| 1. |
- Byrgazov, Konstantin, et al.
(författare)
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Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide
- 2020
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Ingår i: THERAPEUTIC ADVANCES IN MEDICAL ONCOLOGY. - : SAGE PUBLICATIONS LTD. - 1758-8340 .- 1758-8359. ; 12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low survival rates in metastatic high-grade osteosarcoma (HGOS) have remained stagnant for the last three decades. This study aims to investigate the role of aminopeptidase N (ANPEP) in HGOS progression and its targeting with a novel lipophilic peptidase-enhanced cytotoxic compound melphalan flufenamide (melflufen) in HGOS. Methods: Meta-analysis of publicly available gene expression datasets was performed to determine the impact ofANPEPgene expression on metastasis-free survival of HGOS patients. The efficacy of standard-of-care anti-neoplastic drugs and a lipophilic peptidase-enhanced cytotoxic conjugate melflufen was investigated in patient-derived HGOSex vivomodels and cell lines. The kinetics of apoptosis and necrosis induced by melflufen and doxorubicin were compared. Anti-neoplastic effects of melflufen were investigatedin vivo. Results: ElevatedANPEPexpression in diagnostic biopsies of HGOS patients was found to significantly reduce metastasis-free survival. In drug sensitivity assays, melflufen has shown an anti-proliferative effect in HGOSex vivosamples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors. Further, HGOS cells treated with melflufen displayed a rapid induction of apoptosis and this sensitivity correlated with high expression ofANPEP. In combination treatments, melflufen demonstrated synergy with doxorubicin in killing HGOS cells. Finally, Melflufen displayed anti-tumor growth and anti-metastatic effectsin vivo. Conclusion: This study may pave the way for use of melflufen as an adjuvant to doxorubicin in improving the therapeutic efficacy for the treatment of metastatic HGOS.
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| 2. |
- Huijser, Erika, et al.
(författare)
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Serum IFNα2 measured by single-molecule array associates with systemic disease manifestations in Sjögren's syndrome
- 2022
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Ingår i: Rheumatology (Oxford, England). - : Oxford University Press (OUP). - 1462-0332 .- 1462-0324. ; 61:5, s. 2156-2166
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Type I IFN (IFN-I) activation is a prominent feature of primary SS (pSS), SLE, and SSc. Ultrasensitive single-molecule array (Simoa) technology has facilitated the measurement of subfemtomolar concentrations of IFNs. Here, we aimed to measure IFNα2 in serum from pSS, SLE, and SSc using a Simoa immunoassay and correlate these levels to blood IFN-stimulated gene (ISG) expression and disease activity.METHODS: Serum IFNα2 was measured in patients with pSS (n = 85; n = 110), SLE (n = 24), and SSc (n = 23), and healthy controls (HC; n = 68) using an IFNα Simoa assay on a HD-X analyser. IFN-I pathway activation was additionally determined from serum by an IFN-I reporter assay and paired samples of whole blood ISG expression of IFI44, IFI44L, IFIT1, IFIT3, and MxA by RT-PCR or MxA-ELISA.RESULTS: Serum IFNα2 levels were elevated in pSS (median=61.3 fg/mL) compared to HC (median ≤5 fg/mL; p < 0.001) and SSc (median=11.6 fg/mL; p = 0.043), lower compared to SLE (median=313.5 fg/mL; p = 0.068), and positively correlated with blood ISG expression (r = 0.66-0.94; p < 0.001). Comparable to MxA-ELISA (AUC=0.93), IFNα2 measurement using Simoa identified pSS with high ISG expression (AUC=0.90) with 80-93% specificity and 71-84% sensitivity. Blinded validation in an independent pSS cohort yielded a comparable accuracy. Multiple regression indicated independent associations of autoantibodies, IgG, HCQ treatment, cutaneous disease and history of extraglandular manifestations with serum IFNα2 concentrations in pSS.CONCLUSION: Thus, Simoa serum IFNα2 reflects blood ISG expression in pSS, SLE, and SSc. In light of IFN-targeting treatments, Simoa could potentially be applied for patient stratification or retrospective analysis of historical cohorts.
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| 3. |
- Mandl, Benjamin
(författare)
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Cues, Beliefs, and Memory
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This doctoral thesis contains four self-contained chapters. “Not so irrelevant alternatives: How cue informativeness results in cue effects” studies when and why decoys and defaults affect choice behavior. “Overestimation of information demand” demonstrates systematic overestimation of the amount of information that is considered before making a decision. “Motivated beliefs and climate attitudes” studies whether changes in the cost of a pro-environmental action affect the perceived importance of that action. “Forward looking motivated memory” investigates a potential strategic memory bias.
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| 4. |
- Patterson, Nick, et al.
(författare)
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Large-scale migration into Britain during the Middle to Late Bronze Age
- 2022
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Ingår i: Nature. - : Nature Publishing Group. - 0028-0836 .- 1476-4687. ; , s. 588-594
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Tidskriftsartikel (refereegranskat)abstract
- Present-day people from England and Wales harbour more ancestry derived from Early European Farmers (EEF) than people of the Early Bronze Age1. To understand this, we generated genome-wide data from 793 individuals, increasing data from the Middle to Late Bronze and Iron Age in Britain by 12-fold, and Western and Central Europe by 3.5-fold. Between 1000 and 875 BC, EEF ancestry increased in southern Britain (England and Wales) but not northern Britain (Scotland) due to incorporation of migrants who arrived at this time and over previous centuries, and who were genetically most similar to ancient individuals from France. These migrants contributed about half the ancestry of Iron Age people of England and Wales, thereby creating a plausible vector for the spread of early Celtic languages into Britain. These patterns are part of a broader trend of EEF ancestry becoming more similar across central and western Europe in the Middle to Late Bronze Age, coincident with archaeological evidence of intensified cultural exchange2-6. There was comparatively less gene flow from continental Europe during the Iron Age, and Britain's independent genetic trajectory is also reflected in the rise of the allele conferring lactase persistence to ~50% by this time compared to ~7% in central Europe where it rose rapidly in frequency only a millennium later. This suggests that dairy products were used in qualitatively different ways in Britain and in central Europe over this period.
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| 5. |
- Perrotta Berlin, Maria, et al.
(författare)
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Selective attention and the importance of types for information campaigns
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- In this paper we try to contribute to the understanding of the persistence and increase of meat eating in the face of mounting evidence on the ills of meat production and consumption by considering the role of selective attention and learning. We aim to test whether agent type plays a role in this process. If this hypothesis is true, simple informational campaigns about the externalities of meat consumption might be ineffective as the informational content may be lost on precisely the population of interest, omnivores. Policy strategies to reach this goal would then need to be refined. Our conclusions apply more generally to a policy agenda for climate-change curbing action, an area where convergence to nudges or strong incentives is proving very hard for policy makers at all levels, and the potential for information to spark action on its own would be very valuable.
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| 6. |
- Ramos-Casals, Manuel, et al.
(författare)
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EULAR recommendations for the management of Sjögren's syndrome with topical and systemic therapies.
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 79:1, s. 3-18
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Tidskriftsartikel (refereegranskat)abstract
- The therapeutic management of Sjögren syndrome (SjS) has not changed substantially in recent decades: treatment decisions remain challenging in clinical practice, without a specific therapeutic target beyond the relief of symptoms as the most important goal. In view of this scenario, the European League Against Rheumatism (EULAR) promoted and supported an international collaborative study (EULAR SS Task Force) aimed at developing the first EULAR evidence and consensus-based recommendations for the management of patients with SjS with topical and systemic medications. The aim was to develop a rational therapeutic approach to SjS patients useful for healthcare professionals, physicians undergoing specialist training, medical students, the pharmaceutical industry and drug regulatory organisations following the 2014 EULAR standardised operating procedures. The Task Force (TF) included specialists in rheumatology, internal medicine, oral health, ophthalmology, gynaecology, dermatology and epidemiology, statisticians, general practitioners, nurses and patient representatives from 30 countries of the 5 continents. Evidence was collected from studies including primary SjS patients fulfilling the 2002/2016 criteria; when no evidence was available, evidence from studies including associated SjS or patients fulfilling previous sets of criteria was considered and extrapolated. The TF endorsed the presentation of general principles for the management of patients with SjS as three overarching, general consensus-based recommendations and 12 specific recommendations that form a logical sequence, starting with the management of the central triplet of symptoms (dryness, fatigue and pain) followed by the management of systemic disease. The recommendations address the use of topical oral (saliva substitutes) and ocular (artificial tear drops, topical non-steroidal anti-inflammatory drugs, topical corticosteroids, topical CyA, serum tear drops) therapies, oral muscarinic agonists (pilocarpine, cevimeline), hydroxychloroquine, oral glucocorticoids, synthetic immunosuppressive agents (cyclophosphamide, azathioprine, methotrexate, leflunomide and mycophenolate), and biological therapies (rituximab, abatacept and belimumab). For each recommendation, levels of evidence (mostly modest) and TF agreement (mostly very high) are provided. The 2019 EULAR recommendations are based on the evidence collected in the last 16 years in the management of primary 2002 SjS patients and on discussions between a large and broadly international TF. The recommendations synthesise current thinking on SjS treatment in a set of overarching principles and recommendations. We hope that the current recommendations will be broadly applied in clinical practice and/or serve as a template for national societies to develop local recommendations.
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| 7. |
- Retamozo, Soledad, et al.
(författare)
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Therapeutic Recommendations for the Management of Older Adult Patients with Sjögren’s Syndrome
- 2021
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Ingår i: Drugs & Aging. - : Springer Science and Business Media LLC. - 1170-229X .- 1179-1969. ; 38:4, s. 265-284
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Tidskriftsartikel (refereegranskat)abstract
- Primary Sjögren’s syndrome (SjS) is a systemic autoimmune disease most commonly diagnosed in middle-aged women. Although the disease can occur at all ages, it is diagnosed between 30 and 60 years of age in two-thirds of patients. In more than 20% of cases, the people are older than 65 years. In this review, we focus on the therapeutic management of primary SjS in older patients, following the recently published 2020 European League Against Rheumatism (EULAR) recommendations for the management of the disease with topical and systemic therapies. These recommendations are applicable to all patients with primary SjS regardless of age at diagnosis, although the therapeutic management in older patients requires additional considerations. Older patients are more likely to have pulmonary, liver, kidney, or heart-related comorbidities (even cognitive disturbances); caution is required when most drugs are used, including muscarinic agents, systemic corticosteroids and synthetic immunosuppressants. It is also important to monitor the use of eye drops containing steroids due to the increased risk of developing cataracts, a frequent ocular complication in the older population. In contrast, the majority of drugs that can be used topically (pilocarpine rinses, eye drops containing topical non-steroidal anti-inflammatory drugs (NSAIDs) or cyclosporine A, topical dermal formulations of NSAIDs) have shown an acceptable safety profile in older patients, as well as rituximab. A rigorous evaluation of the medical history of older patients is essential when drugs included in the EULAR guidelines are prescribed, with special attention to factors frequently related to ageing, such as polypharmacy, the existence of organ-specific comorbidities, or the enhanced susceptibility to infections.
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| 8. |
- Schweinsberg, Martin, et al.
(författare)
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Same data, different conclusions : Radical dispersion in empirical results when independent analysts operationalize and test the same hypothesis
- 2021
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Ingår i: Organizational Behavior and Human Decision Processes. - : Elsevier BV. - 0749-5978 .- 1095-9920. ; 165, s. 228-249
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Tidskriftsartikel (refereegranskat)abstract
- In this crowdsourced initiative, independent analysts used the same dataset to test two hypotheses regarding the effects of scientists' gender and professional status on verbosity during group meetings. Not only the analytic approach but also the operationalizations of key variables were left unconstrained and up to individual analysts. For instance, analysts could choose to operationalize status as job title, institutional ranking, citation counts, or some combination. To maximize transparency regarding the process by which analytic choices are made, the analysts used a platform we developed called DataExplained to justify both preferred and rejected analytic paths in real time. Analyses lacking sufficient detail, reproducible code, or with statistical errors were excluded, resulting in 29 analyses in the final sample. Researchers reported radically different analyses and dispersed empirical outcomes, in a number of cases obtaining significant effects in opposite directions for the same research question. A Boba multiverse analysis demonstrates that decisions about how to operationalize variables explain variability in outcomes above and beyond statistical choices (e.g., covariates). Subjective researcher decisions play a critical role in driving the reported empirical results, underscoring the need for open data, systematic robustness checks, and transparency regarding both analytic paths taken and not taken. Implications for orga-nizations and leaders, whose decision making relies in part on scientific findings, consulting reports, and internal analyses by data scientists, are discussed.
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