Oxidative DNA Damage associates with Transcription and/or Replication processes

8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) is the most common marker of oxidative stress and its accumulation within the genome has been associated with major human health issues such as cancer, aging, cardiovascular and neurodegenerative diseases. 8-oxodG is considered the main source of dC:dG to dA:dT transversion. The majority of 8-oxodG is preferentially repaired by OGG1 glycosylase/AP (apurinic/apyrimidinic) lyase-initiated BER (Base Excision Repair) pathway. It has been widely demonstrated that the 8-oxodG accumulation in the promoter regions of specific genes can stimulate transcription via the BER pathway. Based on this knowledge, we wondered whether the oxidative DNA damage could globally be correlated with the transcription process. Here, we report the genome-wide distribution of 8-oxodG in human non- tumorigenic epithelial breast cells (MCF10A) using OxiDIP-Seq which combines the immunoprecipitation anti–8-oxodG antibodies with high- throughput sequencing. We show a specific 8-oxodG bimodal distribution within promoter regions and identify a subset of human promoters that accumulate 8-oxodG under steady-state condition. Furthermore, the comparison between OxiDIP-Seq and ChIP-Seq of Ser5- and Ser2- phosphorylated isoforms of RNA Polymerase II or GRO-Seq strongly suggest the association between 8-oxodG accumulation and transcription process. Besides, by performing OxiDIP-seq in quiescent (G0) cells, we classified the oxidized promoters in two subsets. The growing-specific promoters accumulate 8-oxodG through DNA replication-dependent events while the persistently oxidized promoters accumulate 8-oxodG through replication-independent and transcription- associated events

Expanding the Role of the Histone Lysine-Specific Demethylase LSD1 in Cancer

Studies of alterations in histone methylation in cancer have led to the identification of histone methyltransferases and demethylases as novel targets for therapy. Lysine-specific demethylase 1 (LSD1, also known as KDM1A), demethylates H3K4me1/2, or H3K9me1/2 in a context-dependent manner. In addition to the well-studied role of LSD1 in the epigenetic regulation of histone methylation changes, LSD1 regulates the methylation dynamic of several non-histone proteins and participates in the assembly of different long noncoding RNA (lncRNA_ complexes. LSD1 is highly expressed in various cancers, playing a pivotal role in different cancer-related processes. Here, we summarized recent findings on the role of LSD1 in the regulation of different biological processes in cancer cells through dynamic methylation of non-histone proteins and physical association with dedicated lncRNA

The composting process from a waste management method to a remediation procedure

Composting is a controlled technology to enhance the natural aerobic process of organic wastes degradation. The resulting product is a humified material that is principally recyclable for agricultural purpose. The composting process is one of the most important tools for waste management, by the European Community legislation. In recent years composting has been increasingly used as a remediation technology to remove biodegradable contaminants from soil, and to modulate heavy metals bioavailability in phytoremediation strategies. An optimization in the recovery of resources from wastes through composting could enhance soil fertility and promote its use in the remediation biotechnologies of contaminated soils

Towards a comprehensive view of 8-oxo-7,8-dihydro-2'-deoxyguanosine: Highlighting the intertwined roles of DNA damage and epigenetics in genomic instability

8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a major product of DNA oxidation, is a pre-mutagenic lesion which is prone to mispair, if left unrepaired, with 2'-deoxyadenosine during DNA replication. While unrepaired or incompletely repaired 8-oxodG has classically been associated with genome instability and cancer, it has recently been reported to have a role in the epigenetic regulation of gene expression. Despite the growing collection of genome-wide 8-oxodG mapping studies that have been used to provide new insight on the functional nature of 8-oxodG within the genome, a comprehensive view that brings together the epigenetic and the mutagenic nature of the 8-oxodG is still lacking. To help address this gap, this review aims to provide (i) a description of the state-of-the-art knowledge on both the mutagenic and epigenetic roles of 8-oxodG; (ii) putative molecular models through which the 8-oxodG can cause genome instability; (iii) a possible molecular model on how 8-oxodG, acting as an epigenetic signal, could cause the translocations and deletions which are associated with cancer

miRNA Expression May Have Implications for Immunotherapy in PDGFRA Mutant GISTs

Gastrointestinal stromal tumors; MiRNAs; MicroRNAsTumores del estroma gastrointestinal; MiARN; MicroARNTumors de l'estroma gastrointestinal; MiARN; MicroARNGastrointestinal stromal tumors (GISTs) harboring mutations in the PDGFRA gene occur in only about 5–7% of patients. The most common PDGFRA mutation is exon 18 D842V, which is correlated with specific clinico-pathological features compared to the other PDGFRA mutated GISTs. Herein, we present a miRNA expression profile comparison of PDGFRA D842V mutant GISTs and PDGFRA with mutations other than D842V (non-D842V). miRNA expression profiling was carried out on 10 patients using a TLDA miRNA array. Then, miRNA expression was followed by bioinformatic analysis aimed at evaluating differential expression, pathway enrichment, and miRNA-mRNA networks. We highlighted 24 differentially expressed miRNAs between D842V and non-D842V GIST patients. Pathway enrichment analysis showed that deregulated miRNAs targeted genes that are mainly involved in the immune response pathways. The miRNA-mRNA networks highlighted a signature of miRNAs/mRNA that could explain the indolent behavior of the D842V mutated GIST. The results highlighted a different miRNA fingerprint in PDGFRA D842V GISTs compared to non-D842Vmutated patients, which could explain the different biological behavior of this GIST subset.The study was supported by a financial contribution of the Department of Pharmacy and Biotechnology (RFO) to SA and of the AIG (Associazione Italiana GIST) to MA

S50-01 Depression and bipolar disorder: Is prevention of mania possible? Critical issues on diagnostic criteria

Diagnostic criteria for bipolar disorder in DSM IV require the occurrence of a manic or hypomanic episode. The scant appropriateness of these criteria compared with Kraepelin"s concept of manic depressive insanity has been repeatedly reported and the concept of bipolar spectrum has been proposed for more than 30 years. The negative consequences of pure adherence to operational diagnostic criteria on clinical needs are presented in terms of community epidemiology results and in terms of clinical evidences and the inadequate treatment of depressive and anxiety episodes and the risk of manic switch with antidepressant drugs are discussed.The epidemiological survey conducted in Sesto Fiorentino showed that depressive episodes in patients with subthreshold mania or hypomania were different from the clinical presentation of pure unipolar depressives episodes confirming not only the numeric impact but also qualitative differences between these groups of patients.Our clinical study where predictors of mania have been prospectively evaluated in a trans nosographic sample of outpatients demonstrated that aspects related to bipolarity predicted manic shift regardless of the diagnosis. DSM IV criteria seem not to be able to detect and describe a group of patients relevant both on epidemiological and on clinical level. These findings underline the need of a careful examination of patients treatment and validate the rule of further research in definition of mood disorders boundaries for prevention strategies

Au2phen and Auoxo6, Two Dinuclear Oxo-Bridged Gold({III}) Compounds, Induce Apoptotic Signaling in Human Ovarian A2780 Cancer Cells

Au(2)phen ((2,9-dimethyl-1,10-phenanthroline)(2)Au(2)(µ-O)(2))(PF(6))(2) and Auoxo6 ((6,6′-dimethyl-2,2′-bipyridine)(2)Au(2)(µ-O)(2))(PF(6))(2) are two structurally related gold(III) complexes that were previously reported to display relevant and promising anticancer properties in vitro toward a large number of human cancer cell lines. To expand the knowledge on the molecular mechanisms through which these gold(III) complexes trigger apoptosis in cancer cells, further studies have been performed using A2780 ovarian cancer cells as reference models. For comparative purposes, parallel studies were carried out on the gold(III) complex AuL12 (dibromo(ethylsarcosinedithiocarbamate)gold(III)), whose proapoptotic profile had been earlier characterized in several cancer cell lines. Our results pointed out that all these gold(III) compounds manifest a significant degree of similarity in their cellular and proapoptotic effects; the main observed perturbations consist of potent thioredoxin reductase inhibition, disruption of the cell redox balance, impairment of the mitochondrial membrane potential, and induction of associated metabolic changes. In addition, evidence was gained of the remarkable contribution of ASK1 (apoptosis-signal-regulating kinase-1) and AKT pathways to gold(III)-induced apoptotic signaling. Overall, the observed effects may be traced back to gold(III) reduction and subsequent formation and release of gold(I) species that are able to bind and inhibit several enzymes responsible for the intracellular redox homeostasis, in particular the selenoenzyme thioredoxin reductase

Analysis of microbiome in gastrointestinal stromal tumors: Looking for different players in tumorigenesis and novel therapeutic options

Carcinogenesis; Microbiome; Tumor evolutionCarcinogènesi; Microbioma; Evolució del tumorCarcinogénesis; Microbioma; Evolución del tumorPreclinical forms of gastrointestinal stromal tumor (GIST), small asymptomatic lesions, called microGIST, are detected in approximately 30% of the general population. Gastrointestinal stromal tumor driver mutation can be already detected in microGISTs, even if they do not progress into malignant cancer; these mutations are necessary, but insufficient events to foster tumor progression. Here we profiled the tissue microbiota of 60 gastrointestinal specimens in three different patient cohorts—micro, low-risk, and high-risk or metastatic GIST—exploring the compositional structure, predicted function, and microbial networks, with the aim of providing a complete overview of microbial ecology in GIST and its preclinical form. Comparing microGISTs and GISTs, both weighted and unweighted UniFrac and Bray–Curtis dissimilarities showed significant community-level separation between them and a pronounced difference in Proteobacteria, Firmicutes, and Bacteroidota was observed. Through the LEfSe tool, potential microbial biomarkers associated with a specific type of lesion were identified. In particular, GIST samples were significantly enriched in the phylum Proteobacteria compared to microGISTs. Several pathways involved in sugar metabolism were also highlighted in GISTs; this was expected as cancer usually displays high aerobic glycolysis in place of oxidative phosphorylation and rise of glucose flux to promote anabolic request. Our results highlight that specific differences do exist in the tissue microbiome community between GIST and benign lesions and that microbiome restructuration can drive the carcinogenesis process.Francesca Goriini and Federica Zanotti have been supported by Fondazione Cassa di Risparmio di Bologna

Invariant NKT cells contribute to chronic lymphocytic leukemia surveillance and prognosis

Chronic lymphocytic leukemia (CLL) is characterized by the expansion of malignant CD5(+) B lymphocytes in blood, bone marrow and lymphoid organs. CD1d-restricted invariant Natural Killer T (iNKT) cells are innate-like T lymphocytes strongly implicated in tumor surveillance. We investigated the impact of iNKT cells in the natural history of the disease both in Eμ;-Tcl1 (Tcl1) CLL mouse model and 68 CLL patients. We found that Tcl1-CLL cells express CD1d and iNKT cells critically delay the disease onset, but become functionally impaired upon disease progression. In patients, disease progression correlates also with high CD1d expression on CLL cells and impaired iNKT cells. Conversely, disease stability correlates with negative/low CD1d expression on CLL cells and normal iNKT cells, suggesting an indirect leukemia control. iNKT cells indeed hinder CLL survival in vitro by restraining CD1d-expressing Nurse Like Cells, a relevant pro-leukemia macrophage population. Finally, multivariate analysis identifies iNKT cell frequency as independent predictor of disease progression. Together, these results support iNKT cell contribution to CLL immune-surveillance and highlight iNKT cell frequency as prognostic marker for disease progression

Effect of Functional Fitness on Plasma Oxidation Level in Elders: Reduction of the Plasma Oxidants and Improvement of the Antioxidant Barrier

Aging is characterized by a progressive decline in the physiological function due to the gradual alteration of molecules, cells and tissues. Reactive oxygen species (ROS) are the by-product of aerobic metabolism, and their increase is physiologically counteracted by the activation of the antioxidant machinery. A typical hallmark of aging is the imbalance of such equilibrium, due to either an increase of the amount of radicals or a failure of the antioxidant system. Literature reports that physical exercise is able to restore and maintain the homeostasis of oxidants and antioxidants during aging. Recently, growing interest has been turned to functional fitness, a special physical activity aimed to enhance the ability to perform everyday tasks, such as dressing, climbing stairs and preparing meals. The aim of this work was to assess whether a 24 weeksfunctional fitness program carried out on 28 elderly participants (57-86 years old) could be able to improve their oxidative status. For this purpose, dROMs (diacron Reactive Oxygen Metabolites) and BAP (Biological Antioxidant Potential) were analysed at the beginning and at the end of the study. Furthermore, both plasma and saliva protein carbonylation levels were explored through proteomics analysi