Prognostic information from nonmalignant and malignant lymphocytes in follicular lymphoma in relation to therapy

Follicular lymphoma is the most common indolent lymphoma. It is composed of centrocytes and centroblasts, residing in follicles that also harbour nonmalignant immune and stroma cells. Follicular lymphoma is graded according to the World Health Organization criteria that are based on the frequency of centroblasts. There is consensus that grades 1 and 2 are indolent, but not whether grade 3 is aggressive. Differences between grades 3A and 3B are also unclear. The nonmalignant cells in the microenvironment interact with the tumour cells and with each other. These interactions may be important for disease outcome. Since the introduction of the therapeutic monoclonal anti-CD20 antibody rituximab, the prognosis of follicular lymphoma has improved. It is likely that the mechanisms of rituximab affect and involve not only CD20+ follicular lymphoma cells but also the surrounding as well as the systemic immune cells. The aim of this thesis was to identify biological predictors for outcome in follicular lymphoma in relation to therapy. In paper I, using flow cytometry, we reported that higher numbers of CD8+ T cells in diagnostic lymph nodes are an independent predictor of better overall and disease-specific survival. This finding was reproduced in paper II in which computerised quantifications of tissue microarrays were used for a unifying multivariate model. This model showed that many cells in the microenvironment were independently important for outcome. Higher levels of cells positive for CD8 (cytotoxic T cells), forkhead box protein 3 (regulatory T cells) and programmed death-1 (PD-1+ T cells) correlated with good prognosis, but higher levels of cells positive for CD4 (helper T cells) and CD68 (macrophages) with poor. The best predictors for poor outcome were increasing CD4/CD8 and follicular/interfollicular CD4 ratios, suggesting that outcome is influenced by the balance between detrimental follicular B-helper and helper2 T-cells on one hand and favourable cytotoxic and helper1 T cells on the other. In paper III we used prospectively recorded flow cytometry analyses from two randomised trials where all patients received single rituximab with or without interferon-α priming. T cells in tumours (both CD4+ and CD8+) were associated with fast and good clinical responses to rituximab, while T cells in blood (both CD4+ and CD8+) correlated with slower but good and sustained responses, and were more important for survival. Interferon-α abrogated the dependence on high numbers of CD8+ cells (in both blood and tumours) for good rituximab responses. In paper IV we reviewed the follicular lymphoma grades in 828 patients with long follow-up times, of whom 40% received upfront rituximab. Compared with grade 1–3A patients and independently of clinical factors, grade 3B patients showed higher mortality but outcome was improved after upfront anthracyclines. Grade 3B patients experienced no relapses or deaths beyond five years of follow-up. Furthermore, patients with grade 3B were different in their clinical characteristics. In the entire population, patients with grade 3A had similar outcome as those with grade 1–2. However, in patients given upfront rituximab-containing therapy, increasing grades of 1, 2, and 3A correlated with better overall survival and time to treatment-failure, independently of clinical factors. We conclude that outcome in follicular lymphoma is determined by the balance between competing immune cells in the microenvironment and by their interactions with each other and with the tumour cells. Rituximab and interferon-α alter the prognostic properties of the immune cells, and also involve systemic T cells that may be very important for disease outcome. Grade 3B, or follicular large B-cell lymphoma, is a distinct, aggressive but curable entity. Grades 1, 2 and 3A are indolent and incurable. Increasing grades predict better outcome with rituximab therapy. Our findings suggest a future of personalised therapy based on biological characteristics of the patients and of the tumours

Urban trees – for better or for worse : differences in regulating and supporting ecosystem services between broadleaved and conifer trees in the urban environment

Träd har en viktig roll i att klimatanpassa städer genom att leverera ekosystemtjänster. I nordiska städer planteras mest lövträd eftersom det historiskt funnits ett kulturellt motstånd mot barrträd. Flera barrträd tål dock stadens ogästvänliga ståndort och eftersom de flesta barrträden är städsegröna kan de leverera ekosystemtjänster året om. I denna uppsats undersöks skillnader mellan löv- och barrträd utifrån sex reglerande och stödjande ekosystemtjänster med hjälp av en systematisk litteraturstudie. Resultaten visar att barrträd, som har komplexare bladstruktur, större sammanlagd bladyta och städsegrön krona kan vara effektivare på ekosystemtjänsterna luftrening, dagvattenhantering och vindskydd. Lövträd kan, med bredare kronor och lövfällning, vara effektivare på temperaturreglering. Kolupptagning/kolinlagring kan anses vara likvärdiga för löv- och barrträd och i stället bero på andra faktorer såsom trädets biomassa, tillväxthastighet och växtbäddsförhållanden. För biologisk mångfald med avseende på habitat och föda för andra organismer kunde det konstateras att löv- och barrträd fyller olika funktioner och därför behövs båda trädslag i staden. Lokal artsammansättning och om träden är inhemska eller inte kan dock anses vara viktigare faktorer för denna ekosystemtjänst. Resultatet indikerar att skillnaden mellan löv- och barrträd är större för luftrening men mindre för dagvattenhantering i det syd- och mellansvenska klimatet än vad internationell forskning visar. För svenskt klimat är det framför allt rumslig komposition som avgör skillnaden i temperaturreglering och vindskydd. Trädets förmåga att leverera de sex undersökta ekosystemtjänsterna beror på fler faktorer såsom platsen, växtbädd, skötsel, artsammansättning, komposition, förekomst och ålder (tid) och dessa bör tas i beaktning vid trädval. Denna uppsats redogör för vilka ekosystemtjänster man kan förväntas få från löv- och barrträd i stadsmiljö och kan vägleda till ett medvetet trädval.Trees play a significant role in climate adaptation by delivering ecosystem services. Broadleaved trees are commonly planted in Nordic cities because of the historic cultural resistance towards conifers. Yet, many conifers tolerate the harsh urban environment and have potential to deliver ecosystem services all year round since most conifers are evergreen. This essay will investigate differences between broadleaved and conifer trees in six regulating and supporting ecosystem services through systematic literature studies. The results show that conifers, which have a more complex leaf structure, bigger total leaf area and evergreen canopies can be more effective at removing pollutants, managing storm water and to create wind protection. However, broadleaved trees can by being deciduous and by having broader canopies be more effective at mitigating temperature. Carbon sequestration and storage can be considered equal for broadleaved and conifer trees and depend more on other factors like biomass, growth rate and soil conditions. For biodiversity concerning habitat and food provisioning for other organisms, broadleaved and conifer trees have distinct roles and are both needed in urban areas. However, local species composition and whether the trees are native or not could be more crucial factors for this ecosystem service. The results indicate that the differences between broadleaved and conifer trees are bigger for air purification but smaller for storm water management in the climate of south and central Sweden than what international research shows. For Swedish climate, especially spatial composition decides the difference in temperature mitigation and wind protection. The trees’ capacity to deliver these ecosystem services depend on additional factors such site, soil, management, species and spatial composition, frequency and age (time) and these should be considered in tree selection. This essay covers which ecosystem services one can expect from broadleaved and conifer trees in urban areas and can guide a conscious tree selection

Third time’s the charm? Bulgaria’s November elections and the elusive quest for a parliamentary majority

Bulgaria has held three parliamentary elections in 2021, with the latest vote taking place on 14 November alongside the first round of the country’s presidential election. In the second round of the presidential vote, held on 21 November, incumbent President Rumen Radev was re-elected for another five-year term. Kjell Engelbrekt and Petia Kostadinova write that amid widespread frustration with the country’s political leaders, there is now a mandate for a new government to implement real change