Exploring new biomarkers and emerging techniques for breast cancer diagnosis
Notice bibliographique
Résumé
Breast cancer is the most common cancer in Canadian women. The choice of treatment is based on the expression of markers such as the estrogen receptor (ER), the membrane receptor HER2 and the proliferation marker KI-67, detected by immunohistochemistry (IHC). Although some breast tumors may be heavily infiltrated by immune cells, the expression of immune checkpoint inhibitors (ICIs) by both immune and cancer cells promotes tumor growth. In particular, tumor expression of B7H4 has been associated with a high rate of metastasis and an inverse correlation with CD8+ T cells. In order to better characterize B7H4 expression patterns, levels of this protein as well as markers of immune infiltrate, immune checkpoint and EMT were characterized by IHC using six tissue microarrays constructed from 123 FFPE samples from the Centre Hospitalier de l'Université de Montréal (CHUM). B7H4 expression (% positive cells) was quantified by QuPath software (version 0.2.0 m9), while EMT was assessed semi-quantitatively by Khadri et al. (2020). Our results show that B7H4 is highly expressed exclusively by tumor cells in all subtypes (mean 22.5% to 43.3%), with lower levels in luminal B (LB) and HER2-positive (HER2+) tumors. Multivariate analysis of the Metabric cohort of breast tumor transcriptome profiles (1980 tumors) further showed that B7H4 RNA levels are inversely associated with those of Ecad (p=0.0001), the same trend was observed in our cohort, and are strongest in lobular tumors (Ecad-). Furthermore, analysis of a TCGA cohort (754 tumors) revealed a positive correlation of B7H4 transcripts with YAP, TAZ, VGLL1 and TRIM29 (Pearson correlation coefficient >0.4), inducers of TEAD transcription factors repressed by the Hippo signaling pathway. In particular, YAP has a similar expression pattern to B7H4, higher in basal and luminal subtypes. These results suggest that the role of B7H4 in the progression of these tumors may be linked to the Hippo pathway, which controls the growth, proliferation and migration of mammary tumor cells. Capturing the intertumoral and intratumoral tumor heterogeneity necessitates new detection methods enabling higher multiplexing than IHC or immunofluorescence (IF). Nanoparticles (NP) such as carbon-nanotubes (CNT) or gold nanoparticles (AuNPs), which can be functionalized with antibodies and detected without fluorescent labels, are promising to become powerful tools in bioimaging. We have explored the capacity of PEGylated CNT linked to anti-KRT19 and anti-Ecad antibodies to detect the corresponding proteins in breast cancer T47D (ER+/Ecad+/KRT19+) and MDA-MB-231 (ER-/Ecad-/KRT19-) cell lines. NP-Ecad and NP-KRT19 with internalized -sexithiophene and β-carotene dyes, respectively, present specific Raman signature upon excitation with 532 nm laser. Dynamic light scattering detected a shift in the size of functionalized NP and immunogold labeling confirmed the antibodies are in the right orientation. Although NPs remained in cluster, both bound the surface of T47D cells while only background was observed in MDA-MB-231 cells, as expected. In an alternative approach, PEGylated gold-NP were conjugated to anti-HER2 and anti-CD44 antibodies and detected by scattered light in dark-field microscope. NP-HER2 were incubated with HER2+ SKBR3 and MDA-MB-453 cells in increasing concentration and time. Results show an average of 48 NP per cell in SKBR3 and 8 NP-HER2/cell in MDAMB453, consistent with IF detection. NP-CD44 are highly sensitive, as we observed up to 1000 NP-CD44/cell in CD44+ cells versus 10 NP-CD44/cell in CD44- cells, with an average of 250 NP per cell in SKBR3, stratified as CD44+. These promising approaches both bear the potential of multiplexed biomarker detection in a rapid and quantitate manner.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,004 | 0,003 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,001 | 0,001 |
| Bibliométrie | 0,004 | 0,002 |
| Études des sciences et des technologies | 0,000 | 0,001 |
| Communication savante | 0,003 | 0,003 |
| Science ouverte | 0,001 | 0,001 |
| Intégrité de la recherche | 0,001 | 0,002 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,002 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».