Role of regulatory T cells in acute myeloid leukemia patients undergoing relapse-preventive immunotherapy

Regulatory T cells (Tregs) have been proposed to dampen functions of anti-neoplastic immune cells and thus promote cancer progression. In a phase IV trial (Re:Mission Trial, NCT01347996, http://www.clinicaltrials.gov ) 84 patients (age 18-79) with acute myeloid leukemia (AML) in first complete remission (CR) received ten consecutive 3-week cycles of immunotherapy with histamine dihydrochloride (HDC) and low-dose interleukin-2 (IL-2) to prevent relapse of leukemia in the post-consolidation phase. This study aimed at defining the features, function and dynamics of Foxp3+CD25highCD4+ Tregs during immunotherapy and to determine the potential impact of Tregs on relapse risk and survival. We observed a pronounced increase in Treg counts in peripheral blood during initial cycles of HDC/IL-2. The accumulating Tregs resembled thymic-derived natural Tregs (nTregs), showed augmented expression of CTLA-4 and suppressed the cell cycle proliferation of conventional T cells ex vivo. Relapse of AML was not prognosticated by Treg counts at onset of treatment or after the first cycle of immunotherapy. However, the magnitude of Treg induction was diminished in subsequent treatment cycles. Exploratory analyses implied that a reduced expansion of Tregs in later treatment cycles and a short Treg telomere length were significantly associated with a favorable clinical outcome. Our results suggest that immunotherapy with HDC/IL-2 in AML entails induction of immunosuppressive Tregs that may be targeted for improved anti-leukemic efficiency

Therapist-guided internet-based psychodynamic therapy versus cognitive behavioural therapy for adolescent depression in Sweden: a randomised, clinical, non-inferiority trial

BACKGROUND: Adolescent major depressive disorder (MDD) is highly prevalent and associated with lifelong adversity. Evidence-based treatments exist, but accessible treatment alternatives are needed. We aimed to compare internet-based psychodynamic therapy (IPDT) with an established evidence-based treatment (internet-based cognitive behavioural therapy [ICBT]) for the treatment of adolescents with depression. METHODS: In this randomised, clinical trial, we tested whether IPDT was non-inferior to ICBT in the treatment of adolescent MDD. Eligible participants were 15-19 years old, presenting with a primary diagnosis of MDD according to DSM-5. Participants were recruited nationwide in Sweden through advertisements on social media, as well as contacts with junior and senior high schools, youth associations, social workers, and health-care providers. Adolescents who scored 9 or higher on the Quick Inventory of Depressive Symptomatology for Adolescents (QIDS-A17-SR) in an initial online screening were contacted by telephone for a diagnostic assessment using the Mini International Neuropsychiatric Interview. Participants were randomly assigned to ICBT or IPDT. Both interventions comprised eight self-help modules delivered over 10 weeks on a secure online platform. The primary outcome was change in depression severity measured weekly by the QIDS-A17-SR. Primary analyses were based on an intention-to-treat sample including all participants randomly assigned. A non-inferiority margin of Cohen's d=0·30 was predefined. The study is registered at ISRCTN, ISRCTN12552584. FINDINGS: Between Aug 19, 2019, and Oct 7, 2020, 996 young people completed screening; 516 (52%) were contacted for a diagnostic interview. 272 participants were eligible and randomly assigned to ICBT (n=136) or IPDT (n=136). In the ICBT group, 51 (38%) of 136 participants were classified as remitted, and 54 (40%) of 136 participants were classified as remitted in the IPDT group. Within-group effects were large (ICBT: within-group d=1·75, 95% CI 1·49 to 2·01; IPDT: within-group d=1·93, 1·67 to 2·20; both p<0·0001). No statistically significant treatment difference was found in the intention-to-treat analysis. Non-inferiority for IPDT was shown for the estimated change in depression during treatment (d=-0·18, 90% CI -0·49 to 0·13; p=0·34). All secondary outcomes showed non-significant between-group differences. INTERPRETATION: IPDT was non-inferior to ICBT in terms of change in depression for the treatment of adolescents with MDD. This finding increases the range of accessible and effective treatment alternatives for adolescents with depression. FUNDING: Kavli trust

Oxidant-induced cell death in lymphocytes: mechanisms of induction and resistance

Reactive oxygen species (oxidants, oxygen radicals) produced by the phagocytic NADPH oxidase have pivotal roles in immunity. Patients lacking a functional NADPH oxidase suffer from chronic granulomatous disease, which is characterized by recurring bacterial infections and thus manifesting the importance of reactive oxygen species in host defense against bacteria. However, NADPH oxidase-derived radicals also efficiently inhibit lymphocyte-mediated immunity. Oxidant-induced inactivation of lymphocytes is reportedly a control mechanism for autoreactive lymphocytes and hence prevents autoimmunity. In malignant diseases, oxygen radicals have been proposed to contribute to the characteristic state of anergy of cytotoxic lymphocytes, which prevents immune-mediated rejection of the tumor. Studies of the mechanisms of radical-induced inactivation of lymphocytes may therefore be helpful in understanding the pathophysiology of important disease entities. The first paper in this thesis shows that oxidant-induced functional inhibition and cell death in cytotoxic lymphocytes is critically dependent on cooperation between a nuclear enzyme involved in DNA repair, PARP-1, and a mitochondrion-derived protein, AIF. The results presented in Paper II demonstrate that pharmacological inhibition of the PARP-1 enzyme not only prevents oxidant-induced cell death, but also preserves functions of cytotoxic lymphocytes, such as cytotoxicity against malignant cells, cytokine production, and proliferation. Paper III shows that subsets of natural killer (NK) cells display differential sensitivity to oxygen radicals: the cytotoxic CD56dimCD16+ NK cells were found to be highly sensitive to oxidative inactivation and apoptosis, while the immunoregulatory, cytokine-producing CD56brightCD16- NK cells were highly resistant to the toxicity of oxidants. These data were extended in Paper IV, in which the effect of oxygen radical-producing phagocytes on the expression of the activating NK cell receptors, NKp46 and NKG2D, was investigated. The expression of both receptors was efficiently downregulated on CD56dim NK cells, while the expression remained intact on CD56bright cells. Recent data imply that reciprocal interactions between NK cells and dendritic cells (DCs) are important for the development of adaptive immunity. The results presented in Paper V demonstrate that DCs are equipped with an antioxidative system that efficiently protects cytotoxic cells from oxidant-induced inactivation

Pecking order i svenska tillväxtföretag -En kvantitativ studie kring finansiering i svenska gasellföretag

Bakgrund och problem: Ett företag kan antingen finansiera sin verksamhet via internt genererade medel, externa lån eller nyemitterat kapital. Pecking order-teorin beskriver denna hackordning som det internt genererade egna kapitalet som mest föredraget, följt av externa skulder och till sist nyemitterat externt eget kapital som minst föredraget. Tillväxtföretag bidrar till tillväxt i samhället, vilket skapar arbetstillfällen och bidrar till den gemensamma ekonomiska välfärden. På grund av nystartade företags bristande historia och en informationsasymmetri mellan intressenter inom och utanför företag kan det vara svårt för företag att anskaffa externa medel. Syfte: Denna studies syfte är att undersöka företag som har uppvisat en kraftig organisk tillväxt under en kort period och hur förhållandet mellan nytt externt och internt kapital har sett ut under finansieringen av denna tillväxt. Avgränsningar: Studien utgår från svenska gasellföretag under ett år. På grund av kriterierna för att få gasell-utmärkelsen försvinner flera sorters snabbväxande företag, däribland företag yngre än fyra år. Metod: Frank och Goyal (2003) har varit utgångspunkten i analysen för att testa pecking orderteorin på svenska tillväxtföretag, med Dagens Industris lista över gasellföretag som urvalskriterium. Studien är en tvärsnittsstudie med kvantitativ data som har hämtats ur databasen Business Retriever. Ur populationen på 917 gasellföretag har 41 företag valts bort vilket lämnat kvar 876 företag. Det undersökta eventuella sambandet är företags finansiella under- eller överskott och ändringen i deras långfristiga skulder under ett år. Testet görs om för att pröva samtliga variabler i studien. Dessa är branschtillhörighet, soliditet, omsättningstillväxt, ålder, avkastning på eget och totalt kapital, samt omsättning. Resultat och slutsatser: Utifrån en uppdelning av gasellföretag i företag som har ett finansiellt underskott och företag som har ett finansiellt överskott, visar studien på varierande grad av belägg för pecking order-teorin på svenska tillväxtföretag. Studien finner att för företag med ett finansiellt underskott kan pecking order-teorin förklara deras finansieringsbeteende. För företag med ett finansiellt överskott är inte sambandet mellan detta och förändringen i lån lika tydlig. Därför går det inte att utifrån denna studie förklara dessa företags finansiering med pecking order-teorin. Förslag till fortsatt forskning: Vad händer med gasellföretag åren efter de har blivit utsedda och varför? Skiljer sig noterade och onoterade snabbväxande företag sig åt ur ett pecking orderperspektiv och i så fall, varför? Vilken påverkan har företags storlek på sannolikheten att pecking order-teorin följs

Framtidens Lövholmen : Rumsskapande visioner om en post-industriell miljö

I denna kandidatuppsats undersöks stadsomvandlingen av den post-industriella platsen Lövholmen utifrån främst formella visionsplaner, och den process som pågått sedan 1999 för att bygga nya bostäder på platsen. Utifrån rumsliga teorier, visar jag hur stadsplaneringsbegrepp och digitala, illustrerade framställningar som används i visionsplanerna fylls med meningsskapande värderingar. Genom gentrifiering, planering, tolkningsföreträde och makt, industriella arv, ekonomiska incitament och positivt laddade stadsplaneringsbegrepp skapar denna meningsskapande värdering en tänkt, idealiserad medborgare i en utstuderad stadsmiljö. Studiens resultat visar på spänningar i den rumsliga konstruktionen av platsen och på motstridiga visionära, erfarna och praktiska ideal. Studien visar också på slutsatser för vilka som har makten i konstruerandet av nya stadsrum, och hur den idealiserade gruppen har visionärt ska praktiskt leva i det nya stadsrummet och en möjligt ny vändning i värderandet av kulturarv

GIS-tillämpning för verksamhetsområdet mark och miljö

Validerat; 20101217 (root

Wildland / urban interface fire risk model

Wildland/ Urban Interface (WUI) fires and communities at risk are high priorities to federal land management agencies. The Bureau of Land Management (BLM) Upper Snake River District (USRD) Geographic Information Systems (GIS) team, in cooperation with Idaho State University’s (ISU) GIS Training and Research Center (GIS TreC), have created a model to predict potential fire risk areas around the city of Pocatello, Idaho. The study area is Pocatello, Idaho city limits with a buffer of approximately 1 mile surrounding it. To create a wildland/ urban interface fire model the criteria that were considered are topography and vegetation characteristics, and suppression access. Data presented in this report contains detailed conclusions of the effect that each criterion will have on the model, and the result as a complete model. With the data available we believe that we have produced a reliable, accurate, yet not overly complicated model of community areas at risk to wildfire.Validerat; 20101217 (root