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- Keane, Simon, et al.
(författare)
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Inflammation suppresses DLG2 expression decreasing inflammasome formation
- 2022
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Ingår i: Journal of Cancer Research and Clinical Oncology. - : Springer Science and Business Media LLC. - 0171-5216 .- 1432-1335. ; 148:9, s. 2295-2311
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Loss of expression of DLG2 has been identified in a number of cancers to contribute to the disease by resulting in increased tumor cell proliferation and poor survival. In light of the previous evidence that DLG2 alters the cell cycle and affects proliferation, combined with indications that DLG2 is involved in NLRP3 inflammasome axis we speculated that DLG2 has an immune function. So far, there is no data that clearly elucidates this role, and this study was designed to investigate DLG2 in inflammatory colon disease and in colon cancer as well as its impact on inflammasome induction. Methods The DLG2 expression levels were established in publicly available inflammation, colon cancer and mouse model datasets. The overexpression and silencing of DLG2 in colon cancer cells were used to determine the effect of DLG2 expression on the activation of the inflammasome and subsequent cytokine release. Results The expression of DLG2 is repressed in inflammatory colon diseases IBD and Ulcerative colitis as well as colorectal cancer tissue compared to healthy individuals. We subsequently show that induction with inflammatory agents in cell and animal models results in a biphasic alteration of DLG2 with an initial increase followed by an ensuing decrease. DLG2 overexpression leads to a significant increase in expression of IL1B, I kappa B zeta and BAX, components that result in inflammasome formation. DLG2 silencing in THP1 cells resulted in increased release of IL-6 into the microenvironment which once used to treat bystander COLO205 cells resulted in an increase in STAT3 phosphorylation and an increase proliferating cells and more cells in the G2/M phase. Restoration of DLG2 to the colon resulted in reduced AKT and S6 signaling. Conclusion DLG2 expression is altered in response to inflammation in the gut as well as colon cancer, resulting in altered ability to form inflammasomes.
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| 2. |
- Moseby-Knappe, Marion, et al.
(författare)
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Biomarkers of brain injury after cardiac arrest; a statistical analysis plan from the TTM2 trial biobank investigators
- 2022
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Ingår i: Resuscitation Plus. - : Elsevier. - 2666-5204. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Background: Several biochemical markers in blood correlate with the magnitude of brain injury and may be used to predict neurological outcome after cardiac arrest. We present a protocol for the evaluation of prognostic accuracy of brain injury markers after cardiac arrest. The aim is to define the best predictive marker and to establish clinically useful cut-off levels for routine implementation. Methods: Prospective international multicenter trial within the Targeted Hypothermia versus Targeted Normothermia after Out-of-Hospital Cardiac Arrest (TTM2) trial in collaboration with Roche Diagnostics International AG. Samples were collected 0, 24, 48, and 72 hours after randomisation (serum) and 0 and 48 hours after randomisation (plasma), and pre-analytically processed at each site before storage in a central biobank. Routine markers neuron-specific enolase (NSE) and S100B, and neurofilament light, total-tau and glial fibrillary acidic protein will be batch analysed using novel Elecsys (R) electrochemiluminescence immunoassays on a Cobas e601 instrument. Results: Statistical analysis will be reported according to the Standards for Reporting Diagnostic accuracy studies (STARD) and will include comparisons for prediction of good versus poor functional outcome at six months post-arrest, by modified Rankin Scale (0-3 vs. 4-6), using logistic regression models and receiver operating characteristics curves, evaluation of mortality at six months according to biomarker levels and establishment of cut-off values for prediction of poor neurological outcome at 95-100% specificities. Conclusions: This prospective trial may establish a standard methodology and clinically appropriate cut-off levels for the optimal biomarker of brain injury which predicts poor neurological outcome after cardiac arrest.
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| 3. |
- Rolny, P., et al.
(författare)
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Longer term outcome of steroid refractory ulcerative colitis treated with intravenous cyclosporine without subsequent oral cyclosporine maintenance therapy
- 2002
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Ingår i: International Journal of Colorectal Disease. - : Springer Science and Business Media LLC. - 0179-1958 .- 1432-1262. ; 17:2, s. 67-69
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Tidskriftsartikel (refereegranskat)abstract
- Background and aims: Intravenous cyclosporine (Cy) is increasingly used in patients with severe ulcerative colitis who fail to respond to corticosteroids. However, in spite of subsequent oral Cy maintenance therapy almost one-half of the initial responders need colectomy within a year. In light of the drug's limited efficacy and potential toxicity use of oral long-term Cy can be questioned. Patients and methods: Nineteen patients with steroid refractory severe ulcerative colitis were treated intravenously with Cy. Results: Of the 19 patients 14 (76%) achieved remission. Six of the patients (46%) remained in remission for 12-61 months. Eight patients experienced one to four flares during the year after treatment. However, except for one patient who needed another course of intravenous Cy, all responded to corticosteroids. The duration of remission since the last flare in these patients (five received azathioprin) was 10-36 months. None of the patients needed colectomy because of symptoms. Conclusion: These preliminary data suggest that a course of intravenous Cy can turn corticosteroid-refractory ulcerative colitis to corticosteroids responsive. The outcome of patients not receiving oral Cy maintenance therapy appears to be satisfactory. Azathioprin maintenance therapy can probably be reserved for select patients.
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| 4. |
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| 5. |
- Wallerius, Majken, et al.
(författare)
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Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages
- 2016
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Ingår i: Cancer Research. - 0008-5472 .- 1538-7445. ; 76:11, s. 3166-3178
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Tidskriftsartikel (refereegranskat)abstract
- Accumulation of tumor-associated macrophages (TAM) correlates with malignant progression, immune suppression, and poor prognosis. In this study, we defined a critical role for the cell-surface guidance molecule SEMA3A in differential proliferative control of TAMs. Tumor cell-derived SEMA3A restricted the proliferation of protumoral M2 macrophages but increased the proliferation of antitumoral M1, acting through the SEMA3A receptor neuropilin 1. Expansion of M1 macrophages in vivo enhanced the recruitment and activation of natural killer (NK) cells and cytotoxic CD8(+) T cells to tumors, inhibiting their growth. In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8(+) T cells, and NK cells, while inversely correlating with established characters of malignancy. In summary, our results illuminate a mechanism whereby the TAM phenotype is controlled and identify the cell-surface molecule SEMA3A as a candidate for therapeutic targeting.
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