Manual ELISA assays are the most commonly used methods for quantification of biomarkers; however, they often show inter- and intra-laboratory variability that limits their wide use. Here, we compared the Innotest ELISA method with two fully automated platforms (Lumipulse and Elecsys) to determine whether these new methods can provide effective substitutes for ELISA assays. We included 149 patients with AD (n = 34), MCI (n = 94) and non-AD dementias (n = 21). Aβ42, T-tau, and P-tau were quantified using the ELISA method (Innotest, Fujirebio Europe), CLEIA method on a Lumipulse G600II (Fujirebio Diagnostics), and ECLIA method on a Cobas e 601 (Roche Diagnostics) instrument. We found a high correlation between the three methods, although there were systematic differences between biomarker values measured by each method. Both Lumipulse and Elecsys methods were highly concordant with clinical diagnoses, and the combination of Lumipulse Aβ42 and P-tau had the highest discriminating power (AUC 0.915, 95% CI 0.822–1.000). We also assessed the agreement of AT(N) classification for each method with AD diagnosis. Although differences were not significant, the use of Aβ42/Aβ40 ratio instead of Aβ42 alone in AT(N) classification enhanced the diagnostic accuracy (AUC 0.798, 95% CI 0.649–0.947 vs. AUC 0.778, 95% CI 0.617–0.939). We determined the cut-offs for the Lumipulse and Elecsys assays based on the Aβ42/Aβ40 ratio ± status as a marker of amyloid pathology, and these cut-offs were consistent with those recommended by manufacturers, which had been determined based on visual amyloid PET imaging or diagnostic accuracy. Finally, the biomarker ratios (P-tau/Aβ42 and T-tau/Aβ42) were more consistent with the Aβ42/Aβ40 ratio for both Lumipulse and Elecsys methods, and Elecsys P-tau/Aβ42 had the highest consistency with amyloid pathology (AUC 0.994, 95% CI 0.986–1.000 and OPA 96.4%) at the ≥0.024 cut-off. The Lumipulse and Elecsys cerebrospinal fluid (CSF) AD assays showed high analytical and clinical performances. As both automated platforms were standardized for reference samples, their use is recommended for the measurement of CSF AD biomarkers compared with unstandardized manual methods, such as Innotest ELISA, that have demonstrated a high inter and intra-laboratory variability.
T-type Ca 2þ channels (TTCC) have been identified as key regulators of cancer cell cycle and survival. In vivo studies in glioblastoma (GBM) murine xenografts have shown that drugs able to block TTCC in vitro (such as tetralol derivatives mibefradil/NNC-55-096, or different 3,4-dihydroquinazolines) slow tumor progression. However, currently available TTCC pharmacologic blockers have limited selectivity for TTCC and are unable to distinguish between TTCC isoforms. Here we analyzed the expression of TTCC transcripts in human GBM cells and show a prevalence of Cacna1g/Ca v 3.1 mRNAs. Infection of GBM cells with lentiviral particles carrying short hairpin RNA against Ca v 3.1 resulted in GBM cell death by apoptosis. We generated a murine GBM xenograft via subcutaneous injection of U87-MG GBM cells and found that tumor size was reduced when Ca v 3.1 expression was silenced. Furthermore, we developed an in vitro model of temozolomide-resistant GBM that showed increased expression of Ca v 3.1 accompanied by the activation of macroautophagy. We confirmed a positive correlation between Ca v 3.1 and autophagic markers in both GBM cultures and biopsies. Of note, Ca v 3.1 knockdown resulted in transcriptional downregulation of p62/SQSTM1 and deficient autophagy. Together, these data identify Ca v 3.1 channels as potential targets for slowing GBM progression and recurrence based on their role in regulating autophagy.Significance: These findings identify Ca v 3.1 calcium channels as a molecular target to regulate autophagy and prevent progression and chemotherapeutic resistance in glioblastoma.
We have shown that the presence of MHs in patients with newly diagnosed, untreated AD and aMCI is more than controls. MHs were correlated with other behavioral symptoms and a worse cognitive performance. We suggest the specific interrogation for MHs as a clinical feature for this population.
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