| 1. |
- He, Fei, et al.
(author)
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FPR2 Shapes an Immune-Excluded Pancreatic Tumor Microenvironment and Drives T-cell Exhaustion in a Sex-Dependent Manner
- 2023
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In: Cancer Research. - : American Association for Cancer Research (AACR). - 0008-5472 .- 1538-7445. ; 83:10, s. 1628-1645
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Journal article (peer-reviewed)abstract
- Sex-driven immune differences can affect tumor progression and the landscape of the tumor microenvironment. Deeper understanding of these differences in males and females can inform patient selection to improve sex-optimized immunotherapy treatments. In this study, single-cell RNA sequencing and protein analyses uncovered a subpopulation of myeloid cells in pancreatic lesions associated with an immune-excluded tumor phenotype and effector T-cell exhaustion exclusively in females. This myeloid subpopulation was positively correlated with poor survival and genetic signatures of M2-like macrophages and T-cell exhaustion in females. The G-protein coupled receptor formyl peptide receptor 2 (FPR2) mediated these immunosuppressive effects. In vitro, treatment of myeloid cells with a specific FPR2 antagonist prevented exhaustion and enhanced cytotoxicity of effector cells. Proteomic analysis revealed high expression of immunosuppressive secretory proteins PGE2 and galectin-9, enriched integrin pathway, and reduced proinflammatory signals like TNFα and IFNγ in female M2-like macrophages upon FPR2 agonist treatment. In addition, myeloid cells treated with FPR2 agonists induced TIM3 and PD-1 expression only in female T cells. Treatment with anti-TIM3 antibodies reversed T-cell exhaustion and stimulated their ability to infiltrate and kill pancreatic spheroids. In vivo, progression of syngeneic pancreatic tumors was significantly suppressed in FPR2 knockout (KO) female mice compared with wild-type (WT) female mice and to WT and FPR2 KO male mice. In female mice, inoculation of tumors with FPR2 KO macrophages significantly reduced tumor growth compared with WT macrophages. Overall, this study identified an immunosuppressive function of FPR2 in females, highlighting a potential sex-specific precision immunotherapy strategy.
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| 2. |
- Sahl, Mikael, et al.
(author)
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Experimental verification of phased array annular probe in ultrasonic immersion setting : Papers of the ECNDT 2023
- 2023
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In: Research and Review Journal of Nondestructive Testing. - : NDT.net. - 2941-4989. ; 1:1, s. 1-6
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Journal article (peer-reviewed)abstract
- With the ongoing development of materials and manufacturing techniques, new product design opportunities manifest themselves. However, care must be taken when applying techniques and material where there is less inherent knowledge about different parameters’ effect on the integrity of the final component. In conjunction with destructive testing of components, non-destructive evaluation (NDE) provides valuable insight into the manufacturing process reliability, as well as the possibility for subsequent future in-service inspection. Phased array ultrasonic testing (PAUT) facilitates the inspection of complex geometries on a wide set of material. Mathematical modelling of ultrasonic signal facilitates the optimization of inspection procedures by e.g., maximizing the probability of detection (POD) of specific defect types. In this paper, the response from an immersion annular phased array probe is experimentally validated to the output of the simulation software simSUNDT. In order to only validate the probe model (as both transmitter and receiver) a set of well-defined defects are used. The validity of the simulated amplitude response from side-drilled holes at a depth range of 20-115 mm is investigated. A total of 14 SDH holes in one test piece of is used as cases for validation. The results show a good correspondence between simulated and experimental data for the case where the probe is normal to the component surface.
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| 3. |
- Sahl, Mikael, et al.
(author)
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Nondestructive evaluation of additively manufactured components
- 2023. - 1.
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In: Additive Manufacturing of High-Performance metallic Materials. - : Elsevier. - 9780323918855 - 9780323913829 ; , s. 639-675
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Book chapter (peer-reviewed)abstract
- Lightweight and optimized designs through modern metal additivemanufacturing (AM) require reliable manufacturing processes and put highdemands on quality assessment and control. This part addressesnondestructive testing (NDT) technologies and their industrial AMapplications with a focus on process monitoring, control, and development.Data derived from NDT can be used for process monitoring (as sensors), inprocess nondestructive evaluation (NDE), or postprocess NDE. This chapteraims to define and point out the distinction between these differentframeworks. The methods and techniques addressed include (a) Defectsintroduced during manufacturing, welding (pores, lack of fusion, etc.) withthe NDT perspective in focus; (b) in-service inspection (ISI) andmanufacturing control (in-process and postprocess NDE); (c) NDT methodsand associated physics; (d) standards related to NDT for AM, includingprobability of detection (POD); and (e) mathematical modeling andapplication of NDE simulations.
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| 4. |
- Sahl, Mikael
(author)
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Ultrasonic testing of components produced with additive manufacturing : Towards improved detection and classification of defects
- 2024
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Licentiate thesis (other academic/artistic)abstract
- The focus in this work is on the use of ultrasonic testing as a method for inspecting components manufactured through additive manufacturing (AM) processes. The research is rooted in the need for effective non-destructive testingtechniques that can adapt to the unique challenges posed by AM-produced materials, including complex defect geometries and surface conditions.Ultrasonic testing is a versatile form of non-destructive testing, offering theability to detect internal flaws, such as voids, cracks, and inclusions, with highprecision and in real-time. Unlike many competing methods, ultrasonic testing works on most types of materials. Ultrasonic testing has been applied forinspection purposes for a long time. Now with emerging manufacturing methods, there is a need for evaluation techniques to keep up with this development.New data processing algorithms open up possibilities of extracting more information from the acquired signal.The thesis provides a review of UT’s capabilities in detecting and classifyingdefects within AM components, with a particular emphasis on the subtletiesintroduced by the layer-by-layer construction method inherent to AM technologies. The work advances development and validation of simulation modelsaimed at predicting the ultrasonic response from manufactured defects. Thesemodels are crucial for understanding the interaction between ultrasound wavesand material anomalies, offering insights into the potential for enhanced defectdetection strategies.The research also explores the practical case of integrating UT into the quality assurance processes by relying on mathematical simulation rather than experimental data. The findings suggest avenues for the refinement of creation of inspection procedure, including the the use of meta-models to cheaply acquire worst-case scenario defects, to better accommodate the specificities of AM materials.
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| 5. |
- Sarhan, Dhifaf, et al.
(author)
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885 Targeting FPR2 as a novel approach for immunotherapy in pancreatic cancer female patients : studies of sexual immune dimorphism in the tumor microenvironment
- 2021
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In: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 9:Suppl 2, s. A927-A927
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Journal article (peer-reviewed)abstract
- BackgroundImmunotherapy for pancreatic cancer (PC) is inefficient due to a highly immune-suppressive tumor microenvironment (TME) orchestrated by myeloid suppressor cells, which limit the infiltration and function of cytotoxic immune cells. We have evidence that accumulation of a subpopulation of myeloid cells in human pancreatic lesions is associated with immune-exclusive tumor phenotype and effector T cell exhaustion by mechanisms involving the G-coupled protein receptor formyl peptide receptor 2 (FPR2), exclusively in women. We hypothesize that female FPR2+ myeloid cells in tumors induce immune exhaustion and contribute to immune-cold tumor phenotype.MethodsTo test our hypothesis, we first investigated the FPR2 RNA and protein expression in PC transcriptomic data and in murine and human PC tissues. Further, in vitro cytokine differentiated, alternatively tumor conditioned myeloid cells (TCM) were co-cultured with T cells to mimic their interaction in the TME. In vivo, PC cells were injected subcutaneously in FPR2 WT and KO mice to study tumor progression and the immune landscape in male vs. female mice. Later, human myeloid cells were treated with FPR2 agonists and antagonists to study the interaction mechanisms in detail.ResultsWe found high FPR2 expression in tumor compared to healthy tissues and higher in women compared to men. In mice and human, FPR2+ myeloid cells were associated with immune cold-exclusive and cold-ignored tumor phenotype in women and men, respectively. Notably, analysis in PC and other gastrointestinal (GI)-tract cancers revealed a significant association of FPR2 expression and poor survival only in women, emerging the potential impact of sex factors in the TME. Such sexual dimorphism in the TME was associated with T cell exhaustion apparent by high expression of TIM3 and PD1. In vitro, FPR2-agonist treated myeloid-suppressive cells induced TIM3 and PD1 expression in T cells specifically in female T cells. However, a significant repression of TIM3 and a trend of PD1 expression was observed in T cells when interacting with FPR2-inhibited or -deficient myeloid cells. Finally, tumor progression was significantly slower in FPR2 KO female mice compared to WT and male FPR2 WT and KO mice.ConclusionsIn this study, we have shown that sex differences are involved in shaping the TME in PC, where sexual dimorphism is still a largely unknown area allowing novel personalized/sex-specific immunotherapies. We found that FPR2 is highly involved in T cell exhaustion and can potentially be a therapeutic target for immunotherapy in women developing PC and other GI-tract cancers.
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