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- Graff, M., et al.
(författare)
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Genome-wide physical activity interactions in adiposity. A meta-analysis of 200,452 adults
- 2017
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Ingår i: PLoS Genet. - : Public Library of Science (PLoS). - 1553-7404 .- 1553-7390. ; 13:4
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Tidskriftsartikel (refereegranskat)abstract
- Physical activity (PA) may modify the genetic effects that give rise to increased risk of obesity. To identify adiposity loci whose effects are modified by PA, we performed genome-wide interaction meta-analyses of BMI and BMI-adjusted waist circumference and waist-hip ratio from up to 200,452 adults of European (n = 180,423) or other ancestry (n = 20,029). We standardized PA by categorizing it into a dichotomous variable where, on average, 23% of participants were categorized as inactive and 77% as physically active. While we replicate the interaction with PA for the strongest known obesity-risk locus in the FTO gene, of which the effect is attenuated by similar to 30% in physically active individuals compared to inactive individuals, we do not identify additional loci that are sensitive to PA. In additional genome-wide meta-analyses adjusting for PA and interaction with PA, we identify 11 novel adiposity loci, suggesting that accounting for PA or other environmental factors that contribute to variation in adiposity may facilitate gene discovery.
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| 6. |
- Mahajan, Anubha, et al.
(författare)
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Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes
- 2018
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:4, s. 559-571
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Tidskriftsartikel (refereegranskat)abstract
- We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 × 10−7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low-frequency variants: even for these, effect sizes are modest (odds ratio ≤1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent ‘false leads’ with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition.
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| 7. |
- Ferrari, S, et al.
(författare)
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Neoadjuvant chemotherapy with high-dose ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: A joint study by the Italian and Scandinavian Sarcoma Groups
- 2005
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Ingår i: Journal of Clinical Oncology. - 1527-7755. ; 23:34, s. 8845-8852
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Tidskriftsartikel (refereegranskat)abstract
- Purpose To explore the effect of high-dose ifosfamide in first-line treatment for patients <= 40 years of age with nonmetastatic osteosarcoma of the extremity. Patients and Methods From March 1997 to September 2000, 182 patients were evaluated. Primary treatment consisted of two blocks of high-dose ifosfamide (15 g/m(2)), methotrexate (12 g/m(2)), cisplatin (120 mg/m(2)), and doxorubicin (75 mg/m(2)). Postoperatively, patients received two cycles of doxorubicin (go mg/m(2)), and three cycles each of high-dose ifosfamide, methotrexate, and cisplatin (120 to 150 mg/m(2)). Granulocyte colony-stimulating factor support was mandatory after the high-dose ifosfamide/cisplatin/doxorubicin combination. Results No disease progression was recorded during primary chemotherapy, 164 patients (92%) underwent limb-salvage surgery, four patients (2%) underwent rotation plasty, and 11 patients (6%) had limbs amputated. Three (1.6%) patients died as a result of treatment-related toxicity, and one died as a result of pulmonary embolism after pathologic fracture. Grade 4 neutropenia and thrombocytopenia followed 52% and 31% of all courses, respectively, and mild to severe nephrotoxicity was recorded in 19 patients (10%). The median received dose-intensity compared with protocol was 0.82. With a median follow-up of 55 months, the 5-year probability of event-free survival was 64% (95% CI 57% to 71%) and overall survival was 77% (95% CI 67% to 81%), whereas seven patients (4%) experienced local recurrence. Conclusion The addition of high-dose ifosfamide to methotrexate, cisplatin, and doxorubicin in the preoperative phase is feasible, but with major renal and hematologic toxicities, and survival rates similar to those obtained with four-drug regimens using standard-dose ifosfamide. Italian Sarcoma Group/Scandinavian Sarcoma Group study I showed that in a multicenter setting, more than 90% of patients with osteosarcoma of the extremity can undergo conservative surgery.
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| 8. |
- Mahajan, Anubha, et al.
(författare)
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Multi-ancestry genetic study of type 2 diabetes highlights the power of diverse populations for discovery and translation
- 2022
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Ingår i: Nature Genetics. - : Springer Nature. - 1061-4036 .- 1546-1718. ; 54:5, s. 560-572
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Tidskriftsartikel (refereegranskat)abstract
- We assembled an ancestrally diverse collection of genome-wide association studies (GWAS) of type 2 diabetes (T2D) in 180,834 affected individuals and 1,159,055 controls (48.9% non-European descent) through the Diabetes Meta-Analysis of Trans-Ethnic association studies (DIAMANTE) Consortium. Multi-ancestry GWAS meta-analysis identified 237 loci attaining stringent genome-wide significance (P < 5 x 10(-9)), which were delineated to 338 distinct association signals. Fine-mapping of these signals was enhanced by the increased sample size and expanded population diversity of the multi-ancestry meta-analysis, which localized 54.4% of T2D associations to a single variant with >50% posterior probability. This improved fine-mapping enabled systematic assessment of candidate causal genes and molecular mechanisms through which T2D associations are mediated, laying the foundations for functional investigations. Multi-ancestry genetic risk scores enhanced transferability of T2D prediction across diverse populations. Our study provides a step toward more effective clinical translation of T2D GWAS to improve global health for all, irrespective of genetic background. Genome-wide association and fine-mapping analyses in ancestrally diverse populations implicate candidate causal genes and mechanisms underlying type 2 diabetes. Trans-ancestry genetic risk scores enhance transferability across populations.
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| 9. |
- Wheeler, Eleanor, et al.
(författare)
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Impact of common genetic determinants of Hemoglobin A1c on type 2 diabetes risk and diagnosis in ancestrally diverse populations : A transethnic genome-wide meta-analysis
- 2017
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Ingår i: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 14:9
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Tidskriftsartikel (refereegranskat)abstract
- Background: Glycated hemoglobin (HbA1c) is used to diagnose type 2 diabetes (T2D) and assess glycemic control in patients with diabetes. Previous genome-wide association studies (GWAS) have identified 18 HbA1c-associated genetic variants. These variants proved to be classifiable by their likely biological action as erythrocytic (also associated with erythrocyte traits) or glycemic (associated with other glucose-related traits). In this study, we tested the hypotheses that, in a very large scale GWAS, we would identify more genetic variants associated with HbA1c and that HbA1c variants implicated in erythrocytic biology would affect the diagnostic accuracy of HbA1c. We therefore expanded the number of HbA1c-associated loci and tested the effect of genetic risk-scores comprised of erythrocytic or glycemic variants on incident diabetes prediction and on prevalent diabetes screening performance. Throughout this multiancestry study, we kept a focus on interancestry differences in HbA1c genetics performance that might influence race-ancestry differences in health outcomes.Methods & findings: Using genome-wide association meta-analyses in up to 159,940 individuals from 82 cohorts of European, African, East Asian, and South Asian ancestry, we identified 60 common genetic variants associated with HbA1c. We classified variants as implicated in glycemic, erythrocytic, or unclassified biology and tested whether additive genetic scores of erythrocytic variants (GS-E) or glycemic variants (GS-G) were associated with higher T2D incidence in multiethnic longitudinal cohorts (N = 33,241). Nineteen glycemic and 22 erythrocytic variants were associated with HbA1c at genome-wide significance. GS-G was associated with higher T2D risk (incidence OR = 1.05, 95% CI 1.04-1.06, per HbA1c-raising allele, p = 3 x 10-29); whereas GS-E was not (OR = 1.00, 95% CI 0.99-1.01, p = 0.60). In Europeans and Asians, erythrocytic variants in aggregate had only modest effects on the diagnostic accuracy of HbA1c. Yet, in African Americans, the X-linked G6PD G202A variant (T-allele frequency 11%) was associated with an absolute decrease in HbA1c of 0.81%-units (95% CI 0.66-0.96) per allele in hemizygous men, and 0.68%-units (95% CI 0.38-0.97) in homozygous women. The G6PD variant may cause approximately 2% (N = 0.65 million, 95% CI0.55-0.74) of African American adults with T2Dto remain undiagnosed when screened with HbA1c. Limitations include the smaller sample sizes for non-European ancestries and the inability to classify approximately one-third of the variants. Further studies in large multiethnic cohorts with HbA1c, glycemic, and erythrocytic traits are required to better determine the biological action of the unclassified variants.Conclusions: As G6PD deficiency can be clinically silent until illness strikes, we recommend investigation of the possible benefits of screening for the G6PD genotype along with using HbA1c to diagnose T2D in populations of African ancestry or groups where G6PD deficiency is common. Screening with direct glucose measurements, or genetically-informed HbA1c diagnostic thresholds in people with G6PD deficiency, may be required to avoid missed or delayed diagnoses.
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| 10. |
- Griffiths, HR, et al.
(författare)
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Biomarkers
- 2002
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Ingår i: Molecular aspects of medicine. - 0098-2997. ; 23:1-3, s. 101-208
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Tidskriftsartikel (refereegranskat)
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| 12. |
- Bertoni, M. I., et al.
(författare)
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Nano-XRF and micro-Raman Studies of Metal Impurity Decoration around Dislocations in Multicrystalline Silicon
- 2012
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Ingår i: 2012 38TH IEEE PHOTOVOLTAIC SPECIALISTS CONFERENCE (PVSC). - New York, USA : IEEE. - 9781467300667 ; , s. 1613-1616
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Konferensbidrag (refereegranskat)abstract
- We push the resolution limits of synchrotron-based nano-X-ray fluorescence mapping below 100 nm to investigate the fundamental differences between benign and deleterious dislocations in multicystalline silicon solar cells. We observe that after processing recombination-active dislocations contain a high degree of nanoscale iron and copper decoration, while recombination-inactive dislocations appear clean. To study the origins of the distinct metal decorations around different dislocations we analyze as-grown samples as well as specimens at different stages of processing. We complement our X-ray studies with micro-Raman mapping to understand the relationship between metallic decoration and stress fields around dislocations.
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| 14. |
- Macovez, R., et al.
(författare)
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Electronic surface reconstruction and correlation in the fcc and dimer phases of RbC60
- 2007
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Ingår i: Physical Review B. Condensed Matter and Materials Physics. - 1098-0121 .- 1550-235X. ; 75:19, s. 195424-
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Tidskriftsartikel (refereegranskat)abstract
- A combined photoemission and x-ray absorption study of a RbC60 crystalline film is presented. We find evidence for an electronic charge reconstruction of the film surface in both the fcc and the dimer phases of RbC60. We confirm the previous conclusion on less crystalline films that the dimer phase is insulating. Several observations, such as the presence of molecular features in the photoemission spectra, indicate that at least partial electron localization occurs in the high-temperature fcc phase. In the fcc phase, the surface consists in a half-charge C60(111) plane and appears weakly metallic, as found for the bulk. In the dimer phase, the charge reconstruction simply implies the presence of neutral C60 in the surface layer. The identification of neutral molecules in the surface layer drastically improves the agreement between calculations of the electronic density of states and photoelectron spectra in both phases.
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| 17. |
- Sasi, Binu K., et al.
(författare)
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Inhibition of SYK or BTK augments venetoclax sensitivity in SHP1-negative/BCL-2-positive diffuse large B-cell lymphoma
- 2019
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Ingår i: Leukemia. - : NATURE PUBLISHING GROUP. - 0887-6924 .- 1476-5551. ; 33:10, s. 2416-2428
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Tidskriftsartikel (refereegranskat)abstract
- The BCL-2 inhibitor venetoclax has only limited activity in DLBCL despite frequent BCL-2 overexpression. Since constitutive activation of the B cell receptor (BCR) pathway has been reported in both ABC and GCB DLBCL, we investigated whether targeting SYK or BTK will increase sensitivity of DLBCL cells to venetoclax. We report that pharmacological inhibition of SYK or BTK synergistically enhances venetoclax sensitivity in BCL-2-positive DLBCL cell lines with an activated BCR pathway in vitro and in a xenograft model in vivo, despite the only modest direct cytotoxic effect. We further show that these sensitizing effects are associated with inhibition of the downstream PI3K/AKT pathway and changes in the expression of MCL-1, BIM, and HRK. In addition, we show that BCR-dependent GCB DLBCL cells are characterized by deficiency of the phosphatase SHP1, a key negative regulator of the BCR pathway. Re-expression of SHP1 in GCB DBLCL cells reduces SYK, BLNK, and GSK3 phosphorylation and induces corresponding changes in MCL1, BIM, and HRK expression. Together, these findings suggest that SHP1 deficiency is responsible for the constitutive activation of the BCR pathway in GCB DLBCL and identify SHP1 and BCL-2 as potential predictive markers for response to treatment with a venetoclax/BCR inhibitor combination.
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