| 1. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
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- 2019
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Tidskriftsartikel (refereegranskat)
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| 3. |
- Aglago, Elom K., et al.
(författare)
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A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk
- 2023
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Ingår i: Cancer Research. - : American Association For Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:15, s. 2572-2583
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.SIGNIFICANCE: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.
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| 4. |
- Amundadottir, Laufey, et al.
(författare)
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Genome-wide association study identifies variants in the ABO locus associated with susceptibility to pancreatic cancer.
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41, s. 986-990
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Tidskriftsartikel (refereegranskat)abstract
- We conducted a two-stage genome-wide association study of pancreatic cancer, a cancer with one of the lowest survival rates worldwide. We genotyped 558,542 SNPs in 1,896 individuals with pancreatic cancer and 1,939 controls drawn from 12 prospective cohorts plus one hospital-based case-control study. We conducted a combined analysis of these groups plus an additional 2,457 affected individuals and 2,654 controls from eight case-control studies, adjusting for study, sex, ancestry and five principal components. We identified an association between a locus on 9q34 and pancreatic cancer marked by the SNP rs505922 (combined P = 5.37 x 10(-8); multiplicative per-allele odds ratio 1.20; 95% confidence interval 1.12-1.28). This SNP maps to the first intron of the ABO blood group gene. Our results are consistent with earlier epidemiologic evidence suggesting that people with blood group O may have a lower risk of pancreatic cancer than those with groups A or B.
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| 5. |
- Andersson, Joel, et al.
(författare)
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Evolution of structures and hydrothermal alteration in a Palaeoproterozoic supracrustal belt : Constraining paired deformation–fluid flow events in an Fe and Cu–Au prospective terrain in northern Sweden
- 2020
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Ingår i: Solid Earth. - : Copernicus publications. - 1869-9510 .- 1869-9529. ; 11:2, s. 547-578
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Tidskriftsartikel (refereegranskat)abstract
- An approximately 90 km long Palaeoproterozoic supracrustal belt in the northwestern Norrbotten ore province (northernmost Sweden) was investigated to characterize its structural components, assess hydrothermal alteration–structural geology correlations, and constrain a paired deformation–fluid flow evolution for the belt. New geological mapping of five key areas (Eustiljåkk, Ekströmsberg, Tjårrojåkka, Kaitum West, and Fjällåsen–Allavaara) indicates two major compressional events (D1 and D2) have affected the belt, with each associated with hydrothermal alteration types typical for iron oxide–apatite and iron oxide Cu–Au systems in the region. Early D1 generated a regionally distributed, penetrative S1 foliation and oblique reverse shear zones that show a southwest-block-up sense of shear that formed in response to NE–SW crustal shortening. Peak regional metamorphism at epidote–amphibolite facies broadly overlaps with this D1 event. Based on overprinting relationships, D1 is associated with regional scapolite ± albite, magnetite + amphibole, and late calcite alteration of mafic rock types. These hydrothermal mineral associations linked to D1 structures may form part of a regionally pervasive evolving fluid flow event but are separated in this study by crosscutting relationships.During D2 deformation, folding of S0–S1 structures generated F2 folds with steeply plunging fold axes in low-strain areas. NNW-trending D1 shear zones experienced reverse dip-slip reactivation and strike-slip-dominated movements along steep, E–W-trending D2 shear zones, producing brittle-plastic structures. Hydrothermal alteration linked to D2 structures is a predominantly potassic–ferroan association comprising K-feldspar ± epidote ± quartz ± biotite ± magnetite ± sericite ± sulfides. Locally, syn- or post-tectonic calcite is the main alteration mineral in D2 shear zones that intersect mafic rocks. Our results highlight the importance of combining structural geology with the study of hydrothermal alterations at regional to belt scales to understand the temporal–spatial relationship between mineralized systems. Based on the mapping results and microstructural investigations as well as a review of earlier tectonic models presented for adjacent areas, we suggest a new structural model for this part of the northern Fennoscandian Shield. The new model emphasizes the importance of reactivation of early structures, and the model harmonizes with tectonic models presented by earlier workers based mainly on petrology of the northern Norrbotten area.
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| 6. |
- Arslan, Alan A., et al.
(författare)
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Anthropometric Measures, Body Mass Index, and Pancreatic Cancer A Pooled Analysis From the Pancreatic Cancer Cohort Consortium (PanScan)
- 2010
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Ingår i: Archives of Internal Medicine. - 0003-9926. ; 170:9, s. 791-802
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity has been proposed as a risk factor for pancreatic cancer. Methods: Pooled data were analyzed from the National Cancer Institute Pancreatic Cancer Cohort Consortium (PanScan) to study the association, between prediagnostic anthropometric measures and risk of pancreatic cancer. PanScan applied a nested case-control study design and included 2170 cases and 2209 control subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression for cohort-specific quartiles of body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]), weight, height, waist circumference, and waist to hip ratio as well as conventional BMI categories (underweight, <18.5; normal weight, 18.5-24.9; overweight, 25.0-29.9; obese, 30.0-34.9; and severely obese, >= 35.0). Models were adjusted for potential confounders. Results: In all of the participants, a positive association between increasing BMI and risk of pancreatic cancer was observed (adjusted OR for the highest vs lowest BMI guartile, 1.33; 95% Cl, 1.12-1.58; P-trend<.001). In men, the adjusted OR for pancreatic cancer for the highest vs lowest quartile of BMI was 1.33 (95% Cl, 1.04-1.69; P-trend<.03), and in women it was 1.34 (95% Cl, 1.05-1.70; P-trend=.01). Increased waist to hip ratio was associated with increased risk of pancreatic cancer in women (adjusted OR for the highest vs lowest quartile, 1.87; 95% Cl, 1.31-2.69; P-trend=.003) but less so in men. Conclusions: These findings provide strong support for a positive association between BMI and pancreatic cancer risk. In addition, centralized fat distribution may increase pancreatic cancer risk, especially in women. Arch Intern Med. 2010;170(9):791 -802
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| 7. |
- Bauer, Tobias, Associate professor, 1982-, et al.
(författare)
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Structural Controls on Iron Oxide Copper-Gold Mineralization and Related Alteration in a Paleoproterozoic Supracrustal Belt: Insights from the Nautanen Deformation Zone and Surroundings, Northern Sweden
- 2022
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Ingår i: Economic geology and the bulletin of the Society of Economic Geologists. - : Society of Economic Geologists. - 0361-0128 .- 1554-0774. ; 117:2, s. 327-359
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Tidskriftsartikel (refereegranskat)abstract
- The Nautanen deformation zone in the Gällivare area of northern Sweden is a highly Cu-mineralized, magnetite-rich, large-scale shear zone with a long-lived (~100 m.y.) deformation, hydrothermal alteration, and mineralization history. This composite structure hosts the Aitik porphyry Cu-Au-Ag ± Mo deposit and several Cu-Au ± Fe ± Ag ± Mo occurrences assigned to the iron oxide copper-gold (IOCG) deposit class. The Nautanen deformation zone was a locus for polyphase deformation and intermittent metasomatic-hydrothermal activity that overprinted middle Orosirian (ca. 1.90–1.88 Ga) continental arc-related volcanic-plutonic rocks. The deformation zone is characterized by intense shearing fabrics that form a series of subvertical to moderately W-dipping, NNW-SSE–trending, first-order shear zones with oblique reverse kinematics and related NNE-SSW–oriented second-order shear zones that control hydrothermal alteration patterns and Cu-Au mineralization.Hydrothermal alteration in the study area formed during several phases. Volcanic-volcaniclastic rocks to the east and west of the Nautanen deformation zone display low to moderately intense, pervasive to selectively pervasive (i.e., patchy zones or bands, disseminations) sericite ± feldspar, amphibole + biotite + magnetite ± tourmaline, and K-feldspar + hematite alteration. Both the amphibole + biotite and K-feldspar + hematite associations occur adjacent to NNW- and NE-oriented deformation zones and are locally associated with minor sulfide. Within the deformation zone, a moderate to intense biotite + amphibole + garnet + magnetite + tourmaline + sericite alteration assemblage is typically associated with chalcopyrite + pyrrhotite + pyrite and forms linear and subparallel, mainly NNW-oriented seams, bands, and zones that locally appear to overprint possibly earlier scapolite + sericite ± feldspar alteration. Late-stage epidote ± quartz ± feldspar alteration (retrograde saussuritization) forms selectively pervasive zones and epidote veinlets across the area and is partly related to brittle faulting.A magnetite-amphibole-biotite–rich, penetrative S1 foliation records shortening during early Svecokarelian-related deformation (D1) and can be related to ca. 1.88 to 1.87 Ga arc accretion processes and basin inversion that overlaps with regional peak metamorphism to near mid-amphibolite facies conditions and a potential initial Cu mineralization event. Folding and repeated shearing along the Nautanen deformation zone can be assigned to a second, late-Svecokarelian deformation event (D2 stage, ca. 1.82–1.79 Ga) taking place at a higher crustal level. This D2 deformation phase is related to late-stage accretionary processes active during a transition to a stage of postorogenic collapse, and it was accompanied by abundant, syntectonic intrusions. D2-related magmatism produced high-temperature and low-pressure conditions and represents a regional magmatic-hydrothermal event that controlled the recrystallization/remobilization of magnetite, biotite, and amphibole. Associated shear zone reactivation during D2 favors the utilization of the Nautanen deformation zone as a fluid conduit, which preferentially controlled the siting and formation of epigenetic Cu-Au mineralization with distinctive IOCG characteristics within second-order shear zones.
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| 8. |
- Bouras, Emmanouil, et al.
(författare)
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Genome-wide interaction analysis of folate for colorectal cancer risk
- 2023
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Ingår i: American Journal of Clinical Nutrition. - : Elsevier. - 0002-9165 .- 1938-3207. ; 118:5, s. 881-891
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Tidskriftsartikel (refereegranskat)abstract
- Background: Epidemiological and experimental evidence suggests that higher folate intake is associated with decreased colorectal cancer (CRC) risk; however, the mechanisms underlying this relationship are not fully understood. Genetic variation that may have a direct or indirect impact on folate metabolism can provide insights into folate's role in CRC.Objectives: Our aim was to perform a genome-wide interaction analysis to identify genetic variants that may modify the association of folate on CRC risk.Methods: We applied traditional case-control logistic regression, joint 3-degree of freedom, and a 2-step weighted hypothesis approach to test the interactions of common variants (allele frequency >1%) across the genome and dietary folate, folic acid supplement use, and total folate in relation to risk of CRC in 30,550 cases and 42,336 controls from 51 studies from 3 genetic consortia (CCFR, CORECT, GECCO).Results: Inverse associations of dietary, total folate, and folic acid supplement with CRC were found (odds ratio [OR]: 0.93; 95% confidence interval [CI]: 0.90, 0.96; and 0.91; 95% CI: 0.89, 0.94 per quartile higher intake, and 0.82 (95% CI: 0.78, 0.88) for users compared with nonusers, respectively). Interactions (P-interaction < 5×10-8) of folic acid supplement and variants in the 3p25.2 locus (in the region of Synapsin II [SYN2]/tissue inhibitor of metalloproteinase 4 [TIMP4]) were found using traditional interaction analysis, with variant rs150924902 (located upstream to SYN2) showing the strongest interaction. In stratified analyses by rs150924902 genotypes, folate supplementation was associated with decreased CRC risk among those carrying the TT genotype (OR: 0.82; 95% CI: 0.79, 0.86) but increased CRC risk among those carrying the TA genotype (OR: 1.63; 95% CI: 1.29, 2.05), suggesting a qualitative interaction (P-interaction = 1.4×10-8). No interactions were observed for dietary and total folate.Conclusions: Variation in 3p25.2 locus may modify the association of folate supplement with CRC risk. Experimental studies and studies incorporating other relevant omics data are warranted to validate this finding.
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| 9. |
- Cioaca, Mihaela-Elena, et al.
(författare)
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Mineralogical Setting of Precious Metals at the Assarel Porphyry Copper-Gold Deposit, Bulgaria, as Supporting Information for the Development of New Drill Core 3D XCT-XRF Scanning Technology
- 2020
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Ingår i: Minerals. - : MDPI AG. - 2075-163X. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- A petrographic investigation of ore samples from the Assarel porphyry copper deposit in the Srednogorie metallogenic zone (Bulgaria) constrains the setting and character of precious metals (Au, Ag, PGE) and related minerals within the deposit. This work supports renewed interest in understanding the deportment of precious metals and provides mineralogical knowledge during the testing and validation of novel drill core 3D X-ray computed tomography-X-ray fluorescence (XCT-XRF) scanning technology being developed as part of the X-MINE project. Scanning electron microscopy-energy dispersive spectrometry (SEM-EDS) results indicate precious metals occur in their native state (Au, Ag), as sulfides (Ag), sulfosalts (Au), tellurides (Ag, Pd), and selenides (Ag), and typically form micron-sized inclusions in pyrite and chalcopyrite or are disseminated in the groundmass of the rock. Preservation of early Fe oxide-chalcopyrite +/- bornite assemblage as relics in the more dominant pyrite-chalcopyrite mineralization assemblage supports mineral disequilibrium relationships and multi-stage mineralization events. Several rare minerals (e.g., merenskyite, acanthite, sorosite, tetra-auricupride, auricupride, greenokite, bismuthinite, nagyagite, native Ni) are reported for the first time at Assarel and highlight the mineralogical diversity of the ore. The occurrence of precious metals and related minerals at Assarel attest to a complex hydrothermal system that underwent progressive physicochemical changes during the evolution of the mineralizing system (e.g., redox conditions, fluid chemistry).
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| 10. |
- Drew, David A., et al.
(författare)
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Two genome-wide interaction loci modify the association of nonsteroidal anti-inflammatory drugs with colorectal cancer
- 2024
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Ingår i: Science Advances. - : American Association for the Advancement of Science (AAAS). - 2375-2548. ; 10:22
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Tidskriftsartikel (refereegranskat)abstract
- Regular, long-term aspirin use may act synergistically with genetic variants, particularly those in mechanistically relevant pathways, to confer a protective effect on colorectal cancer (CRC) risk. We leveraged pooled data from 52 clinical trial, cohort, and case-control studies that included 30,806 CRC cases and 41,861 controls of European ancestry to conduct a genome-wide interaction scan between regular aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and imputed genetic variants. After adjusting for multiple comparisons, we identified statistically significant interactions between regular aspirin/NSAID use and variants in 6q24.1 (top hit rs72833769), which has evidence of influencing expression of TBC1D7 (a subunit of the TSC1-TSC2 complex, a key regulator of MTOR activity), and variants in 5p13.1 (top hit rs350047), which is associated with expression of PTGER4 (codes a cell surface receptor directly involved in the mode of action of aspirin). Genetic variants with functional impact may modulate the chemopreventive effect of regular aspirin use, and our study identifies putative previously unidentified targets for additional mechanistic interrogation.
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