TRIM8 Blunts the Pro-proliferative Action of ΔNp63α in a p53 Wild-Type Background

The p53 gene family network plays a pivotal role in the control of many biological processes and therefore the right balance between the pro-apoptotic and pro-survival isoforms is key to maintain cellular homeostasis. The stability of the p53 tumor suppressor protein and that of oncogenic ΔNp63α, is crucial to control cell proliferation. The aberrant expression of p53 tumor suppressor protein and oncogenic ΔNp63α contributes to tumorigenesis and significantly affects anticancer drug response. Recently, we demonstrated that TRIM8 increases p53 stability, potentiating its tumor suppressor activity. In this paper, we show that TRIM8 simultaneously reduces the level of the pro-proliferative ΔNp63α protein, in both a proteasomal and caspase-1 dependent way, thereby playing a critical role in the cellular response to DNA damaging agents. Moreover, we provided evidence that ΔNp63α in turn, suppresses TRIM8 gene expression by preventing p53-mediated transactivation of TRIM8, therefore suggesting the existence of a negative feedback loop. These findings indicate that TRIM8 exerts its anticancer power through a joint action that provides on one hand, the activation of the p53 tumor suppressor role, and on the other the quenching of the oncogenic ΔNp63α protein activity. The enhancement of TRIM8 activity may offer therapeutic benefits and improve the management of chemoresistant tumors

Novel Cellular and Molecular Interactions During Limb Development, Revealed from Studies on the Split Hand Foot Congenital Malformation

The embryonic development of the limbs is widely used as a paradigm for the comprehension of the cellular processes and molecular mechanisms underlying organogenesis and pattern formation. The chick, mouse and (recently), zebrafish embryos are excellent models, for the ease of experimental manipulation and the availability of several mutant strains with limb malformation defects

A Symphony of Regulations Centered on p63 to Control Development of Ectoderm-Derived Structures

The p53-related transcription factor p63 is critically important for basic cellular functions during development of the ectoderm and derived structure and tissues, including skin, limb, palate, and hair. On the one side, p63 is required to sustain the proliferation of keratinocyte progenitors, while on the other side it is required for cell stratification, commitment to differentiate, cell adhesion, and epithelial-mesenchymal signaling. Molecules that are components or regulators of the p63 pathway(s) are rapidly being identified, and it comes with no surprise that alterations in the p63 pathway lead to congenital conditions in which the skin and other ectoderm-derived structures are affected. In this paper, we summarize the current knowledge of the molecular and cellular regulations centered on p63, derived from the comprehension of p63-linked human diseases and the corresponding animal models, as well as from cellular models and high-throughput molecular approaches. We point out common themes and features, that allow to speculate on the possible role of p63 downstream events and their potential exploitation in future attempts to correct the congenital defect in preclinical studies

A Haspin-ARHGAP11A axis regulates epithelial morphogenesis through Rho-ROCK dependent modulation of LIMK1-Cofilin

Throughout mitosis, a plethora of processes must be efficiently concerted to ensure cell proliferation and tissue functionality. The mitotic spindle does not only mediate chromosome segregation, but also defines the axis of cellular division, thus determining tissue morphology. Functional spindle orientation relies on precise actin dynamics, shaped in mitosis by the LIMK1-Cofilin axis. The kinase Haspin acts as a guardian of faithful chromosome segregation that ensures amphitelic chromosome attachment and prevents unscheduled cohesin cleavage. Here, we report an unprecedented role for Haspin in the determination of spindle orientation in mitosis. We show that, during mitosis, Haspin regulates Rho-ROCK activity through ARHGAP11A, a poorly characterized GAP, and that ROCK is in turn responsible for the mitotic activation of LIMK1 and stabilization of the actin cytoskeleton, thus supporting a functional spindle orientation. By exploiting 3D cell cultures, we show that this pathway is pivotal for the establishment of a morphologically functional tissue

Occurrence of ESKAPE bacteria in healthy cattle population and the related zoonotic risk

1. Introduction. Antimicrobial-resistant ESKAPE bacteria (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) represent a global threat to human health. Since the role of healthy and/or asymptomatic animals as carrier of ESKAPE opportunistic bacteria is less investigated, we aimed at collecting data regarding the occurrence of the ESKAPE isolates in healthy cattle population, evaluating their antimicrobial resistant profiles. 2. Materials and Methods. A prospective epidemiological study was carried out in dairy farms on 180 bovine ocular, nasal, auricular, oral swabs, milk and faecal samples. Standard cultures on nutritive and selective agar media were performed and bacterial colonies were identified by MALDI-TOF MS. Susceptibility of ESKAPE strains to a panel of 30 different antibiotics belonging to 17 classes was evaluated by Kirby-Bauer and E-test methods (EUCAST, 2023). As suggested by Magiorakos et al. (2012), multidrug-resistant (MDR), extensively drug-resistant (XDR) and pandrug-resistant (PDR) isolates were defined. 3. Results. Enterococcus faecium (n=17), Staphylococcus aureus (n=5), Klebsiella pneumoniae ssp. pneumoniae and Klebsiella pneumoniae ssp. ozaenae (n=15), Acinetobacter baumannii (n=7), Pseudomonas aeruginosa (n=7), and Enterobacter cloacae (n=12) were identified. The ESKAPE bacteria resulted susceptible to carbapenems, except P. aeruginosa strains, to polymyxins, sulphonamides, amynoglycosides, glycopeptides (vancomycin and teicoplanin), and S. aureus to β-lactams. No PDR strains were recorded, while XDR (28.6%, n=63) and MDR (68.2%) were observed with resistance towards cephalosporins (92.1%), monobactams (57.1%), fluoquinolones (55.5%) and tetraciclines (38.1%). Nose and mouth of healthy cattle represent the anatomical sites at major zoonotic risk (RR=28.55; AR=0.93) for A. baumannii, K. pneumoniae, E. cloacae. 4. Discussion and Conclusions. The obtained preliminary data contribute to acquire epidemiological informations about ESKAPE pathogens spread from healthy cattle population and to coordinate antimicrobial resistance surveillance in a One Health approach

Feasibility and Acceptability of a Real-Time Telerehabilitation Intervention for Children and Young Adults with Acquired Brain Injury During the COVID-19 Pandemic: An Experience Report

This study examined the feasibility and acceptability of a telerehabilitation intervention during the COVID-19 pandemic in a sample of children and young adults with Acquired Brain Injury (ABI). Thirteen patients and/or their families agreed to participate in the speech and neuropsychological telerehabilitation sessions. The treatment was synchronous, patient centered and aimed at improving specific abilities. Sessions were held twice a week over a 10-week period. Two questionnaires were completed both by parents and therapists to assess feasibility and acceptability. Neither technical issues nor clinical obstacles were found. The quality of the therapeutic relationship played a key role in the intervention. Synchronous telerehabilitation provided several advantages both for patients and therapists. Moreover, the patient centered intervention eased the burden of the caregivers at a time of high stress. The real-time telerehabilitation treatments were deemed suitable for children and young adults with ABI. Further studies are needed to support the use of telerehabilitation as an integral part of their standard care