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Dadgar, A., et al.
(author)
Fever of unknown origin in a multiple sclerosis patient on immunomodulatory therapy was due to neoehrlichiosis
2017
In: Läkartidningen. - 0023-7205. ; 114:38
Journal article (peer-reviewed) abstract
The emerging tick-borne bacterium Candidatus Neoehrlichia mikurensis is the etiologic agent of neoehrlichiosis, a febrile illness that may be accompanied by vascular complications. Severe cases of neoehrlichiosis have been described in patients with hematologic malignancies and systemic rheumatic diseases. We present the first case of neoehrlichiosis in a patient with multiple sclerosis undergoing rituximab therapy. © 2017, Swedish Medical Association. All rights reserved.
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Gustafsson, Lars, et al.
(author)
Infectious disease, reproductive effort and the cost of reproduction in birds
1994
In: Philosophical transactions of the Royal Society of London: Series B. ; :346, s. 1655-1658
Journal article (pop. science, debate, etc.) abstract
Reproductive effort can have profound effects on subsequent performance. Field experiments on the collared flycatcher (Ficedula albicollis) have demonstrated a number of trade-offs between life-history traits at different ages. The mechanism by which reproductive effort is mediated into future reproductive performance remains obscure. Anti-parasite adaptations such as cell-mediated immunity may probably also be costly. Hence the possibility exists of a trade-off between reproductive effort and the ability to resist parasitic infection. Serological tests on unmanipulated collared flycatchers show that pre-breeding nutritional status correlates positively with reproductive success and negatively with susceptibility to parasitism (viruses, bacteria and protozoan parasites). Both immune response and several indicators of infectious disease correlate negatively with reproductive success. Similar relations are found between secondary sexual characters and infection parameters. For brood-size-manipulated birds there was a significant interaction between experimentally increased reproductive effort and parasitic infection rate with regard to both current and future fecundity. It seems possible that the interaction between parasitic infection, nutrition and reproductive effort can be an important mechanism in the ultimate shaping of life-history variation in avian populations.
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Storm, Petter
(author)
The mechanism of HAMLET-induced cell death - cellular signalling, oncogenes and clinical perspectives
2012
Doctoral thesis (other academic/artistic) abstract
Despite recent advances in cancer treatment, truly innovative approaches are required to move beyond the modest benefits achieved to date. HAMLET is a human protein-lipid complex originally discovered in breast milk able to kill a wide range of tumour cells while leaving healthy, differentiated cells unaffected. The aim of this thesis was to identify mechanisms dictating HAMLET sensitivity and to define the events that lead to cell death in response to HAMLET. In Paper I we show that the properties sensitising cells to HAMLET coincide with the ‘’Hallmarks of cancer’’. Using a combination of shRNA screens, proteomic and metabolomic technology, we identified the c-Myc oncogene and hexokinase as essential determinants of HAMLET sensitivity. HAMLET sensitivity was modified by the glycolytic state of tumor cells and HAMLET induced a metabolic paralysis in tumour cells. In paper II the initiating events for tumour cell death are elucidated. By rapid activation of a single ion channel HAMLET disturbs the flux of cations in tumour cells and subsequent cellular responses are shown to rely on this mechanism for their initiation. Ion fluxes activated p38 MAPK signalling, which was found to be crucially involved in tumour cell death. Paper III identifies oleate as the functional ligand in HAMLET formation and shows that oleate actively contributes to the induction of the cellular response to HAMLET. Both protein and lipid are needed for HAMLET’s tumoricidal effect, however. Finally, in paper IV we identify HAMLET as a new therapeutic agent in colon cancer. HAMLET caused a significant reduction in tumour numbers as well as mortality in mice carrying a human APC mutation. In tumours surviving HAMLET challenge a reduction in onco-protein expression was detected as well as an increase in expression of glycolic enzymes. By long-term prophylaxis, prevention of tumour development was achieved.
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Abolhalaj, Milad, et al.
(author)
Transcriptional profiling demonstrates altered characteristics of CD8 + cytotoxic T-cells and regulatory T-cells in TP53-mutated acute myeloid leukemia
2022
In: Cancer Medicine. - : Wiley. - 2045-7634. ; 11:15, s. 3023-3032
Journal article (peer-reviewed) abstract
Background: Acute myeloid leukemia (AML) patients have limited effect from T-cell-based therapies, such as PD-1 and CTLA-4 blockade. However, recent data indicate that AML patients with TP53 mutation have higher immune infiltration and other immunomodulatory therapies could thus potentially be effective. Here, we performed the transcriptional analysis of distinct T-cell subpopulations from TP53-mutated AML to identify gene expression signatures suggestive of altered functional properties.Methods: CD8+ cytotoxic T lymphocytes (CTLs), conventional helper T cells (Th), and regulatory T cells (Tregs) were sorted from peripheral blood of AML patients with TP53 mutation (n = 5) and healthy donors (n = 3), using FACS, and the different subpopulations were subsequently subjected to RNA-sequencing. Differentially expressed genes were identified and gene set enrichment analysis (GSEA) was performed to outline altered pathways and exhaustion status. Also, expression levels for a set of genes encoding established and emerging immuno-oncological targets were defined.Results: The results showed altered transcriptional profiles for each of the T-cell subpopulations from TP53-mutated AML as compared to control subjects. IFN-α and IFN-γ signaling were stronger in TP53-mutated AML for both CTLs and Tregs. Furthermore, in TP53-mutated AML as compared to healthy controls, Tregs showed gene expression signatures suggestive of metabolic adaptation to their environment, whereas CTLs exhibited features of exhaustion/dysfunction with a stronger expression of TIM3 as well as enrichment of a gene set related to exhaustion.Conclusions: The results provide insights on mechanisms underlying the inadequate immune response to leukemic cells in TP53-mutated AML and open up for further exploration toward novel treatment regimens for these patients.
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