| 1. |
- Backman, Max, et al.
(author)
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Extending the immune phenotypes of lung cancer: Oasis in the desert
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Other publication (other academic/artistic)abstract
- Introduction: Tumor infiltrating immune cells are key elements of the tumor microenvironment and mediate the anti-tumor effects of immunotherapy. The aim of the study was to characterize patterns of immune cell infiltration in non-small cell lung cancer (NSCLC) in relation to tumor mutations and clinicopathological parameters. Methods: Lymphocytes (CD4+, CD8+, CD20+, FOXP3+, CD45RO+), macrophages (CD163+), plasma cells (CD138+), NK cells (NKp46+) and PD-L1+ were annotated on a tissue microarray including 357 operated NSCLC cases. Somatic mutations and tumor mutational burden were analyzed by targeted sequencing for 82 genes, and transcriptomic immune patterns were established in 197 patients based on RNAseq data. Results: We identified somatic mutations (TP53, NF1, KEAP1, CSMD3, LRP1B) that correlated with specific immune cell infiltrates. Hierarchical clustering revealed four immune classes: with (1) high immune cell infiltration (“inflamed”), (2) low immune cell infiltration (“desert”), (3) a mixed phenotype, and (4) a new phenotype with an overall muted inflammatory cell pattern but with an imprint of NK and plasma cells. This latter class exhibited low expression of immune response-related genes (e.g. CXCL9, GZMB, INFG, TGFB1), but was linked to better survival and therefore designated “oasis”. Otherwise, the four immune classes were not related to the presence of specific mutations (EGFR, KRAS, TP53) or histologic subtypes. Conclusion: We present a compartment-specific immune cell analysis in the context of the molecular and clinical background of NSCLC and identified the novel immune class “oasis”. The immune classification helps to better define the immunogenic potency of NSCLC in the era of immunotherapy.
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| 2. |
- Backman, Max, 1987-, et al.
(author)
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Spatial immunophenotyping of the tumor microenvironment in non-small cell lung cancer
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Other publication (other academic/artistic)abstract
- Introduction: Immune cells in the tumor microenvironment are associated with prognosis and response to therapy. We aimed to comprehensively characterize the spatial immune phenotypes in the mutational and clinicopathological background of non-small cell lung cancer (NSCLC).Methods: We established a multiplexed fluorescence multispectral imaging pipeline to spatially quantify 13 immune cell subsets in 359 NSCLC cases: CD4 effector cells (CD4 Eff), CD4 regulatory cells (CD4 Treg), CD8 effector cells (CD8 Eff), CD8 regulatory cells (CD8 Treg), B-cells, NK-cells, NKT-cells, M1 macrophages (M1), CD163+ myeloid cells (CD163), M2 macrophages (M2), immature dendritic cells (iDCs), mature dendritic cells (mDCs), and plasmacytoid dendritic cells (pDCs). Results: CD4 Eff cells, CD8 Eff cells, and M1 macrophages were the most abundant immune cells invading the tumor cell compartment and indicated a patient group with a favorable prognosis in the cluster analysis. Likewise, single densities of lymphocytic subsets (CD4 Eff, CD4 Treg, CD8 Treg, and B-cells), as well as pDCs, were independently associated with longer survival. However, when these immune cells were located close to CD8 Treg cells, the favorable impact was attenuated. In the multivariate Cox regression model including cell densities and distances, the densities of M1 and CD163 cells and distances between cells (CD8 Treg–B-cells, CD8 Eff–cancer cells, and B-cells–CD4 Treg) demonstrated positive prognostic impact, while short M2–M1 distances were prognostically unfavorable.Conclusion: We present a unique spatial profile of the in situ immune cell landscape in NSCLC as a publicly available data set. Cell densities and cell distances contribute independently to prognostic information on clinical outcomes, suggesting that spatial information is also crucial for diagnostic use.
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| 4. |
- Isaksson, Johan, et al.
(author)
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Predictors of long-term survival and recurrence patterns after definitive chemoradiotherapy in stage III NSCLC – a multicenter cohort study from Mid Sweden
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Other publication (other academic/artistic)abstract
- Background: Stage III NSCLC is heterogeneous but often recurs despite intensive treatment with curative intent. Clinical tools to predict the risk and pattern of recurrence and long-term survival in individual patients are largely lacking. Methods: NSCLC stage III patients (N=193) treated 2009-2018 with definitive, curatively intended chemoradiotherapy (CRT, 60Gy+) were retrospectively identified from three healthcare regions in Mid Sweden. Outcome variables included overall survival (OS), progression-free survival (PFS) and recurrence patterns. Results: Median follow-up of patients alive was 52 months. 1, 2 and 5-year OS was 80%, 63% and 34% with a mOS of 32 months. Pre-treatment serum inflammatory markers were associated with inferior OS, including leukocyte count > 10 (HR 1.58, 95% CI 1.08-2.31, p=0.018) and CRP > 5 (HR 1.81, 95% CI 1.16-2.83, p=0.009). CRP remained independently associated with OS in multivariable analysis, HR 1.67 (1.05-2.65, p=0.029). No other pre-treatment variable was significantly associated with OS. Progressive disease (PD) was documented in 65% of patients after a median time of 9.5 months, 96% within 3 years from CRT, and was typically either distant or locoregional (12% mixed). Distant PD developed earlier (6.3 months) than locoregional PD (11.5 months; p=0.052). N3 disease (OR 2.7, 95% CI 1.2-6.3,; p=0.022) and presence of driver mutations (OR 4.6, 95% CI 1.5-14.0; p=0.0076) increased the risk of distant PD, while ≥2 concurrent chemotherapy courses was protective of locoregional PD (OR 0.38, 9% CI 0.1-1.0; p=0.049). Brain metastases were the first indication of PD in 22 patients (12%) and were in all cases isolated without synchronous extracranial PD. A post-CRT 18F-FDG-PET SUVmax of ≥7 was associated with a shorter time to PD (HR 0.41, 95% CI 0.21-0.79, p=0.008). Conclusions: The study reinforces the prognostic role of systemic inflammation in stage III NSCLC and provides clinically useful indicators of relapse pattern as a basis for rational disease monitoring following CRT.
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| 5. |
- Caldenby, Claes, 1946, et al.
(author)
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Architecture and Engineering - 10 Years Anniversary Book
- 2016
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Other publication (other academic/artistic)abstract
- A Jubilee Book will tell our story, a common share of moments and activities, thoughts and reflections, from 10 years of Architecture and Engineering, in short AT. A creative mixture of strong professional cultures, a desire and an enthusiasm for searching out and taking on the challanges of the future in architecture and engineering of the built environment.
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| 6. |
- Darmanis, Spyros, et al.
(author)
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Multiplexed solid-phase proximity ligation assays: Highly specific and parallel protein measurements with DNA sequencing readout
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Other publication (other academic/artistic)abstract
- Identification and validation of protein biomarkers is a very important step towards the understanding of the underlying mechanisms of disease, early diagnosis and efficient patient treatment. To carry out this task, methods are needed that would allow us to mine the proteome with sufficient sensitivity and specificity in large sets of samples. We present herein the development of a Multiplexed Proximity Ligation Assay (MultiPLAy), to facilitate efficient protein profiling in a parallel, sensitive and specific manner. We showed that for the simultaneous analysis of 35 proteins MultiPLAy exhibited an improved sensitivity over conventional sandwich assays as well as a smaller susceptibility to background signal increase in the transition from singleplex to multiplex. We used MultiPLAy to identify putative biomarkers in two separate sample cohorts of colorectal cancer (CRC) and cardiovascular disease (CVD) and with the use a novel multivariate analysis approach were able to identify new, as well as already known diagnostic biomarkers. Furthermore we were able to combine MultiPLAy with the use of next-generation sequencing allowing for the first time digital recording of protein profiles in blood. We demonstrated good reproducibility of MultiPLAy coupled to next-generation sequencing, as well as a satisfactory correlation to standard real-time PCR readout. We conclude that MultiPLAy has great potential as a basis for highly multiplexed protein detection assays that can be utilized for the identification of large numbers of proteins or protein variants. This will allow extensive validation of protein expression patterns in biobanked samples and in prospective studies, and can provide a much-needed platform for efficient validation of diagnostic markers for clinical use.
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| 7. |
- Fiedler, Markus, et al.
(author)
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Communication requirements of generic services for Intelligent Transport Systems
- 2004
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Other publication (other academic/artistic)abstract
- In order to meet their users’ expectations and to be of efficient help for people using or maintaining Intelligent Transport Systems (ITS), related services need efficient support from the underlying communication systems, which in turn requires profound knowledge of those needs. This paper presents an approach to gather services into generic groups and a framework to classify their needs in terms of availability, performance, security and cost in a generic manner. These needs are consequently seen from the user’s perspective, but formulated in a way such that the matching towards technical parameters as e.g. throughput offered by a communication network can be performed. Upon comparing needs with offers, the feasibility of a certain communication technology for a certain type of service can be determined, which in turn helps to choose the right kind of connectivity in order to yield the desired degree of availability, performance, security and cost. This work is carried out within the VINNOVA-sponsored project PIITSA (Personal Information for Intelligent Transport Systems through Seamless communications and Autonomous decisions) conducted by Aerotech Telub, Blekinge Tekniska Högskola, Statens Provningsanstalt Borås and Vägverket, respectively.
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| 8. |
- Larsson, Tobias, et al.
(author)
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Project: ProViking THINK - Team för Heterogen Innovationskunskap
- 2008
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Other publication (pop. science, debate, etc.)abstract
- Begreppet product-service systems (PSS), eller funktionella produkter, förutspås ha betydande påverkan för ett framtida hållbart samhälle. Ett PSS-synsätt kommer att förändra hur produkter och tjänster används, men också förändra tillvägagångssättet i utvecklingen, eftersom ansvaret för den fysiska produkten genom hela dess livscykel kvarstår hos företaget eller konsortiet som utvecklar PSS-lösningen. I och med detta kan aktiviteterna med omkonstruktion, återanvändning och återvinning, utföras på ett totalt annorlunda sätt än i dag. I den här situationen blir kapaciteten att ständigt förbättra kundupplevt värde genom nya lösningar en viktig förmåga. Således står utvecklingsteam idag inför två stora utmaningar; dels ska de kunna hantera mer abstrakta kundbehov, dels ska de på ett effektivt sätt ständigt bidra till nya lösningar. Det här projektets mål är att stödja PSS-utvecklingsteamets innovationsprocess genom att föreslå faciliterande metoder och verktyg. Specifikt fokus ligger på följande aspekter för att bidra till utvecklingen av en sammanhängande metodologi för team-baserad innovation:- Identifiering, analys och kommunikation av kundbehov samt modellering av värde- Tvärfunktionella team- Effektiv kunskapsdelning- Modellering och visualisering av lösningar baserat på ett kunskapslivscykel perspektiv Projektet kommer att vara en gemensam prestation av industri- och akademirepresentanter. Det praktiska arbetet kommer att utföras i ett nära samarbete. I stort vägleds projektet av antagandet att – visualisering av affärs- och utvecklingsrelaterad kunskap samt snabba modellerings- och simuleringsmöjligheter i tidiga faser stödjer PSS-teamets förmåga att finna nya lösningar och genomföra hållbar utveckling. Förutom ökad kunskap om strategier och tillvägagångssätt för team-baserad innovation kommer demonstratorer av verktyg och metoder vara ett resultat av projektarbetet.
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