| 1. |
- Chen, Kaixuan, et al.
(författare)
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Mapping formation mechanisms and transformation regimes of multiple Fe precipitates in Cu-Fe-Co alloy during casting process
- 2024
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Ingår i: Scripta Materialia. - : Elsevier BV. - 1359-6462 .- 1872-8456. ; 246
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Tidskriftsartikel (refereegranskat)abstract
- Precipitate features including size, morphology, crystal structure, etc., are important parameters determining the performance of precipitate-strengthened alloys. Multiple Fe precipitates were identified in as-cast Cu alloys exhibiting the distinct features, which dramatically influence mechanical properties. However, a complete understanding of precipitation behaviors of Fe particles during casting, in terms of both microscopic kinetics and thermodynamics, remains experimentally challenging. Here, we report the combined implementation of transmission electron microscopy, Thermo-Calc calculations and First-principles calculations to map mechanisms and growth regimes of Fe precipitation in a Cu-Fe-Co system. Our analyses support the idea that to understand the microstructural evolution in the system, both thermodynamic and kinetic arguments must be taken into account. Then, using our multi-approach strategy, the complete picture of the formation and transformation of Fe precipitates is proposed. This work is vital to promote microstructural design for Cu-Fe(-Co) systems, and sheds new insights into understanding of intricate precipitation in alloys.
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| 2. |
- Chen, Ziqing, et al.
(författare)
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Phosphodiesterase 4A confers resistance to PGE2-mediated suppression in CD25(+)/CD54(+) NK cells
- 2021
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Ingår i: EMBO Reports. - : EMBO Press. - 1469-221X .- 1469-3178. ; 22:3
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Tidskriftsartikel (refereegranskat)abstract
- Inadequate persistence of tumor-infiltrating natural killer (NK) cells is associated with poor prognosis in cancer patients. The solid tumor microenvironment is characterized by the presence of immunosuppressive factors, including prostaglandin E2 (PGE2), that limit NK cell persistence. Here, we investigate if the modulation of the cytokine environment in lung cancer with IL-2 or IL-15 renders NK cells resistant to suppression by PGE2. Analyzing Cancer Genome Atlas (TCGA) data, we found that high NK cell gene signatures correlate with significantly improved overall survival in patients with high levels of the prostaglandin E synthase (PTGES). In vitro, IL-15, in contrast to IL-2, enriches for CD25(+)/CD54(+) NK cells with superior mTOR activity and increased expression of the cAMP hydrolyzing enzyme phosphodiesterase 4A (PDE4A). Consequently, this distinct population of NK cells maintains their function in the presence of PGE2 and shows an increased ability to infiltrate lung adenocarcinoma tumors in vitro and in vivo. Thus, strategies to enrich CD25(+)/CD54(+) NK cells for adoptive cell therapy should be considered.
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| 3. |
- Dang, Junhua, et al.
(författare)
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Individual differences in dopamine level modulate the ego depletion effect
- 2016
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Ingår i: International Journal of Psychophysiology. - : Elsevier. - 0167-8760 .- 1872-7697. ; 99, s. 121-124
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Tidskriftsartikel (refereegranskat)abstract
- Initial exertion of self-control impairs subsequent self-regulatory performance, which is referred to as the ego depletion effect. The current study examined how individual differences in dopamine level, as indexed by eye blink rate (EBR), would moderate ego depletion. An inverted-U-shaped relationship between EBR and subsequent self regulatory performance was found when participants initially engaged in self-control but such relationship was absent in the control condition where there was no initial exertion, suggesting individuals with a medium dopamine level may be protected from the typical ego depletion effect. These findings are consistent with a cognitive explanation which considers ego depletion as a phenomenon similar to switch costs that would be neutralized by factors promoting flexible switching.
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| 4. |
- Degorce, Sebastien L, et al.
(författare)
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Discovery of PROTAC molecules that selectively degrade the IRAK3 pseudokinase
- 2020
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 63:18, s. 10460-10473
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Tidskriftsartikel (refereegranskat)abstract
- We report the first disclosure of IRAK3 degraders in the scientific literature. Taking advantage of an opportune by-product obtained during our efforts to identify IRAK4 inhibitors, we identified ready to use, selective IRAK3 ligands in our compound collection with the required properties for conversion into PROTAC degraders. This work culminated with the discovery of PROTAC 23, which we demonstrated to be a potent and selective degrader of IRAK3. 23 induced proteasome-dependent degradation of IRAK3 and required both CRBN and IRAK3 binding for activity. We conclude that PROTAC 23 constitutes an excellent in vitro tool with which to interrogate the biology of IRAK3.
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| 5. |
- Eissler, Nina, et al.
(författare)
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Regulation of myeloid cells by activated T cells determines the efficacy of PD-1 blockade
- 2016
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Ingår i: Oncoimmunology. - : Taylor & Francis. - 2162-4011 .- 2162-402X. ; 5:12
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Tidskriftsartikel (refereegranskat)abstract
- Removal of immuno-suppression has been reported to enhance antitumor immunity primed by checkpoint inhibitors. Although PD-1 blockade failed to control tumor growth in a transgenic murine neuroblastoma model, concurrent inhibition of colony stimulating factor 1 receptor (CSF-1R) by BLZ945 reprogrammed suppressive myeloid cells and significantly enhanced therapeutic effects. Microarray analysis of tumor tissues identified a significant increase of T-cell infiltration guided by myeloid cell-derived chemokines CXCL9, 10, and 11. Blocking the responsible chemokine receptor CXCR3 hampered T-cell infiltration and reduced antitumor efficacy of the combination therapy. Multivariate analysis of 59 immune-cell parameters in tumors and spleens detected the correlation between PD-L1-expressing myeloid cells and tumor burden. In vitro, anti-PD-1 antibody Nivolumab in combination with BLZ945 increased the activation of primary human T and NK cells. Importantly, we revealed a previously uncharacterized pathway, in which T cells secreted M-CSF upon PD-1 blockade, leading to enhanced suppressive capacity of monocytes by upregulation of PD-L1 and purinergic enzymes. In multiple datasets of neuroblastoma patients, gene expression of CD73 correlated strongly with myeloid cell markers CD163 and CSF-1R in neuroblastoma tumors, and associated with worse survival in high-risk patients. Altogether, our data reveal the dual role of activated T cells on myeloid cell functions and provide a rationale for the combination therapy of anti-PD-1 antibody with CSF-1R inhibitor.
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| 6. |
- Mao, Yumeng, et al.
(författare)
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IL-15 activates mTOR and primes stress-activated gene expression leading to prolonged antitumor capacity of NK cells
- 2016
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Ingår i: Blood. - : AMER SOC HEMATOLOGY. - 0006-4971 .- 1528-0020. ; 128:11, s. 1475-1489
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Tidskriftsartikel (refereegranskat)abstract
- Treatment of hematological malignancies by adoptive transfer of activated natural killer (NK) cells is limited by poor postinfusion persistence. We compared the ability of interleukin-2 (IL-2) and IL-15 to sustain human NK-cell functions following cytokine withdrawal to model postinfusion performance. In contrast to IL-2, IL-15 mediated stronger signaling through the IL-2/15 receptor complex and provided cell function advantages. Genome-wide analysis of cytosolic and polysome-associated messenger RNA (mRNA) revealed not only cytokine-dependent differential mRNA levels and translation during cytokine activation but also that most gene expression differences were primed by IL-15 and only manifested after cytokine withdrawal. IL-15 augmented mammalian target of rapamycin (mTOR) signaling, which correlated with increased expression of genes related to cell metabolism and respiration. Consistently, mTOR inhibition abrogated IL-15-induced cell function advantages. Moreover, mTOR-independent STAT-5 signaling contributed to improved NK-cell function during cytokine activation but not following cytokine withdrawal. The superior performance of IL-15-stimulated NK cells was also observed using a clinically applicable protocol for NK-cell expansion in vitro and in vivo. Finally, expression of IL-15 correlated with cytolytic immune functions in patients with B-cell lymphoma and favorable clinical outcome. These findings highlight the importance of mTOR-regulated metabolic processes for immune cell functions and argue for implementation of IL-15 in adoptive NK-cell cancer therapy.
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| 7. |
- Mao, Yumeng
(författare)
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To kill two birds with one stone : targeting myeloid cells in cancers
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cancer progression is often accompanied by chronic inflammation and severe impairment of the immune system. In recent years, therapies eliciting tumor-specific immunity have resulted in striking tumor control and survival benefits in cancer patients. However, establishment of effective and durable immune responses is hampered by various tumor-dependent mechanisms. Besides the direct suppression mediated by tumor cells, a number of immune cell types, including regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), ‘M2-biased’ tumor-associated macrophages (TAMs) and regulatory dendritic cells, occur in the periphery and tumor microenvironment. These cells conduct potent inhibition of anti-tumor immunity and are associated with poor prognosis in patients. Studies included in this thesis aim to elucidate the molecular machinery that tumor cells utilize to induce suppressive functions from healthy myeloid cells (Study I, II and IV) and how the resulted suppressive myeloid cells could limit functions of T cells (Study I), natural killer (NK) cells (Study II) and differentiation of the immune-stimulating dendritic cells (DCs) (Study III). Finally, we tested the role of a myeloid-specific chemical inhibitor in antagonizing the induction of these suppressive myeloid cells in vitro. In a transgenic murine model developing highly aggressive spontaneous tumors, treatment with the inhibitor elicited robust control of established tumors and potentiated the anti-tumor effects of checkpoint blocking antibodies (Study IV). In summary, this thesis provides mechanistic insights for the induction of suppressive myeloid cells and demonstrates the therapeutic potential of targeting these cells for the treatment of solid tumors.
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| 8. |
- Mao, Yumeng
(författare)
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What industry can teach academia
- 2019
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 365:6459, s. 1342-1342
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 9. |
- Natoli, Marina, et al.
(författare)
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Human ovarian cancer intrinsic mechanisms regulate lymphocyte activation in response to immune checkpoint blockade
- 2020
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Ingår i: Cancer Immunology and Immunotherapy. - : Springer Nature. - 0340-7004 .- 1432-0851. ; 69:8, s. 1391-1401
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Tidskriftsartikel (refereegranskat)abstract
- Immune checkpoint blocking antibodies are currently being tested in ovarian cancer (OC) patients and have shown some responses in early clinical trials. However, it remains unclear how human OC cancer cells regulate lymphocyte activation in response to therapy. In this study, we have established and optimised an in vitro tumour-immune co-culture system (TICS), which is specifically designed to quantify the activation of multiple primary human lymphocyte subsets and human cancer cell killing in response to PD-1/L1 blockade. Human OC cell lines and treatment naïve patient ascites show differential effects on lymphocyte activation and respond differently to PD-1 blocking antibody nivolumab in TICS. Using paired OC cell lines established prior to and after chemotherapy relapse, our data reveal that the resistant cells express low levels of HLA and respond poorly to nivolumab, relative to the treatment naïve cells. In accordance, knockdown of IFNγ receptor expression compromises response to nivolumab in the treatment naïve OC cell line, while enhanced HLA expression induced by a DNA methyltransferase inhibitor promotes lymphocyte activation in TICS. Altogether, our results suggest a 'cross resistance' model, where the acquired chemotherapy resistance in cancer cells may confer resistance to immune checkpoint blockade therapy through down-regulation of antigen presentation machinery. As such, agents that can restore HLA expression may be a suitable combination partner for immunotherapy in chemotherapy-relapsed human ovarian cancer patients.
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| 10. |
- O' Donovan, Daniel H., et al.
(författare)
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The Next Generation of Pattern Recognition Receptor Agonists : Improving Response Rates in Cancer Immunotherapy
- 2020
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Ingår i: Current Medicinal Chemistry. - : Bentham Science Publishers Ltd.. - 0929-8673 .- 1875-533X. ; 27:34, s. 5654-5674
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Tidskriftsartikel (refereegranskat)abstract
- The recent success of checkpoint blocking antibodies has sparked a revolution in cancer immunotherapy. Checkpoint inhibition activates the adaptive immune system leading to durable responses across a range of tumor types, although this response is limited to patient populations with pre-existing tumor infiltrating T cells. Strategies to stimulate the immune system to prime an antitumor response are of intense interest and several groups are now working to develop agents to activate the pattern recognition receptors (PRRs), proteins which detect pathogenic and damage-associated molecules and respond by activating the innate immune response. Although early efforts focused on the Toll-like receptor (TLR) family of membrane-bound PRRs, TLR activation has been associated with both pro- and antitumor effects. Nonetheless, TLR agonists have been deployed as potential anticancer agents in a range of clinical trials. More recently, the cytosolic PRR Stimulator of IFN genes (STING) has attracted attention as another promising target for anticancer drug development, with early clinical data beginning to emerge. Besides STING, several other cytosolic PRR targets have likewise captured the interest of the drug discovery community, including the RIG-I-like receptors (RLRs) and NOD-like receptors (NLRs). In this review, we describe the outlook for activators of PRRs as anticancer therapeutic agents and contrast the earlier generation of TLR agonists with the emerging focus on cytosolic PRR activators, both as single agents and in combination with other cancer immunotherapies.
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