| 1. |
- Hägerbrand, Karin, et al.
(författare)
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Bispecific antibodies targeting CD40 and tumor-associated antigens promote cross-priming of T cells resulting in an antitumor response superior to monospecific antibodies
- 2022
-
Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11
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Tidskriftsartikel (refereegranskat)abstract
- Background Indications with poor T-cell infiltration or deficiencies in T-cell priming and associated unresponsiveness to established immunotherapies represent an unmet medical need in oncology. CD40-targeting therapies designed to enhance antigen presentation, generate new tumor-specific T cells, and activate tumor-infiltrating myeloid cells to remodel the tumor microenvironment, represent a promising opportunity to meet this need. In this study, we present the first in vivo data supporting a role for tumor-associated antigen (TAA)-mediated uptake and cross-presentation of tumor antigens to enhance tumor-specific T-cell priming using CD40×TAA bispecific antibodies, a concept we named Neo-X-Prime. Methods Bispecific antibodies targeting CD40 and either of two cell-surface expressed TAA, carcinoembryonic antigen-related cell adhesion molecule 5 (CEA) or epithelial cell adhesion molecule (EpCAM), were developed in a tetravalent format. TAA-conditional CD40 agonism, activation of tumor-infiltrating immune cells, antitumor efficacy and the role of delivery of tumor-derived material such as extracellular vesicles, tumor debris and exosomes by the CD40×TAA bispecific antibodies were demonstrated in vitro using primary human and murine cells and in vivo using human CD40 transgenic mice with different tumor models. Results The results showed that the CD40×TAA bispecific antibodies induced TAA-conditional CD40 activation both in vitro and in vivo. Further, it was demonstrated in vitro that they induced clustering of tumor debris and CD40-expressing cells in a dose-dependent manner and superior T-cell priming when added to dendritic cells (DC), ovalbumin (OVA)-specific T cells and OVA-containing tumor debris or exosomes. The antitumor activity of the Neo-X-Prime bispecific antibodies was demonstrated to be significantly superior to the monospecific CD40 antibody, and the resulting T-cell dependent antitumor immunity was directed to tumor antigens other than the TAA used for targeting (EpCAM). Conclusions The data presented herein support the hypothesis that CD40×TAA bispecific antibodies can engage tumor-derived vesicles containing tumor neoantigens to myeloid cells such as DCs resulting in an improved DC-mediated cross-priming of tumor-specific CD8 + T cells. Thus, this principle may offer therapeutics strategies to enhance tumor-specific T-cell immunity and associated clinical benefit in indications characterized by poor T-cell infiltration or deficiencies in T-cell priming.
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| 2. |
- Sumaila, U. Rashid, et al.
(författare)
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WTO must ban harmful fisheries subsidies
- 2021
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 374:6567, s. 544-544
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 3. |
- Alder-Rangel, Alene, et al.
(författare)
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The Third International Symposium on Fungal Stress – ISFUS
- 2020
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Ingår i: Fungal Biology. - : Elsevier BV. - 1878-6146. ; 124:5, s. 235-252
-
Tidskriftsartikel (refereegranskat)abstract
- Stress is a normal part of life for fungi, which can survive in environments considered inhospitable or hostile for other organisms. Due to the ability of fungi to respond to, survive in, and transform the environment, even under severe stresses, many researchers are exploring the mechanisms that enable fungi to adapt to stress. The International Symposium on Fungal Stress (ISFUS) brings together leading scientists from around the world who research fungal stress. This article discusses presentations given at the third ISFUS, held in São José dos Campos, São Paulo, Brazil in 2019, thereby summarizing the state-of-the-art knowledge on fungal stress, a field that includes microbiology, agriculture, ecology, biotechnology, medicine, and astrobiology.
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| 4. |
- Bergström, Lena, et al.
(författare)
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Interim Report of the ICES/HELCOM Working Group on Integrated Assessments of the Baltic Sea (WGIAB) : 18-22 April 2016 Helsinki, Finland
- 2016
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The ICES/HELCOM Working Group on Integrated Assessments of the Baltic Sea (WGIAB) meeting was held in Helsinki (Finland), 18-22 April 2016. The meeting was attended by 26 participants from five countries and chaired by Laura Uusitalo, Fin-land, Saskia Otto, Germany, Martin Lindegren, Denmark, and Lena Bergström, Swe-den. This was the first year of the new three-year Terms of Reference (ToR) for WGIAB. The main working activities in 2016 were to A) develop the trait-based ap-proach of understanding the ecosystem function, and B) explore the social-ecological system, including indicator development, revising the conceptual model, and devel-oping case studies. As a primary outcome of the ToR A, we built on our previous work on integrated ecosystem assessments (IEAs) in the Baltic Sea, but extended it beyond considering changes in abundances of a few dominant species, to accounting for community-wide changes in a number of key traits across multiple trophic levels. These traits represent various ecosystem functions upon which we derive important ecosystem services. By investigating temporal changes in the community weighted mean traits of phyto-plankton, zooplankton, zoobenthos, and fish, we demonstrated whether trait reor-ganizations at the level of entire communities occurred in the Central Baltic Sea as a result of the 1980s regime shift. Using in total 29 traits combined for all groups we found indications of two breakpoints across all four taxonomic groups over the last decades, i.e. one around 1990 and one around 2000. Further work will focus on ex-ploring the nature of the changes in trait composition and on standardizing the num-ber of traits and data types (i.e. binary, continuous or categorical) across taxonomic group.In addition, we collected data on key functional groups and abiotic variables in all main sub-basins of the Baltic Sea, setting the stage for a cross-regional comparison of temporal patterns and trends in lower trophic level in the face of recent develop-ments in climate-related drivers.With reference to Tor B, to explore how social indicators could be used in parallel with biological indicators in an integrated assessment framework, we developed a conceptual model of interrelationships between ecosystem and society. We used the model as a basis for mapping factors to be accounted for in the ecosystem-based management using the Baltic salmon and clupeid species as case studies. The models depict 1) the structure of the foodweb relevant to the target species, 2) the key com-munity level and population traits that contribute to the state of the species, 3) main pressures affecting the foodweb and their effects on the species, 4) key management measures, and 5) benefits that the species can produce for society.To support the development of Ecosystem Overview the group members evaluated the probability of occurrence and the magnitude of the effect of 15 pressures occur-ring in the Baltic Sea. The top five pressures identified were input of nutrients, in-creased temperature, decreased salinity, input of hazardous substances, and input or spread of non-indigenous species.The work will continue intersessionally and the next meeting of WGIAB is planned to be held in Lisbon, Portugal, back-to-back with WGCOMEDA and WGEAWESS.
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| 5. |
- Bergström, Lena, et al.
(författare)
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Report of the ICES/HELCOM Working Group on Integrated Assessments of the Baltic Sea (WGIAB)
- 2015
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- The ICES/HELCOM Working Group on Integrated Assessments of the Baltic Sea(WGIAB) was established in 2007 as a forum for developing and combining ecosystembasedmanagement efforts for the Baltic Sea. The group intends to serve as a scientificcounterpart and support for the ICES Baltic Fisheries Assessment Working Group(WGBFAS) as well as for efforts and projects related to Integrated Ecosystem Assessments(IEA) within ICES and HELCOM. The group works in cooperation with similargroups within the ACOM/SCICOM Steering Group on Integrated Ecosystem Assessments(SSGIEA).The 2015 WGIAB meeting was held in Cádiz, Spain, from 9–13 March, back-to-backwith the meeting of its counterpart in the Working Group on Ecosystem Assessmentof Western European Shelf Seas (WGEAWESS). The meetings had joint sessions as wellas WG specific work, and some participants effectively participated in both meetings.The WGIAB meeting was attended by 27 participants from nine countries. The meetingwas chaired by Christian Möllmann, Germany, Laura Uusitalo, Finland and Lena Bergström,Sweden.This was the last year of the ongoing three-year Terms of Reference (ToR) for WGIAB.The main working activities in 2015 were to i) conduct studies on Baltic Sea ecosystemfunctioning with the goal to publish case studies from different parts of the Baltic Seain peer-reviewed journals, ii) work on the demonstration exercise to develop ecosystem-based assessment and advice for Baltic fish stocks focusing on cod (DEMO) withmultiple approaches, iii) plan further how to integrate the social and economic aspectsmore tightly in the WGIAB work, and iv) discuss the future focus and format of theWGIAB work.The Baltic ecosystem functioning activity focused on identifying and exploring keytrends and linkages in the Baltic Sea foodweb. This was pursued by presentation andfurther discussion of ongoing intersessional work on foodweb modelling and integratedanalyses, and by exercises to develop conceptual models Baltic Sea foodwebsand the links to ecosystem function. Long-term monitoring datasets on the abiotic andbiotic parts of the Baltic Sea Proper ecosystem were updated for use in the continuedwork to develop environmental indicators for fisheries and marine management.The focus of the DEMO 3 (DEMOnstration exercise for Integrated Ecosystem Assessmentand Advice of Baltic Sea cod) was on finding a way to use the results from theDEMO1 and DEMO2 workshops in short and midterm projections/scenarios of Balticcod dynamics based on different types of modelling, as well as designing methodologyand modelling data for practical implementation of Integrated Advice for Baltic cod.The WGIAB was positively inclined towards including social and economic aspectsinto the integrated assessment. Openings to this path were provided by presentationon ongoing project work, and discussing their linkages to ecological aspects. It wasseen as crucial that experts on social and economic analysis should be included andtake an active part in the future work of the group.The group concluded that its upcoming work should focus more closely on functionaldiversity, which was identified as a recurring issue in the Baltic Sea. This approach wasalso identified as a useful connection point between scientific and management aspectsin order for the group to continue serving as a forum for developing ecosystem-basedmanagement efforts in the Baltic Sea. A focus on functional diversity was also seen as2 | ICES WGIAB REPORT 2015a potentially feasible way of bringing together management aspects for different sectors,by linking to ecosystem services concepts.The group proposed Saskia Otto, Germany and Martin Lindegren, Denmark as newincoming Chairs, together with Lena Bergström, Sweden and Laura Uusitalo, Finland.Having four Chairs is justified due to the wide scope of the group's work, as well asthe increased work load due to the planned new foci.
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| 6. |
- DeMott, Paul J., et al.
(författare)
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The Fifth International Workshop on Ice Nucleation phase 2 (FIN-02) : Laboratory intercomparison of ice nucleation measurements
- 2018
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 11:11, s. 6231-6257
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Tidskriftsartikel (refereegranskat)abstract
- The second phase of the Fifth International Ice Nucleation Workshop (FIN-02) involved the gathering of a large number of researchers at the Karlsruhe Institute of Technology's Aerosol Interactions and Dynamics of the Atmosphere (AIDA) facility to promote characterization and understanding of ice nucleation measurements made by a variety of methods used worldwide. Compared to the previous workshop in 2007, participation was doubled, reflecting a vibrant research area. Experimental methods involved sampling of aerosol particles by direct processing ice nucleation measuring systems from the same volume of air in separate experiments using different ice nucleating particle (INP) types, and collections of aerosol particle samples onto filters or into liquid for sharing amongst measurement techniques that post-process these samples. In this manner, any errors introduced by differences in generation methods when samples are shared across laboratories were mitigated. Furthermore, as much as possible, aerosol particle size distribution was controlled so that the size limitations of different methods were minimized. The results presented here use data from the workshop to assess the comparability of immersion freezing measurement methods activating INPs in bulk suspensions, methods that activate INPs in condensation and/or immersion freezing modes as single particles on a substrate, continuous flow diffusion chambers (CFDCs) directly sampling and processing particles well above water saturation to maximize immersion and subsequent freezing of aerosol particles, and expansion cloud chamber simulations in which liquid cloud droplets were first activated on aerosol particles prior to freezing. The AIDA expansion chamber measurements are expected to be the closest representation to INP activation in atmospheric cloud parcels in these comparisons, due to exposing particles freely to adiabatic cooling. The different particle types used as INPs included the minerals illite NX and potassium feldspar (K-feldspar), two natural soil dusts representative of arable sandy loam (Argentina) and highly erodible sandy dryland (Tunisia) soils, respectively, and a bacterial INP (Snomax®). Considered together, the agreement among post-processed immersion freezing measurements of the numbers and fractions of particles active at different temperatures following bulk collection of particles into liquid was excellent, with possible temperature uncertainties inferred to be a key factor in determining INP uncertainties. Collection onto filters for rinsing versus directly into liquid in impingers made little difference. For methods that activated collected single particles on a substrate at a controlled humidity at or above water saturation, agreement with immersion freezing methods was good in most cases, but was biased low in a few others for reasons that have not been resolved, but could relate to water vapor competition effects. Amongst CFDC-style instruments, various factors requiring (variable) higher supersaturations to achieve equivalent immersion freezing activation dominate the uncertainty between these measurements, and for comparison with bulk immersion freezing methods. When operated above water saturation to include assessment of immersion freezing, CFDC measurements often measured at or above the upper bound of immersion freezing device measurements, but often underestimated INP concentration in comparison to an immersion freezing method that first activates all particles into liquid droplets prior to cooling (the PIMCA-PINC device, or Portable Immersion Mode Cooling chAmber-Portable Ice Nucleation Chamber), and typically slightly underestimated INP number concentrations in comparison to cloud parcel expansions in the AIDA chamber; this can be largely mitigated when it is possible to raise the relative humidity to sufficiently high values in the CFDCs, although this is not always possible operationally. Correspondence of measurements of INPs among direct sampling and post-processing systems varied depending on the INP type. Agreement was best for Snomax® particles in the temperature regime colder than -10°C, where their ice nucleation activity is nearly maximized and changes very little with temperature. At temperatures warmer than -10°C, Snomax® INP measurements (all via freezing of suspensions) demonstrated discrepancies consistent with previous reports of the instability of its protein aggregates that appear to make it less suitable as a calibration INP at these temperatures. For Argentinian soil dust particles, there was excellent agreement across all measurement methods; measures ranged within 1 order of magnitude for INP number concentrations, active fractions and calculated active site densities over a 25 to 30°C range and 5 to 8 orders of corresponding magnitude change in number concentrations. This was also the case for all temperatures warmer than -25°C in Tunisian dust experiments. In contrast, discrepancies in measurements of INP concentrations or active site densities that exceeded 2 orders of magnitude across a broad range of temperature measurements found at temperatures warmer than -25°C in a previous study were replicated for illite NX. Discrepancies also exceeded 2 orders of magnitude at temperatures of -20 to -25°C for potassium feldspar (K-feldspar), but these coincided with the range of temperatures at which INP concentrations increase rapidly at approximately an order of magnitude per 2°C cooling for K-feldspar. These few discrepancies did not outweigh the overall positive outcomes of the workshop activity, nor the future utility of this data set or future similar efforts for resolving remaining measurement issues. Measurements of the same materials were repeatable over the time of the workshop and demonstrated strong consistency with prior studies, as reflected by agreement of data broadly with parameterizations of different specific or general (e.g., soil dust) aerosol types. The divergent measurements of the INP activity of illite NX by direct versus post-processing methods were not repeated for other particle types, and the Snomax° data demonstrated that, at least for a biological INP type, there is no expected measurement bias between bulk collection and direct immediately processed freezing methods to as warm as -10°C. Since particle size ranges were limited for this workshop, it can be expected that for atmospheric populations of INPs, measurement discrepancies will appear due to the different capabilities of methods for sampling the full aerosol size distribution, or due to limitations on achieving sufficient water supersaturations to fully capture immersion freezing in direct processing instruments. Overall, this workshop presents an improved picture of present capabilities for measuring INPs than in past workshops, and provides direction toward addressing remaining measurement issues.
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| 7. |
- El-Sayed, Najib M., et al.
(författare)
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The genome sequence of Trypanosoma cruzi, etiologic agent of Chagas disease.
- 2005
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 309:5733, s. 409-15
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Tidskriftsartikel (refereegranskat)abstract
- Whole-genome sequencing of the protozoan pathogen Trypanosoma cruzi revealed that the diploid genome contains a predicted 22,570 proteins encoded by genes, of which 12,570 represent allelic pairs. Over 50% of the genome consists of repeated sequences, such as retrotransposons and genes for large families of surface molecules, which include trans-sialidases, mucins, gp63s, and a large novel family (>1300 copies) of mucin-associated surface protein (MASP) genes. Analyses of the T. cruzi, T. brucei, and Leishmania major (Tritryp) genomes imply differences from other eukaryotes in DNA repair and initiation of replication and reflect their unusual mitochondrial DNA. Although the Tritryp lack several classes of signaling molecules, their kinomes contain a large and diverse set of protein kinases and phosphatases; their size and diversity imply previously unknown interactions and regulatory processes, which may be targets for intervention.
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| 8. |
- Elsler, Laura G., et al.
(författare)
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Local, Global, Multi-Level : Market Structure and Multi-Species Fishery Dynamics
- 2019
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Ingår i: Ecological Economics. - : Elsevier BV. - 0921-8009 .- 1873-6106. ; 156, s. 185-195
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Tidskriftsartikel (refereegranskat)abstract
- Price and market structures in fisheries change rapidly, now 40% of seafood is traded internationally and are associated with overharvesting of marine species. We have developed a bio-economic fishery model to address the pressing need of managing the interplay of different markets. We first regard local, multi-level and global markets individually and then analyze the effect of transitioning between markets on the exploitation of species and the stability of income. We find that in gradually globalizing markets, transition management needs to account for non-linear price changes since earlier policies may not be suitable after globalization. We hypothesize that short-term policies to ban harvest in the interest of species recovery benefit a local market in which incentives prevent overharvesting. In global markets we expect that sustained initiatives are needed to prevent overharvesting. Individual fisheries using contextualized models representing local ecological and trade structures may benefit from assessing the price dynamics presented in this analysis.
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| 9. |
- Elsler, Laura G., et al.
(författare)
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Protecting ocean carbon through biodiversity and climate governance
- 2022
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Ingår i: Frontiers in Marine Science. - : Frontiers Media SA. - 2296-7745. ; 9
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Tidskriftsartikel (refereegranskat)abstract
- Global policy goals for halting biodiversity loss and climate change depend on each other to be successful. Marine biodiversity and climate change are intertwined through foodwebs that cycle and transport carbon and contribute to carbon sequestration. Yet, biodiversity conservation and fisheries management seldom explicitly include ocean carbon transport and sequestration. In order to effectively manage and govern human activities that affect carbon cycling and sequestration, international biodiversity and climate agreements need to address both biodiversity and climate issues. International agreements that address issues for climate and biodiversity are best poised to facilitate the protection of ocean carbon with existing policies. The degree to which the main international biodiversity and climate agreements make reference to multiple issues has however not been documented. Here, we used a text mining analysis of over 2,700 binding and non-binding policy documents from ten global ocean-related agreements to identify keywords related to biodiversity, climate, and ocean carbon. While climate references were mostly siloed within climate agreements, biodiversity references were included in most agreements. Further, we found that six percent of policy documents (n=166) included ocean carbon keywords. In light of our results, we highlight opportunities to strengthen the protection of ocean carbon in upcoming negotiations of international agreements, and via area-based management, environmental impact assessment and strategic environmental assessment.
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| 10. |
- Elsler, Laura G.
(författare)
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The complexity of seafood trade relations across scales
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- There is growing concern about the unprecedented rise in international seafood trade that relies on increasingly overused and climate-driven fisheries. Seafood trade relations, the multi-dimensional relations between fishers, traders, and countries for seafood exchange and other interactions, are central in the process of globalization. Despite empirical evidence of their importance, (bio-)economic models that inform fisheries management usually reduce trade relations to price dynamics. Here, I aim to understand better the role of seafood trade relations for models that guide the sustainable and equitable management of globalizing fisheries. I studied traders' collusion in Mexico (Paper I), fisher-trader relations in Indonesia (Paper II), countries trade relations in a global network study (Paper III), and fisher-market relations in a theoretical model (Paper IV). I demonstrate that seafood trade relations are affected by social-ecological change (SEC), such as climate change. Their responses, in turn, influence how other fishery actors, such as fishers, are affected. Together these interactions shape the importance of seafood trade relations to SEC. These insights suggest that seafood trade emerges from, interacts, and co-evolves with seafood trade relations across scales, which needs to be represented in management models that analyze the 'interplay of seafood trade relations with globalizing fisheries'.
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| 11. |
- Jiang, Rays H. Y., et al.
(författare)
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Distinctive Expansion of Potential Virulence Genes in the Genome of the Oomycete Fish Pathogen Saprolegnia parasitica
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 9:6, s. e1003272-
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Tidskriftsartikel (refereegranskat)abstract
- Oomycetes in the class Saprolegniomycetidae of the Eukaryotic kingdom Stramenopila have evolved as severe pathogens of amphibians, crustaceans, fish and insects, resulting in major losses in aquaculture and damage to aquatic ecosystems. We have sequenced the 63 Mb genome of the fresh water fish pathogen, Saprolegnia parasitica. Approximately 1/3 of the assembled genome exhibits loss of heterozygosity, indicating an efficient mechanism for revealing new variation. Comparison of S. parasitica with plant pathogenic oomycetes suggests that during evolution the host cellular environment has driven distinct patterns of gene expansion and loss in the genomes of plant and animal pathogens. S. parasitica possesses one of the largest repertoires of proteases (270) among eukaryotes that are deployed in waves at different points during infection as determined from RNA-Seq data. In contrast, despite being capable of living saprotrophically, parasitism has led to loss of inorganic nitrogen and sulfur assimilation pathways, strikingly similar to losses in obligate plant pathogenic oomycetes and fungi. The large gene families that are hallmarks of plant pathogenic oomycetes such as Phytophthora appear to be lacking in S. parasitica, including those encoding RXLR effectors, Crinkler's, and Necrosis Inducing-Like Proteins (NLP). S. parasitica also has a very large kinome of 543 kinases, 10% of which is induced upon infection. Moreover, S. parasitica encodes several genes typical of animals or animal-pathogens and lacking from other oomycetes, including disintegrins and galactose-binding lectins, whose expression and evolutionary origins implicate horizontal gene transfer in the evolution of animal pathogenesis in S. parasitica.
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| 12. |
- Levin, Johannes, et al.
(författare)
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α-Synuclein seed amplification assay detects Lewy body co-pathology in autosomal dominant Alzheimer's disease late in the disease course and dependent on Lewy pathology burden
- 2024
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Ingår i: Alzheimer's and Dementia. - 1552-5260. ; 20:6, s. 4351-4365
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Tidskriftsartikel (refereegranskat)abstract
- INTRODUCTION: Amyloid beta and tau pathology are the hallmarks of sporadic Alzheimer's disease (AD) and autosomal dominant AD (ADAD). However, Lewy body pathology (LBP) is found in ≈ 50% of AD and ADAD brains. METHODS: Using an α-synuclein seed amplification assay (SAA) in cerebrospinal fluid (CSF) from asymptomatic (n = 26) and symptomatic (n = 27) ADAD mutation carriers, including 12 with known neuropathology, we investigated the timing of occurrence and prevalence of SAA positive reactivity in ADAD in vivo. RESULTS: No asymptomatic participant and only 11% (3/27) of the symptomatic patients tested SAA positive. Neuropathology revealed LBP in 10/12 cases, primarily affecting the amygdala or the olfactory areas. In the latter group, only the individual with diffuse LBP reaching the neocortex showed α-synuclein seeding activity in CSF in vivo. DISCUSSION: Results suggest that in ADAD LBP occurs later than AD pathology and often as amygdala- or olfactory-predominant LBP, for which CSF α-synuclein SAA has low sensitivity. Highlights: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) detects misfolded α-synuclein in ≈ 10% of symptomatic autosomal dominant Alzheimer's disease (ADAD) patients. CSF RT-QuIC does not detect α-synuclein seeding activity in asymptomatic mutation carriers. Lewy body pathology (LBP) in ADAD mainly occurs as olfactory only or amygdala-predominant variants. LBP develops late in the disease course in ADAD. CSF α-synuclein RT-QuIC has low sensitivity for focal, low-burden LBP.
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| 13. |
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| 14. |
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| 15. |
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| 16. |
- Menkveld, Albert J., et al.
(författare)
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Nonstandard Errors
- 2024
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Ingår i: JOURNAL OF FINANCE. - : Wiley-Blackwell. - 0022-1082 .- 1540-6261. ; 79:3, s. 2339-2390
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Tidskriftsartikel (refereegranskat)abstract
- In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty-nonstandard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for more reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants.
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| 17. |
- Nyesiga, Barnabas, et al.
(författare)
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RUBY® - a tetravalent (2+2) bispecific antibody format with excellent functionality and IgG-like stability, pharmacology and developability properties
- 2024
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Ingår i: mAbs. - : Taylor & Francis. - 1942-0862 .- 1942-0870. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Despite the large number of existing bispecific antibody (bsAb) formats, the generation of novel bsAbs is still associated with development and bioprocessing challenges. Here, we present RUBY, a novel bispecific antibody format that allows rapid generation of bsAbs that fulfill key development criteria. The RUBYTM format has a 2 + 2 geometry, where two Fab fragments are linked via their light chains to the C-termini of an IgG, and carries mutations for optimal chain pairing. The unique design enables generation of bsAbs with mAb-like attributes. Our data demonstrate that RUBY bsAbs are compatible with small-scale production systems for screening purposes and can be produced at high yields (>3 g/L) from stable cell lines. The bsAbs produced are shown to, in general, contain low amounts of aggregates and display favorable solubility and stress endurance profiles. Further, compatibility with various IgG isotypes is shown and tailored Fc gamma receptor binding confirmed. Also, retained interaction with FcRn is demonstrated to translate into a pharmacokinetic profile in mice and non-human primates that is comparable to mAb controls. Functionality of conditional active RUBY bsAbs is confirmed in vitro. Anti-tumor effects in vivo have previously been demonstrated, and shown to be superior to a comparable mAb, and here it is further shown that RUBY bsAbs penetrate and localize to tumor tissue in vivo. In all, the RUBY format has attractive mAb-like attributes and offers the possibility to mitigate many of the development challenges linked to other bsAb formats, facilitating both high functionality and developability.
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| 18. |
- Petzold, Axel, et al.
(författare)
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Diagnosis and classification of optic neuritis
- 2022
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Ingår i: Lancet Neurology. - : ELSEVIER SCIENCE INC. - 1474-4422 .- 1474-4465. ; 21:12, s. 1120-1134
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Forskningsöversikt (refereegranskat)abstract
- There is no consensus regarding the classification of optic neuritis, and precise diagnostic criteria are not available. This reality means that the diagnosis of disorders that have optic neuritis as the first manifestation can be challenging. Accurate diagnosis of optic neuritis at presentation can facilitate the timely treatment of individuals with multiple sclerosis, neuromyelitis optica spectrum disorder, or myelin oligodendrocyte glycoprotein antibody-associated disease. Epidemiological data show that, cumulatively, optic neuritis is most frequently caused by many conditions other than multiple sclerosis. Worldwide, the cause and management of optic neuritis varies with geographical location, treatment availability, and ethnic background. We have developed diagnostic criteria for optic neuritis and a classification of optic neuritis subgroups. Our diagnostic criteria are based on clinical features that permit a diagnosis of possible optic neuritis; further paraclinical tests, utilising brain, orbital, and retinal imaging, together with antibody and other protein biomarker data, can lead to a diagnosis of definite optic neuritis. Paraclinical tests can also be applied retrospectively on stored samples and historical brain or retinal scans, which will be useful for future validation studies. Our criteria have the potential to reduce the risk of misdiagnosis, provide information on optic neuritis disease course that can guide future treatment trial design, and enable physicians to judge the likelihood of a need for long-term pharmacological management, which might differ according to optic neuritis subgroups.
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| 19. |
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| 20. |
- Yasmeen, Najeeda, et al.
(författare)
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Targeted therapies for patients with moderate-to-severe psoriasis: a systematic review and network meta-analysis of PASI response at 1 year
- 2022
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Ingår i: Journal of dermatological treatment (Print). - : TAYLOR & FRANCIS LTD. - 0954-6634 .- 1471-1753. ; 33:1, s. 204-218
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Forskningsöversikt (refereegranskat)abstract
- Purpose: To compare PASI outcomes of approved biologics and apremilast after 1 year of treatment. Methods: A systematic review identified RCTs and long-term extensions reporting PASI 75, 90, and 100 responses in adults with moderate-to-severe psoriasis. Data for analysis were modeled using a Bayesian multinomial likelihood model with probit link. Results: Twenty-eight studies reporting PASI responses were included in the network meta-analysis. Differences in study design led to a stepwise approach to synthesis, consisting of two analyses. The primary analysis included nine RCTs investigating comparative efficacy at 1 year. Results indicated risankizumab, brodalumab, and guselkumab were the most effective therapies, followed by ixekizumab and secukinumab; all demonstrated superiority to ustekinumab and etanercept. The secondary analysis extended the primary analysis with 19 further studies comparing active interventions to placebo outcomes extrapolated from induction. The interventions generating the highest PASI response were the same as the primary analysis. These therapies were more effective than apremilast, ustekinumab, adalimumab, certolizumab, etanercept, and infliximab. Conclusions: This NMA demonstrated that evaluated IL-17 and IL-23 inhibitors outperformed other biological therapies after 1 year. Risankizumab had a higher probability of achieving PASI outcomes than all other biologics, except brodalumab and guselkumab, where no significant difference could be concluded.
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| 21. |
- Yuh, Esther L, et al.
(författare)
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Pathological computed tomography features associated with adverse outcomes after mild traumatic brain injury : A TRACK-TBI study with external validation in CENTER-TBI.
- 2021
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 78:9, s. 1137-1148
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE: A head computed tomography (CT) with positive results for acute intracranial hemorrhage is the gold-standard diagnostic biomarker for acute traumatic brain injury (TBI). In moderate to severe TBI (Glasgow Coma Scale [GCS] scores 3-12), some CT features have been shown to be associated with outcomes. In mild TBI (mTBI; GCS scores 13-15), distribution and co-occurrence of pathological CT features and their prognostic importance are not well understood.OBJECTIVE: To identify pathological CT features associated with adverse outcomes after mTBI.DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, observational Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study enrolled patients with TBI, including those 17 years and older with GCS scores of 13 to 15 who presented to emergency departments at 18 US level 1 trauma centers between February 26, 2014, and August 8, 2018, and underwent head CT imaging within 24 hours of TBI. Evaluations of CT imaging used TBI Common Data Elements. Glasgow Outcome Scale-Extended (GOSE) scores were assessed at 2 weeks and 3, 6, and 12 months postinjury. External validation of results was performed via the Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study. Data analyses were completed from February 2020 to February 2021.EXPOSURES: Acute nonpenetrating head trauma.MAIN OUTCOMES AND MEASURES: Frequency, co-occurrence, and clustering of CT features; incomplete recovery (GOSE scores <8 vs 8); and an unfavorable outcome (GOSE scores <5 vs ≥5) at 2 weeks and 3, 6, and 12 months.RESULTS: In 1935 patients with mTBI (mean [SD] age, 41.5 [17.6] years; 1286 men [66.5%]) in the TRACK-TBI cohort and 2594 patients with mTBI (mean [SD] age, 51.8 [20.3] years; 1658 men [63.9%]) in an external validation cohort, hierarchical cluster analysis identified 3 major clusters of CT features: contusion, subarachnoid hemorrhage, and/or subdural hematoma; intraventricular and/or petechial hemorrhage; and epidural hematoma. Contusion, subarachnoid hemorrhage, and/or subdural hematoma features were associated with incomplete recovery (odds ratios [ORs] for GOSE scores <8 at 1 year: TRACK-TBI, 1.80 [95% CI, 1.39-2.33]; CENTER-TBI, 2.73 [95% CI, 2.18-3.41]) and greater degrees of unfavorable outcomes (ORs for GOSE scores <5 at 1 year: TRACK-TBI, 3.23 [95% CI, 1.59-6.58]; CENTER-TBI, 1.68 [95% CI, 1.13-2.49]) out to 12 months after injury, but epidural hematoma was not. Intraventricular and/or petechial hemorrhage was associated with greater degrees of unfavorable outcomes up to 12 months after injury (eg, OR for GOSE scores <5 at 1 year in TRACK-TBI: 3.47 [95% CI, 1.66-7.26]). Some CT features were more strongly associated with outcomes than previously validated variables (eg, ORs for GOSE scores <5 at 1 year in TRACK-TBI: neuropsychiatric history, 1.43 [95% CI .98-2.10] vs contusion, subarachnoid hemorrhage, and/or subdural hematoma, 3.23 [95% CI 1.59-6.58]). Findings were externally validated in 2594 patients with mTBI enrolled in the CENTER-TBI study.CONCLUSIONS AND RELEVANCE: In this study, pathological CT features carried different prognostic implications after mTBI to 1 year postinjury. Some patterns of injury were associated with worse outcomes than others. These results support that patients with mTBI and these CT features need TBI-specific education and systematic follow-up.
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- Zamora, Juan Carlos, et al.
(författare)
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Considerations and consequences of allowing DNA sequence data as types of fungal taxa
- 2018
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Ingår i: IMA Fungus. - : INT MYCOLOGICAL ASSOC. - 2210-6340 .- 2210-6359. ; 9:1, s. 167-185
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Tidskriftsartikel (refereegranskat)abstract
- Nomenclatural type definitions are one of the most important concepts in biological nomenclature. Being physical objects that can be re-studied by other researchers, types permanently link taxonomy (an artificial agreement to classify biological diversity) with nomenclature (an artificial agreement to name biological diversity). Two proposals to amend the International Code of Nomenclature for algae, fungi, and plants (ICN), allowing DNA sequences alone (of any region and extent) to serve as types of taxon names for voucherless fungi (mainly putative taxa from environmental DNA sequences), have been submitted to be voted on at the 11th International Mycological Congress (Puerto Rico, July 2018). We consider various genetic processes affecting the distribution of alleles among taxa and find that alleles may not consistently and uniquely represent the species within which they are contained. Should the proposals be accepted, the meaning of nomenclatural types would change in a fundamental way from physical objects as sources of data to the data themselves. Such changes are conducive to irreproducible science, the potential typification on artefactual data, and massive creation of names with low information content, ultimately causing nomenclatural instability and unnecessary work for future researchers that would stall future explorations of fungal diversity. We conclude that the acceptance of DNA sequences alone as types of names of taxa, under the terms used in the current proposals, is unnecessary and would not solve the problem of naming putative taxa known only from DNA sequences in a scientifically defensible way. As an alternative, we highlight the use of formulas for naming putative taxa (candidate taxa) that do not require any modification of the ICN.
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