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Webinar 2020

Webinar 20th November, how to join us

To attend the meeting, simply join us at this link.

 

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.

20 November 2020 - abstracts available

2.30 pm

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

Abstract:

Neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), represent a group of complex disorders resulting from the interaction between genetic and non-genetic factors. Epigenetic mechanisms, such as DNA methylation, are able to change gene expression under the influence of environmental factors and their deregulation has been suggested to contribute to the neurodegenerative process. Indeed, several epigenetic changes in nuclear DNA have been documented post-mortem in brain regions of patients affected by major neurodegenerative diseases, as well as in animal models of those disorders, paving the way to the search of peripheral epigenetic biomarkers of neurodegeneration. Increasing evidence suggests that changes in DNA methylation occur also in mitochondrial DNA (mtDNA), likely regulating both mtDNA replication and gene expression levels, and it has been observed that altered mtDNA methylation could contribute to the aetiology of several complex human diseases, including neurodegenerative ones. The majority of these studies investigated DNA methylation levels of the mtDNA regulatory region (D-loop), which plays a fundamental role in regulating mtDNA replication and transcription, revealing that D-loop methylation levels were dysregulated in central nervous system tissues of AD and ALS animal models, and were significantly different from those seen in human postmortem AD and PD brains compared to healthy controls. However, none of those studies investigated mtDNA methylation levels in specimens from living patients.

In our laboratory we investigated D-loop methylation levels in peripheral blood of patients with different neurodegenerative diseases, including late-onset AD and ALS, observing altered methylation levels in AD patients and in sporadic ALS patients, as well as in ALS patients with germinal causative mutations in the SOD1 gene compared to healthy matched controls. Our results also suggested that D-loop methylation levels were able to regulate mtDNA replication. Moreover we identified polymorphisms of genes related to DNA methylation reactions that significantly associated with D-loop methylation levels. Overall our results suggest that D-loop methylation and mitochondrial replication are strictly related to each other and their evaluation could provide useful information for a better understanding of the etiopathology underlying neurodegenerative diseases, as well as useful disease biomarkers.

In this webinar we will discuss the results of our investigation of mtDNA methylation levels in patients with late-onset AD, ALS, PD, as well as preliminary results in AD individuals at the very early stage of the disease.

 

 

3.00 pm

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

 

Abstract:

Lung cancer is the first cause of cancer related death worldwide. Although low-dose CT can definitely contribute to increase the percentage of tumors diagnosed at early stage (stage I) in lung screening programs (Aberle et al., N Engl J Med 2011; Zhao et al., Cancer Imaging 2011), a significant fraction of these patients (~30%) still experience recurrence and acquire chemoresistance (Siegel et al., CA Cancer J Clin 2018). Using a multi-tiered approach relying on multiomics we found that early stage but aggressive lung cancer is characterized by loss of pulmonary lineage, gain of EMT/stem-like features, alongside the occurrence of mutator and immune-evasion phenotypes. We refined a gene expression signature diagnostic of this aggressive lung cancer molecular subtype which surpasses current prognostic biomarkers and former molecular classifications. Our results pave the way for development of new therapeutic approaches for early stage lung cancer.

 

 

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.

 

 

3.00 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.

 

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.

 

3.00 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.