Targeting the Antibody Checkpoints to Enhance Cancer Immunotherapy–Focus on FcγRIIB

Immunotherapy with therapeutic antibodies has increased survival for patients with hematologic and solid cancers. Still, a significant fraction of patients fails to respond to therapy or acquire resistance. Understanding and overcoming mechanisms of resistance to antibody drugs, and in particular those common to antibody drugs as a class, is therefore highly warranted and holds promise to improve response rates, duration of response and potentially overall survival. Activating and inhibitory Fc gamma receptors (FcγR) are known to coordinately regulate therapeutic activity of tumor direct-targeting antibodies. Similar, but also divergent, roles for FcγRs in controlling efficacy of immune modulatory antibodies e.g., checkpoint inhibitors have been indicated from mouse studies, and were recently implicated in contributing to efficacy in the human clinical setting. Here we discuss evidence and mechanisms by which Fc gamma receptors–the “antibody checkpoints”–regulate antibody-induced antitumor immunity. We further discuss how targeted blockade of the sole known inhibitory antibody checkpoint FcγRIIB may help overcome resistance and boost activity of clinically validated and emerging antibodies in cancer immunotherapy

Utveckling av lekotoper för barns naturmöten

I projekt efter projekt där lekmiljöer för barn skall iordningställas så ser vi hur leken undermineras genom att ytor med naturmark decimeras, vegetationen hålls tillbaka och konstgjorda material ersätter natur. Mot denna utveckling behövs nya strategier för att bevaka naturvärden, underlätta naturmarksetablering och säkra barns och ungas tillgång till en god utemiljö i enlighet med Plan och Bygglagen. Då naturbaserade lekmiljöer är dynamiska platser med levande material behöver man samtidigt göra sig medveten om olika möjliga skötselstrategier redan från start. Det kräver nya typer av dialoger mellan experter för att undersöka villkoren på platser där naturen skall samsas med barns aktivitet. Är det möjligt att tänka sig ett perspektiv där barnen genom sin användning bidrar till platsens skötsel och utveckling? Med stöd från SLU:s miljöanalysprogram Bebyggd miljö har i detta projekt ett antal forskare och praktiker ingått i dialog kring den problematik och de utmaningar som finns när man skall identifiera och anlägga naturmark som passar barns behov och intressen. Projektet under beteckningen Utveckling av "lekotoper" för barns naturmöten (SLU.ltv.2020.4.1-255) har handlat om att utveckla en förståelse för problematiken, hitta gemensamma perspektiv och en fungerande terminologi för att diskutera frågorna vidare på tvärs av olika fack och praktiker. Viktiga personer för projektets genomförande som vi särskilt vill tacka är personal vid parkenheten i Örebro med Mimmi Beckman i spetsen samt Emma Simonsson vid Urbio, som generöst har bjudit på kunskap och konkreta exempel. Det är denna duo som tillsammans med oss forskare vid SLU, Björn Wiström och Åsa Ode Sang vid institutionen för landskapsarkitektur, planering och förvaltning i Alnarp, Marcus Hedblom vid institutionen för stad och land i Uppsala samt Fredrika Mårtensson och Anna Litsmark vid institutionen för människa och samhälle i Alnarp, som har riggat de olika workshopparna som har varit grunden för dialogen. Idén till workshopparna uppstod inom ramen för en dialog mellan ett arbetspaket inom EU-projektet REGREEN med forskare från SLU samt Vinnovaprojektet Hållbara lekmiljöer i Staden där KTH, SLU, Örebro kommun och Urbio ingår. De två projekten har utbyten emellan sig och under ett möte om möjliga synergieffekter väcktes behovet av att behandla frågor kring anläggning av naturmark. I det praktiska arbetet kring lekotoputvecklingen som sker i Örebro efterfrågades kunskap och input på frågor kring design och anläggning av gröna leklandskap med fokus på topografi och växtbäddar. Till de frågor som lyftes fram hörde växtval, etableringsfrågor och frågor om plantors kvalitet, tid för plantering, jordbäddar, skydd, täckodling mm. Forskargruppen har stått för dokumentation och efterföljande reflektioner i rapporten. Vi vill också passa på att tacka alla deltagare i workshopparna som bidragit med sin tid, kunskap och engagemang! Från universitet deltog flera forskare med specialexpertis på området i processen och även antal studenter med examensarbete i ämnet. Det pågår också en 3 mängd olika initiativ runt om i Sverige för att göra barns utomhusliv rikare som vi på detta sätt fått ta del av. Deltagarna finns listade i bilaga 5. Forskarnas insatser i projektet har också stöttats ekonomiskt genom samordning med EU-projektet REGREEN ( https://www.regreen-project.eu/). Projektgruppen från SLU har stått för inramningen till workshoppar, föreliggande dokumentation och avslutande analys i rapporten. Då projektet ägde rum under den globala pandemin har inplanerade fysiska möten behövt ställas in. De behov som ändå finns av att inventera, undersöka och föra dialog på plats hoppas vi få tillgodose i ett kommande partnerskaps-Moviumprojekt som startar under 2021: I projektet Naturbaserade leklandskap med barn och unga får vi chansen att gå vidare och pröva nyvunna insikter på en kommande testbädd i Örebro. Avnämare för arbetet är samhällsplaneringen i stort med fokus på forskares, myndigheters och kommuners arbete med god bebyggd miljö till gagn för friluftsliv och folkhälsa. Fokus ligger på kunskapsstöd till personer från olika sektorer som arbetar med att kartera och tillgängliggöra närnatur för barn - på deras och naturens villkor. Vår förhoppning är att det framöver skall bli lika vanligt att tänka i lekotoper som det är idag att tänka och planera med lekredskap vid anläggning av lekmiljö. Genom processen med workshops och efterföljande dokumentation hoppas vi ha visat prov på hur ett professionellt stöd kan se ut i det viktiga arbetet med att identifiera och utveckla naturbaserade lekmiljöer

The "Free from housing accessibility problems" app

Publisher Copyright: © 2016 The authors and IOS Press.The present study concerns the development of a computerized tool targeting housing accessibility issues. A user-centered approach involving professionals from the housing sector and senior citizens from four European countries resulted in a fully functional prototype of a mobile application (app) including an apartment database. The app raises awareness on housing accessibility and has the potential to support decision making and strengthen all citizens regardless of functional capacity to be more active in their endeavors for a satisfying housing solution. Further refinements and additional features are needed to enhance the potential benefits; they include addressing potential challenges facing senior citizens, developing interactive features that allow users to provide input and adapting to different national contexts to make the app applicable for the European market.publishersversionPeer reviewe

Update on the EFFECTS study of fluoxetine for stroke recovery: a randomised controlled trial in Sweden

Studies have suggested that fluoxetine might improve neurological recovery after stroke, but the results remain inconclusive. The EFFECTS (Efficacy oF Fluoxetine – a randomisEd Controlled Trial in Stroke) reached its recruitment target of 1500 patients in June 2019. The purpose of this article is to present all amendments to the protocol and describe how we formed the EFFECTS trial collaboration in Sweden. Methods In this investigator-led, multicentre, parallel-group, randomised, placebo-controlled trial, we enrolled non-depressed stroke patients aged 18 years or older between 2 and 15 days after stroke onset. The patients had a clinical diagnosis of stroke (ischaemic or intracerebral haemorrhage) with persisting focal neurological deficits. Patients were randomised to fluoxetine 20 mg or matching placebo capsules once daily for 6 months. Results Seven amendments were made and included clarification of drug interaction between fluoxetine and metoprolol and the use of metoprolol for severe heart failure as an exclusion criterion, inclusion of data from central Swedish registries and the Swedish Stroke Register, changes in informed consent from patients, and clarification of design of some sub-studies. EFFECTS recruited 1500 patients at 35 centres in Sweden between 20 October 2014 and 28 June 2019. We plan to unblind the data in January 2020 and report the primary outcome in May 2020. Conclusion EFFECTS will provide data on the safety and efficacy of 6 months of treatment with fluoxetine after stroke in a Swedish health system setting. The data from EFFECTS will also contribute to an individual patient data meta-analysis

Effects of Fluoxetine on Outcomes at 12 Months After Acute Stroke:Results From EFFECTS, a Randomized Controlled Trial

Background and Purpose: The EFFECTS (Efficacy of Fluoxetine—a Randomised Controlled Trial in Stroke) recently reported that 20 mg fluoxetine once daily for 6 months after acute stroke did not improve functional outcome but reduced depression and increased fractures and hyponatremia at 6 months. The purpose of this predefined secondary analysis was to identify if any effects of fluoxetine were maintained or delayed over 12 months. Methods: EFFECTS was an investigator-led, randomized, placebo-controlled, double-blind, parallel group trial in Sweden that enrolled adult patients with stroke. Patients were randomized to 20 mg oral fluoxetine or matching placebo for 6 months and followed for another 6 months. The primary outcome was functional outcome (modified Rankin Scale), at 6 months. Predefined secondary outcomes for these analyses included the modified Rankin Scale, health status, quality of life, fatigue, mood, and depression at 12 months. Results: One thousand five hundred patients were recruited from 35 centers in Sweden between 2014 and 2019; 750 were allocated fluoxetine and 750 placebo. At 12 months, modified Rankin Scale data were available in 715 (95%) patients allocated fluoxetine and 712 (95%) placebo. The distribution of modified Rankin Scale categories was similar in the 2 groups (adjusted common odds ratio, 0.92 [95% CI, 0.76–1.10]). Patients allocated fluoxetine scored worse on memory with a median value of 89 (interquartile range, 75–100) versus 93 (interquartile range, 82–100); P =0.0021 and communication 93 (interquartile range, 82–100) versus 96 (interquartile range, 86–100); P =0.024 domains of the Stroke Impact Scale compared with placebo. There were no other differences in secondary outcomes. Conclusions: Fluoxetine after acute stroke had no effect on functional outcome at 12 months. Patients allocated fluoxetine scored worse on memory and communication on the Stroke Impact Scale compared with placebo, but this is likely to be due to chance. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02683213

Safety and efficacy of fluoxetine on functional recovery after acute stroke (EFFECTS): a randomised, double-blind, placebo-controlled trial

Background Studies have suggested that fluoxetine could improve neurological recovery after stroke. The Efficacy oF Fluoxetine—a randomisEd Controlled Trial in Stroke (EFFECTS) trial aimed to assess whether administration of oral fluoxetine for 6 months after acute stroke improves functional outcome. Methods EFFECTS was an investigator-led, multicentre, randomised, placebo-controlled, double-blind, parallel group trial that enrolled patients aged 18 years or older between 2 and 15 days after stroke onset in 35 stroke and rehabilitation centres in Sweden. Eligible patients had a clinical diagnosis of ischaemic or intracerebral haemorrhage, brain imaging that was consistent with intracerebral haemorrhage or ischaemic stroke, and had at least one persisting focal neurological deficit. A web-based randomisation system that incorporated a minimisation algorithm was used to randomly assign (1:1) participants to receive oral fluoxetine 20 mg once daily or matching placebo capsules for 6 months. Patients, care providers, investigators, and outcomes assessors were masked to the allocation. The primary outcome was functional status, measured with the modified Rankin Scale (mRS) at 6 months, analysed in all patients with available mRS data at the 6-month follow-up; we did an ordinal analysis adjusted for the minimisation variables used in the randomisation. This trial is registered with EudraCT, 2011-006130-16; ISRCTN, 13020412; and ClinicalTrials.gov, NCT02683213. Findings Between Oct 20, 2014, and June 28, 2019, 1500 patients were enrolled, of whom 750 were randomly assigned to fluoxetine and 750 were randomly assigned to placebo. At 6 months, mRS data were available for 737 (98%) patients in the fluoxetine group and 742 (99%) patients in the placebo group. There was no effect of fluoxetine on the primary outcome—distribution across mRS score categories—compared with placebo (adjusted common odds ratio 0·94 [95% CI 0·78 to 1·13]; p=0·42). The proportion of patients with a new diagnosis of depression was lower with fluoxetine than with placebo (54 [7%] patients vs 81 [11%] patients; difference −3·60% [–6·49 to −0·71]; p=0·015), but fluoxetine was associated with more bone fractures (28 [4%] vs 11 [2%]; difference 2·27% [0·66 to 3·87]; p=0·0058) and hyponatraemia (11 [1%] vs one [<1%]; difference 1·33% [0·43 to 2·23]; p=0·0038) at 6 months. Interpretation Functional outcome after acute stroke did not improve with oral fluoxetine 20 mg once daily for 6 months. Fluoxetine reduced the occurrence of depression but increased the risk of bone fractures and hyponatraemia. Our results do not support the use of fluoxetine after acute stroke

Robust T cell immunity in convalescent individuals with asymptomatic or mild COVID-19

SARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19

Fc Effector Function Contributes to the Activity of Human Anti-CTLA-4 Antibodies.

With the use of a mouse model expressing human Fc-gamma receptors (FcγRs), we demonstrated that antibodies with isotypes equivalent to ipilimumab and tremelimumab mediate intra-tumoral regulatory T (Treg) cell depletion in vivo, increasing the CD8+ to Treg cell ratio and promoting tumor rejection. Antibodies with improved FcγR binding profiles drove superior anti-tumor responses and survival. In patients with advanced melanoma, response to ipilimumab was associated with the CD16a-V158F high affinity polymorphism. Such activity only appeared relevant in the context of inflamed tumors, explaining the modest response rates observed in the clinical setting. Our data suggest that the activity of anti-CTLA-4 in inflamed tumors may be improved through enhancement of FcγR binding, whereas poorly infiltrated tumors will likely require combination approaches

Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

The Timbral and Quality Affect from Pitch Correction Software on a Recorded Vocal Performance

Pitch correction has been a part of music production ever since the introduction of AutoTune, back in 1997. Previous research regarding the topic has not found any significant differences when comparing pitch correctors to one another, in terms of how they correct pitch, however little to no research has been done on pitch correctors introduction of timbral and quality differences, when compared to an un-processed original. This study aims to test the notion that the usage of pitch correction software affects the timbre and quality of a vocal performance. The two pitch correctors chosen for this study was Antares Auto-Tune and Celemony Melodyne. 17 experienced listeners participated in an ABX-style listening test during which pitch corrected stimuli were compared to one another, and to un-tuned stimuli to find if subjects could differentiate between the different excerpts. The subjects also gave qualitative motivations for the perceived difference between the excerpts. The result of the listening test verifies the notion that pitch correction signal processing affects the timbre and quality, as it was found that subjects could, with statistical significance, differentiate the different excerpts. The result also shows that the most prevalent differentiating factor was the treble of the material.