P15

In a recently published study combining transcranial magnetic stimulation and electroencephalography (TMS-EEG), an early component of TMS-evoked potentials (TEPs), i.e., M1-P15, was proposed as a measure of transcallosal inhibition between motor cortices. Given that early TEPs are known to be highly variable, further evidence is needed before M1-P15 can be considered a reliable index of effective connectivity. Here, we conceived a new preregistered TMS-EEG study with two aims. The first aim was validating the M1-P15 as a cortical index of transcallosal inhibition by replicating previous findings on its relationship with the ipsilateral silent period (iSP) and with performance in bimanual coordination. The second aim was inducing a task-dependent modulation of transcallosal inhibition. A new sample of 32 healthy right-handed participants underwent behavioral motor tasks and TMS-EEG recording, in which left and right M1 were stimulated both during bimanual tasks and during an iSP paradigm. Hypotheses and methods were preregistered before data collection. Results show a replication of our previous findings on the positive relationship between M1-P15 amplitude and the iSP normalized area. Differently, the relationship between M1-P15 latency and bimanual coordination was not confirmed. Finally, M1-P15 amplitude was modulated by the characteristics of the bimanual task the participants were performing, and not by the contralateral hand activity during the iSP paradigm. In sum, the present results corroborate our previous findings in validating the M1-P15 as a cortical marker of transcallosal inhibition and provide novel evidence of its task-dependent modulation. Importantly, we demonstrate the feasibility of preregistration in the TMS-EEG field to increase methodological rigor and transparency.

The p15 gene (also known as CDKN2B, INK4B, p15INK4B), located in band 9p21, encodes a protein that induces a G1-phase cell cycle arrest through inhibition of CDK4/6 (cyclin-dependent kinase 4/6). It also plays an important role in the regulation of cellular commitment of hematopoietic progenitor cells and myeloid cell differentiation. p15 can be silenced by several mechanisms, including deletion and hypermethylation of its promoter. Homozygous p15 deletion is rare in acute myeloblastic leukemia (AML) and myelodysplastic syndromes (MDS) but frequent in acute lymphoblastic leukemia (ALL). On the contrary, methylation of the p15 promoter is identified in some 50% of the patients with AML and MDS, but is less frequent in ALL. The analysis of the 28 studies available in the literature revealed conflicting results (unfavorable, favorable or no impact) that can be due, at least in part, to methodological and/or biological pitfalls. Among those, are the heterogeneity of the methylation patterns of the p15 gene and the lack of a comprehensive analysis including transcriptional and translational inactivation that have major impact on its expression. Therefore, detection of the p15 mRNA expression (quantitative or not) may represent a more appropriate method to determine the prognostic impact of the p15 gene.

Objective: This study was performed to investigate the correlation between P15 methylation and hepatocellular carcinoma (HCC) and hepatocirrhosis using a meta-analysis of available case control studies. Methods: Previous studies have primarily evaluated the incidence of P15 methylation in HCC and corresponding control groups, and compared the incidence of P15 methylation in liver cirrhosis and control groups. Data regarding publication information, study characteristics, and incidence of P15 methylation in both groups were collected from these studies and summarized. Results: Ten studies that assessed P15 gene methylation in 824 HCC tumour tissues and five studies analyzing P15 methylation in 155 liver cirrhosis tissues met our inclusion criteria. Our meta-analysis revealed that the rate of P15 methylation was significantly higher in HCCs than in adjacent non-tumour tissues (OR 9.04, 95% CI 5.80-14.09, P < 0.00001). Moreover, P15 methylation was significantly higher in liver cirrhosis tissues than in control tissues (OR 7.82, 95% CI 3.58-17.07, P < 0.00001). Conclusions: we found that P15 methylation was associated with an increased risk of HCC and liver cirrhosis. P15 hypermethylation induced the inactivation of the P15 gene, which played an important role in hepatocarcinogenesis.