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Objectives: Meta-analyses show that nonbound ceruloplasmin copper (Non-Cp-Cu, also known as "free" or labile copper) in serum is higher in patients with Alzheimer disease (AD). It was demonstrated that ATP7B gene associates with AD, and being carriers of some ATP7B variants accounted for a large proportion of serum Non-CpCu levels, suggesting a "copper dysfunction" phenotype of sporadic AD. However, a dedicated genetic study to demonstrate the existence of a copper subtype of AD has not yet been performed. Methods: The study analyzed an independent patient sample, including 345 AD patients. We assessed levels of Non-Cp-Cu, informative genetic variants of ATP7B and APOE4 genotype. Patients were stratified on the basis of a Non-Cp-Cu cut-off (1.9 µm, C4D test). A binary logistic regression analysis -with age, sex and MMSE as covariates -was applied to compare the AD subgroups for ATP7B and APOE4 frequencies. Results: Concentrations of Non-Cp-Cu in the AD population had a bimodal distribution. ATP7B and APOE4 frequencies were different between the two AD groups, with a significant increase of the rs1801243 CC, rs1061472 GG and rs732774 TT genotypes in the AD group with Non-Cp-Cu > 1.9 µm, accounting for a percentage of the disease risk. Interpretation: Diverse genetic frequencies of ATP7B between the two AD groups confirm the existence of a copper subtype of AD, which has a genetic basis, and Non-Cp-Cu appears as reliable marker to identify this form of AD. Copper modifying drugs can be effective to stop or delay cognitive decline in this for AD.

The purpose of this study was to compare the performance in the detection of the E6/E7 mRNA expression of hrHPV, using the NucliSENS EasyQ test (bioMerieux), a RT-PCR based method, or HPV OncoTect (IncellDx) a test based on the flow cytometry-FISH method. Moreover, we investigated the potential role, for the detection of high grade lesions, of the HPV OncoTect compared to pap smears in an effort to improve cervical cancer screening. We enrolled 173 patients positive for HR-HPV DNA and/or pap smear and referred for evaluation by means of the NucliSENS EasyQ. All patients were tested with HPV OncoTect and 87 of 173 underwent a colposcopy and histological evaluation according to clinical protocol. Stratified by cytologic grades, the mRNA testing with HPV OncoTect displayed a reactivity of 25% in negative samples, 40% in atypical squamous cells of undetermined significance ASCUS, 48% in low-grade squamous intraepithelial lesion LSIL and 80% in high-grade squamous intraepithelial lesion HSIL. The corresponding figures for NuciliSENS EasyQ assay were 42%, 60%, 74%, and 90%, respectively. Histology analysis revealed that the sensitivity of HPV OncoTect compared to NucliSENS EasyQ was with normal specimens 20% vs 54%, with CIN1 45% vs 69% and with CIN2+ 87% vs 74%, respectively. Higher specificity was observed when analyzing CIN2+ samples with HPV OncoTect (69%) compared with NucliSENS EasyQ (36%). HPV E6/E7 mRNA detection test with flow cytometry is more specific than NucliSENS EasyQ in identifying women with CIN2+ but has a lower sensitivity. HPV OncoTect is a promising tool for early prediction of persistent HPV infection and seems to be an interesting method to evaluate the preneoplastic lesions of the cervix and improve cancer screening.