Comparative effects of dimethyl and monomethyl fumarate (DMF/MMF) on human myeloid cells. (P4.008)
Bibliographic record
Abstract
OBJECTIVE: To compare the in vivo and in vitro effects of DMF and MMF on human monocytes. BACKGROUND: DMF therapy reduces relapse rates in multiple sclerosis (MS). In experimental models, DMF inhibits production of pro-inflammatory molecules, and induces anti-oxidant responses. In vivo, DMF is rapidly metabolized to MMF, thought to be the biologically active agent. Expression of the pro-inflammatory cytokine regulator microRNA-155 (miR-155) is up-regulated in monocytes in untreated MS patients compared to healthy controls. DESIGN/METHODS: Monocytes obtained from healthy controls, DMF-treated or untreated MS patients were isolated using CD14-coated immunomagnetic beads. Cells were used for RNA extraction or cultured up to 24 hours under basal or LPS activated conditions ± DMF or MMF (1-50μM). Tumor necrosis factor (TNF) production was measured by ELISA. Expression of miR-155 and mRNAs encoding anti-oxidant genes OSGIN1, HO-1, and NQO1 were measured by qPCR. Cell viability was determined by trypan blue or flow cytometry. RESULTS: MiR-155 levels were significantly decreased in monocytes of DMF-treated patients, compared to untreated MS patients. MMF (50μM) in vitro did not modulate miR-155 expression and TNF secretion in monocytes obtained from healthy controls. DMF induced significant reduction of miR-155 expression and TNF secretion, but only at concentrations (10-50 uM) also associated with significant cytotoxic effects. No such effects were seen using monocyte-derived macrophages. Absolute monocyte numbers, viability up to 24 hours after isolation, and anti-oxidant gene expression were comparable between DMF treated and untreated MS patients, as was LPS-induced TNF secretion. CONCLUSIONS: Our in vitro results indicate that the in vivo effects of DMF on miR-155 cannot be ascribed to direct effects of MMF on monocytes. We cannot exclude a non-cytotoxic effect of residual DMF on monocyte properties in vivo, or an indirect effect of fumarate therapy on the overall inflammatory response, in vivo. Study Supported by: Biogen Idec
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".