To assess the role of platelets and lymphocyterelated immunological mechanisms in livedo vasculopathy (LV) and cutaneous small vessel vasculitis (CSVV). Livedo vasculopathy is thought to be related to the thrombotic occlusion of small and medium-sized dermal vessels. Cutaneous small vessel vasculitis comprises a heterogeneous group of disorders in which the main pathogenetic events could be modulated by circulating cytokines.Design: Case series study of 2 groups of patients affected respectively with LV and CSVV. Setting: A large clinical and research institute for the study and treatment of cutaneous diseases. Patients: Consecutive patients with clinically and histologically proved idiopathic LV (n = 8) and CSVV (n = 20) were studied and compared with healthy donors (n = 20). Patients with potentially correlated systemic diseases were excluded. Main Outcome Measures: Surface expression of platelet P-selectin and circulating level of interleukin (IL) 1␤, tumor necrosis factor ␣ (TNF-␣), IL-8, IL-2, and soluble IL-2 receptor.Results: The IL-2 and soluble IL-2 receptor levels were significantly higher in serum samples from patients with

MRE11 is a component of the MRE11/RAD50/NBS1 (MRN) complex, whose activity is essential to control faithful DNA replication and to prevent accumulation of deleterious DNA double-strand breaks. In humans, hypomorphic mutations in these genes lead to DNA damage response (DDR)-defective and cancer-prone syndromes. Moreover, MRN complex dysfunction dramatically affects the nervous system, where MRE11 is required to restrain MYCN-dependent replication stress, during the rapid expansion of progenitor cells. MYCN activation, often due to genetic amplification, represents the driving oncogenic event for a number of human tumors, conferring bad prognosis and predicting very poor responses even to the most aggressive therapeutic protocols. This is prototypically exemplified by neuroblastoma, where MYCN amplification occurs in about 25% of the cases. Intriguingly, MRE11 is highly expressed and predicts bad prognosis in MYCN-amplified neuroblastoma. Due to the lack of direct means to target MYCN, we explored the possibility to trigger intolerable levels of replication stress-dependent DNA damage, by inhibiting MRE11 in MYCN-amplified preclinical models. Indeed, either MRE11 knockdown or its pharmacological inhibitor mirin induce accumulation of replication stress and DNA damage biomarkers in MYCN-amplified cells. The consequent DDR recruits p53 and promotes a p53-dependent cell death, as indicated by p53 loss- and gain-of-function experiments. Encapsulation of mirin in nanoparticles allowed its use on MYCN-amplified neuroblastoma xenografts in vivo, which resulted in a sharp impairment of tumor growth, associated with DDR activation, p53 accumulation, and cell death. Therefore, we propose that MRE11 inhibition might be an effective strategy to treat MYCN-amplified and p53 wild-type neuroblastoma, and suggest that targeting replication stress with appropriate tools should be further exploited to tackle MYCN-driven tumors.

The aggregation of platelets induced by soluble and particulate stimuli is enhanced by the addition of minute amounts of H2O2. Externally added catalase strongly inhibits the aggregation induced by particulate stimuli and by phorbol myristate acetate (PMA). The addition of aminotriazole to stimulated platelets causes a significant inhibition of intracellular catalase. This indicates the formation of H2O2 inside the platelets during activation. No effects were observed when the platelets were stimulated by the ionophore A23187.

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