The Italian outbreak of COVID-19 cases is a public health emergency and there is a worldwide tremendous interest in the evaluation of the Italian epidemic evolution.Indeed, from February 2020, Italy is facing an explosion of COVID-19 cases. In particular, the Italian observed case fatality rate (CFR) is much higher than the other countries. Recently, it has been hypothesized that the extensive number of intergenerational contacts-typical of Italian culture-could contribute to explain the high number of deaths observed in Italy. However, through an analysis performed for all the Italian regions, here it is shown that the deaths are localized in specific regions and that the CFRs of different Italian regions are overlapping with the rates of European countries. Moreover, through correlation analyses between CFRs and different social habits, it is shown that no positive correlation is observed between social behaviors and CFRs. In conclusion, this analysis clearly rejects the possibility that social habits and intergenerational contacts can contribute to explaining such a profound effect on the number of deaths observed in Italy during the COVID-19 outbreak and more effort should be addressed to evaluate the real amount of positive cases.

The subversion of endocytic routes leads to malignant transformation and has been implicated in human cancers. However, there is scarce evidence for genetic alterations of endocytic proteins as causative in high incidence human cancers. Here, we report that Epsin 3 (EPN3) is an oncogene with prognostic and therapeutic relevance in breast cancer. Mechanistically, EPN3 drives breast tumorigenesis by increasing E-cadherin endocytosis, followed by the activation of a β-catenin/TCF4-dependent partial epithelial-to-mesenchymal transition (EMT), followed by the establishment of a TGFβ-dependent autocrine loop that sustains EMT. EPN3-induced partial EMT is instrumental for the transition from in situ to invasive breast carcinoma, and, accordingly, high EPN3 levels are detected at the invasive front of human breast cancers and independently predict metastatic rather than loco-regional recurrence. Thus, we uncover an endocytic-based mechanism able to generate TGFβ-dependent regulatory loops conferring cellular plasticity and invasive behavior.

Circulating tumor cell (CTC) clusters are associated with increased metastatic potential and worse patient prognosis, but are rare, difficult to count, and poorly characterized biophysically. The PillarX device described here is a bimodular microfluidic device (Pillar‐device and an X‐magnetic device) to profile single CTCs and clusters from whole blood based on their size, deformability, and epithelial marker expression. Larger, less deformable clusters and large single cells are captured in the Pillar‐device and sorted according to pillar gap sizes. Smaller, deformable clusters and single cells are subsequently captured in the X‐device and separated based on epithelial marker expression using functionalized magnetic nanoparticles. Clusters of established and primary breast cancer cells with variable degrees of cohesion driven by different cell‐cell adhesion protein expression are profiled in the device. Cohesive clusters exhibit a lower deformability as they travel through the pillar array, relative to less cohesive clusters, and have greater collective invasive behavior. The ability of the PillarX device to capture clusters is validated in mouse models and patients of metastatic breast cancer. Thus, this device effectively enumerates and profiles CTC clusters based on their unique geometrical, physical, and biochemical properties, and could form the basis of a novel prognostic clinical tool.