Un Tour di eventi che ha l'obiettivo di decentrare a livello locale la condivisione della conoscenza, portando il dibattito sui motori di ricerca e sulla promozione dei siti web dal Forum GT direttamente nelle varie Regioni Italiane. GT Idea ti invita a scoprire il perchè degli eventi. Il Tour di eventi si conclude come di consueto a Novembre con il Convegno Nazionale sul Search Marketing dove si concentrano i maggiori esperti del settore.
Giuseppe Testa, Professore ordinario di Biologia Molecolare - Università degli Studi di Milano Direttore del centro di Neurogenomica - Human Technopole
Rita Cucchiara, Professoressa ordinaria di Visione Artificiale e Sistemi Cognitivi - Università degli Studi di Modena e Reggio Emilia Stefano Triberti, Ricercatore e Docente di intelligenza artificiale - Università degli Studi di Milano Arianna Manzini, Ricercatrice di Etica della Salute Mentale e Psichiatrica - Università di Bristol, United Kingdom
During this workshop, you will be guided through the basic processes of technology transfer applied to biomedical research – from patenting to pitching for investment, and negotiating deals
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The workshop will provide an overview of AIRC activities and funding opportunities, with a particular focus on those dedicated to young scientists. We will then share useful tips for the preparation of a competitive application. Both fellowships and grants will be thoroughly discussed, with practical examples. Participants will have the possibility to ask questions and interact with the speakers. AIRC supports cancer researchers in all phases of their career through grants and fellowships awarded after a selective peer review.
In this course created specifically for researchers, you will learn the principles of effective science communication and public engagement. Understand the features of different communication formats and narratives to develop your own practice and reach wider audiences.
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Transferable skills are competences that are acquired and can be transferred into a different career setting. The good news is that scientists, at this stage of career, have already lots of transferable skills that they acquired through their academic path, education, internships, formal and informal training.
The goals of this module are to: • raise awareness of own skill set • develop a competences profile Meeting ID: 823 9044 9593 Passcode: 755406,
Scientists are often trap in the loop of not knowing what to do next in their career path, being this inside or outside academia. In this module, we aim at guiding participants to understand where their interests lie, reflect on their goals and better assess which jobs might suit them most.
The goals of this module are to: • enable participants to make an informed decision about their future career • stimulate a more proactive approach towards career choices Meeting ID: 830 2990 8342 Passcode: 135135
This interactive workshop will introduce you to the world of Translational Research. In this workshop we will explore why translational scientists have the potential to become lifesavers, what skills it takes to be a successful translational scientist and the wide range of employing organisations including European Research Infrastructures. You will be introduced to a technique to discover and explore your natural talents and how to use them for job hunting
Meeting ID: 839 7883 6413 Passcode: 839474,
Participants will learn what are the characteristics of good goals are and how to set them properly, in career-related decision making and in their scientific projects. Setting clear goals has a direct impact on the way we manage our time and our quality of life. We will introduce a framework for organizing the work productively, setting priorities efficiently and managing time proactively.
The goals of this workshop are to: • practice useful techniques for goal setting in scientific projects and career choices • equip participants with a strategy for managing their time more efficiently Meeting ID: 863 7798 2922 Passcode: 135135,
Personal resilience and effective stress management are key skills that help scientists to successfully navigate their way through this competitive career stage. Sharpening the awareness for the external and internal drivers of stress and understanding one’s own needs fosters building personal resilience. This process supports a healthy and self-supporting work-life-integration.
The goals of this workshop are to: • Sharpen awareness for the internal and external drivers of stress • Introduce the concept of personal resilience Meeting ID: 851 8227 5030 Passcode: 214379
During this workshop, we will overview the process of entrepreneurship, focusing on the key aspects to take into consideration in the creation of spin-off companies. We will continue the journey of monetizing research by navigating between creating value, complementing skills, convincing investors and multitasking
How to communicate your personal brand on LinkedIn and benefit from a good professional networking. The webinar intends to provide participants with an overview of the potential of LinkedIn as a tool to promote one's personal brand, develop relationships and find professional opportunities
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Nowadays we live in the so called "knowledge society", which bases its sustainment and growth on research, innovation and technology. Knowledge therefore assumes a central role in the life of each individual from an economic, social and political point of view. Sharing of research results thus becomes crucial to make knowledge a tool available to all. In this context, the researcher is called to cross the boundaries of the laboratory and to take on a fundamental role in society: to promote the dialogue between the scientific community and different types of public. This meeting is designed to help scientists improve their ability to talk about their research to a lay audience, starting with a quick overview on how science communication is evolving, what are its difficulties and the approaches used. Practical suggestions for effective communication will be provided: the role of the public, the power of metaphors and storytelling, mistakes to be avoided. This is no small responsibility: as we are experiencing at this very moment in history, communication carried out in the wrong way may cause many problems.
Despite the prevalence of sexual dimorphism in mammalian phenotypic traits, sex has often been overlooked in biomedical studies. Indeed, sex and gender are two potentially critical factors in experimental design. Strong evidence is now available regarding the damages produced by the underestimation of gender and sex variables, ranging from low quality research, inefficacy of new drugs, inaccurate or late diagnosis, waste of resources and investments, and preventable deaths and pain. Recently, a movement in science is supporting the “Sex/Gender Dimension of Research”: I will discuss and show the importance of integrating sex and gender into all phases of research
Giovanni Giangreco, The Francis Crick Institute, London, UK
Cell-Olympic Games
Valentin Flury, University of Copenhagen, Centre for Protein Research, Copenahagen, Denmark
Epigenetic memory – how cells remember U and me
Francesco Brunelli, University of Pavia, Italy
Il sorprendente ruolo della serina nella malattia di Parkinson: nuove prospettive terapeutiche?
2 teams both owned by Chinese companies... Milan is really international! But football is not the only sport we love over here, you will see
Milan like Amsterdam?? This was a city full of canals and water, and still it is that way, just few steps out of the city center...
Italian dress or shoes are on the top of desires by the Ladies and Gentlemen everywhere... come with us to admire the Excellence
9:00-9:10 Cecilia Restelli, chair of the Scientific Organising Committee of ENABLE
9:10-9:15 Pier Giuseppe Pelicci, president of the European School of Molecular Medicine (SEMM), Milan 9:15-9:20 Francesc Posas, director of the Institute for Research in Biomedicine (IRB), Barcelona 9:20-9:25 René Bindels, scientific director of the Radboud Institute for Molecular Life Sciences (RIMLS), Nijmegen 9:25-9:30 Jesper Velgaard Olsen, vice director of the Novo Nordisk Foundation Center for Protein Research (CPR), Copenhagen 9:30-9:35 Ana Arana Antelo, Deputy Director General of DG R&I European Commission 9:35-9:40 Irene Diaz, FEBS 9:40-9:45 Francesco Bonomi, IUBMB 9:45-9:50 Francesco Biancardi, ZEISS Business Development Manager,
Linda Duits, Public Speaker and researcher at the Utrecht University, NL
Nikoline Borgermann, Sustainable Research Consultant, Copenhagen Nereo Kalebic, group leader at Neurogenomics center, Human Technopole, Milan IT Rita Vassena, Scientific Director EUGIN group, Barcelona, SP
Correlative Microscopy has been known for many years. However, progress can be seen in many imaging technologies and therefore also in correlative microscopy. Nowadays, microscopes are well-known and widely spread in almost every biological lab, together with laser scanning microscopes and super-resolution microscopes, which can be seen as standard tools to study samples in 3D and with high resolution. Zeiss offers also other sophisticated imaging techniques, for instance field emission scanning electron microscopes or X-ray microscopes, to achieve new insights into the sample. Field emission scanning electron microscopes open the world into the ultrastructure of the samples - cell structures with resolutions in the range of nanometers become visible whereas X-ray microscope allow to image large objects like bones and plants in 3D without sectioning. Each microscope has its strengths and gives access to information that was hidden before. As everybody knows, biological samples can be as heterogenous as life can be: whole organisms have to be investigated in its holistic nature as well as in its components. The challenge for a scientist or a microscopist is the need to image and to visualize huge organisms to get an impression of the entire subject as well as gaining information in a high depth of detail. Getting an overview of the morphology is highly interesting as the behavior of cells which is facilitated by protein interactions. How tremendous and powerful is it to combine multiple perspectives of a sample - across scales, different image modalities and analytical approaches and finally to provide answers to the scientific questions. Now ZEISS offers a new tool to bring together the different imaging techniques, which is called ZEN Connect, that brings the imaging techniques together - that means ZEN Connect enables to go beyond correlative microscopy and provides an open platform to connect your data into the context of research.
Cells organize many of their biochemical reactions by formation and dissolution of non-membrane-bound compartments. Recent experiments show that a common mechanism for such biochemical organization is phase separation of unstructured proteins to form liquid-like compartments, which can subsequently harden to form compartments with new material properties such as gels and glasses. These compartments can be described by principles elucidated from condensed-matter physics and are therefore termed biomolecular condensates. I will discuss potential roles of phase separation in organization of cellular biochemistry and the role of aberrant phase separation in disease. I will also describe how these discoveries were facilitated by the establishment of the Max Planck Institutes for Cell Biology and Genetics and the Physics of Complex systems, in Dresden.
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Many patients with non-metastatic breast tumors are successfully treated. However, small tumor cell populations such as those found in: micro-metastases, or dormant, residual disease present a major hurtle to successful therapy. Throughout nature the fitness of individual organisms is modulated by population density. This phenomenon, termed the Allee Effect, means that sparse populations are more vulnerable to extinction than their denser counterparts. The Allee Effect’s role in governing the growth of sparse cancer cell populations remains unclear. To address this question, the MDA-MB-231 cell line, a triple negative breast cancer model, was selected. A cohort of phenotypically distinct clones was isolated from the parental culture. The cell populations were seeded into wells across a range of densities from extremely sparse to dense. The experiment was conducted in both: regular growth media, and conditioned media derived from a dense population. Each well was imaged daily using an Operetta Imaging platform which facilitated precise cell counting. The data was used to calculate the per-capita growth rates of the cell populations as a function of cell density. The results demonstrate that per capita growth is positively influenced by population size. Suggesting that the Allee Effect does modulate the fitness of both, the MDA-MB-231 cell line and clonal populations therein. Moreover, exposure to media conditioned by a dense, parental population blunts the Allee Effect, implicating soluble factor exchange as a mediator of this phenotype. Interestingly, the clonal populations were not equally impacted by the Allee Effect, indicating the presence of an Allee Spectrum. The unique characteristics that dictate, and result from, a clone’s position on the Allee Spectrum may shed light on the mechanisms governing the growth of small tumor cell populations. This could reveal novel vulnerabilities in residual and metastatic cancer cell populations.
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Gaining new knowledge from data is at the heart of biomedical research. Randomized controlled clinical trials are at the top of the evidence pyramid in clinical research. Biostatistics plays an important role in planning, performing, analysing and interpreting randomized controlled clinical trials. I will introduce and explain the various responsibilities of a biostatistician working on clinical trials using several examples I have worked on myself in the last two years. I won't be able to show the details of the results since the studies have not been published yet. Instead, I will focus on underlying statistical principles and how understanding and applying them might help researchers, also those with an experimental focus, to improve their study planning and analysis and ultimately lead to gaining new knowledge.
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Pediatric high-risk brain tumors remain the leading cause of cancer-related death in children. For the last 30 years, all treatment approaches for the most aggressive types of these tumors have failed, leaving a terrible prospect of survival at five years for these children virtually of zero. Thus, it is clear that new therapeutic strategies are required that allow for more effective treatments of these tumors and defer the severe side effects derived from the current therapeutic choices. Oncolytic adenoviruses designed to replicate in and destroy tumor cells selectively represent a promising therapeutic strategy that could improve the outcome of this malignancy. Delta-24-RGD is a tumor-selective oncolytic virus that has been being tested in a phase I clinical trial in adults with brain tumors with very promising results. The virus showed a lack of toxicity and some degree of efficacy due to the trigger of an immune response against the tumor. Taking advantage of the safety profile demonstrated by Delta-24-RGD in adult brain tumors during the last ten years, we have dedicated our efforts to characterize the preclinical and clinical efficacy of Delta-24-RGD in pediatric brain tumors. Preclinical studies demonstrated the virus's efficacy and allowed us to open the first-in-human clinical trial for diffuse intrinsic pontine glioma. Twelve patients were treated within this trials. The procedure was well-tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. Lessons learned from the clinic allow us to engineered other viruses based in the Delta-24-platform to boost the immune response. The intratumoral administration of armed oncolytic viruses was safe and significantly increased the survival of mice bearing orthotopic pediatric murine tumors, leading to long-term survivors. We observed a significant increase of immune infiltration in the tumor with an active functional phenotype. These data indicate that incorporating positive immune modulators into the Delta-24-platform could improve the oncolytic effect of the virus by boosting the immune response while maintaining a safe profile in immunocompetent models offering a feasible option treatment for pediatric brain tumors. Our data underscore that oncolytic viruses are becoming a real option for the treatment of these tumors.
The transcription factor EB (TFEB) is a master regulator of lysosomal biogenesis and autophagy. In normal growth conditions, TFEB is sequestered in the cytoplasm through phosphorylation. Following starvation, TFEB is dephosphorylated and translocates into the nucleus promoting the activation of its target genes. The aim of my research is to investigate TFEB dynamics observed experimentally following a shift from nutrient-rich to nutrient-poor conditions. This will be achieved by integrating mathematical modelling and quantitative single-cell experiments by means of a microfluidic platform. Specifically, I performed a series of experiments where I monitored the nuclear localization of TFEB in real-time in the microfluidics device following alternating stimulation of cells either with nutrient rich medium or medium depleted of amino acids. Preliminary experiments revealed a novel dynamic never observed before: as cells are supplied with starvation medium, TFEB accumulates in the nucleus in less than fifteen minutes, then it slowly decreases during the starvation phase generating what we called “overshoot”, reaching a set-point after about three hours. I modelled the observed dynamics with a two-compartment (nucleus and cytoplasm) model with two different species (dephosphorylated and phosphorylated TFEB) for each of the two compartments. I considered transport and de/phosphorylation reactions and a conservation of the total TFEB amount. I further introduced a negative feedback. The model was able to correctly predict the experimental data and was used to hypothesize the existence of a novel feedback loop driving TFEB localization regulation (in silico analysis). New experiments were performed by inhibiting key pathways (autophagy, mTOR signaling, translation, transcription) to validate in vitro this hypothesis. Recently, I further performed a drug screening on kinase inhibitors and few of them were identified as key candidates to be tested in microfluidics. Ongoing work will be focused on these kinases to elucidate their role in the overshoot dynamic.
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The improvement of novel sequencing technologies is quickly transforming the scientific investigation and the therapeutic treatments of rare genetic diseases, which research is hampered by the limited cohort of diagnosed patients. To address this point, the MITE-seq (Mutagenesis by Integrated Tiles) is a novel saturation mutagenesis technique that allows to easily test thousands of potentially pathogenic protein variants in a single assay. This approach has already been applied to many oncogenes to evaluate the oncogenic potential of their missense variants. However, MITE-seq great potential has not yet been fully exploited. To this end, we decided to apply MITEseq to mutagenize two different transcription factors, P63 and MYOD1, which besides an oncogenic function, are also main regulators of developmental processes in, respectively, skin formation and muscle differentiation. To follow the biological activity of each variant of the two transcription factors, I settled up very efficient conversion strategies from fibroblasts to keratinocytes-like-cells (through P63-KLF4 induction) or myotubes (overexpressing MYOD1). In this way, using surface proteins as a marker of conversion, I was able to separate the converted and non-converted cells, study the enrichment of each variant in the different populations and rank them according to their phenotypic severity. Moreover, I was able to identify new putative hotspots, whose loss of function was validated through biochemical and genomics approaches together with known causative and silent mutations. Starting from these preliminary results, we aim to develop a system to easily expand such method to any other transcription factor by generating a reporter cell line with the consensus sequence of a given transcription factor. This tool will represent a milestone in rare diseases field, providing to the scientific community a robust and easy to use method to dissect the molecular bases of genetic diseases due to mutations in transcription factors.
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One of the key components of generating new biomedicines is the generation of specific binding proteins. Historically, this has started from synthetic antibodies, where our laboratory had played an important role in initially developing this technology [1,2]. At the same time, it was essential to devise strategies to not only select, but to evolve proteins in the test tube, to ever higher affinity and specificity. This led to our development of ribosome display, the first Darwinian evolution system for proteins not requiring any cells [3,4,5].
Having these synthetic technologies in hand, it becomes apparent that the antibody molecule itself is no longer needed, and that other scaffolds may be more advantageous, as they are more robust and versatile. This led to the development of Designed Ankyrin Repeat Proteins (DARPins) [6,7], which are now in the clinic for a variety of applications. Finally, bringing all technologies together, we developed the SHielded REtargeted ADenovirus (SHREAD) system [8,9,10], which allows to produce a cocktail of therapeutics in the body at a location of choice. It is based on an Adenovirus without any viral genes, which can be retargeted by a DARPin-based adapter to any cell surface receptor desired, and it is shielded from undesired interaction by a designed protein shield. Application examples will be shown.
Parkinson’s Disease (PD) is the second most common neurodegenerative disease characterized by the progressive loss of dopaminergic (DA) neurons of substantia nigra (SN) pars compacta. Mitochondrial dysfunction has a prominent role in neurodegenerative events, especially in PD. MicroRNAs (miRNAs) are fine regulators of gene expression with a promising therapeutic role for their ability to concomitantly regulate different pathways. Over the past decade, dysregulation of miRNAs expression in PD has been reported. miR-181a and miR-181b (miR-181a/b) are highly expressed in the SN and striatum and enriched in the brains of PD patients. Recently, our group showed that miR-181a/b regulate key genes involved in mitochondrial biogenesis and function (i.e. NRF1, PPARGC1A) and we now further demonstrate that miR181a targets TFAM. Moreover we showed that mir-181a/b dowregulation ameliorates neurodegeneration in models of mitochondrial disorders. To test the effect of mir-181a/b modulation in PD, we generated chemical PD models in Medakafish and mice by using the neurotoxin 6-OHDA which causes a selective destruction of nigrostriatal dopaminergic (DA) neurons. Interestingly, our results revealed that, in both fish and mouse, inactivation of miR-181a/b reduces the extent of 6-OHDA-induced DA neurons death. Behavioral analysis of 6-OHDA injected mice also showed recovery of L-DOPA-induced rotations in miR-181KO mice. Moreover, since pathological accumulation of alpha-synuclein is considered a major hallmark for the disease, and contributes to the progressive loss of DA neurons by different mechanisms including mitochondrial dysfunction, we are validating the neuroprotective effect of miR-181a/b modulation in in vivo and in vitro model of α-synucleinopathy PD. Finally, we are now evaluating if miR181a/b could be considered as PD biomarkers. We are thus performing RT-qPCR to estimate miRNAs levels in plasma of PD patients. In conclusion our preliminary results suggest that miR181a/b may represent both reliable and easy to measure biomarkers, and effective therapeutic targets in PD.
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T cells in immunosuppressed tumour microenvironments (TME) are often stymied in their effector functions and ability to recognize and eliminate tumour cells. To rescue an immunosuppressed TME, T cell stimulatory signals must be supplied to restore their tumour killing capacity and avoid dysfunction. Herein we describe the identification and characterization of RNA aptamers –¨RNA antibodies¨- agonistic to the CD3 receptor complex, capable of enhancing T cell activation and proliferation in vitro, in vivo, and reducing tumour growth in a murine melanoma model. To identify a T cell stimulating aptamer, six rounds of Systematic Evolution of Ligands by Exponential Enrichment (SELEX) were performed against the CD3 protein complex. After High Throughput Sequencing, and preliminary binding experiments, four aptamer candidates were chosen for further characterization. Specific binding to the target CD3 protein and CD3 expressing cell lines was confirmed using control proteins and CD3 KO cells generated using CRISPR/Cas9, respectively. CD3 aptamers enhanced proliferation of T cells suboptimally activated with an agonistic CD3 antibody as well as an antigenic p-MHC stimulus in vitro. Likewise, co-administration of the CD3 aptamer boosted the immune response generated via tumour antigen vaccines in vivo. Lastly, adoptive transfer of tumour reactive T cells pre-treated with CD3 aptamers showed enhanced ability to reduce tumour growth in melanoma bearing mice in vivo. Tumour-targeted delivery of this T cell activating aptamer, may convert an immunosuppressive TME into an immunoresponsive one. Our studies show that CD3 aptamers can be novel therapeutic agents for cancer immunotherapy as they enhance T-cell-mediated anti-tumour immune responses in vivo.
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Coronavirus Disease 2019 (COVID-19) is caused by the Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). It first appeared in 2019 in China as a new respiratory disease of humans, ranging from asymptomatic to fatal. Its precipitous global spread ignited a devastating and ongoing pandemic. The zoonotic emergence of two prior deadly betacoronavirus (CoV) infections of humans preceded the appearance of COVID-19: the SARS-CoV pandemic in 2003 and the Middle East Respiratory Syndrome (MERS-CoV) epidemic in 2012 (still ongoing). It is also projected that the endemic common cold CoVs arose from interspecies zoonotic transmission events from animals (bats and ruminants) to humans centuries ago, becoming established and continuing to circulate in humans. All these CoVs likely originated in bat host reservoirs, with some further infecting an intermediate animal host (farmed civet cats for SARS or camels for MERS) prior to spillover and adaptation to humans. Similar interspecies CoV transmission events have occurred for animal CoVs. Several swine CoVs likely emerged from bat CoV reservoirs. Notably there is evidence for experimental transmission of beta CoVs from wild ruminants to cattle, and from cattle to other species (dogs, poultry). Factors that influence interspecies transmission and zoonotic spillovers include an environment that facilitates close contact between reservoir species and humans (i.e., wet markets in Asia), properties of the pathogen [e.g., dose, stability and transmissibility (aerosols, feces)] as well as reservoir-host interactions (i.e., type and frequency of exposure, superspreaders, etc). For example, close or sustained contact of humans with (multiple) infected animals or animal secretions and products, that may occur at live animal markets, has been implicated in the SARS-CoV, and possibly the SARS-CoV-2 outbreaks.
Coronaviruses possess unique features that enable them to evolve and transmit to new hosts and acquire new tissue tropisms that result in altered disease syndromes or transmission routes. They include: 1) the largest viral RNA genome and resultant mutations, insertions and deletions during replication (high genome plasticity); 2) a broad and diverse host range for beta-CoVs (high host plasticity); and 3) high recombination frequencies. Besides the high transmissibility of SARS-CoV-2 in humans and the emergence of variants, a major concern for viral persistence is its spillover and adaptation to animals (reverse zoonoses). SARS-CoV-2 infects pets (cats, dogs) in COVID-19 infected households, but currently without evidence of transmission back to humans. More concerning is the spillover and effective replication and spread of SARS-CoV-2 in mink farms and evidence for transmission between infected mink and humans. To date at least 14 species, many of them wildlife, are susceptible to SARS-CoV as documented by natural or experimental infections. A major concern is that if SARS-CoV-2 becomes established in an animal reservoir(s), the virus can mutate and continue to evolve in the new host species, thereby extending its host range, with the potential to reinfect humans or other species, including livestock. Based on historical precedent and the continued presence of SARS-related CoVs in bats, novel coronaviruses are likely to continue to emerge in animals and humans in the future. A One Health approach encompassing global disease surveillance with international reporting and collaboration of teams across human medical and animal/veterinary scientists as well as wildlife biologists, ecologists, and social scientists is critical to identify and control future pandemic threats, such as the unknown Disease X projected by WHO.
Usher syndrome type 1B (USH1B) is characterized by combined deafness and retinitis pigmentosa (Millan et al., 2011) and is caused by biallelic mutations in MYO7A which encodes for Myosin 7A. MYO7A coding sequence (∽6.7 Kb) exceeds the cargo capacity of adeno-associated viral (AAV) which is the preferred vector for retinal gene therapy and was recently approved by both FDA and EMA for treatment of a congenital form of blindness (www.luxturna.com). Our group has developed dual AAV vectors which upon sub-retinal administration rescue both the expression of hMYO7A and the localization of retinal pigmented epithelium melanosomes in the Shaker-1 (sh1) mouse model of USH1B (Trapani et al., 2014). We received support from the European Union (H2020-SC1 EU Grant, N. 754848 - UshTher) to test the safety and efficacy of this approach in the retina of patients with USH1B. During production of AAV-5’hMYO7A, we found a contaminant vector resulting from recombination between two homologous sequences within the vector. This was addressed by changing one of the two sequences while maintaining the same hMYO7A expression levels in vivo. Vectors production was performed under good manufacturing (GMP)-like practices and we defined the transgene-related potency of dual AAV-hMYO7A in subretinally injected sh1 mice to ensure biological activity of the clinical lot. As this trial represents the first use of dual AAV in human retina, we selected three doses (1.37E+10 - 4.4E+9 - 1.37E+9 total GC/eye) of GMP dual AAV-hMYO7A in sh1 mice to be translated in USH1B subjects. All doses induce expression of full length hMYO7A and show dose-dependent effects on correctly localized melanosomes. Overall, the results of these studies support the clinical translation of dual AAV vectors for gene therapy of USH1B retinitis pigmentosa.
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Pancreatic cancer is one of the most lethal cancers with 5-year survival rate below 10%. Thus, new therapeutic strategies to tackle this disease are urgently needed. Based on the key role mitochondria play in cancer cells, our strategy focuses on improving treatment outcomes by inactivating these organelles using multimodal strategies, such as a combination of a mitochondria-targeted ROS inducer (verteporfin) and metformin, a clinically approved type II diabetes drug that has shown mitochondrial inhibition properties. Aims Our aim is to determine the therapeutic response as well as the mechanism of action of the above-mentioned combination treatment targeting mitochondria on clinically relevant patient derived PDAC models as well as in in vivo models. Materials and Methods The clinically approved photosensitiser (verteporfin) and metformin were co-administrated to a panel of patient derived xenografts (PDXs) models. Metabolic and proliferation activities post-treatment were analysed using MTT and BrdU assays. Cell morphology was analysed by neutral red staining. Moreover, changes in mitochondrial activity, cell viability and reactive oxygen species (ROS) production post-treatment were measured by flow cytometry. Results Even though some degree of cell toxicity was observed when using the drugs individually (monotherapy treatment), the combination protocol showed to significantly enhance cell death. Moreover, compared to monotherapy, combining both drugs had a greater effect on mitochondrial activity, ROS production level and cell morphology changes. Conclusion Our data presents promising results of light-based therapies in combination with metformin which could be a potential strategy used for improving the outcome of pancreatic cancer.
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A virtual tour of the Classic milanese highlights: the "must see" in the very heart of the city
Prof. Harry Collins, School of Social Sciences, Cardiff University, UK
Matteo Polettini, Research Assistant, Complex Systems and Statistical Mechanics group, University of Luxemburg
I will discuss my journey in big data - both scientifically and careerwise over the last 20 years and talk about pitfalls, barriers, solutions, and excitement.
The concept that any cell type, upon delivery of the right “cocktail” of transcription factors (TF), can acquire an identity that otherwise would be unattainable, revolutionized the way we approach the study of developmental biology. This in turn, invoked the emergence of unprecedented boost in the study of TFs to precisely shape cellular fate in-vitro. Despite the wide range of new TF-discoveries, the absence of unbiased screening to understand TF capacity in different genomic backgrounds limits our ability to fully unlock the potential of pioneer TFs repertoire. Therefore, in this project, we perform for the first time transcriptomic, epigenomic and morphological screenings of ~300 different Transcription Factors (TFs) potentially involved in developmental processes in order to identify crucial dynamics which drive cell fate decisions. To this end, we used human fibroblast cells from different germ layer origins to explore the importance of the genomic background. Morphological variations were assessed using High-Content Screening, revealing significant cellular morphology changes, which are currently investigated through comprehensive transcriptomic approaches. As expected, preliminary results indicate significant conversion-specific changes, thus implying an important role in cell fate decisions. We also added ATAC-seq and CHIP-seq, to associate transcriptional profiling to deterministic phenotype by characterizing chromatin remodeling events and inferring potential TF binding sites. Next, we will use state-of-the-art multi-omics data integration approaches to gain more comprehensive insights in order to identify pioneer TFs and understand which TFs mutually regulate specific developmental networks. These TFs will be further tested in combination using a conversion assay toward a specific cell fate, and in Medaka fish embryos for the in vivo validation. Eventually, the expected data will represent a state-of-the-art encyclopedia of pioneer-TF landscapes, including binding sites, downstream target genes, and enriched functional pathways.
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The discovery of human induced pluripotent stem cells (hiPSCs) has emphasized the function of transcription factors in controlling cell identity, overlooking the role of cell-extrinsic signals. The reprogramming of somatic cells into hiPSCs is paradigmatic of a transcription factor-driven change of cell identity in three distinct and well-defined phases: cells exit a somatic state, transition through a transgene-dependent promiscuous transcriptional and epigenetic state, finally establish a self-renewing pluripotent identity. Several studies have established hallmarks and roadmaps of hiPSC formation, and new technological advancements, such as single-cell analyses, further refined our understanding of the reprogramming process. These works better characterized initial and final stages of human reprogramming in detail but connected intermediate stages via hypothetical and more uncertain trajectories. Whilst there is a body of literature describing reprogramming trajectory in mouse, the fine dynamics of human reprogramming intermediates, which constitute the bottleneck of the process, remain largely unexplored due to the complexity of recognizing and selecting rare phenotypes that will evolve into a hiPSC fate. Therefore, we take advantage of high efficiency reprogramming in microfluidics and temporal multi-omics to identify and resolve distinct sub-populations and their interactions. The combination of secretome analysis and single-cell transcriptomics shows functional extrinsic pathways of protein communication between reprogramming sub-populations and the re-shaping of a permissive extracellular environment. We pinpointed the HGF/MET/STAT3 axis as a potent enhancer of reprogramming, which acts via HGF accumulation within the confined system of microfluidics, and in conventional dishes needs to be supplied exogenously to enhance efficiency. Our data integrate the notion of human cellular reprogramming as a transcription factor-driven process with the concept that it is deeply dependent on extracellular context and cell population determinants.
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Metagenomic analysis of the human microbiome has uncovered multiple links between our microbial complement and our health. However, several challenges have to be overcome to exploit the human microbiome in personalized medicine strategies, including its inter- and intra-personal variability, its extensive genetic diversity, and its still hidden components. In my talk I will introduce such challenges and discuss how large-scale high-resolution integrative metagenomics can address them and have an impact on biomedical applications.
Post-translational modifications (PTMs) regulate the function of a protein, its folding and stability, or its capacity to form complexes with other molecules. Tandem Mass Spectrometry (MS/MS) has emerged as one of the major techniques to investigate PTMs in an unbiased way, since they invariably result in a change of the proteins mass. Thus, the aim of my PhD project is to apply computational methods to MS data, in order to study PTMs from two points of view. On the one hand, I analysed arginine (R) methylation at a global level; on the other hand, I investigated the diverse PTMs that occur on histones. In order to annotate R methylation, I developed hmSEEKER, a computational tool to analyse heavy methyl SILAC data and confidently detect in vivo methyl-peptides through a machine learning model. We also collected significantly regulated R-methyl-peptides from a set of SILAC experiments in which we profiled methylation changes in response to different stimuli (Cisplatin treatment; inhibitors of arginine methyltransferases; PRMT1 knock-down and over-expression). Upon integration of the heavy methyl and dynamic SILAC datasets we found that di-methylated R occur more frequently in low complexity regions and are more likely to change in response to a stimulus compared to mono-methylated ones. Within the context of histone PTMs (hPTMs) we used hmSILAC to identify and orthogonally validate histone methylations on residues other than lysine and arginine. This analysis led to the high-confidence annotation of two novel histone mono-methyl-marks on serine 28 and threonine 32 of histone H3. Finally, we are testing the application of a novel “open search” peptide identification software, named IonBot, to histone MS data. We believe such software will allow us to systematically identify and profile hPTMs beyond those that are more commonly studied, such as citrullination, formylation or crotonylation.
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The study of the somatic mutations in human tumors has led to the characterization of a diverse set of mechanisms which can create multiple genetic changes in a single event. The activity of APOBEC3 (A3) mutagenic enzymes is the major contributor to these clustered events and is known for its striking mutation showers (kataegis) occurring during the repair of DNA breakpoints. However, the mechanisms underlying the overall A3 mutation burden, which can be considerable in lung, breast, bladder, and head-and-neck cancers, are less understood. We systematically measured and classified the diverse patterns of clustered mutations in tumors focusing on APOBEC activity. We identified a new pattern (“omikli”, greek for fog) of non-recurrent and diffuse hypermutation which is highly predictive of the overall mutagenic activity of this enzyme in a cancer, and the burden of cancer driver mutations. This mechanism is independent of that underlying kataegis, and generates short clusters of 2 to 4 mutations. While kataegis predominantly results from the activity of the APOBEC3B paralog, omikli results from the APOBEC3A paralog. Our data suggests an association with the activity of mismatch repair (MMR) machinery which can provide the single stranded DNA needed as a substrate for the A3 activity. Due to this association, mutations coming from the omikli mechanism accumulate in the early-replicating and gene-rich parts of the genome. Thus, APOBEC mutagenesis has a high propensity to generate impactful, gene-altering mutations, exceeding other well known carcinogens such as tobacco smoking and UV-light.
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A cell is the common unit structure shared by all living organisms, but even ‘simple’ prokaryotic cells are extremely complex chemical reactors. One of the grand fundamental challenges of modern science is to reveal the basic operating principles of life. While we have extensive knowledge about the molecular building blocks that form the basis of modern life, we do not understand how these building blocks collectively operate to define life as we know it. Cellular life, which provides the fundament of all organisms, appears to be the result of a collection of highly controlled, energy consuming, dynamic self-assembly and self-organization processes that lead to autonomous entities that can reproduce, transfer information, interact, and evolve.
Understanding the physical-chemical principles of these collective processes poses a formidable challenge, which needs to be overcome if we want to be able to understand life itself, and influence biological processes in a rational way in the future. In our research, we use microfluidic techniques to create cell-like environments that allow us to probe the impact of the physical aspects of the cell on key biochemical processes such as transcription and translation. I will also give an overview of our current attempts to reconstruct a living cell.
The DNA damage checkpoint (DDC) is a surveillance mechanism evolved to preserve genome integrity in response to DNA lesion(s). Checkpoints halt cell cycle progression to provide cells with the opportunity to repair the damage before dividing. When the DNA damage is successfully repaired, the checkpoint is satisfied and cells can resume the division in a process called checkpoint recovery. Contrariwise, when the DNA damage is irreparable, cells eventually die. Possibly, few cells reenter the cell cycle with damaged DNA. This process, known as adaptation to the DDC, poses a threat to genomic stability as daughter cells can accumulate genomic aberrations. While the molecular events leading to DDC activation have been intensely studied, the molecular events driving checkpoint adaptation remain unclear. We tackled this problem in S. cerevisiae by integrating different approaches, including genetics, single cell analyses, and fluorescence microscopy techniques. In yeast, the DDC arrests cell cycle progression in metaphase by inhibiting cohesin cleavage and the pathways controlling exit from mitosis, namely the Cdc fourteen early anaphase release (FEAR) network and the mitotic exit network (MEN). Since it was reported that the activity of the FEAR network is essential for the adaptation process, we set to investigate how this anaphase pathway impacts the DDC. We found that FEAR activity is not required for checkpoint adaptation per se but it is rather needed for completing mitosis. Indeed, while FEAR activity is dispensable to exit from mitosis in unperturbed conditions or after repair, it becomes essential only when cells enter mitosis with faulty DNA. As many cancer therapies are designed to induce and retain DNA lesions and resistance to treatments is becoming a menace, having unveiled a novel essential requirement for the successful survival of cells carrying damaged DNA may provide insights for a novel combination therapy strategy in the cancer treatment.
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The Alternative Lengthening of Telomeres (ALT) pathway, active in 10-15% of cancers, is characterized by homologous recombination (HR)-dependent telomere lengthening. We discovered that non-coding RNAs transcribed de novo at damaged sites, including telomeres, support DNA damage signaling and downstream repair. Here, we investigated the role of telomeric non-coding RNAs (tncRNAs) in ALT. First, we uncovered an upregulation of tncRNAs in ALT cells with respect to non-ALT cells, then to probe their function we inhibited their activity with antisense oligonucleotides (ASOs). As telomeres are composed of TTAGGG repeats tncRNAs can be C-rich or G-rich, named here teloC and teloG, respectively. Inhibition of teloC tncNRAs with antiteloC ASOs reduced viability and induced apoptosis specifically in ALT cells. Inhibition of teloC tncRNAs also led to an arrest in S-phase, pointing towards a potential role in resolving telomeric replication stress. As telomeres are inherently difficult to replicate, their spontaneous damage and transcription in ALT cells may be due to increased levels of endogenous replication stress. Interestingly, in both ALT and non-ALT cells hydroxyurea-induced replication stress led to increased tncRNA levels as well as exacerbated sensitivity to antiteloC ASOs, while non-replicating ALT cells were insensitive to ASOs. To investigate the molecular function of tncRNAs in ALT, we probed for promyelocytic leukemia (PML) protein, an ALT-related protein involved in telomeric recombination events in ALT cells, and the HR protein RAD51, and found that in both cases, co-localization events with telomeres were reduced by antiteloC ASOs. These results suggest that ALT cells express high levels of tncRNAs due to elevated endogenous replication stress, and that teloC species serve to recruit various proteins to damaged telomeres, thereby allowing for continued cell viability. The specific importance of teloC tncRNAs in ALT cells provides for the possibility of their targeting for cancer therapy.
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Our laboratory seeks to investigate the role of senescence programs in the human hematopoietic compartment with a focus on Hematopoietic STem and Progenitor Cells (HSPC), the cells at the top of the hematopoietic hierarchy with the potential to self-renew and give rise to all hematopoietic lineages. Our goal is to dissect the mechanisms governing HSPC response to stress and devise innovative strategies to ameliorate their repopulation capacity for translational applications in the field of regenerative medicine and for anti-aging strategies
Serine is an amino acid playing several roles in the human body; recent studies are suggesting a correlation between serine and neurodegeneration. The gene PINK1 causes autosomal recessive Parkinson Disease (PD). Our study investigates ties between serine biosynthesis and PINK1, PD and neurodegeneration at large. We differentiated dopaminergic neurons from iPSCs following Reinhardt protocol. In wild-type neurons, PINK1 was silenced via lentiviral transduction with two shRNAs seven days before harvest. A scramble shRNA served as control. RT-qPCR data confirmed a statistically significant downregulation (~50%) of all genes responsible for serine biosynthesis (PHGDH, PSAT1, PSPH) and of SLC1A4, which encodes a channel used to import serine. Western Blots confirmed a reduction which is statistically significant for one shRNA. Serine, besides contributing to protein and nucleobase synthesis, is used to produce glutathione and D-serine. Glutathione is an essential antioxidant; this is of particular interest because PD has been linked to oxidative damage (of which PINK1 is a sensor), and dopamine synthesis itself generates ROS as byproduct. D-serine, instead, is synthesized specifically in neurons and acts as neurotransmitter. We outlined a second experimental setup using three independent lines carrying the pathogenic mutation Q456X in PINK1 and isogenic gene-corrected lines as controls; all lines were differentiated as described. Mutant dopaminergic neurons, however, did not show any downregulation of PHGDH, PSAT1, and PSPH at level of RNA nor protein. We hypothesized that either the chronic depletion of PINK1 results in activation of the biosynthetic pathway via another mechanism, or the truncated protein resulting from the mutation Q456X is still able to activate the pathway. To verify the latter hypothesis, we intend to use neurons carrying different pathogenic PINK1 mutations. At the same time, we are planning a metabolomic analysis to quantify the serine content of differentiated neurons.
Please provide your feedback on this talk here: ENABLE 2021 Short Talk Evaluation
Wnt1 is a member of the Wnt family present in almost all organisms. Wnt1 is involved in the development, regenerative capacity and tumorigenic growth of many organs and tissues. In Drosophila, Wingless (Wg, Drosophila Wnt1) not only triggers the specification of the wing during normal development but also contributes to the regenerative capacity of the wing and to the emergence of wing-derived epithelial tumours. Interestingly, a single wingless enhancer mediates these radically different tasks. Using a combination of reporter assays and CRISPR/Cas9-driven defined deletions, we have identified the logic behind the context-dependent use of this enhancer by developmental and stress-induced signalling pathways. Our work will certainly contribute to our better understanding of the use of the same signalling molecules during development and disease.
Please provide your feedback on this talk here: ENABLE 2021 Short Talk Evaluation
18:30-18:45 Cecilia Restelli & the rest of SOCs on stage
Price announcement and Closing Remarks
18:45-19:00 The ENABLE project: past, present and future René Bindels, scientific director of RIMLS, Nijmegen Clara Caminal, ENABLE project coordinator, IRB Barcelona Joan Guinovart, Group leader at IRB, Barcelona,
Italy is known as the Country of Art and Beauty, and Milan is considered the world capital of Design: here you will discover why!
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