Icgeb
S. A. Tooze - Molecular Mechanisms of Mammalian Autophagy
updated
#shorts #biotechnology #geneticengineering
Abstract
Gastric cancer (GC) was the world’s third leading cause of cancer mortality in 2018. In spite of significant therapeutic advances, the overall clinical outcome for patients with advanced GC is poor, with median survival less than 1 year. In spite of whole genome molecular profiling which shed light on the genetic landscape of this tumor, at present few targeted therapies are licenced to treat GC.
The postulate of precision oncology is to exploit treatments targeting the molecular characteristics of a specific tumour. At present, only around 5-10% of cancer patients can benefit from targeted therapies. Delivering the right drug to the right cancer patient requires a detailed understanding of how genomic alterations are coupled to drug response. Thus, to improve the value of a target therapy it is mandatory to: (i) molecularly annotate tumors, (ii) properly select patients that could benefit from that therapy, (iii) validate the real biological relevance of the identified targets in a specific tumor type and (iv) identify molecular alterations that could affect the responsiveness to treatment. Targeted therapies licenced to treat GC are restricted to Trastuzumab (and its derivative Trastuzumab deruxtecan), Ramucirumab and the ICIs nivolumab and pembrolizumab. Most of the clinical trials performed during the last years in GC patients to identify new targets and to test new drugs failed. The reason for this failure, in many cases, can be ascribed to the lack of proper patient selection and/or to the inadequacy of robust preclinical data. These considerations imply that, before going to clinic, we need a better knowledge of the genomic environment associated to each oncogenic driver and necessitate predictive biomarkers to better select patients.
At present, the best strategy to fulfil all the above-mentioned prerequisites is the use of a large series of human cancer specimens directly transplanted into mice (Patient-derived xenografts, PDXs), in order to generate a study population that could be concomitantly profiled for biomarker assessment and randomized for prospective treatment with targeted agents. This approach combines the flexibility of preclinical analysis with the informative value of population-based studies. We aimed at identifying and validating novel targeted therapeutic strategies in GC, taking advantage of a multi-level platform of GC models, comprising more than 250 PDXs, primary cell lines and organoids. Exploiting this proprietary and unique resource, we: (1) provided a scientific basis for the rational selection of GC patients for anti-HER2 therapies through the identification of positive and negative predictors of response; (2) investigated mechanisms of acquired resistance to Trastuzumab; (3) re- evaluated EGFR as a therapeutic target in a subgroup of GC patients; (4) fighted drug-resistance through targeting persister cancer cells; (5) investigated genetic dependencies guiding response to PARP1 inhibitors; (6) dissected intratumor mismatch repair (MMR) heterogeneity.
As a whole, the results of our work have provided a scientific basis for future clinical applications and for guiding the rational design of molecularly oriented clinical trials for gastric cancer.
Abstract
Telomere dysfunction is a hallmark and driver of aging and age-related diseases (Rossiello, Nat Cell Bio 2022). We previously reported that damage-induced non-coding RNAs (dincRNAs) are generated at DNA breaks, including dysfunctional telomeres. Their sequence-specific targeting with antisense oligonucleotides (ASOs) results in DDR inhibition (Francia, Nature 2012; Michelini, Nat Cell Bio 2017; Pessina, Nat Cell Bio 2019).
We will discuss published and unpublished results supporting this approach in the study and treatment of age-related conditions. We will also discuss how DNA damage in different settings related to aging cancer and, recently viral infections, brings about the process of cellular senescence and its multipronged consequences. Biosketch
Dr. d’Adda di Fagagna is a cell and molecular biologist that studies the involvement of the DNA damage response (DDR) pathways in physiologically-relevant processes such as aging and cancer. Fabrizio obtained his PhD working at ICGEB under the guidance of Mauro Giacca and Arturo Falaschi. As a research associate and postdoc in Cambridge, UK, he discovered the engagement of DDR factors in the maintenance of telomeres and demonstrated that replicative cellular senescence, a form of cell aging, is the outcome of DDR activation caused by the direct recognition of critically short telomeres. He then set up his own research group at IFOM (FIRC Institute of Molecular Oncology) in Milan, Italy, in 2003. Here, he demonstrated that oncogene activation is an intrinsically genotoxic event that, by altering DNA replication, causes DDR activation and cellular senescence establishment. Since then, he continued working on several aspects of cellular senescence. His most exciting recent finding is the discovery of an unanticipated role of non-coding RNAs in the direct activation of the DDR. This discovery fuels most of his present investigative efforts. In 2014, he was awarded a permanent position “for exceptional merits” at the Italian National Research Council (CNR) in Pavia, Italy, where he runs a laboratory. Fabrizio is an EMBO member and received several awards for his work, including the European Association for Cancer Research (EACR) Young Cancer Researcher Award and the EMBO Young Investigator Award. He received two ERC advanced grants.
to respond to epidemics and pandemics. Today there is growing evidence that the versatility of mRNA technologies could allow for worldwide development of new vaccines or improving existing vaccines. However, mRNA technology for vaccines and therapeutics have to overcome significant challenges to reach its full value proposition for public health applications at a global level. These challenges includes access (IP
restrictions), high cost of goods, raw material supply and the capabilities and manufacturing capacity to ensure universal access to vaccines particularly for Africa and other LMICs. The WHO/MPP mRNA technology development and transfer Programme is dedicated to empower LMICs to develop and manufacturing mRNA vaccines to ensure sustainable access to this future relevant technology for health.
This presentation will focus on mRNA technology and the amazing women frontiers written into the mRNA history books and the next generation of women in the WHO/MPP mRNA Center for technology development and transfer located in the Southern Tip of Africa. A team dedicated to technology development and transfer in a quest for making mRNA vaccine development and manufacturing accessible to LMICs.
For further information visit the project web site at: www.tbfvnet.eu The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
and secondary outbreaks. Reducing pesticide dependency is, therefore, a key goal of sustainable agriculture. One approach is to explore using environmentally safe products and biological control agents as alternatives. Natural insecticide molecules show promise as they offer higher specificity and selectivity, reducing the need for chemical insecticides. The shift to more natural products would improve agricultural practices and enhance the quality of consumer products. The biodiversity of insect parasitoids provides a valuable source of bioactive genes/peptides that could be used to develop safer strategies for controlling crop pests. Researchers can develop new
bioinsecticides and plant protection methods by studying the molecular and functional aspects of host-parasitoid interactions in insects. This case study focuses on isolating and characterizing insecticidally bioactive genes from the reproductive secretion of the female parasitoid wasp Aenasius arizonensis (Girault) (=Aenasius bambawalei Hayat). This wasp is highly effective in controlling the cotton mealybug Phenacoccus solenopsis Tinsley, a significant pest that has caused substantial losses in cotton production in Pakistan since 2005. Through an integrated approach of
functional and molecular studies, the isolated genes/peptides from the parasitoids were studied/examined to understand the host-parasitoid interactions and their potential to develop effective insect pest control methods.
Urological Research Institute, DiBit2, Scientific Institute San Raffaele Milan - ITALY speaks on "Detect the undetectable: gold nanorods- assisted imaging and thermal treatment of bladder cancer lesions smaller than 1 mm".
Abstract
The diagnostic imaging does not detect bladder tumor smaller than 1 mm, and chemoresistance to intravesical therapy occurs in 50% of bladder cancer patients. As a consequence of technological and therapeutic limitations 60% of bladder cancer patients experience tumor relapse at 3 years follow up, with a consequent poor quality of life and the highest cost per patient among all cancers.
Preclinical model of orthotopic bladder cancer expressing the same target identified on the human bladder in situ carcinoma was used. Photoacoustic imaging of targeted gold nanorods allowed for the detection of bladder tumor lesions smaller than 1 mm, and the same contrast agent was exploited for assisted thermal therapy.
We have demonstrated the feasibility of a solution that allows for the detection and thermal therapy of tumors smaller than 1 mm at the same time.
Massimo Alfano, PhD, group leader of the Extracellular Microenvironment Unit at IRCCS Ospedale San Raffaele (Milan, Italy). Master’s degree of Science and PhD degree at the University of Milan. The focus of his research is to apply knowledge from basic science to techniques and tools that may really address clinical unmet needs. The group collaborates with several national and international researchers with different scientific skills to achieve an integrated vision of the disease, and is supported by peer-reviewed competitive grants and industrial sponsors.
Abstract
The stability of viral envelopes relies on a complex and dynamic network of intermolecular interactions that are only fully understood in the context of the entire virus structure.
Experimental determinations face significant challenges due to the small size of virus particles. However, modern multiscale molecular dynamics simulations enable the simulation of complete virus particles.
I will provide an overview of recent whole virus simulations and present several application examples illustrating the utility of these simulations. They include the identification of protein-lipid interactions in Flaviviruses that store energy in the membrane coat of the mature form; the thermal stabilization of circovirus capsid through a single point mutation; and the design of a potent variant-insensitive SARS- CoV-2 entry inhibitor.
Short Biosketch: Sergio Pantano got his degree in Physics at the National University of San Luis (Argentina) and his Ph.D. at the SISSA (Trieste, Italy) in 2001. Currently, he runs the group of Biomolecular Simulations at the Institut Pasteur de Montevideo. His research interests focus on the assembly and stability of Flavi and Circo viruses, for which he develops and applies multiscale simulation methods.
affect drug metabolizing enzymes & transporters, that have been shown to affect the pharmacodynamics (PD) or the pharmacokinetics (PK) of some medicines. Mechanistic and clinical studies have gone on to show that some of these effects can have a profound effect on treatment outcomes. Most of this work has been done in people of European ancestry. The relatively few studies done in people of African ancestry, are however, revealing important observations; that whole genome sequence and variation in pharmacogenes among African populations is much higher than in Caucasians and Asians and that for clinically relevant pharmacogenes African populations have either unique variants or significantly different population frequencies compared to Caucasian and Asians. At a clinical level, observations of differential response with respect to efficacy and safety of some medicines in African patients compared to Caucasian patients have been made. The WHO pharmacovigilance database, Vigibase, shows that for most drugs,
African populations have higher ADRs incidences than other world populations.
In response to this gap in basic and clinical PGx knowledge, over the past twenty five years my group has been working on discovering genetic variants associated with pharmacogenes and exploring drug-gene interactions potentially important for people of African Ancestry. This work has culminated in the design and analytical validation of a pharmacogenetic testing open array, GenoPharmR, that can predict clinical response for many medicines on the market. In this presentation I will present our journey from research lab work to patient bedside implementation studies that are likely to profoundly change the standard-of-care from one treatment fits all or generalisation of findings from one population to another to an approach that is individualised at personal and population level. Examples of drug-gene interactions involving CYP2B6-efavirenz, CYP2D6-tamoxifen, CYP2C19-clopidogrel, DPYD-5FU, and others will be covered.
and dynamics. This highlighted an unexplored role for methylation in regulating mitochondrial biogenesis, contributing to mitochondrial dysfunction in ASD. To identify the pathways that crosstalk
with mitochondrial pathways, we completed an analysis of 19 molecular datasets to identify common pathways that were implicated with ASD. We found that ASD data converged on four biological pathways, namely mitochondrial metabolism, neurogenesis and neuroinflammation. We
identified key players in specific pathways that are now being experimentally tested in a neuronal cell model system. My current research examines the intersection of mitochondrial metabolism with neuronal cell fate in a cell model system. ASD research spans disparate psychosocial and biomedical disciplines that traditionally work in isolation; however, autism research requires an integrative approach. Molecular research is moving towards a biopsychosocial framework that can be informed by autistic experiences. I will also discuss my group’s approach to trying to integrate autistic experiences within a molecular framework.
Conduce Antonio Maconi, curatore Galileo Festival della Scienza e Innovazione
In collaborazione con ICGEB-International Centre for Genetic Engineering and Biotechnologies
He also collaborated with the laboratory of Daniel Ruzek, at the Veterinary Research Insitute (VRI) in Brno, in the Czech Republic.
The results of this collaboration are part of Adam Kevely's first author scientific paper.
Here, he recounts how his involvement in the TBFVnet project has advanced his scientific knowledge and career.
He also considers how the possibility to collaborate with other Groups in different countries enriches scientific experience.
For further information visit the project web site at: www.tbfvnet.eu
The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
She tells us her background and what has fuelled her passion for science, by discussing the aim of her project. Since the end of January 2023, she has worked to set up a molecular diagnostic method for TBEV detection.
Her involvement in the TBFVnet project at ICGEB Trieste has been predominantly to become familiar with state-of-the-art techniques, equipment, and methodologies. She explains how this has consolidated her research.
We also ask about her vision for the future.
Her visit has been funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation as part of the Tick-Borne Flavivirus network project.
Department of Medicine, Pulmonary and Critical Care Division, Perelman School of Medicine, University of Pennsylvania , USA speaks on "Epithelial Cell Dysfunction In Lung Fibrosis: It’s About Proteostasis and Quality Control".
He tells us about the role of ICGEB in this project, the European Economic Area and the Norway Fund.
He also explains why it is important to sustain international cooperation in science, and a One Health approach, revealing how this project might be pivotal in finding new therapies or strategies to prevent infection.
The Molecular Virology Laboratory in Trieste, Italy studies human pathogenic viruses. Within this project the lab is involved in developing viral diagnostic methods and studies the host cell response to TBEV infection to discover antiviral drugs.
The International Centre for Genetic Engineering and Biotechnology has the expertise to promote, facilitate, increment and assist international networking and communication.
For further information visit the project web site at: www.tbfvnet.eu
The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
He also discusses uses of genome editing in plants. The ICGEB experience and lessons learnt/messages for policy makers.
An outline on omics technologies and human health - as prepared for the United Nations Science, Technology and Innovation Forum 2023
She also explains the most typical symptoms, and defines encephalitis. She further explains why is it underestimated, and what the scientific community (and the TBFVnet team) can do to improve the surveillance and diagnosis of TBEV and other TickBorne FlaviViruses.
Dr. Andreasson touches upon the broader impact of the project to similar studies in this field.
NIPH is sequencing and analyzing the genome of TBE isolated viruses in relation to their inflammation potential to the central nervous system. This work will bring new knowledge to improve the diagnostic potential of encephalitis in humans.
For further information visit the project web site at: www.tbfvnet.eu The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
RNA binding proteins or RBPs play an indispensable role in cellular machinery, especially processes such as transcription, post-transcriptional modification of RNA, RNA transport, and stabilization. Post-transcriptional modifications of RNA are a major route through which eukaryotes regulate gene expression. These modifications include splicing, mRNA polyadenylation, 5’ capping, and RNA editing. RBPs bind DNA and RNA through specific RNA binding domains (RBDs) or modules. Binding affinities and specificities vary throughout this family of proteins. The RNA recognition motif, or RRM, is the most widely distributed RBD in nature. RRMs are canonically identified through the presence of two RNA binding consensus motifs (RNP). They have a typical three-dimensional architecture, which classically consists of a four-stranded β-sheet supported by two α-helices, with the β-sheet serving as the primary surface for nucleic-acid recognition.
Despite these unifying traits of RRMs, they possess remarkably diverse DNA and RNA recognition capabilities. Our recent structural studies on DNA and RNA recognition by RRMs paint an interesting picture of how a single fold is able to recognize different cognate RNAs and DNAs by virtue of minor but crucial alterations to its binding surface. In addition, delineating nucleic acid binding specificities of RRMs has provided molecular clues to the progression of debilitating diseases.
Biomass: fuelling the future, with
Vittorio Venturi, Group Leader, Bacteriology lab, ICGEB Trieste
Syed Shams Yazdani, Group Leader, Microbial Engineering lab, ICGEB New Delhi
The move from fossil fuels to renewables is one of the keystones in the battle against climate change and in the transition to a sustainable world. Among the available types of renewable energy, biomass is unique in its ability to provide solid, liquid and gaseous fuels which can be stored and transported. Biofuels have several advantages in terms of emissions savings, fuel security, rural economic development. However, the various challenges associated with the conversion process limit their production. Scientific research and the development of new technologies play an important role in accelerating the transition to a sustainable energy system.
Event curated by Science & the City Italy – ICGEB.
Xanthomonas oryzae pv. oryzae (Xoo) causes bacterial blight, a serious rice disease. As part of its virulence repertoire, Xoo secretes a battery of cell wall degrading enzymes (CWDEs) that target different components of the rice cell wall. However, the CWDEs are double edged swords as the damage that they cause serves as a mark of infection and results in induction of Damage Triggered Immune responses that are part of pathogen triggered immunity (PTI). Xoo suppresses these defense responses using four different effector proteins that it secretes into rice cells via a type 3 secretion system (T3SS). Mutational analysis indicates that these four proteins function redundantly in suppression of PTI. Three of these T3SS effectors have 14-3-3 protein binding motifs. Each of these T3SS effectors interacts with different rice 14-3-3 proteins and this interaction is necessary for the ability of the effectors to suppress PTI. Some of the effectors that suppress PTI also appear to trigger a second layer of the plant immune response that is commonly referred to as Effector Triggered Immunity (ETI). Xoo is able to suppress ETI using five other T3SS effectors. At least for one of these effectors, the suppression of ETI appears to be due to physical interaction with effectors that elicit ETI and alteration of their intracellular localization. These results suggest a complex interplay of Xanthomonas T3SS effectors in suppression of both PTI and ETI to promote virulence on rice.
The autonomic nervous system is an important player in many cardiac disorders. However, the lack of a proper human model led to an elusive understanding of the molecular and functional mechanisms behind the autonomic control of the heart.
We successfully created an in vitro neurocardiac model system based on the co-culture of cardiomyocytes (CMs) and sympathetic neurons (SNs) derived by human induced pluripotent stem cells (hiPSCs).
The implementation of this co-culture system with patient hiPSCs can lead to a significant contribution in deciphering the role sympathetic neuronal activation in many disease, including not only cardiac disorders but also neurological conditions associated with cardiac autonomic dysfunction such as Parkinson’s disease and multiple system atrophy.
Here, he describes how this impacts a One Health approach.
The Biomedical Research Center has long-standing expertise in a TBEV-tick-model. This expertise allows characterisation of new virus isolates in terms of their tick replication and transmission efficiency.
For further information visit the project web site at: www.tbfvnet.eu
The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
He also explains how this is important for international collaboration and introduces the work of the VRI.
The Czech Republic is at the heart of the endemic area for TBFV, between Western Europe and the East. The research of the Veterinary Research Institute focuses on the pathogenesis of TBE, development and testing vaccines and antivirals and is also involved in national and international surveillance and diagnostic programs. Therefore, the Veterinary Research Institute is best placed to coordinate the activities of TBFVnet.
For further information visit the project web site at: www.tbfvnet.eu
The project is funded by Iceland, Liechtenstein and Norway through the EEA and Norway Grants Fund for Regional Cooperation.
Medicines are a great achievement for humankind. Today we have medicines to treat many diseases, but these are not always available to everyone in the world. Can science help provide patients around the world with wider and cheaper access to innovative medicines?
Natasa Skoko is Group Leader of Biotechnology Development at ICGEB in Trieste and focuses her research activity on biopharmaceutical development. Her team studies production strategies for biosimilars, biological drugs developed from commercial products whose patents have expired. The aim is not only to produce drugs in a new way but to increase the know-how and capabilities of the pharmaceutical industries in ICGEB Member States.
This story recounts how ICGEB's scientific research can improve healthcare and therapies.
comorbidities, and diverse population groups in South Africa – and globally, it is vital that genetic variants of key molecules implicated in pathologies, are identified. This information will, ultimately and ideally, contribute to a more personalised approach to patient care.
Professor of Allergy and Respiratory Genetics, Faculty of Medicine, University of Southampton, Human Genetics and Genomic Medicine Southampton General Hospital, UK speaks on "Exploring the (epi)genome for the origins of allergy and asthma".
Abstract: It has been recognized for centuries that allergic disease runs in families, implying a role for genetic factors in determining individual susceptibility. More recently, a range of evidence shows that many of these genetic factors, together with in utero environmental exposures, lead to the development of allergic disease through altered immune and organ development. Environmental exposures during pregnancy including diet, nutrient intake and toxin exposures can alter the epigenome and interact with inherited genetic and epigenetic risk factors to directly and indirectly influence organ development and immune programming. Understanding of these factors will be essential in identifying at-risk individuals and possible development of therapeutic interventions for the primary prevention of allergic disease. In this presentation I will summarise our work on understanding the complex interplay between genetic – epigenetic and environmental factors in determining susceptibility to allergic disease and asthma including genome-wide association, epigenome-wide association studies and studies of intergenerational effects of environmental exposures.
Biosketch: John Holloway is originally from New Zealand where he graduated from Otago University and undertook his PhD in the Malaghan Institute on the genetic basis of asthma. He is now Associate Vice President (Interdisciplinary Research) and Professor of Allergy and Respiratory Genetics in the Faculty of Medicine, University of Southampton, UK and his research program focuses on genetics, epigenetics and functional genomics of allergic and respiratory diseases such as asthma and COPD. His current research includes exploring the mechanisms of prenatal programming of respiratory disease and epigenetic mechanisms underlying atopy and asthma susceptibility; gene-environment interactions in the early life origins of asthma and COPD; characterisation of genetic factors influencing asthma severity; and identification and validation of novel asthma susceptibility genes. Professor Holloway has published extensively in the field of allergy and respiratory genomics and details of his publications and research.
On International Women's Day 2023, we celebrate Women in Science