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Faecal microbiota transplantation (FMT) is regarded as an efficacious treatment for recurrent C. difficile infection. Unfortunately, widespread patient access is hindered by regulatory hurdles, which are the primary barriers to incorporating FMT into clinical practice. At the European and International level, there is no uniform perspective on FMT classification, and a coordinated effort is desirable to solve this regulatory puzzle. In this communication, we report the regulatory principles and the implementation approach for FMT application in Italy. Our experience suggests that the EU Tissue and Cell Directives are suited to ensure safe and efficient FMT for C. difficile management, especially through extensive high-quality donor selection and full traceability maintenance.

Sirtuin 6 (SIRT6) is a member of nicotinamide adenine dinucleotide-dependent deacetylase protein family and has been implicated in the control of glucose and lipid metabolism, cancer, genomic stability and DNA repair. Moreover, SIRT6 regulates the expression of a large number of genes involved in stress response and aging. The role of SIRT6 in brain function and neuronal survival is largely unknown. Here, we biochemically characterized SIRT6 in brain tissues and primary neuronal cultures and found that it is highly expressed in cortical and hippocampal regions and enriched in the synaptosomal membrane fraction. Immunoblotting analysis on cortical and hippocampal neurons showed that SIRT6 is downregulated during maturation in vitro, reaching the lowest expression at 11 days in vitro. In addition, SIRT6 overexpression in terminally differentiated cortical and hippocampal neurons, mediated by a neuron-specific recombinant adeno-associated virus, downregulated cell viability under oxidative stress condition. By contrast, under control condition, SIRT6 overexpression had no detrimental effect. Overall these results suggest that SIRT6 may play a role in synaptic function and neuronal maturation and it may be implicated in the regulation of neuronal survival.

Accumulation of DNA damage and deficiency in DNA repair potentially contribute to the progressive neuronal loss in neurodegenerative disorders, including Alzheimer disease (AD). In multicellular eukaryotes, double strand breaks (DSBs), the most lethal form of DNA damage, are mainly repaired by the nonhomologous end joining pathway, which relies on DNA-PK complex activity. Both the presence of DSBs and a decreased end joining activity have been reported in AD brains, but the molecular player causing DNA repair dysfunction is still undetermined. β-Amyloid (Aβ), a potential proximate effector of neurotoxicity in AD, might exert cytotoxic effects by reactive oxygen species generation and oxidative stress induction, which may then cause DNA damage. Here, we show that in PC12 cells sublethal concentrations of aggregated Aβ(25-35) inhibit DNA-PK kinase activity, compromising DSB repair and sensitizing cells to nonlethal oxidative injury. The inhibition of DNA-PK activity is associated with down-regulation of the catalytic subunit DNA-PK (DNA-PKcs) protein levels, caused by oxidative stress and reversed by antioxidant treatment. Moreover, we show that sublethal doses of Aβ(1-42) oligomers enter the nucleus of PC12 cells, accumulate as insoluble oligomeric species, and reduce DNA-PK kinase activity, although in the absence of oxidative stress. Overall, these findings suggest that Aβ mediates inhibition of the DNA-PK-dependent nonhomologous end joining pathway contributing to the accumulation of DSBs that, if not efficiently repaired, may lead to the neuronal loss observed in AD.

Thymosin beta4 (Tb4) is an actin-binding peptide overexpressed in several tumors, including colon carcinomas. The aim of this study was to investigate the role of Tb4 in promoting the tumorigenic properties of colorectal cancer stem cells (CR-CSCs), which are responsible for tumor initiation and growth. We first found that CR-CSCs from different patients have higher Tb4 levels than normal epithelial cells. Then, we used a lentiviral strategy to down-regulate Tb4 expression in CR-CSCs and analyzed the effects of such modulation on proliferation, survival, and tumorigenic activity of CR-CSCs. Empty vector-transduced CR-CSCs were used as a control. Targeting of the Tb4 produced CR-CSCs with a lower capacity to grow and migrate in culture and, interestingly, reduced tumor size and aggressiveness of CR-CSC-based xenografts in mice. Moreover, such loss in tumorigenic activity was accompanied by a significant increase of phosphatase and tensin homologue (PTEN) and a concomitant reduction of the integrin-linked kinase (ILK) expression, which resulted in a decreased activation of protein kinase B (Akt). Accordingly, exogenous expression of an active form of Akt rescued all the protumoral features lost after Tb4 targeting in CR-CSCs. In conclusion, T?4 may have important implications for therapeutic intervention for treatment of human colon carcinoma.

The synthesis of ribosomal proteins (RPs) has long been known to be a process strongly linked to the growth status of the cell. In vertebrates, this coordination is dependent on RP mRNA translational efficiency, which changes according to physiological circumstances. Despite many years of investigation, the trans-acting factors and the signaling pathways involved in this regulation are still elusive. At the same time, however, new techniques and classic approaches have opened up new perspectives as regards RP regulation and function. In fact, the proteasome seems to play a crucial and unpredicted role in regulating the availability of RPs for subunit assembly. In addition, the study of human ribosomal pathologies and animal models for these diseases has revealed that perturbation in the synthesis and/or function of an RP activates a p53-dependent stress response. Surprisingly, the effect of the ribosomal stress is more dramatic in specific physiological processes: hemopoiesis in humans, and pigmentation in mice. Moreover, alteration of each RP impacts differently on the development of an organism.