| 1. |
- Nyberg, Lars, 1966-, et al.
(author)
-
Individual differences in brain aging : heterogeneity in cortico-hippocampal but not caudate atrophy rates
- 2023
-
In: Cerebral Cortex. - : Oxford University Press. - 1047-3211 .- 1460-2199. ; 33:9, s. 5075-5081
-
Journal article (peer-reviewed)abstract
- It is well documented that some brain regions, such as association cortices, caudate, and hippocampus, are particularly prone to age-related atrophy, but it has been hypothesized that there are individual differences in atrophy profiles. Here, we document heterogeneity in regional-atrophy patterns using latent-profile analysis of 1,482 longitudinal magnetic resonance imaging observations. The results supported a 2-group solution reflecting differences in atrophy rates in cortical regions and hippocampus along with comparable caudate atrophy. The higher-atrophy group had the most marked atrophy in hippocampus and also lower episodic memory, and their normal caudate atrophy rate was accompanied by larger baseline volumes. Our findings support and refine models of heterogeneity in brain aging and suggest distinct mechanisms of atrophy in striatal versus hippocampal-cortical systems.
|
|
| 2. |
- Adesiyun, Adewole, et al.
(author)
-
Review and Evaluation of NRAs : Deliverable D2
- 2023
-
Reports (other academic/artistic)abstract
- Connected and Automated Driving (CAD) is an important area of digital technology that will bring disruption to individuals, economies, and societies. Most forms of CAD require some level of infrastructure support for their safe operation. Additional infrastructure and services to support CAD have the potential to improve safety even further, and to bring other benefits such as increased efficiency or reduced congestion. However, the infrastructure requirements from Original Equipment Manufacturer (OEMs) are not always clear, and it is difficult for National Road Authorities (NRAs) to predict and plan for the future levels of support needed for CAD given rapidly evolving technology and uncertain projections of future CAD demand. In addition, there is also a need for better dialogue among NRAs, OEMs and service providers to articulate those requirements and to define a roadmap and responsibilities for achieving safe and smart roads through CAD.The aim of DiREC is to establish a CAV Readiness Framework and a set of toolkits dedicated to CAVs (Connected and Autonomous Vehicles) that incorporates a wide range of components that affect CAD and the ability of highway infrastructure to support it. These components include machine readability of physical infrastructure, digital services, connectivity, in addition to aspects such as governance of the infrastructure and services, and legal and regulatory requirements. Together these components influence the ability of the NRA to become a digital road operator. The DiREC project will thus provide a framework for NRAs, service providers and OEMs to support CAD. It will consolidate and combine standards, research, and recommendations from other projects and extend research into new areas such as creating a common vision for digital twins among NRAs, understanding connectivity and connectivity requirements to support digital services and analysing how these can be met, reviewing the quality management processes around digital data, and documenting existing legal and regulatory frameworks in all areas relating to CAD.
|
|
| 3. |
- Andersson, Anders, 1983-, et al.
(author)
-
Co-simulation architecture with pedestrian, vehicle, and traffic simulators
- 2021
-
In: Actes (IFSTTAR). - : Driving Simulation Association. ; , s. 181-184
-
Conference paper (peer-reviewed)abstract
- Automated and connected traffic systems with cooperative functionality need effective testing. One way to enable such testing is to represent the current traffic environment by co-simulating different simulators using a communication layer between the simulators for cooperative functionality. With this approach, this paper presents a platform with its included simulators (vehicle, pedestrian, and traffic simulators), the used run-time infrastructure (RTI) for co-simulation, and the connection to the Unreal Engine based visual system for the simulators. The architecture was tested with two vehicle simulators (one autonomous bus and a truck), one pedestrian simulator, and one traffic simulator connected using a cloud-based service for the RTI.
|
|
| 4. |
- Andersson, Emma, 1983-, et al.
(author)
-
Increasing robustness at single-track lines using the indicator robustness in passing pointss
- 2023
-
Conference paper (other academic/artistic)abstract
- When several trains are planned to use the same infrastructure resource, there is always a risk for spreading of delays, which can be hard to recover from. It is a challenge for the Infrastructure Manager to make timetables that accommodate as much traffic as possible, without causing bad on-time performance. Timetable planners are in need of quantitative indicators to assess timetable robustness and accurate methods for how to make the timetable more robust.In this paper we assess the robustness for single-track lines with non-periodic timetables. At single-track lines, trains use the line for running in both directions and the trains can only pass or overtake each other at passing loops. This makes the system more sensitive for delays. In this paper we present a robustness indicator which captures the dependencies between trains at a single-track line. The indicator can be used to illustrate weaknesses in a timetable and also to indicate where and how to insert more robustness. In a simulation study, we show that it is possible to improve the performance by making small timetable adjustments according the indicator, without increasing runtimes or capacity utilization.
|
|
| 5. |
- Andersson White, Pär, 1983-
(author)
-
Social Inequalities in Child Health : Type 1 Diabetes, Obesity, Cardiovascular Risk Factors and the Role of Self-control
- 2024
-
Doctoral thesis (other academic/artistic)abstract
- The Swedish Commission on Health Inequality defined health inequality as systematic differences in health between groups in society with different social positions. All avoidable socioeconomic health inequalities are unfair, and as stated by WHO's Commission on the Social Determinants of Health, we have a moral obligation to try to reduce them. "Putting these inequities right is a matter of social justice. Reducing health inequities is, for the Commission on Social Determinants of Health, an ethical imperative." This ethical imperative is especially apparent regarding the health of children and adolescents. Children’s right to the highest attainable standard of health is also enshrined in Article 24 of the Convention on the Rights of the Child. To reach the goal of a reduction of health inequalities, research is necessary to describe the social gradients of health. Research is also needed to better understand why these gradients occur. A better understanding and knowledge about health inequalities can lead to policies that reduce these inequalities and ensure children’s right to health.This thesis investigates social inequality in child health using data from a Swedish population-based prospective birth cohort, the All Babies in Southeast Sweden (ABIS) cohort. Social inequality in obesity in the ABIS cohort is also compared with other birth cohorts participating in the Elucidating Pathways to Child Health Inequality (EPOCH) collaboration which includes cohorts from six high-income countries; Sweden, the Netherlands, Canada (one national and one cohort from Quebec), UK, Australia, and USA.In Paper 1 we show that health inequalities in overweight and obesity are detectable already at two years of age and that these inequalities increase during childhood. In adolescents, low socioeconomic status increases the risk of becoming overweight and the risk of components of the metabolic syndrome, including high blood pressure and dyslipidemia (low high-density cholesterol).The level of inequality in obesity in the Swedish ABIS cohort was lower than in the other participating countries in the EPOCH collaboration (Paper 2). Inequality was lower in absolute and relative terms when SES was measured by household income. Inequality was also lower in absolute, but not relative, terms when SES was measured by maternal education. This finding indicates that some of the policies implemented in Sweden may attenuate social inequalities in obesity in children. Examples of such policies with evidence for reducing social inequality in obesity implemented in Sweden include universal preschools and free school meals.This thesis also investigates health inequalities in autoimmune disease (Paper 3). In this study, we found that low socioeconomic status increased the risk of Type 1 Diabetes but not the other autoimmune diseases investigated. Path analysis indicated that part of the increased risk in children with low SES of Type 1 Diabetes might be mediated by a higher body mass index and an elevated risk of serious life events.In the final paper, this thesis tests the hypothesis that differences in maternal and child self-control mediate social inequalities in obesity. Two measures of self-control were used; for mothers, the self-control variable was based on behaviors related to self-control (smoking during pregnancy, smoking during the child’s first year of life, breastfeeding duration, and participating in the ABIS study with biological samples). For the children, the self-control variable was based on questionnaire data on the impulsivity subscale of the Strengths and Difficulties Questionnaire (SDQ). The results showed that the two measures of self-control mediated 87.5 % of the increased risk of obesity at age 19 years in children with low maternal education and 93 % of the risk if maternal BMI was also included in the selfcontrol variable.In the discussion part of this thesis, the conclusions that can be deduced from understanding the mechanisms of social inequality in child health are discussed. A theory with a central role of self-control for health inequality predicts that social inequality will increase without interventions. In an environment with rising numbers of stimuli of the human reward system, stimuli that also have negative long-term consequences (socalled Limbic traps), child and adolescent health, in general, will decrease. Because of the mechanisms related to SES and self-control, children with low SES will be disproportionally affected. The result of this development will be increasing levels of social inequalities in child health.The discussion also includes implications for policies that may improve health and reduce inequalities. These policies should reduce the exposure of children and adolescents to harmful behaviors/limbic traps. Examples of policies that have this effect include universal preschools for all children, free healthy meals in preschools and schools, increased after-school activities for all children, and longer school days for adolescents with increased hours for physical activity, music, and art. Mobile phones and social media restrictions in schools and policies to reduce use at home should also be implemented. Finally, policies should be implemented to reduce residential and school segregation in the community.
|
|
| 6. |
- Eltahir, Mohamed, et al.
(author)
-
An Adaptable Antibody-Based Platform for Flexible Synthetic Peptide Delivery Built on Agonistic CD40 Antibodies
- 2022
-
In: Advanced Therapeutics. - : Wiley. - 2366-3987. ; 5:7
-
Journal article (peer-reviewed)abstract
- The agonistic potentials of therapeutic anti-CD40 antibodies have been profiled in relation to antibody isotype and epitope specificity. Still, clinical impact relies on a well-balanced clinical efficacy versus target-mediated toxicity. As CD40-mediated immune activation must rely on a combination of stimulation of antigen-presenting cells (APCs) alongside antigen presentation, for efficient T cell priming, alternative approaches to improve the therapeutic outcome of CD40-targeting strategies should focus on providing optimal antigen presentation together with CD40 stimulation. Herein, a bispecific antibody targeting CD40 as a means to deliver cargo (i.e., synthetic peptides) into APCs through a non-covalent, high-affinity interaction between the antibody and the cargo peptide, further referred to as the Adaptable Drug Affinity Conjugate (ADAC) technology, has been developed. The ADAC platform demonstrated a target-specific CD4+ and CD8+ T cell expansion in vitro and significantly improved peptide-specific CD8+ T cell proliferation in vivo. In addition, the strategy dramatically improved the in vitro and in vivo half-life of the synthetic peptides. Future applications of ADAC involve pandemic preparedness to viral genetic drift as well as neoepitope vaccination strategies where the bispecific antibody is an off-the-shelf product, and the peptide antigen is synthesized based on next-generation sequencing data mining.
|
|
| 7. |
- Hjort, Mattias, 1972-, et al.
(author)
-
Smarta gator : VR-simulering av framtida stadsmiljöer
- 2022
-
Reports (other academic/artistic)abstract
- Denna rapport beskriver arbetet av arbetspaket 6 och 8 i det Vinnova-finansierade projektet Smarta gator. Utifrån arkitektoniska beskrivningar har tre olika VR-miljöer skapats – så kallade ”digitala tvillingar” av en idag existerande gatumiljö i Stockholm, samt två olika tänkbara framtida versioner av gatumiljön. Den simulerade miljön kan upplevas av fotgängare i VTI:s fotgängarsimulator, och alternativt också av bilist genom co-simulering med annan körsimulator. De två tänkbara framtidsvisionerna utvärderades från ett fotgängarperspektiv genom en workshop med 30 försökspersoner i VTI:s fotgängarsimulator i Linköping. Deltagarnas svar visar tydligt att upplevelsen av trygghet, prioritet samt trevlighet/trivsel ökade i de smarta miljöerna jämfört med den ursprungliga miljön. Läsbarheten av gaturummet upplevdes i de smarta miljöerna dock något sämre än i ursprungsmiljön. En förklaring kan vara att många känner igen ursprungsmiljön eftersom det är en relativt vanlig gatutyp – breda körfält för bil, kantstensparkering och trottoarer, medan de smarta miljöerna är uppbyggda på ett annorlunda sätt vilket kan innebära en omställning för att förstå en ”ny typ” av gata. Sammantaget visar studien på hur man kan skapa gaturum som upplevs trevligare och tryggare genom att prioritera gång- och cykeltrafik genom en större yta tillägnat gång, cykel och vistelse än för motortrafik. Även skapandet av vistelseytor och sociala funktioner längs gatan hade en positiv effekt på upplevelsen av gaturummet. Att placera träd och grönska längs gatan är utöver de ekologiska fördelarna också viktigt för trivseln och upplevelsen av gaturummet. Vi konstaterar att VR-simulering kan vara ett användbart verktyg för att på ett tidigt stadium bedöma olika designlösningar. VTI:s fotgängarsimulator har ett state-of-the-art bildsystem, men dess fria yta om 3x6 meter är för liten för att på ett smidigt sätt kunna promenera runt i stadsmiljön. Autonoma fotgängare, styrda av spelmotorn Unreal Engine, upplevdes av de flesta försökspersoner som väldigt verklighetstrogna, och de bidrog till illusionen om att vara på plats i miljön.
|
|
| 8. |
- Klar, Robert, 1995-, et al.
(author)
-
Container Relocation and Retrieval Tradeoffs Minimizing Schedule Deviations and Relocations
- 2024
-
In: IEEE Open Journal of Intelligent Transportation Systems. - : Institute of Electrical and Electronics Engineers (IEEE). - 2687-7813. ; 5, s. 360-379
-
Journal article (peer-reviewed)abstract
- Ports are striving to improve operational efficiency in the context of constantly growing volumes of trade. In this context, port terminal storage yard operation is key, since complexity and poor coordination lead to containers stacked without consideration of retrieval schedules, resulting in time and energy-consuming reshuffling operations. This problem, known as the block relocation (and retrieval) problem (BRP), has recently gained considerable attention. Indeed, there are promising solutions to the BRP. However, the literature views the problem in isolation, optimizing one operational parameter for one of the many port stakeholders. This often leads to efficiency losses since port processes involve different stakeholders and port parts. In this work, we explicitly focus on scheduling trucks for pick-up for hinterland distribution. Appointments are often postponed in order to minimize reshuffling operations, leading to losses for the transport forwarders and decreasing the competitiveness of the port.We discuss the trade-off between minimizing container reshuffling operations while maintaining scheduled time windows for container retrieval. We describe the multi-objective optimization problem as a weighted sum of the two objectives. Given the complexity of the problem, we also present a greedy heuristic. Our results indicate that the number of schedule deviations can be reduced without significantly affecting the number of relocations compared to solutions that consider only the latter. Ideally, a weighting of 0.4 and 0.6 should be applied, reflecting schedule deviations and relocations, respectively, to achieve the highest joint optimization potential. This demonstrates that in complex environments, such as ports, with multiple interacting stakeholders and processes, coordination of solutions yields significant benefits.
|
|
| 9. |
- Klar, Robert
(author)
-
Digital twinning for ports : from characterization to operations’ modelling
- 2024
-
Licentiate thesis (other academic/artistic)abstract
- Ports are actively pursuing greater operational efficiency to effectively handle the increasing global flow of goods, while striving to improve the energy efficiency of their operations to comply with new environmental regulations. As a result, innovation-leading ports have begun to recognize the potential of digital twins to overview, coordinate and optimize port processes, resulting in energy savings, and reductions of costs and of CO2 emissions. While digital twins have gained momentum in other domains such as smart manufacturing and aerospace, their adoption in ports has been comparatively slow. This can be explained, among other things, by the multi-stakeholder nature of the port and the high complexity of the often interconnected port processes. Thus, this thesis, grounded in the context of ports, discusses what constitutes a digital twin, proposes characteristics to assess the maturity of existing digital twins, and introduces and evaluates mathematical models to support a key port process, which can be used as components of a digital twin for the port.
|
|
| 10. |
- Onerup, Aron, 1983, et al.
(author)
-
Effect of Short-Term Homebased Pre- and Postoperative Exercise on Recovery after Colorectal Cancer Surgery (PHYSSURG-C): A Randomized Clinical Trial.
- 2022
-
In: Annals of surgery. - 1528-1140. ; 275:3, s. 448-455
-
Journal article (peer-reviewed)abstract
- To determine the effect of a short-term, unsupervised exercise intervention before and after colorectal cancer surgery on self-assessed physical recovery.Preoperative exercise interventions could help improve recovery after colorectal cancer surgery and is currently recommended.A randomized, parallel, open-label trial in six university or regional hospitals in Sweden. Inclusion criteria were age ≥20years and planned elective colorectal cancer surgery. Participants were randomised to either a physical activity intervention with aerobic activity and inspiratory muscle training two weeks pre- and four weeks postoperatively or usual care. The primary outcome measure was self-assessed physical recovery four weeks postoperatively. Analyses were performed according to intention to treat. Outcome assessors were masked regarding the intervention while both participants and physiotherapists were informed due to the nature of the intervention.Between Jan 22, 2015, and May 28, 2020, 761 participants were recruited and assigned to either intervention (I) (n = 379) or control (C) (n = 382). After exclusions 668 participants (I = 317, C = 351) were included in the primary analysis. There was no effect from the intervention on the primary outcome measure (adjusted odds ratio (OR) 0.84, 95% confidence interval (CI) 0.62 - 1.15) with 13% and 15% of participants feeling fully physically recovered in I and C respectively. There were no reported adverse events.There was no effect from a physical activity intervention before and after colorectal cancer surgery on short-term self-assessed physical recovery. The results from this study call for reconsiderations regarding current recommendations for preoperative physical activity interventions.
|
|
| 11. |
|
|
| 12. |
- Pinhassi, Jarone, et al.
(author)
-
Functional responses of key marine bacteria to environmental change - toward genetic counselling for coastal waters
- 2022
-
In: Frontiers in Microbiology. - : Frontiers Media S.A.. - 1664-302X. ; 13
-
Journal article (peer-reviewed)abstract
- Coastal ecosystems deteriorate globally due to human-induced stress factors, like nutrient loading and pollution. Bacteria are critical to marine ecosystems, e.g., by regulating nutrient cycles, synthesizing vitamins, or degrading pollutants, thereby providing essential ecosystem services ultimately affecting economic activities. Yet, until now bacteria are overlooked both as mediators and indicators of ecosystem health, mainly due to methodological limitations in assessing bacterial ecosystem functions. However, these limitations are largely overcome by the advances in molecular biology and bioinformatics methods for characterizing the genetics that underlie functional traits of key bacterial populations - "key" in providing important ecosystem services, being abundant, or by possessing high metabolic rates. It is therefore timely to analyze and define the functional responses of bacteria to human-induced effects on coastal ecosystem health. We posit that categorizing the responses of key marine bacterial populations to changes in environmental conditions through modern microbial oceanography methods will allow establishing the nascent field of genetic counselling for our coastal waters. This requires systematic field studies of linkages between functional traits of key bacterial populations and their ecosystem functions in coastal seas, complemented with systematic experimental analyses of the responses to different stressors. Research and training in environmental management along with dissemination of results and dialogue with societal actors are equally important to ensure the role of bacteria is understood as fundamentally important for coastal ecosystems. Using the responses of microorganisms as a tool to develop genetic counselling for coastal ecosystems can ultimately allow for integrating bacteria as indicators of environmental change.
|
|
| 13. |
- Solé-Padullés, Cristina, et al.
(author)
-
No Association Between Loneliness, Episodic Memory and Hippocampal Volume Change in Young and Healthy Older Adults : A Longitudinal European Multicenter Study
- 2022
-
In: Frontiers in Aging Neuroscience. - : Frontiers Media S.A.. - 1663-4365. ; 14
-
Journal article (peer-reviewed)abstract
- Background: Loneliness is most prevalent during adolescence and late life and has been associated with mental health disorders as well as with cognitive decline during aging. Associations between longitudinal measures of loneliness and verbal episodic memory and brain structure should thus be investigated.Methods: We sought to determine associations between loneliness and verbal episodic memory as well as loneliness and hippocampal volume trajectories across three longitudinal cohorts within the Lifebrain Consortium, including children, adolescents (N = 69, age range 10–15 at baseline examination) and older adults (N = 1468 over 60). We also explored putative loneliness correlates of cortical thinning across the entire cortical mantle.Results: Loneliness was associated with worsening of verbal episodic memory in one cohort of older adults. Specifically, reporting medium to high levels of loneliness over time was related to significantly increased memory loss at follow-up examinations. The significance of the loneliness-memory change association was lost when eight participants were excluded after having developed dementia in any of the subsequent follow-up assessments. No significant structural brain correlates of loneliness were found, neither hippocampal volume change nor cortical thinning.Conclusion: In the present longitudinal European multicenter study, the association between loneliness and episodic memory was mainly driven by individuals exhibiting progressive cognitive decline, which reinforces previous findings associating loneliness with cognitive impairment and dementia.
|
|
| 14. |
- Sonderby, Ida E., et al.
(author)
-
Dose response of the 16p11.2 distal copy number variant on intracranial volume and basal ganglia
- 2020
-
In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:3, s. 584-602
-
Journal article (peer-reviewed)abstract
- Carriers of large recurrent copy number variants (CNVs) have a higher risk of developing neurodevelopmental disorders. The 16p11.2 distal CNV predisposes carriers to e.g., autism spectrum disorder and schizophrenia. We compared subcortical brain volumes of 12 16p11.2 distal deletion and 12 duplication carriers to 6882 non-carriers from the large-scale brain Magnetic Resonance Imaging collaboration, ENIGMA-CNV. After stringent CNV calling procedures, and standardized FreeSurfer image analysis, we found negative dose-response associations with copy number on intracranial volume and on regional caudate, pallidum and putamen volumes (β = −0.71 to −1.37; P < 0.0005). In an independent sample, consistent results were obtained, with significant effects in the pallidum (β = −0.95, P = 0.0042). The two data sets combined showed significant negative dose-response for the accumbens, caudate, pallidum, putamen and ICV (P = 0.0032, 8.9 × 10−6, 1.7 × 10−9, 3.5 × 10−12 and 1.0 × 10−4, respectively). Full scale IQ was lower in both deletion and duplication carriers compared to non-carriers. This is the first brain MRI study of the impact of the 16p11.2 distal CNV, and we demonstrate a specific effect on subcortical brain structures, suggesting a neuropathological pattern underlying the neurodevelopmental syndromes.
|
|
| 15. |
- Ståhle, Alexander, et al.
(author)
-
Designguide för Smarta gator
- 2022
-
Book (other academic/artistic)abstract
- Designguiden för smarta gator konkretiserar hur de fyra megatrenderna urbanisering, digitalisering, samhällsförändringar och miljöförändringar leder till nya krav och utformningsprinciper för framtidens gator. Guiden är tänkt att fungera som en inspiration och ett underlag för att förnya svensk gatupolicy på nationell, regional och kommunal nivå.Guiden innehåller utöver en inledning följande kapitel: en historisk tillbakablick (gatans utveckling), gatans användning, gatans delar, gatans design, designprocessen, guidens genomförande.
|
|
| 16. |
- Svensson, Nina, 1988-, et al.
(author)
-
Ride the future – strategisk satsning : fem studier med fokus på autonoma bussar i städer
- 2022
-
Reports (other academic/artistic)abstract
- Fem noga utvalda förstudier har initierats av VTI som en del i den strategiska satsningen ”Ride the future” kopplad till framtidens mobilitetslösningar. Förstudiernas titel är följande: ▪ Databearbetning och visualisering av mobila luftkvalitetsmätningar. ▪ SUMO och Unreal Engine för co-simulering. ▪ Exploring spatio-temporal accessibility in Lambohov: a pre-study. ▪ Vägytans betydelse för vibrationer och komfort i långsamma fordon. ▪ Infrastrukturbehov vid busshållplatser. Föreliggande pm innehåller en kort beskrivning av studierna och den mer utförliga redovisningen återfinns i bilagan.
|
|
| 17. |
- Söfteland, John M., 1977, et al.
(author)
-
Longevity of anti-spike and anti-nucleocapsid antibodies after COVID-19 in solid organ transplant recipients compared to immunocompetent controls.
- 2022
-
In: American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons. - : Elsevier BV. - 1600-6143. ; 22:4, s. 1245-1252
-
Journal article (peer-reviewed)abstract
- Solid organ transplant recipients (SOTRs) are on lifelong immunosuppression, which may interfere with adaptive immunity to COVID-19. The data on dynamics and duration of antibody response in SOTRs are limited. This longitudinal study examined the longevity of both anti-spike (S)- and anti-nucleocapsid (N)-specific IgG-antibodies after COVID-19 in SOTRs compared to matched immunocompetent persons. SOTRs (n=65) were matched with controls (n=65) for COVID-19 disease severity, age, and sex in order of priority. Serum-IgG-antibodies against N- and S-antigens of SARS-CoV-2 were analyzed. At 1 and 9 months after COVID-19, anti-S-IgG detectability decreased from 91% to 82% in SOTRs versus 100% to 95% in controls, whereas the anti-N-IgG decreased from 63% to 29% in SOTRs versus 89% to 46% in controls. A matched paired analysis showed SOTRs having significantly lower levels of anti-N-IgG at all time points (1-month P=0.007, 3-months P<0.001, 6-months P=0.019 and 9-months P=0.021) but not anti-S-IgG at any time points. A mixed-model analysis confirmed these findings except for anti-S-IgG at one month (p=0.005) and identified severity score as the most important predictor of antibody response. SOTRs mount comparable S-specific, but not N-specific, antibody responses to SARS-CoV-2 infection compared to immunocompetent controls.
|
|
| 18. |
- Walsh, Claire, 1983, et al.
(author)
-
The mevalonate precursor enzyme HMGCS1 is a novel marker and key mediator of cancer stem cell enrichment in luminal and basal models of breast cancer
- 2020
-
In: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:7
-
Journal article (peer-reviewed)abstract
- The definitive characterization of common cancer stem cell (CSCs) subpopulations in breast cancer subtypes with distinct genotypic and phenotypic features remains an ongoing challenge. In this study, we have used a non-biased genome wide screening approach to identify transcriptional networks that may be specific to the CSC subpopulations in both luminal and basal breast cancer subtypes. In depth studies of three CSC-enriched breast cancer cell lines representing various subtypes of breast cancer revealed a striking hyperactivation of the mevalonate metabolic pathway in comparison to control cells. The upregulation of metabolic networks is a key feature of tumour cells securing growth and proliferative capabilities and dysregulated mevalonate metabolism has been associated with tumour malignancy and cellular transformation in breast cancer. Furthermore, accumulating evidence suggests that Simvastatin therapy, a mevalonate pathway inhibitor, could affect breast cancer progression and reduce breast cancer recurrence. When detailing the mevalonate pathway in breast cancer using a single-cell qPCR, we identified the mevalonate precursor enzyme, HMGCS1, as a specific marker of CSC-enriched subpopulations within both luminal and basal tumour subtypes. Down-regulation of HMGCS1 also decreased the CSC fraction and function in various model systems, suggesting that HMGCS1 is essential for CSC-activities in breast cancer in general. These data was supported by strong associations between HMGCS1 expression and aggressive features, such as high tumour grade, p53 mutations as well as ER-negativity in lymph node positive breast cancer. Importantly, loss of HMGCS1 also had a much more pronounced effect on CSC-activities compared to treatment with standard doses of Simvastatin. Taken together, this study highlights HMGCS1 as a potential gatekeeper for dysregulated mevalonate metabolism important for CSC-features in both luminal and basal breast cancer subtypes. Pharmacological inhibition of HMGCS1 could therefore be a superior novel treatment approach for breast cancer patients via additional CSC blocking functions.
|
|
