| 1. |
- Sampson, Joshua N., et al.
(författare)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 2. |
- Figueroa, Jonine D., et al.
(författare)
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Identification of a novel susceptibility locus at 13q34 and refinement of the 20p12.2 region as a multi-signal locus associated with bladder cancer risk in individuals of European ancestry
- 2016
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Ingår i: Human Molecular Genetics. - : Oxford University Press. - 0964-6906 .- 1460-2083. ; 25:6, s. 1203-1214
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Tidskriftsartikel (refereegranskat)abstract
- Candidate gene and genome-wide association studies (GWAS) have identified 15 independent genomic regions associated with bladder cancer risk. In search for additional susceptibility variants, we followed up on four promising single-nucleotide polymorphisms (SNPs) that had not achieved genome-wide significance in 6911 cases and 11 814 controls (rs6104690, rs4510656, rs5003154 and rs4907479, P < 1 × 10−6), using additional data from existing GWAS datasets and targeted genotyping for studies that did not have GWAS data. In a combined analysis, which included data on up to 15 058 cases and 286 270 controls, two SNPs achieved genome-wide statistical significance: rs6104690 in a gene desert at 20p12.2 (P = 2.19 × 10−11) and rs4907479 within the MCF2L gene at 13q34 (P = 3.3 × 10−10). Imputation and fine-mapping analyses were performed in these two regions for a subset of 5551 bladder cancer cases and 10 242 controls. Analyses at the 13q34 region suggest a single signal marked by rs4907479. In contrast, we detected two signals in the 20p12.2 region—the first signal is marked by rs6104690, and the second signal is marked by two moderately correlated SNPs (r2 = 0.53), rs6108803 and the previously reported rs62185668. The second 20p12.2 signal is more strongly associated with the risk of muscle-invasive (T2-T4 stage) compared with non-muscle-invasive (Ta, T1 stage) bladder cancer (case–case P ≤ 0.02 for both rs62185668 and rs6108803). Functional analyses are needed to explore the biological mechanisms underlying these novel genetic associations with risk for bladder cancer.
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| 5. |
- Sundal, Christina, et al.
(författare)
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An AARS variant as the likely cause of Swedish type hereditary diffuse leukoencephalopathy with spheroids
- 2019
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Ingår i: Acta Neuropathologica Communications. - : Springer Science and Business Media LLC. - 2051-5960. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Swedish type Hereditary Diffuse Leukoencephalopathy with Spheroids (HDLS-S) is a severe adult-onset leukoencephalopathy with the histopathological hallmark of neuraxonal degeneration with spheroids, described in a large family with a dominant inheritance pattern. The initial stage of the disease is dominated by frontal lobe symptoms that develop into a rapidly advancing encephalopathy with pyramidal, deep sensory, extrapyramidal and optic tract symptoms. Median survival is less than 10 years. Recently, pathogenic mutations in CSF1R were reported in a clinically and histologically similar leukoencephalopathy segregating in several families. Still, the cause of HDLS-S remained elusive since its initial description in 1984, with no CSF1R mutations identified in the family. Here we update the original findings associated with HDLS-S after asystematic and recent assessment of several family members. We also report the results from exome sequencing analysesindicating the p.Cys152Phe variant in the alanyl tRNA synthetase (AARS) gene as the probable cause of this disease. The variant affects an amino acid located in the aminoacylation domain of the protein and does not cause differences in splicing or expression in the brain. Brain pathology in one case after 10 years of disease duration showed the end stage of the disease to be characterized by widespread liquefaction of the white matter leaving only some macrophages and glial cells behind the centrifugally progressing front. These results point to AARS as a candidate gene for rapidly progressing adult onset CSF1R-negative leukoencephalopathies.
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| 6. |
- Vrieling, Alina, et al.
(författare)
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One-carbon metabolism biomarkers and risk of urothelial cell carcinoma in the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 145:9, s. 2349-2359
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Tidskriftsartikel (refereegranskat)abstract
- Published associations between dietary folate and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status. This nested case-control analysis within the European Prospective Investigation into Cancer and Nutrition (EPIC) investigated associations between pre-diagnostic serum folate, homocysteine, vitamins B6 and B12 and the risk of urothelial cell carcinomas of the bladder (UCC). A total of 824 patients with newly diagnosed UCC were matched with 824 cohort members. Serum folate, homocysteine, and vitamins B6 and B12 were measured. Odds ratios (OR) and 95% confidence intervals (CI) for total, aggressive, and non-aggressive UCC were estimated using conditional logistic regression with adjustment for smoking status, smoking duration and intensity, and other potential confounders. Additionally, statistical interaction with smoking status was assessed. A halving in serum folate concentrations was moderately associated with risk of UCC (OR: 1.18; 95% CI: 0.98-1.43), in particular aggressive UCC (OR: 1.34; 95% CI: 1.02-1.75; p-heterogeneity = 0.19). Compared to never smokers in the highest quartile of folate concentrations, this association seemed only apparent among current smokers in the lowest quartile of folate concentrations (OR: 6.26; 95% CI: 3.62-10.81, p-interaction = 0.07). Dietary folate was not associated with aggressive UCC (OR: 1.26; 95% CI: 0.81-1.95; p-heterogeneity = 0.14). No association was observed between serum homocysteine, vitamins B6 and B12 and risk of UCC. This study suggests that lower serum folate concentrations are associated with increased UCC risk, in particular aggressive UCC. Residual confounding by smoking cannot be ruled out and these findings require confirmation in future studies with multiple measurements.
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| 7. |
- Carlsson, Åsa, 1978, et al.
(författare)
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The influence of cardiac triggering time and an optimization strategy for improved cardiac MR spectroscopy.
- 2017
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Ingår i: Zeitschrift fur medizinische Physik. - : Elsevier BV. - 1876-4436 .- 0939-3889. ; 27:4, s. 310-317
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Tidskriftsartikel (refereegranskat)abstract
- To study how cardiac motion affects the spectral quality in cardiac MR spectroscopy and to establish an optimization strategy for the cardiac triggering time for improved quality and success rate of cardiac MRS.Water spectra were acquired while the cardiac triggering time was varied over the cardiac cycle, and five different spectral quality parameters were studied (frequency, phase, linewidth, amplitude and noise). Furthermore, three different optimization strategies for the cardiac triggering time were tested, and finally, a comparison was made between water suppressed lipid spectra acquired in systole and diastole.The cardiac triggering time had a high impact on the spectral quality, especially on the mean signal amplitude and the standard deviation of the signal amplitude, phase and linewidth. Generally, the highest spectral quality was observed for spectra acquired in mid to end systole, at approximately 23% of the cardiac cycle. The exact optimal triggering time differed between subjects and needed to be individually optimized. To optimize the triggering time with our proposed MRS-method gave in average 13% higher signal than when the triggering time was determined through imaging. Lipid spectra acquired in systole demonstrated higher quality with improved SNR compared with acquisitions made in diastole.This study shows that the spectral quality in cardiac MRS is strongly dependent on the cardiac triggering time, and that the spectral quality as well as the repeatability between acquisitions is greatly improved when the cardiac triggering time is individually optimized in mid to end systole using MRS.
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| 8. |
- Dalmo, Johanna, et al.
(författare)
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Priming increases the anti-tumor effect and therapeutic window of 177Lu-octreotate in nude mice bearing human small intestine neuroendocrine tumor GOT1.
- 2017
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Ingår i: EJNMMI Research. - : Springer Science and Business Media LLC. - 2191-219X. ; 7:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: 177Lu-[DOTA0, Tyr3]-octreotate (177Lu-octreotate) is used for treatment of patients with somatostatin receptor (SSTR) expressing neuroendocrine tumors. However, complete tumor remission is rarely seen, and optimization of treatment protocols is needed. In vitro studies have shown that irradiation can up-regulate the expression of SSTR1, 2 and 5, and increase 177Lu-octreotate uptake. The aim of the present study was to examine the anti-tumor effect of a 177Lu-octreotate priming dose followed 24 h later by a second injection of 177Lu-octreotate compared to a single administration of 177Lu-octreotate, performed on the human small intestine neuroendocrine tumor cell line, GOT1, transplanted to nude mice. RESULTS: Priming resulted in a 1.9 times higher mean absorbed dose to the tumor tissue per administered activity, together with a reduced mean absorbed dose for kidneys. Priming gave the best overall anti-tumor effects. Magnetic resonance imaging showed no statistically significant difference in tumor response between treatment with and without priming. Gene expression analysis demonstrated effects on cell cycle regulation. Biological processes associated with apoptotic cell death were highly affected in the biodistribution and dosimetry study, via differential regulation of, e.g., APOE, BAX, CDKN1A, and GADD45A. CONCLUSIONS: Priming had the best overall anti-tumor effects and also resulted in an increased therapeutic window. Results indicate that potential biomarkers for tumor regrowth may be found in the p53 or JNK signaling pathways. Priming administration is an interesting optimization strategy for 177Lu-octreotate therapy of neuroendocrine tumors, and further studies should be performed to determine the mechanisms responsible for the reported effects.
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| 9. |
- Elf, Anna-Karin, et al.
(författare)
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Radioembolization Versus Bland Embolization for Hepatic Metastases from Small Intestinal Neuroendocrine Tumors: Short-Term Results of a Randomized Clinical Trial.
- 2018
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Ingår i: World Journal of Surgery. - : Springer Science and Business Media LLC. - 0364-2313 .- 1432-2323. ; 42:2, s. 506-513
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Tidskriftsartikel (refereegranskat)abstract
- Radioembolization (RE) with intra-arterial administration of 90Y microspheres is a promising technique for the treatment of liver metastases from small intestinal neuroendocrine tumors (SI-NET) not amenable to surgery or local ablation. However, studies comparing RE to other loco-regional therapies are lacking. The aim of this randomized study was to compare the therapeutic response and safety after RE and bland hepatic arterial embolization (HAE), and to investigate early therapy-induced changes with diffusion-weighted MRI (DWI-MRI).Eleven patients were included in a prospective randomized controlled pilot study, six assigned to RE and five to HAE. Response according to RECIST 1.1 using MRI or CT at 3 and 6months post-treatment was recorded as well as changes in DWI-MRI parameters after 1month. Data on biochemical tumor response, toxicity, and side effects were also collected.Three months after treatment, all patients in the HAE group showed partial response according to RECIST while none in the RE group did (p=0.0022). After 6months, the response rates were 4/5 (80%) and 2/6 (33%) in the HAE and RE groups, respectively (NS). DWI-MRI metrics could not predict RECIST response, but lower pretreatment ADC(120-800) and larger ADC(0-800) increase at 1month were related to larger decrease in tumor diameter when all tumors were counted.HAE resulted in significantly higher RECIST response after 3months, but no difference compared to RE remained after 6months. These preliminary findings indicate that HAE remains a safe option for the treatment of liver metastases from SI-NET, and further studies are needed to establish the role of RE and the predictive value of MR-DWI.
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| 10. |
- Eriksson Sörman, Daniel, et al.
(författare)
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Longitudinal effects of bilingualism on dual-tasking
- 2017
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:12
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Tidskriftsartikel (refereegranskat)abstract
- An ongoing debate surrounds whether bilinguals outperform monolinguals in tests of executive processing. The aim of this study was to investigate if there are long-term (10 year) bilingual advantages in executive processing, as indexed by dual-task performance, in a sample that were 40–65 years at baseline. The bilingual (n = 24) and monolingual (n = 24) participants were matched on age, sex, education, fluid intelligence, and study sample. Participants performed free-recall for a 12-item list in three dual-task settings wherein they sorted cards either during encoding, retrieval, or during both encoding and retrieval of the word-list. Free recall without card sorting was used as a reference to compute dual-task costs. The results showed that bilinguals significantly outperformed monolinguals when they performed card-sorting during both encoding and retrieval of the word-list, the condition that presumably placed the highest demands on executive functioning. However, dual-task costs increased over time for bilinguals relative to monolinguals, a finding that is possibly influenced by retirement age and limited use of second language in the bilingual group.
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