| 1. |
- Adolfsson, Dan E., 1989-, et al.
(författare)
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Intramolecular Povarov Reactions for the Synthesis of Chromenopyridine fused 2-Pyridone Polyheterocycles Binding to α-Synuclein and Amyloid-β fibrils
- 2020
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 85:21, s. 14174-14189
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- A BF3×OEt2 catalyzed intramolecular Povarov reaction was used to synthesize a library of 15 chromenopyridine fused thiazolino-2-pyridone peptidomimetics. The reaction works with a range of O-alkylated salicylaldehydes and amino functionalized thiazolino-2-pyridones, to generate polyheterocycles with diverse substitution. The synthesized compounds were screened for their ability to bind α-synuclein and amyloid β fibrils in vitro. Analogs substituted with a nitro group bind to mature amyloid fibrils, and the activity moreover depends on the positioning of this functional group.
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| 2. |
- Bharate, Jaideep B., et al.
(författare)
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K2S2O8-mediated coupling of 6-amino-7-aminomethyl-thiazolino-pyridones with aldehydes to construct amyloid affecting pyrimidine-fused thiazolino-2-pyridones
- 2021
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Ingår i: Organic and biomolecular chemistry. - : The Royal Society of Chemistry. - 1477-0520 .- 1477-0539. ; 19:44, s. 9758-9772
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Tidskriftsartikel (refereegranskat)abstract
- We herein present the synthesis of diversely functionalized pyrimidine fused thiazolino-2-pyridones via K2S2O8-mediated oxidative coupling of 6-amino-7-(aminomethyl)-thiazolino-2-pyridones with aldehydes. The developed protocol is mild, has wide substrate scope, and does not require transition metal catalyst or base. Some of the synthesized compounds have an ability to inhibit the formation of Amyloid-β fibrils associated with Alzheimer's disease, while others bind to mature amyloid-β and α-synuclein fibrils.
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| 3. |
- Hultberg, Jonas, et al.
(författare)
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In-depth immune profiling reveals advanced B- and T-cell differentiation to be associated with Th1-driven immune dysregulation in common variable immunodeficiency
- 2023
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Ingår i: Clinical Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1521-6616 .- 1521-7035. ; 257
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Tidskriftsartikel (refereegranskat)abstract
- Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by low levels of an-tibodies. In addition to infections, many patients also suffer from T-helper 1-driven immune dysregulation, which is associated with increased mortality. The aim of this study was to perform in-depth characterization of the T and the B cell compartments in a well-defined cohort of patients affected by CVID and correlate the findings to the level of clinical immune dysregulation. We used mass cytometry, targeted proteomics, flow cytometry and functional assays to delineate the immunological phenotype of 15 CVID-affected patients with different levels of immune dysregulation. Unbiased clustering of T cell mass cytometry data correlated with CVID-related immune dysregulation and plasma protein profiles. Expanded CXCR3+ T-bet-expressing B cells correlated with effector memory CD4+ T cell clusters, and increased plasma levels of CXCR3-ligands. Our findings indicate an interplay between B cells and T cells in CVID-related immune dysregulation and provide a better understanding of the underlying pathological mechanisms.
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| 4. |
- Lind, Alexander, et al.
(författare)
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Immunocyte single cell analysis of vaccine-induced narcolepsy
- 2021
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Ingår i: European Journal of Immunology. - : John Wiley & Sons. - 0014-2980 .- 1521-4141. ; 51:1, s. 247-249
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Increased incidence of narcolepsy type 1 (NT1) was observed following Pandemrix®-vaccination, initiated as a preventive measure against the 2009 Influenza pandemic. Here, single cell analysis was conducted to suggest a lower number of CD8+CD27+ T cells among these patients. These findings provide understanding into the autoimmune pathogenesis of NT1.
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| 5. |
- Mehmeti-Ajradini, Meliha, et al.
(författare)
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Human G-MDSCs are neutrophils at distinct maturation stages promoting tumor growth in breast cancer
- 2020
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Ingår i: Life Science Alliance. - : LIFE SCIENCE ALLIANCE LLC. - 2575-1077. ; 3:11
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Tidskriftsartikel (refereegranskat)abstract
- Myeloid-derived suppressor cells (MDSCs) are known to contribute to immune evasion in cancer. However, the function of the human granulocytic (G)-MDSC subset during tumor progression is largely unknown, and there are no established markers for their identification in human tumor specimens. Using gene expression profiling, mass cytometry, and tumor microarrays, we here demonstrate that human G-MDSCs occur as neutrophils at distinct maturation stages, with a disease-specific profile. G-MDSCs derived from patients with metastatic breast cancer and malignant melanoma display a unique immature neutrophil profile, that is more similar to healthy donor neutrophils than to G-MDSCs from sepsis patients. Finally, we show that primary G-MDSCs from metastatic breast cancer patients co-transplanted with breast cancer cells, promote tumor growth, and affect vessel formation, leading to myeloid immune cell exclusion. Our findings reveal a role for human G-MDSC in tumor progression and have clinical implications also for targeted immunotherapy.
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| 6. |
- Rörby, Emma, et al.
(författare)
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Multiplexed single-cell mass cytometry reveals distinct inhibitory effects on intracellular phosphoproteins by midostaurin in combination with chemotherapy in AML cells
- 2021
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Ingår i: Experimental Hematology & Oncology. - : BMC. - 2162-3619. ; 10:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundFms-related tyrosine kinase 3 (FLT3) receptor serves as a prognostic marker and therapeutic target in acute myeloid leukemia (AML). Approximately one-third of AML patients carry mutation in FLT3, associated with unfavourable prognosis and high relapse rate. The multitargeted kinase inhibitor midostaurin (PKC412) in combination with standard chemotherapy (daunorubicin and cytarabine) was recently shown to increase overall survival of AML patients. For that reason, PKC412 has been approved for treatment of AML patients with FLT3-mutation. PKC412 synergizes with standard chemotherapy, but the mechanism involved is not fully understood and the risk of relapse is still highly problematic.MethodsBy utilizing the unique nature of mass cytometry for single cell multiparameter analysis, we have explored the proteomic effect and intracellular signaling response in individual leukemic cells with internal tandem duplication of FLT3 (FLT3-ITD) after midostaurin treatment in combination with daunorubicin or cytarabine.ResultsWe have identified a synergistic inhibition of intracellular signaling proteins after PKC412 treatment in combination with daunorubicin. In contrast, cytarabine antagonized phosphorylation inhibition of PKC412. Moreover, we found elevated levels of FLT3 surface expression after cytarabine treatment. Interestingly, the surface localization of FLT3 receptor increased in vivo on the blast cell population of two AML patients during day 3 of induction therapy (daunorubicin; once/day from day 1-3 and cytarabine; twice/day from day 1-7). We found FLT3 receptor expression to correlate with intracellular cytarabine (AraC) response. AML cell line cultured with AraC with or without PKC412 had an antagonizing phosphorylation inhibition of pAKT (p=0.042 and 0.0261, respectively) and pERK1/2 (0.0134 and 0.0096, respectively) in FLT3(high) compared to FLT3(low) expressing cell populations.ConclusionsOur study provides insights into how conventional chemotherapy affects protein phosphorylation of vital signaling proteins in human leukemia cells. The results presented here support further investigation of novel strategies to treat FLT3-mutated AML patients with PKC412 in combination with chemotherapy agents and the potential development of novel treatment strategies.
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| 7. |
- Tyagi, Mohit, et al.
(författare)
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Tandem Ring Opening/Intramolecular [2 + 2] Cycloaddition Reaction for the Synthesis of Cyclobutane Fused Thiazolino-2-Pyridones
- 2021
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Ingår i: Journal of Organic Chemistry. - : American Chemical Society (ACS). - 0022-3263 .- 1520-6904. ; 86:23, s. 16582-16592
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Tidskriftsartikel (refereegranskat)abstract
- Reaction of thiazoline fused 2-pyridones with alkyl halides in the presence of cesium carbonate opens the thiazoline ring via S-alkylation and generates N-alkenyl functionalized 2-pyridones. In the reaction with propargyl bromide, the thiazoline ring opens and subsequently closes via a [2 + 2] cycloaddition between an in situ generated allene and the α,β-unsaturated methyl ester. This method enabled the synthesis of a variety of cyclobutane fused thiazolino-2-pyridones, of which a few analogues inhibit amyloid β1–40 fibril formation. Furthermore, other analogues were able to bind mature α-synuclein and amyloid β1−40 fibrils. Several thiazoline fused 2-pyridones with biological activity tolerate this transformation, which in addition provides an exocyclic alkene as a potential handle for tuning bioactivity.
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