development. - : The Company of Biologists. - 0950-1991 .- 1477-9129. ; 136:1, s. 73-83
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Tidskriftsartikel (refereegranskat)abstract
- The non-neural ectoderm is divided into neural plate border and epidermal cells. At early blastula stages, Wnt and BMP signals interact to induce epidermal fate, but when and how cells initially acquire neural plate border fate remains poorly defined. We now provide evidence in chick that the specification of neural plate border cells is initiated at the late blastula stage and requires both Wnt and BMP signals. Our results indicate, however, that at this stage BMP signals can induce neural plate border cells only when Wnt activity is blocked, and that the two signals in combination generate epidermal cells. We also provide evidence that Wnt signals do not play an instructive role in the generation of neural plate border cells, but promote their generation by inducing BMP gene expression, which avoids early simultaneous exposure to the two signals and generates neural plate border instead of epidermal cells. Thus, specification of neural plate border cells is mediated by a novel Wnt-regulated BMP-mediated temporal patterning mechanism.
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| 44. |
- Persson, Erik, 1972-, et al.
(författare)
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Very Low Energy High Yield Pulping
- 2022
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Ingår i: Proceedings of the International Mechanical Pulping Conference. ; , s. 41-46
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- The project goal was to efficiently separate spruce fibers with preserved fiber stiffness and a low content of unsepa-rated fibers (shive content max~1%) using minimal amounts of electricity. The project tested process variants based on the .HT-CTMP-process concept. Above room temperature, the mechanical properties of water saturated wood are pri-marily determined by the lignin, which softens with increas-ing temperature and water content. The lignin is not evenly distributed in the wood structure, and the pattern of fiber separation in wood will therefore to a large extent be de-pendent on the properties of the lignin. The relative softening temperature increases with increasing strain rate. In me-chanical defibration at temperatures below the lignin soften-ing temperature, a large proportion of the fibers will frac-ture across the fiber direction. At elevated temperatures, above the lignin softening interval, an increasing proportion of the fibers will be separated in the middle lamella along the fiber axis, i.e. with a higher fiber separation selectivity. Sulfonation of wood reduces the degree of crosslinking in lignin and increases the charge. The structural change makes the wood softer at a certain temperature. In a pilot trial Norway spruce (Picea abies (L.) Karst.) chips were re-fined at 130, 160 or 180 degrees C after impregnation with 25 or 50 kg/ton sodium sulfite in a pH range from 4,5 to 12. The temperature was the most important factor affecting the shives/energy relation. The sulfite charge and the pH-level also affect the results, but less than the temperature within the evaluated range. The results show there is a potential to produce pulps with a shive content of about 1% using less than 200 kWh/ton at 180 °C in the pre-heater and inlet of the refiner. Producing a high yield, fiber material with pre-served fiber dimensions and low content of shives using a few hundred kWh/ton opens for new opportunities both in paper and board production, but also in new applications where the bonding between fibers is achieved by other means than in traditional paper and paperboard products.
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| 45. |
- Pfeiffer, Thomas, et al.
(författare)
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Predicting the replicability of social and behavioural science claims in a crisis: The COVID-19 Preprint Replication Project
- 2023
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Replications are important for assessing the reliability of published findings. However, they are costly, and it is infeasible to replicate everything. Accurate, fast, lower-cost alternatives such as eliciting predictions could accelerate assessment for rapid policy implementation in a crisis. We elicited judgments from participants on 100 claims from preprints about an emerging area of research (COVID-19 pandemic) using an interactive structured elicitation protocol, and we conducted 29 new high-powered replications. After interacting with their peers, participant groups with lower task expertise (‘beginners’) updated their estimates and confidence in their judgements significantly more than groups with greater task expertise (‘experienced’). For experienced individuals, the average accuracy was 0.57 (95% CI: [0.53, 0.61]) after interaction, and they correctly classified 61% of claims; beginners’ average accuracy was 0.58 (95% CI: [0.54, 0.62]), correctly classifying 69% of claims. The difference in accuracy between groups was not statistically significant, and their judgments on the full set of claims were correlated (r=.48). These results suggest that both beginners and more experienced participants using a structured process have some ability to make better-than-chance predictions about the reliability of ‘fast science’ under conditions of high uncertainty. However, given the importance of such assessments for making evidence-based critical decisions in a crisis, more research is required to understand who the right experts in forecasting replicability are and how their judgements ought to be elicited.
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| 46. |
- Rao, Shuan, et al.
(författare)
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RANK rewires energy homeostasis in lung cancer cells and drives primary lung cancer
- 2017
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Ingår i: Genes & Development. - : Cold Spring Harbor Laboratory. - 0890-9369 .- 1549-5477. ; 31:20, s. 2099-2112
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Tidskriftsartikel (refereegranskat)abstract
- Lung cancer is the leading cause of cancer deaths. Besides smoking, epidemiological studies have linked female sex hormones to lung cancer in women; however, the underlying mechanisms remain unclear. Here we report that the receptor activator of nuclear factor-kB (RANK), the key regulator of osteoclastogenesis, is frequently expressed in primary lung tumors, an active RANK pathway correlates with decreased survival, and pharmacologic RANK inhibition reduces tumor growth in patient-derived lung cancer xenografts. Clonal genetic inactivation of KRas(G12D) in mouse lung epithelial cells markedly impairs the progression of KRas(G12D)-driven lung cancer, resulting in a significant survival advantage. Mechanistically, RANK rewires energy homeostasis in human and murine lung cancer cells and promotes expansion of lung cancer stem-like cells, which is blocked by inhibiting mitochondrial respiration. Our data also indicate survival differences in KRas(G12D)-driven lung cancer between male and female mice, and we show that female sex hormones can promote lung cancer progression via the RANK pathway. These data uncover a direct role for RANK in lung cancer and may explain why female sex hormones accelerate lung cancer development. Inhibition of RANK using the approved drug denosumab may be a therapeutic drug candidate for primary lung cancer.
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| 47. |
- Reihill, Mark, et al.
(författare)
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Synthesis of a B-Antigen Hexasaccharide, a B-Lewis b Heptasaccharide and Glycoconjugates Thereof to Investigate Binding Properties of Helicobacter pylori
- 2023
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Ingår i: Chemistry - A European Journal. - : Wiley. - 0947-6539 .- 1521-3765. ; 29:16
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Tidskriftsartikel (refereegranskat)abstract
- Infecting the stomach of almost 50 % of people, Helicobacter pylori is a causative agent of gastritis, peptic ulcers and stomach cancers. Interactions between bacterial membrane-bound lectin, Blood group Antigen Binding Adhesin (BabA), and human blood group antigens are key in the initiation of infection. Herein, the synthesis of a B-antigen hexasaccharide (B6) and a B-Lewis b heptasaccharide (BLeb7) and Bovine Serum Albumin glycoconjugates thereof is reported to assess the binding properties and preferences of BabA from different strains. From a previously reported trisaccharide acceptor a versatile key Lacto-N-tetraose tetrasaccharide intermediate was synthesized, which allowed us to explore various routes to the final targets, either via initial introduction of fucosyl residues followed by introduction of the B-determinant or vice versa. The first approach proved unsuccessful, whereas the second afforded the target structures in good yields. Protein conjugation using isothiocyanate methodology allowed us to reach high glycan loadings (up to 23 per protein) to mimic multivalent displays encountered in Nature. Protein glycoconjugate inhibition binding studies were performed with H. pylori strains displaying high or low affinity for Lewis b hexasaccharide structures showing that the binding to the high affinity strain was reduced due to the presence of the B-determinant in the Bleb7-conjugates and further reduced by the absence of the Lewis fucose residue in the B6-conjugate.
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| 48. |
- Schmidt, Marcus, et al.
(författare)
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A comprehensive analysis of human gene expression profiles identifies stromal immunoglobulin kappa C as a compatible prognostic marker in human solid tumors
- 2012
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Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 18:9, s. 2695-2703
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE:Although the central role of the immune system for tumor prognosis is generally accepted a single robust marker is not yet available.EXPERIMENTAL DESIGN:Based on ROC (receiver operating characteristic) analyses robust markers were identified from a 60 gene B-cell derived metagene and analyzed in gene expression profiles of 1810 breast cancer, 1056 non-small cell lung cancer, 513 colorectal and 426 ovarian cancer patients. Protein and RNA levels were examined in paraffin embedded tissue of 330 breast cancer patients. The cell types were identified using immunohistochemical co-staining and confocal fluorescence microscopy.RESULTS:We identified immunoglobulin kappa C (IGKC) which as a single marker is similarly predictive and prognostic as the entire B-cell metagene. IGKC was consistently associated with metastasis free survival across different molecular subtypes in node-negative breast cancer (n=965) and predicted response to anthracycline-based neoadjuvant chemotherapy (n=845) [P less than 0.001]. In addition, IGKC gene expression was prognostic in non-small cell lung cancer and colorectal cancer. No association was observed in ovarian cancer. IGKC protein expression was significantly associated with survival in paraffin embedded tissues of 330 breast cancer patients. Tumor infiltrating plasma cells were identified as the source of IGKC expressionCONCLUSION:Our findings provide IGKC as a novel diagnostic marker for risk stratification in human cancer and support concepts to exploit the humoral immune response for anti-cancer therapy. It could be validated in several independent cohorts and performed similarly well in RNA from fresh frozen as well as from paraffin tissue and on protein level by immunostaining.
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| 49. |
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| 50. |
- Sundqvist, Bertil, et al.
(författare)
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Structural and physical properties of pressure polymerized C60
- 1998
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Ingår i: Carbon, vol. 36 issue 5-6. - : Elsevier B.V.. ; 36:5-6, s. 657-660
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Konferensbidrag (refereegranskat)abstract
- We discuss the structural and dynamic properties of C60 polymerized under low-P, low-T conditions, and suggest that the disordered mixed orthorhombic-tetragonal-rhombohedral phases produced under these conditions arise from nucleation of molecular chains in random directions because of the quasi-free molecular rotation under standard reaction conditions in the fcc phase of C60. Polymerization in He gives results qualitatively different from those obtained in other media.
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