| 1. |
- Chen, Hongjie, et al.
(author)
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Large-scale cross-cancer fine-mapping of the 5p15.33 region reveals multiple independent signals
- 2021
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In: Human Genetics and Genomics Advances. - : Cell Press. - 2666-2477. ; 2:3
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) have identified thousands of cancer risk loci revealing many risk regions shared across multiple cancers. Characterizing the cross-cancer shared genetic basis can increase our understanding of global mechanisms of cancer development. In this study, we collected GWAS summary statistics based on up to 375,468 cancer cases and 530,521 controls for fourteen types of cancer, including breast (overall, estrogen receptor [ER]-positive, and ER-negative), colorectal, endometrial, esophageal, glioma, head/neck, lung, melanoma, ovarian, pancreatic, prostate, and renal cancer, to characterize the shared genetic basis of cancer risk. We identified thirteen pairs of cancers with statistically significant local genetic correlations across eight distinct genomic regions. Specifically, the 5p15.33 region, harboring the TERT and CLPTM1L genes, showed statistically significant local genetic correlations for multiple cancer pairs. We conducted a cross-cancer fine-mapping of the 5p15.33 region based on eight cancers that showed genome-wide significant associations in this region (ER-negative breast, colorectal, glioma, lung, melanoma, ovarian, pancreatic, and prostate cancer). We used an iterative analysis pipeline implementing a subset-based meta-analysis approach based on cancer-specific conditional analyses and identified ten independent cross-cancer associations within this region. For each signal, we conducted cross-cancer fine-mapping to prioritize the most plausible causal variants. Our findings provide a more in-depth understanding of the shared inherited basis across human cancers and expand our knowledge of the 5p15.33 region in carcinogenesis.
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| 2. |
- Fredricsson, Malin, et al.
(author)
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Nationell luftövervakning Sakrapport med data från övervakning inom Programområde Luft t.o.m 2019
- 2021
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Reports (other academic/artistic)abstract
- Naturvårdsverket ansvarar för den nationella luftövervakningen i bakgrundsmiljö i Sverige. I rapporten redovisas resultat från verksamheten inom Programområde Luft avseende mätningar (genomförda av IVL, SU, SLU och SMHI) till och med 2019 och regionala modellberäkningar (utförda av SMHI) till och med 2018.För flertalet av de luftföroreningskomponenter som övervakas inom den nationella miljöövervakningen har det, sedan mätningarna startade för mellan 20 och 40 år sedan, generellt sett skett en avsevärd förbättring avseende såväl halter i luft som deposition i bakgrundsmiljö. Utvecklingen har dock varierat i något olika utsträckning beroende på komponenter och lokalisering i landet. Föroreningsbelastningen är oftast lägre ju längre norrut i landet man kommer.För de flesta ämnen som det finns miljökvalitetsnormer (MKN) respektive miljömål för ligger halterna i regional bakgrund avsevärt lägre än angivna gräns- och målvärden. Halterna av ozon överskrider dock i dagsläget (2019) MKN för hälsa.
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| 3. |
- Hillgren, Per-Anders, et al.
(author)
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Glossary: Collaborative Future-Making
- 2020
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Other publication (other academic/artistic)abstract
- Collaborative Future-Making is a research platform at the Faculty of Culture and Society at Malmö University that is concerned with how to envision, elaborate and prototype multiple, inclusive, and sustainable futures. The platform gathers around 20 researchers that share a methodological interest in how critical perspectives from the humanities and social sciences can be combined with the constructive and collaborative aspects of making and prototyping in design research.The research centers around two major themes:Critical imagination, which focuses on how basic assumptions, norms and structures can be challenged to widen the perspectives on what can constitute socially, culturally, ecologically and economically sustainable and resilient futures.Collaborative engagements, which focuses on how we can set up more inclusive collaborations to prototype and discuss alternative futures, engaging not only professionals and policy makers but also citizens and civil society.During 2019 the research group set out to make a shared glossary for collaborative future-making. The glossary is multiple in purpose and exists in several versions. Hopefully there will be more to come. At first, the making and articulation of the glossary was used within the research group as an exercise to share concepts that we found central to collaborative future-making, coming from different disciplines. This published version of the glossary was assembled to be used during a workshop called Imagining Collaborative Future-Making, which gathered a group of international researchers from different disciplines.The collection of concepts reflects the heterogeneous and diverse character of the research group and a strong belief in that plurality regarding ontologies and epistemologies will be crucial to be able to handle the multiple uncertainties and complex challenges we have to face in the future. Some of the concepts are already well established within different research communities, but gain a specific meaning in relation to the research area. Others are more preliminary attempts to advance our understanding or probe into new potential practices within collaborative future-making. In that sense the concepts in the glossary are well situated and grounded in past and ongoing research within this research group, at the same time as they are meant to suggest, propose and point towards practices and approaches yet to come.The concepts in this glossary are not only meant to be descriptive but also performative. In that sense, assembling and circulating this glossary is part of collaborative future-making. As pointed out by Michelle Westerlaken in her articulation of “Doing Concepts” (see page 15), “...without proposing, critiquing, or working towards a common or uncommon understanding of certain concepts, it becomes impossible to ‘make futures’ in any deliberate fashion.”
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| 4. |
- Klein, Alison P., et al.
(author)
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An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population.
- 2013
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In: PLOS ONE. - : Public Library of Science. - 1932-6203. ; 8:9
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Journal article (peer-reviewed)abstract
- PURPOSE: We developed an absolute risk model to identify individuals in the general population at elevated risk of pancreatic cancer.PATIENTS AND METHODS: Using data on 3,349 cases and 3,654 controls from the PanScan Consortium, we developed a relative risk model for men and women of European ancestry based on non-genetic and genetic risk factors for pancreatic cancer. We estimated absolute risks based on these relative risks and population incidence rates.RESULTS: Our risk model included current smoking (multivariable adjusted odds ratio (OR) and 95% confidence interval: 2.20 [1.84-2.62]), heavy alcohol use (>3 drinks/day) (OR: 1.45 [1.19-1.76]), obesity (body mass index >30 kg/m(2)) (OR: 1.26 [1.09-1.45]), diabetes >3 years (nested case-control OR: 1.57 [1.13-2.18], case-control OR: 1.80 [1.40-2.32]), family history of pancreatic cancer (OR: 1.60 [1.20-2.12]), non-O ABO genotype (AO vs. OO genotype) (OR: 1.23 [1.10-1.37]) to (BB vs. OO genotype) (OR 1.58 [0.97-2.59]), rs3790844(chr1q32.1) (OR: 1.29 [1.19-1.40]), rs401681(5p15.33) (OR: 1.18 [1.10-1.26]) and rs9543325(13q22.1) (OR: 1.27 [1.18-1.36]). The areas under the ROC curve for risk models including only non-genetic factors, only genetic factors, and both non-genetic and genetic factors were 58%, 57% and 61%, respectively. We estimate that fewer than 3/1,000 U.S. non-Hispanic whites have more than a 5% predicted lifetime absolute risk.CONCLUSION: Although absolute risk modeling using established risk factors may help to identify a group of individuals at higher than average risk of pancreatic cancer, the immediate clinical utility of our model is limited. However, a risk model can increase awareness of the various risk factors for pancreatic cancer, including modifiable behaviors.
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| 5. |
- Klemetz, Viktor, et al.
(author)
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Nationell luftövervakning : Sakrapport med data från övervakning inom Programområde Luft t. o. m. 2021
- 2023
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Reports (other academic/artistic)abstract
- Naturvårdsverket ansvarar för den nationella luftövervakningen i bakgrundsmiljö. I rapporten redovisas resultat från verksamheten inom Programområde Luft avseende mätningar (genomförda av IVL Svenska Miljöinstitutet (IVL),Institutionen för Miljövetenskap vid Stockholms universitet (SU), Institutionen för Mark och Miljö vid Sveriges lantbruksuniversitet (SLU), Chalmers tekniska högskola och Sveriges meteorologiska och hydrologiska institut (SMHI) till och med 2021 samt regionala modellberäkningar (utförda av SMHI) till och med 2020. För flertalet av de luftföroreningskomponenter som övervakas inom den nationella miljöövervakningen har det, sedan mätningarna startade för mellan 20 och 45 år sedan, generellt skett en avsevärd förbättring avseende såväl halter i luft som deposition i bakgrundsmiljö.Utvecklingen har dock varierat i något olika utsträckning beroende på komponenter och lokalisering i landet. Föroreningsbelastningen är oftast lägre ju längre norrut i landet man kommer.För de flesta ämnen som det finns miljökvalitetsnormer (MKN) respektive miljömål för ligger halterna avsevärt lägre än angivna gräns- och målvärden. Halterna av marknära ozon överskrider i dagsläget MKN för hälsa vid ett flertal mätstationer i södra Sverige.För såväl partiklar (i form av PM2,5) och bensen (i urban bakgrund) är risken låg att haltnivåer överstiger miljömålens preciseringar.
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| 6. |
- Lindström, Michelle
(author)
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Functional roles of protein phase separated assemblies in cellular stress response and proteinopathies
- 2022
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Doctoral thesis (other academic/artistic)abstract
- For a long time, pertinent biological conundrums, such as the organization and compartmentalization of the cytoplasm and nucleoplasm, perplexed the scientific community. The organization of the complex biochemistry in an accurate space and time manner could not be explained without the enclosure of a membrane. In recent years, many of the processes relating to membraneless cellular organization and cytoplasmic regulation have become illuminated by the incorporation of liquid-liquid phase separation (LLPS) into biology. Phase separation entails a process by which a homogenous liquid solution of macromolecules, such as proteins or nucleic acids, separates into two distinct co-existing phases, a dense and dilute phase. LLPS thereby enables a spatiotemporal control over complex biochemical reactions, a vital process for cellular functions. Altered phase separation dynamics can lead to aberrant condensate assemblies that mature into a more solid-like state and are associated with disease. The list of cell compartments and biological processes thought to be formed and regulated through the process of phase separation has grown at a fast pace and includes a plethora of cellular functions, such as stress granule (SG) formation and disease associated protein aggregation. However, the mechanisms regulating the formation, and subsequent impact, of these phase-separated assemblies still remain elusive. In this thesis, regulation of SG formation is explored using genome-wide phenomic screening. The results show a signaling cascade involving e.g. long-chain-base sphingolipids and ubiquitin, regulating the phase separation behavior of Lsm7 and further SG induction. Cellular consequences of cytotoxic aggregation of the ALS-associated disease protein FUS (fused in sarcoma) are also explored. A cytotoxic gain-of-function involving protein sequestration, resulting in delayed cell cycle progression, is identified. Overall, our findings elucidate the underlying mechanisms and cellular impacts of phase separated assemblies in health and disease.
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| 7. |
- Lindström, Michelle, et al.
(author)
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Lsm7 phase-separated condensates trigger stress granule formation
- 2022
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 13:1
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Journal article (peer-reviewed)abstract
- Stress granules are non-membranous organelles connected to stress responses and age-related disease. Here, the authors identify a conserved yeast protein, Lsm7, that facilitates stress granule formation through dynamic liquid-liquid phase separation condensates upon 2-deoxy-D-glucose-induced stress. Stress granules (SGs) are non-membranous organelles facilitating stress responses and linking the pathology of age-related diseases. In a genome-wide imaging-based phenomic screen, we identify Pab1 co-localizing proteins under 2-deoxy-D-glucose (2-DG) induced stress in Saccharomyces cerevisiae. We find that deletion of one of the Pab1 co-localizing proteins, Lsm7, leads to a significant decrease in SG formation. Under 2-DG stress, Lsm7 rapidly forms foci that assist in SG formation. The Lsm7 foci form via liquid-liquid phase separation, and the intrinsically disordered region and the hydrophobic clusters within the Lsm7 sequence are the internal driving forces in promoting Lsm7 phase separation. The dynamic Lsm7 phase-separated condensates appear to work as seeding scaffolds, promoting Pab1 demixing and subsequent SG initiation, seemingly mediated by RNA interactions. The SG initiation mechanism, via Lsm7 phase separation, identified in this work provides valuable clues for understanding the mechanisms underlying SG formation and SG-associated human diseases.
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| 8. |
- Lindström, Michelle, et al.
(author)
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Yeast as a Model to Unravel Mechanisms Behind FUS Toxicity in Amyotrophic Lateral Sclerosis
- 2018
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In: Frontiers in Molecular Neuroscience. - : Frontiers Media SA. - 1662-5099. ; 11
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Journal article (peer-reviewed)abstract
- Fused in sarcoma (FUS) is a multifunctional DNA/RNA-binding protein predominantly localized in the cell nucleus. However, FUS has been shown to accumulate and form aggregates in the cytoplasm when mislocalized there due to mutations. These FUS protein aggregates are known as pathological hallmarks in a subset of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) cases. In this review, we discussed recent research developments on elucidating the molecular mechanisms behind FUS protein aggregation and toxicity. We mainly focus on studies using the budding yeast (Saccharomyces cerevisiae) as a model system, especially on results acquired from yeast genome-wide screens addressing FUS aggregation and toxicity. Human homologs of the FUS toxicity suppressors, identified from these studies, indicate a strong relevance and correlation to a human disease model. By using yeast as a FUS cytotoxicity model these studies provided valuable clues on potential novel targets for therapeutic intervention in ALS.
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| 9. |
- Liu, Qian, et al.
(author)
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Yeast mismatch repair components are required for stable inheritance of gene silencing
- 2020
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In: Plos Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 16:5
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Journal article (peer-reviewed)abstract
- Alterations in epigenetic silencing have been associated with ageing and tumour formation. Although substantial efforts have been made towards understanding the mechanisms of gene silencing, novel regulators in this process remain to be identified. To systematically search for components governing epigenetic silencing, we developed a genome-wide silencing screen for yeast (Saccharomyces cerevisiae) silent mating type locus HMR. Unexpectedly, the screen identified the mismatch repair (MMR) components Pms1, Mlh1, and Msh2 as being required for silencing at this locus. We further found that the identified genes were also required for proper silencing in telomeres. More intriguingly, the MMR mutants caused a redistribution of Sir2 deacetylase, from silent mating type loci and telomeres to rDNA regions. As a consequence, acetylation levels at histone positions H3K14, H3K56, and H4K16 were increased at silent mating type loci and telomeres but were decreased in rDNA regions. Moreover, knockdown of MMR components in human HEK293T cells increased subtelomeric DUX4 gene expression. Our work reveals that MMR components are required for stable inheritance of gene silencing patterns and establishes a link between the MMR machinery and the control of epigenetic silencing. Author summary During aging, gene silencing also decreases and it has been hypothesized that the collapse of epigenetic control networks may in part explain age-related diseases. For example, changes in epigenetic silencing are linked with different stages of tumor formation and progression. Great efforts have been made on investigating the mechanisms of establishment and maintenance silencing at silent mating cassettes in yeast. In this work, by applying a genome-wide silencing screening approach, we identified the conserved subunits of the mismatch repair (MMR) machinery (Pms1, Mlh1 and Msh2) as new components of the epigenetic silencing regulation machinery in yeast. We also found that depletion of mismatch repair subunits (Mlh1 and Msh2) led to impaired telomere-length related expression in mammalian cells. This indicates that these components probably have an evolutionarily conserved role on influencing gene silencing from yeast to humans. Further studies the functional roles of these MMR components on epigenetic silencing in mammalian model systems or relevant cancer patient samples will increase our understanding of MMR-related oncogenesis.
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| 10. |
- Lundgren, Markus, et al.
(author)
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Analgesic antipyretic use among young children in the TEDDY study : No association with islet autoimmunity
- 2017
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In: BMC Pediatrics. - : Springer Science and Business Media LLC. - 1471-2431. ; 17:1
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Journal article (peer-reviewed)abstract
- Background: The use of analgesic antipyretics (ANAP) in children have long been a matter of controversy. Data on their practical use on an individual level has, however, been scarce. There are indications of possible effects on glucose homeostasis and immune function related to the use of ANAP. The aim of this study was to analyze patterns of analgesic antipyretic use across the clinical centers of The Environmental Determinants of Diabetes in the Young (TEDDY) prospective cohort study and test if ANAP use was a risk factor for islet autoimmunity. Methods: Data were collected for 8542 children in the first 2.5 years of life. Incidence was analyzed using logistic regression with country and first child status as independent variables. Holm's procedure was used to adjust for multiplicity of intercountry comparisons. Time to autoantibody seroconversion was analyzed using a Cox proportional hazards model with cumulative analgesic use as primary time dependent covariate of interest. For each categorization, a generalized estimating equation (GEE) approach was used. Results: Higher prevalence of ANAP use was found in the U.S. (95.7%) and Sweden (94.8%) compared to Finland (78.1%) and Germany (80.2%). First-born children were more commonly given acetaminophen (OR 1.26; 95% CI 1.07, 1.49; p = 0.007) but less commonly Non-Steroidal Anti-inflammatory Drugs (NSAID) (OR 0.86; 95% CI 0.78, 0.95; p = 0.002). Acetaminophen and NSAID use in the absence of fever and infection was more prevalent in the U.S. (40.4%; 26.3% of doses) compared to Sweden, Finland and Germany (p < 0.001). Acetaminophen or NSAID use before age 2.5 years did not predict development of islet autoimmunity by age 6 years (HR 1.02, 95% CI 0.99-1.09; p = 0.27). In a sub-analysis, acetaminophen use in children with fever weakly predicted development of islet autoimmunity by age 3 years (HR 1.05; 95% CI 1.01-1.09; p = 0.024). Conclusions: ANAP use in young children is not a risk factor for seroconversion by age 6 years. Use of ANAP is widespread in young children, and significantly higher in the U.S. compared to other study sites, where use is common also in absence of fever and infection.
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