I seminari dipartimentali si svolgeranno secondo il seguente calendario, due volte al mese, dalle 13:00 alle 13:40 in aula seminari al II piano di largo Donegani 2 (ex Wild), a Novara.
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1) Pharmacogenetics and genetics of migraine: our contribution to the field
03 ottobre 2018; Sarah Cargnin (UNIUPO - DSF)
Episodic migraine is a disabling neurovascular disease that affects around 10% of the worldwide adult population. Despite triptans are now considered as the gold-standard acute treatment for migraine, their use is limited by at least two main drawbacks: first, a consistent proportion of migraineurs do not benefit from these medications; second, it has been shown that the overuse of triptans per se is, paradoxically, one of the major causes of migraine chronification into Medication Overuse Headache (MOH). In the last years we conducted several studies aimed at identifying single neuclotide polymorphisms as genetic predictors of the clinical response to triptans or of the risk of developing MOH. We herein propose the use of a polygenic risk score approach as an adequate tool to unravel the genetic/pharmacogenetic basis of migraine and its chronification.
2) Role of the epigenetic modulators KDM6B and EZH2 in malignant mesothelioma
17 ottobre 2018; Giulia Pinton (UNIUPO – DSF)
Mesothelioma is a type of cancer that forms on the thin protective lining that cover the lungs and other internal organs, often associated with exposure to asbestos. For patients with relapsed or refractory mesothelioma, there are currently no approved treatment options.
Tazemetostat, a first-in-class EZH2 (Enhancer of Zeste homology 2) inhibitor, is currently being studied as a monotherapy in ongoing Phase 1 and 2 programs. EZH2 is a methyltransferase that trimethylates histone H3 lysine 27 (H3K27me3) on chromatin. This repressive mark is removed by the lysine demethylase KDM6B. We assessed the role of EZH2 and KDM6B in mesothelioma derived cells, cultured as monolayer or as spheroids.
3) From mass spectrometry to biochemistry: in vitro and in vivo applications
07 novembre 2018; Marcello Manfredi (UNIUPO – IRCAD)
Today, mass spectrometry methods are utilized in an increasing number of molecular and biology studies that aim for a better understanding of the biochemistry of living organisms. Biological processes, pathways and biomarkers are only some of the information that can be obtained through mass spectrometry. A selection of these studies will be presented: firstly, using a multi-omics approach we will show the specific behavior of serum proteins, metabolites and lipids during sport activity. The second case research is related to the use of proteomics to study the effect of a drug and its possible targets. The third case study will show the use of a multi-omics approach to analyze the content and the effect of platelet rich plasma.
4) MORPHEUS: an automated tool for unbiased and reproducible cell morphometry
21 novembre 2018; Federico Ruffinatti (UNIUPO – DSF)
Cell morphometry can be defined as the quantitative description of cell shape for the inference of important information about cell functionality and/or its correlation with certain biological process of interest, such as proliferation, differentiation, migration, motility, growth dynamics or adhesion to particular substrates. In recent years, a plethora of shape descriptors has been proposed to virtually capture every geometrical feature of a cell, or subcellular compartment. However, the simultaneous use of multiple descriptors rapidly raises the level of complexity, making the analysis multivariate and highly redundant. Moreover, the visual inspection of the whole dataset of images for manual cell selection, together with the lack of standardized protocols of analysis, is likely to introduce a heavy operator-dependent bias into the procedure, thus impairing its reproducibility. In order to solve most of these problems, we developed a new plug-in for ImageJ called MORPHEUS, that combines within a single pipeline the evaluation of the most relevant cell-shape descriptors, the extraction of nucleus features and an advanced analysis of orientation. Morpheus is a first proposal for the standardization of cell morphometric analysis in which the automation descending from the adaptative nature of the algorithm eliminates the user-bias factor and translates into a reproducibility-oriented approach to cell morphometry.
5) Relazioni struttura-attività del diterpene antitumorale EBC-46
05 dicembre 2018; Giovanni Battista Appendino (UNIUPO – DSF)
The diterpene ester tiglianol tigliate (EBC-46) occurs in high concentration in the unpalatable seeds of Fontainea picrosperma C.T. White (blushwood), a subcanopy euphorbiaceous tree endemic to a restricted (ca. 20 Km2) area of the Queensland rainforest. Tiglianol tigliate is remarkably efficacious in the treatment of localized tumors, and has successfully completed Phase III clinical development for veterinarian use and Phase I human clinical studies. Intra-tumor injection of EBC46 triggers a triad of responses (massive destruction of tumor vasculature, tumor hemorrhagic necrosis, stimulation of wound healing) sensitive to PKC pan-inhibitors, suggesting that modulation of PKC is part of its mechanism of action. The PKC isoform activation of EBC-6 is significantly different from the one of tetradecanoyl phorbol acetate (PMA) and ingenol mebutate, and studies aimed at clarifying the role of PKC in the mechanism of action of EBC-46 by systematically modifying the functional groups of the natural product will be presented.
6) Nucleotide Excision Repair and direct DNA damage reversal in Mycobacterium tuberculosis: a biochemical and structural perspective
19 dicembre 2018; Riccardo Miggiano (UNIUPO – DSF)
Mycobacterium tuberculosis (MTB) is a human pathogen that during its complex life cycle is continuously exposed to a variety of DNA-damaging stresses. The mutagenic effects of O6-alkylated guanine in DNA is counteracted by the action of the suicidal O6-methylguanine methyltransferase protein (OGT). I will present the crystal structure of wild-type MTB OGT in complex with a modified dsDNA, gaining structural insights into the OGT cooperative DNA-binding mechanism. The MTB DNA repair toolbox includes also multi-enzymatic DNA repair systems such as the Nucleotide Excision Repair (NER). The first steps in NER are carried out by the coordinated action of the UvrA, UvrB and UvrC proteins. We analyzed the hydrodynamic properties and the oligomeric state of the MTB UvrB showing that the protein forms dimers in solution, which are characterized by an elongated shape, as determined by SAXS analysis. Moreover, we analyzed the UvrA/UvrB lesion sensing/tracking complex by adopting a SEC-based approach followed by SAXS-and cryo-EM-based structural analysis, revealing that the two proteins interact in solution, in the absence of ligands, with an A2B2 stoichiometry. Surface plasmon resonance analysis showed that the dissociation constant of the complex falls in the low micromolar range that could represent the basis for a fine modulation of the complex architecture. Finally, the characterization of such complexes in terms of thermodynamics and stoichiometry provides an experimental framework to screen molecules for their capability to interfere with the DNA-lesion searching response in mycobacterial NER.
7) Real World Evidence: quanto è davvero reale?
09 gennaio 2019; Francesco Barone Adesi (UNIUPO – DSF)
According to the British Academy of Medical Sciences, Real-World Evidence (RWE) is the evidence generated from clinically relevant data collected outside of the context of conventional Randomized Controlled Trials (RCT). This includes data available through electronic health records, medical claims, drug and disease registries, patient lifestyle-related activities and health-monitoring devices. RWE studies are regarded as complementary to RCT in the generation of scientific evidence. For example, results of RWE studies have usually a larger generalizability, because they often involve subjects that would not be recruited in RCT. However, several methodological challenges should be considered when interpreting findings based on RWE studies. In particular, the observational design of these studies makes them more vulnerable to bias and confounding than RCT. The seminar illustrates some limitations in the evaluation of drug safety and effectiveness through RWE studies and proposes possible solutions to mitigate them.
8) A new possibility on acute myelogenous leukemia (AML): targeting myeloid differentiation using potent and innovative human dihydroorotate dehydrogenase (hDHODH) inhibitors
16 gennaio 2019; Marco Lolli (UNITO)
Acute myelogenous leukemia (AML) is a clinically most devastating disease with dismal prognosis and survival rate. Efforts to identify new therapeutic targets to overcome myeloid differentiation blockade were largely unsuccessful until the breakthrough study in 2016 by Sykes et al. who demonstrated that inhibition of dihydroorotate dehydrogenase (hDHODH) enables myeloid differentiation in both human and mouse AML models. The development of potent and optimized hDHODH inhibitors has become a potential new strategy for the treatment of AML. After several series of optimization in the development of hDHODH inhibitors using state-of-the-art designing paradigms, including synthesis, structure-activity relationships (SAR), crystallographic and molecular modelling studies, biological assays (cell viability, proliferation, cytotoxicity, immunosuppression and myeloid differentiation), and physicochemical characterization, we have recently discovered a novel small molecule, representative of a novel class of hDHODH inhibitors based on a hydroxylpyrazole-pyridine scaffold, that is able to restore the myeloid differentiation in leukemia cell lines at a 1-log lower concentration compared to the lead brequinar. To our knowledge, it is one of the most potent hDHODH inhibitor, with a safety profile, so far discovered.
9) Lipotoxicity-mediated disruption of adult hypothalamic neural progenitor cells as a potential contributor in Metabolic Syndrome
06 febbraio 2019; Heather Bondi (UNIUPO – DSF)
Metabolic syndrome (MetS) represents a risk factor for the onset of type 2 diabetes (T2D) and other chronic diseases, including neurodegenerative disorders. The hypothalamus (Hyt) is the brain region that plays a key role in regulation of food intake and energy expenditure. In mice, high-fat diet (HFD) induces an increase of circulating and brain free fatty acids (FFA), which, in turn, can exert toxic effects (lipotoxicity) and potentially compromise Hyt functions. Adult neurogenesis (aNG) is a key form of neuroplasticity which also occurs in Hyt (aHytNG) and is impaired in mice exposed to HFD. This observation has generated the hypothesis that lack of remodelling in the Hyt network as a consequence of disrupted NG may potentially contribute to MetS. Little is currently known about the direct effects of lipotoxicity on aHytNG. The present project aims at understanding the in vitro effects of a FFA-enriched microenvironment on adult Hyt neural progenitor cells (aHytNPC), using an innovative and highly throughput image-based approach, namely High Content Analysis (HCA). We will use Palmitic acid (PA) to reproduce lipotoxicity and its potential underlying cellular and molecular effects on aHytNPC. Moreover, we want: i) to assess whether aHytNPC impairment by PA may be pharmacologically counteractable; ii) to identify novel drugs with protective properties against lipotoxicity. Our results may shed light on novel pathophysiological mechanisms that link MetS and brain dysfunction.
10) Regulation of neuronal protein expression and function by astroglial calcineurin
20 febbraio 2019; Laura Tapella (UNIUPO – DSF)
Astrocytes play fundamental homeostatic functions in the brain. Calcineurin (CaN) is a Ca2+-activated phosphatase that, in astrocytes, is known to trigger reactive gliosis and neuroinflammation. Surprisingly, nothing is known about a role of astroglial CaN in brain physiology. For that reason, we have generated a conditional CaN KO mouse model specific in astroglial cells, (ACN-KO). ACN-KO mice grew normal in terms of body and brain weight but starting from 2 month of age develop memory impairment and later on spontaneous tonic-clonic seizures. In this seminar, I will present data on: 1) the role of astroglial CaN in neuronal excitability through the modulation of Na+/K+ ATPase (NKA) activity; 2) preliminary results of proteomic analysis on ACN-KO mice. In summary, our data suggest that astroglial CaN controls phenotype and function of neurons in term of protein expression and excitability.
11) Italian pigmented rice varieties: an overview on the phenolic composition, nutraceutical potentiality and technological aspects
06 marzo 2019 Monica Locatelli (UNIUPO – DSF)
12) The importance of being a bitter natural compound
20 marzo 2019 Federica Pollastro (UNIUPO – DSF)
13) Macrophage plasticity in inflammatory diseases and cancers
03 aprile 2019 Chiara Porta (UNIUPO – DSF)
14) Mono- and multi species biofilm infections on medical devices: prevention and eradication strategies by microbial biosurfactants
17 aprile 2019 Chiara Ceresa (UNIUPO – DSF)
15) ADME properties as an useful tool in development of new bioactive substances: applications and perspectives
08 maggio 2019 Silvio Aprile (UNIUPO – DSF)
16) Microencapsulation: principles and practice
22 maggio 2019 Andrea Foglio Bonda (UNIUPO – APTsol)
17) The hidden world of minor cannabinoids: our contribution to the synthesis and discovery of novel bioactive derivatives
05 giugno 2019 Diego Caprioglio (UNIUPO – DSF)
18) Fighting diseases with protein structures
19 giugno 2019 Davide Ferraris (UNIUPO – DSF)
20) Boron Neutron Capture Therapy: the renaissance of an old anticancer treatment
03 luglio 2019 Daniela Imperio (UNIUPO – DSF)
21) Targeting aldehyde dehydrogenase 1A3 in gliomas by using curcumin-based probes