SONIC HEDGEHOG (SHH) PROMOTES BLOOD-BRAIN BARRIER (BBB) INTEGRITY IN DIFFUSE MIDLINE GLIOMA OF THE PONS
Bibliographic record
Abstract
Abstract Diffuse Midline Glioma of the Pons (DMG-P) is the most common brainstem tumor in children and is universally lethal in this age group. The intact Blood-Brain Barrier (BBB) in these tumors are believed to play a major role in preventing systemically administered therapeutic agents from reaching therapeutic concentrations in the tumor. The factors that contribute to the integrity of BBB in DMG-P is not well understood. Sonic Hedgehog (SHH) signaling promotes BBB integrity in the developing and adult brain and plays an important role in the formation and maintenance of DMG-P tumors. In the present study, we show that DMG-P tumor cells secrete SHH ligand. Secreted SHH present in the tumor conditioned media (TCM) tightens the BBB by increasing electrical impedance and decreased paracellular and transcellular permeability in BBB Endothelial cells (ECs). Mechanistically, SHH in TCM causes tightening of the BBB by increasing the expression of junctional proteins in BBB-ECs, likely by signaling through non- canonical pathways. SHH in the TCM also increased the expression of ATP-binding cassette (ABC) transporter proteins ABCB1(P- glycoprotein) and ABCG2 (BCRP- Breast cancer resistance protein) in the Endothelial cells. These pro-barrier functions of SHH in TCM can be reversed by pharmacological inhibition of the S-acylation of the SHH ligand using Hedgehog acyltransferase (HHAT) inhibitor RUSKI-201. Our study demonstrates a potential therapeutic strategy of altering the BBB permeability to increase the efficacy of systemic therapies in DMG-P tumors. Ongoing studies will validate these findings in orthotopic murine models of DMG-P.
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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) | 0.001 | 0.000 |
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".