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Webinar 2020

First SIMAG Webinar Series

The Italian Society of Environmental Mutagenesis and Genomics (SIMAG) is launching three webinars to improve communication and discussion in this period of travel restrictions.

In this first series, three new members of the Society will present themselves.  In parallel, recent research advances of three laboratories of SIMAG members will be communicated by a young component of the team.

To attend the webinars, a link will be available 1 h in advance.

28 October 2020 - abstracts available

2.30 pm
Valeria Simonelli (Istituto Superiore di Sanità, Roma) “High-fat diet, oxidative damage and susceptibility to chronic-degenerative diseases: a pilot study in transgenic mice”.

Abstract:

Several lines of evidence, obtained both in murine models and in epidemiological studies, show that an increase in body fat mass is linked to oxidative stress and that the accumulation of radical oxygen species (ROS) contributes to develop the metabolic syndrome (Marseglia et al., Int J Mol Sci. 2015).

ROS induce DNA damage with a consequent activation of DNA damage response (DDR), an orchestrated set of proteins which are able to trigger early/late and intra/extra-cellular warnings (Rodier et al., Nature Cell Biol. 2009; Malaquin et al., Frontiers in Genetics 2015).

Mice defective in DNA damage processing genes are highly susceptible to obesity if exposed to high-fat diet (HFD) (Sampath et al. PLOS ONE 2012; Sampath et al., Am. J. Physiol. Endocrinol. Metab. 2011; Chen et al. PNAS 2015). This evidence suggests a link between genomic instability and metabolic dysfunction. 

In our laboratory we have obtained a transgenic mouse which expresses high levels of the human MutT homologue (hMTH1). MTH1 is a hydrolase which is able to protect cells by oxidative damage by removing oxidized precursors (8-oxodGTP e 2-OHdATP) from pool of nucleotides, thus avoiding their incorporation in DNA. Interestingly, when compared with wild-type counterpart, our transgenic mouse (hMTH1-Tg) shows: a) protection against neurodegeneration induced by treatment with 3-nitropropionic acid, which causes symptoms that resemble those of Huntington's disease (De Luca et al, PLOS Genetics 2008); b) a decrease in oxidative damage, both in nuclear and in mitochondrial DNA; c) an increased longevity (De Luca et al., Aging Cell 2013); d) a delay in the ageing process; e) a reduced anxiety and an enhanced investigation of environmental and social cues; f) a best mitochondrial functionality.

Our preliminary data suggest that MTH1 plays a pivotal role in modulating oxidative DNA damage in response to HFD. The ongoing Nuclear Magnetic Resonance spectroscopy/imaging and neuro-behavioral analysis will help to clarify the role of oxidative stress and response to oxidative damage in the modulation of risk of chronic-degenerative diseases.

 

3.30 pm
Laura Bisini (European Research Biology Center, Pomezia, Roma) “Performance improvement for in vitro genotoxicity testing: the experience of a CRO”.

Abstract:

Information on genotoxicity is a key component of the safety assessment for all type of substances whatever their use and intended purpose. The three major endpoints involved in carcinogenesis and heritable diseases (gene mutation, structural and numerical chromosome damage) need to be evaluated and testing requirements across different regulatory sectors usually include two or three validated in vitro tests in order to cover these endpoints. According to the type of test chemical under regulation and the region, in vivo assays may be required as follow-up studies in case of positive results in any of the in vitro genotoxicity studies.

Based on this, it is evident that the in vitro test battery plays a key role in the genotoxicity assessment and special care and considerable expertise and experience are required to ensure that the outcome is not misleading due to the intrinsic potential of these assays to generate false negative and positive results. In order to reach valid conclusions and limit at the same time the use of animals, it is necessary to be aware of the reasons which could lead to misleading results (e.g. in vitro metabolism, non physiological conditions, extreme toxicity) and to enhance in vitro testing performance.

Thanks to the variety of substances analyzed and the number of studies conducted, the experience of a CRO can give an important contribution to further investigate possible critical areas of improvement.

Several case studies will be illustrated giving real examples of the experimental approaches applied during the assessment of genotoxicity.

 

 

 

 

 

20 November 2020

2.30 pm

Fabrizio Bianchi (Fondazione Casa Sollievo della Sofferenza, San Giovanni Rotondo, Foggia) “Deciphering cancer transcriptomics to improve diagnostics and therapeutics”.

The Abstract will be available before the Webinar

3.30 pm

Andrea Stoccoro and Fabio Coppedè (Università di Pisa, Pisa) “Mitochondrial epigenetics in neurodegenerative  diseases”.

The Abstract will be available before the Webinar

30 November 2020 - abstracts available

2.30 pm

Bartolomeo Bosco and Alberto Inga (Università di Trento, Trento) “Translational controls in p53-dependent responses: exploring the role of the RNA helicase DHX30”.

Abstract:

p53 is a critical tumor suppressor protein, and, consistently, it is mutated or lost in about 50% of all human cancers. Traditionally, research has focused on p53’s role as a sequence-specific transcription factor that becomes activated in response to several stress stimuli and orchestrates various cell responses through an extensive transcriptional network. However, recent findings have added translational control as another critical layer of the p53 response. Our group has described that enhanced translation of pro-apoptotic mRNAs carrying one or several so-called CGPD motifs (CG-rich motif mediating p53-dependent death) in their 3’-UTR can shift the cellular response towards apoptosis in p53 wild-type cancer cells. Intriguingly, this translational impact on CGPD-containing transcripts can be counteracted by specific RNA binding proteins (RBPs), which have been demonstrated to associate with and possibly shield the CGPD motif. One such protein is the RNA helicase DHX30. Indeed, DHX30 depletion enhanced p53-dependent apoptosis in cancer cells treated with the MDM2 inhibitor nutlin-3, and its overexpression led to the reduced translation of pro-apoptotic CGPD-containing transcripts. However, our recent work revealed that DHX30 exhibits a more general function in translation control by integrating the activities exerted by one isoform expressed in the cytoplasm and another, more abundant, localized to the mitochondria. Results based on both stable and transient DHX30 depletion, including the selective silencing of the cytoplasmic isoform, lead us to propose that DHX30 contributes to cell homeostasis by coordinating ribosome biogenesis, global translation, and mitochondrial metabolism. Notably, a gene signature comprising DHX30 and fourteen mitoribosome protein transcripts that are its candidate direct targets showed prognostic value in distinct cancer types of the TGCA dataset.

 

 

3.30 pm

Giulia Vecchiotti, Massimo Aloisi and Anna MG Poma (Università dell’Aquila, L’Aquila) “Cyto and genotoxicity of polystyrene nanoparticles in vitro”.

Abstract:

Plastics materials are the most spread polymers-based physicals since they were invented in the middle of 19th century to stand in for the ivory usage and elephants extinction. Nowadays they are a real environmental and health emergency. In fact every year more than 300 tons are produced worldwide and they are spilled in the environment. Therefore they are considered as emergent pollutants. Once they are spread in different frameworks they, in several years, are deteriorated in smaller particles called micro- and nanoplastics. The first ones have a diameter in the range of 101 nm and 5 mm; the second ones have a diameter lower than 100 nm.