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- Bojmar, Linda, et al.
(författare)
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Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer
- 2024
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Ingår i: Nature Medicine. - : NATURE PORTFOLIO. - 1078-8956 .- 1546-170X.
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Tidskriftsartikel (refereegranskat)abstract
- Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B(+) natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B(+) NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection.<br />
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- Hansson, EM, et al.
(författare)
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Control of Notch-ligand endocytosis by ligand-receptor interaction
- 2010
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Ingår i: Journal of cell science. - : The Company of Biologists. - 1477-9137 .- 0021-9533. ; 123:17Pt 17, s. 2931-2942
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Tidskriftsartikel (refereegranskat)abstract
- In Notch signaling, cell-bound ligands activate Notch receptors on juxtaposed cells, but the relationship between ligand endocytosis, ubiquitylation and ligand-receptor interaction remains poorly understood. To study the specific role of ligand-receptor interaction, we identified a missense mutant of the Notch ligand Jagged1 (Nodder, Ndr) that failed to interact with Notch receptors, but retained a cellular distribution that was similar to wild-type Jagged1 (Jagged1WT) in the absence of active Notch signaling. Both Jagged1WT and Jagged1Ndr interacted with the E3 ubiquitin ligase Mind bomb, but only Jagged1WT showed enhanced ubiquitylation after co-culture with cells expressing Notch receptor. Cells expressing Jagged1WT, but not Jagged1Ndr, trans-endocytosed the Notch extracellular domain (NECD) into the ligand-expressing cell, and NECD colocalized with Jagged1WT in early endosomes, multivesicular bodies and lysosomes, suggesting that NECD is routed through the endocytic degradation pathway. When coexpressed in the same cell, Jagged1Ndr did not exert a dominant-negative effect over Jagged1WT in terms of receptor activation. Finally, in Jag1Ndr/Ndr mice, the ligand was largely accumulated at the cell surface, indicating that engagement of the Notch receptor is important for ligand internalization in vivo. In conclusion, the interaction-dead Jagged1Ndr ligand provides new insights into the specific role of receptor-ligand interaction in the intracellular trafficking of Notch ligands.
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- Ibrahim, Yasir H., et al.
(författare)
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An affinity tool for the isolation of endogenous active mTORC1 from various cellular sources
- 2023
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Ingår i: Journal of Biological Chemistry. - : ELSEVIER. - 0021-9258 .- 1083-351X. ; 299:5
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Tidskriftsartikel (refereegranskat)abstract
- The mechanistic target of rapamycin complex 1 (mTORC1) is a central regulator of mammalian cell growth that is dysregulated in a number of human diseases, including metabolic syndromes, aging, and cancer. Structural, biochemical, and pharmacological studies that have increased our understanding of how mTORC1 executes growth control often relied upon purified mTORC1 protein. However, current immunoaffinitybased purification methods are expensive, inefficient, and do not necessarily isolate endogenous mTORC1, hampering their overall utility in research. Here we present a simple tool to isolate endogenous mTORC1 from various cellular sources. By GTPases from Escherichia coli and using them as affinity probes, we demonstrate that mTORC1 can be isolated from mouse, bovine, and human sources. Our results indicate that mTORC1 isolated by this relatively inexpensive method is catalytically active and amenable to scaling. Collectively, this tool may be utilized to isolate mTORC1 from various cellular sources, organs, and disease contexts, aiding mTORC1-related research.
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- Mutvei, Harry, et al.
(författare)
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Carboniferous coleoids with mixed coleoid-orthocerid characteristics: a new light oncephalopod evolution
- 2018
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Ingår i: GFF. - London : Taylor & Francis. - 1103-5897 .- 2000-0863. ; 140, s. 11-24
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Tidskriftsartikel (refereegranskat)abstract
- Orthocerid-like coleoids with mixed orthocerid-coleoid characteristics are described for the first time from the Carboniferous of USA. The appearance of these coleoids represents transitional morphology between the orthoconic nautiloid and coleoid lineages. This transitional state is based on the new genus Colorthoceras n. gen. with three assigned new species (C. inflata n. sp., C. tubulata n. sp. and C. concavus n. sp.) in the new family Colorthoceridae of the new order Colorthocerida. Orthocerid nautiloid characteristics include a longiconic phragmocone with a well-developed body chamber, and a central, sub-central or sub-ventral siphuncle with endosiphuncular deposits. The shell wall in the new order Colorthocerida is characterized by the coleoid characteristics of a lack of the nacreous layer, with a high content of chitin that created a somewhat semi-elastic shell. The connecting rings are uni-layered, directly continuous from the septal neck, and have a mixed chitinous-calcareous composition similar to that in order Mixosiphonata. The shell wall structure in these unique orthocerid-like coleoids is similar to that in the previously described Carboniferous bactritoid-like coleoids. The evolution of these coleoid characteristics appears to represent an unsuccessful evolutionary experiment, as the diversity of this nautiloid lineage was in gradual decline in the Upper Paleozoic.
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