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"Rosato, Antonio"
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Issues on risk analysis for critical infrastructure protection
Critical infrastructure provides essential services to citizens. The mutual dependencies of services between systems form a complex 'system of systems' with a large perturbation surface, prone to be damaged by natural and anthropic events. Their intrinsic and extrinsic vulnerabilities could be overcome by providing them adaptive properties to allow fast and effective recovery from loss of functionality. Resilience is thus the key issue, and its enhancement, at the systemic level, is a priority goal to be achieved. This volume reviews recent insights into the different domains (resilience-enhancing strategies, impact and threats knowledge, and dependency-related issues) and proposes new strategies for better critical infrastructure protection.
Book
Genome-wide association between YAP/TAZ/TEAD and AP-1 at enhancers drives oncogenic growth
YAP/TAZ are nuclear effectors of the Hippo pathway regulating organ growth and tumorigenesis. Yet, their function as transcriptional regulators remains underinvestigated. By ChIP-seq analyses in breast cancer cells, we discovered that the YAP/TAZ transcriptional response is pervasively mediated by a dual element: TEAD factors, through which YAP/TAZ bind to DNA, co-occupying chromatin with activator protein-1 (AP-1, dimer of JUN and FOS proteins) at composite
cis
-regulatory elements harbouring both TEAD and AP-1 motifs. YAP/TAZ/TEAD and AP-1 form a complex that synergistically activates target genes directly involved in the control of S-phase entry and mitosis. This control occurs almost exclusively from distal enhancers that contact target promoters through chromatin looping. YAP/TAZ-induced oncogenic growth is strongly enhanced by gain of AP-1 and severely blunted by its loss. Conversely, AP-1-promoted skin tumorigenesis is prevented in YAP/TAZ conditional knockout mice. This work highlights a new layer of signalling integration, feeding on YAP/TAZ function at the chromatin level.
Piccolo and colleagues report that the YAP/TAZ factors form ternary complexes with TEAD and AP-1 factors to drive a transcriptional program that promotes cell proliferation and tumour growth.
Journal Article
Acute myeloid leukemia: from NGS, through scRNA-seq, to CAR-T. dissect cancer heterogeneity and tailor the treatment
Acute myeloid leukemia (AML) is a malignant blood cancer with marked cellular heterogeneity due to altered maturation and differentiation of myeloid blasts, the possible causes of which are transcriptional or epigenetic alterations, impaired apoptosis, and excessive cell proliferation. This neoplasm has a high rate of resistance to anticancer therapies and thus a high risk of relapse and mortality because of both the biological diversity of the patient and intratumoral heterogeneity due to the acquisition of new somatic changes. For more than 40 years, the old gold standard “one size fits all” treatment approach included intensive chemotherapy treatment with anthracyclines and cytarabine.
The manuscript first traces the evolution of the understanding of the pathology from the 1970s to the present. The enormous strides made in its categorization prove to be crucial for risk stratification, enabling an increasingly personalized diagnosis and treatment approach.
Subsequently, we highlight how, over the past 15 years, technological advances enabling single cell RNA sequencing and T-cell modification based on the genomic tools are affecting the classification and treatment of AML. At the dawn of the new millennium, the advent of high-throughput next-generation sequencing technologies has enabled the profiling of patients evidencing different facets of the same disease, stratifying risk, and identifying new possible therapeutic targets that have subsequently been validated. Currently, the possibility of investigating tumor heterogeneity at the single cell level, profiling the tumor at the time of diagnosis or after treatments exist. This would allow the identification of underrepresented cellular subclones or clones resistant to therapeutic approaches and thus responsible for post-treatment relapse that would otherwise be difficult to detect with bulk investigations on the tumor biopsy. Single-cell investigation will then allow even greater personalization of therapy to the genetic and transcriptional profile of the tumor, saving valuable time and dangerous side effects. The era of personalized medicine will take a huge step forward through the disclosure of each individual piece of the complex puzzle that is cancer pathology, to implement a “tailored” therapeutic approach based also on engineered CAR-T cells.
Journal Article
Commercial Small-Scale Horizontal and Vertical Wind Turbines: A Comprehensive Review of Geometry, Materials, Costs and Performance
The effective exploitation of renewable energy sources is one of the most effective solutions to counter the energy, environmental and economic problems associated with the use of fossil fuels. Small-scale wind turbines (converting wind energy into electric energy with a power output lower than 50 kW) have received tremendous attention over the past few decades thanks to their reduced environmental impact, high efficiency, low maintenance cost, high reliability, wide wind operation range, self-starting capability at low wind speed, limited installation space, reduced dependence on grid-connected power and long transmission lines, low capital costs, as well as the possibility to be installed in some urban settings. However, there are significant challenges and drawbacks associated with this technology from many different perspectives, including the significant discrepancy between theoretical performance data provided by the manufacturers and real field operation, that need to be investigated in greater depth in order to enable a more widespread deployment of small-scale wind turbines. In this review, a complete and updated list of more than 200 commercially available small-scale horizontal and vertical wind turbine models is provided and analysed, detailing the corresponding characteristics in terms of the number and material of blades, start-up wind speed, cut-in wind speed, cut-out wind speed, survival wind speed, maximum power, noise level, rotor diameter, turbine length, tower height, and specific capital cost. In addition, several scientific papers focusing on the experimental assessment of field performance of commercially available small-scale horizontal and vertical wind turbines have been reviewed and the corresponding measured data have been compared with the rated performance derived from the manufacturers’ datasheets in order to underline the discrepancies. This review represents an opportunity for the scientific community to have a clear and up-to-date picture of small-scale horizontal as well as vertical wind turbines on the market today, with a precise summary of their geometric, performance, and economic characteristics, which can enable a more accurate and informed choice of the wind turbine to be used depending on the application. It also describes the differences between theoretical and in-situ performance, emphasizing the need for further experimental research and highlighting the direction in which future studies should be directed for more efficient design and use of building-integrated small-scale wind turbines.
Journal Article
The Relationship between Environmental Dioxygen and Iron-Sulfur Proteins Explored at the Genome Level
About 2 billion years ago, the atmosphere of the Earth experienced a great change due to the buildup of dioxygen produced by photosynthetic organisms. This transition caused a reduction of iron bioavailability and at the same time exposed living organisms to the threat of oxidative stress. Iron-sulfur (Fe-S) clusters require iron ions for their biosynthesis and are labile if exposed to reactive oxygen species. To assess how the above transition influenced the usage of Fe-S clusters by organisms, we compared the distribution of the Fe-S proteins encoded by the genomes of more than 400 prokaryotic organisms as a function of their dioxygen requirements. Aerobic organisms use less Fe-S proteins than the majority of anaerobic organisms with a similar genome size. Furthermore, aerobes have evolved specific Fe-S proteins that bind the less iron-demanding and more chemically stable Fe2S2 clusters while reducing the number of Fe4S4-binding proteins in their genomes. However, there is a shared core of Fe-S protein families composed mainly by Fe4S4-binding proteins. Members of these families are present also in humans. The distribution of human Fe-S proteins within cell compartments shows that mitochondrial proteins are inherited from prokaryotic proteins of aerobes, whereas nuclear and cytoplasmic Fe-S proteins are inherited from anaerobic organisms.
Journal Article
Metabolic control of YAP and TAZ by the mevalonate pathway
The YAP and TAZ mediators of the Hippo pathway (hereafter called YAP/TAZ) promote tissue proliferation and organ growth. However, how their biological properties intersect with cellular metabolism remains unexplained. Here, we show that YAP/TAZ activity is controlled by the SREBP/mevalonate pathway. Inhibition of the rate-limiting enzyme of this pathway (HMG-CoA reductase) by statins opposes YAP/TAZ nuclear localization and transcriptional responses. Mechanistically, the geranylgeranyl pyrophosphate produced by the mevalonate cascade is required for activation of Rho GTPases that, in turn, activate YAP/TAZ by inhibiting their phosphorylation and promoting their nuclear accumulation. The mevalonate–YAP/TAZ axis is required for proliferation and self-renewal of breast cancer cells. In
Drosophila melanogaster
, inhibition of mevalonate biosynthesis and geranylgeranylation blunts the eye overgrowth induced by Yorkie, the YAP/TAZ orthologue. In tumour cells, YAP/TAZ activation is promoted by increased levels of mevalonic acid produced by SREBP transcriptional activity, which is induced by its oncogenic cofactor mutant p53. These findings reveal an additional layer of YAP/TAZ regulation by metabolic cues.
Del Sal and colleagues demonstrate that the YAP and TAZ effectors of the Hippo pathway are under the control of the mevalonate pathway. They show that mutant p53 and SREBP-dependent activation of mevalonate signalling activates YAP and TAZ and promotes tumour formation in mice, a growth phenotype also conserved in
Drosophila
.
Journal Article
Sacituzumab govitecan in triple-negative breast cancer: from bench to bedside, and back
Triple-negative breast cancer (TNBC) represents a major therapeutic challenge due to its heterogeneous and aggressive phenotype, and limited target-specific treatment options. The trophoblast cell surface antigen (Trop-2), a transmembrane glycoprotein overexpressed in various cancers, has emerged as a promising target for TNBC. Sacituzumab govitecan (SG), an antibody-drug conjugate (ADC) that targets Trop-2, has recently entered treatment algorithms for advanced and metastatic TNBC, independently from Trop-2 expression status, with manageable toxicity. Despite the impressive results, questions remain unsolved regarding its efficacy, safety profile, and Trop-2 biological role in cancer. Currently, Trop-2 cannot be designated as a predictive biomarker in SG treatment, albeit its expression correlates with disease outcome, yet its levels are not uniform across all TNBCs. Additionally, data regarding Trop-2 expression variations in primary and metastatic sites, and its interplay with other biomarkers are still ambiguous but mandatory in light of future applications of SG in other indications and settings. This poses the questions of a careful evaluation of the efficacy and toxicity profile of SG in such early stages of disease, and in personalized and combinatorial strategies. Research and clinical data are mandatory to address SG drawbacks and minimize its benefits, to realize its full potential as therapeutic agent in different epithelial tumors.
Journal Article
CAR-NK cell therapy: promise and challenges in solid tumors
Over the past few years, cellular immunotherapy has emerged as a promising treatment for certain hematologic cancers, with various CAR-T therapies now widely used in clinical settings. However, challenges related to the production of autologous cell products and the management of CAR-T cell toxicity highlight the need for new cell therapy options that are universal, safe, and effective. Natural killer (NK) cells, which are part of the innate immune system, offer unique advantages, including the potential for off-the-shelf therapy. A recent first-in-human trial of CD19-CAR-NK infusion in patients with relapsed/refractory lymphoid malignancies demonstrated safety and promising clinical activity. Building on these positive clinical outcomes, current research focuses on enhancing CAR-NK cell potency by increasing their in vivo persistence and addressing functional exhaustion. There is also growing interest in applying the successes seen in hematologic malignancies to solid tumors. This review discusses current trends and emerging concepts in the engineering of next-generation CAR- NK therapies. It will cover the process of constructing CAR-NK cells, potential targets for their manufacturing, and their role in various solid tumors. Additionally, it will examine the mechanisms of action and the research status of CAR-NK therapies in the treatment of solid tumors, along with their advantages, limitations, and future challenges. The insights provided may guide future investigations aimed at optimizing CAR-NK therapy for a broader range of malignancies.
Journal Article
Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance
Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse.
Romani et al. report that cells on soft extracellular matrix have increased mitochondrial fission, with subsequent production of mitochondrial reactive oxygen species and NRF2, which may increase resistance to reactive oxygen species-dependent chemotherapy drugs in breast cancer cells in vitro and in mouse lungs.
Journal Article
A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment
Background
The intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response.
Methods
The composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis.
Results
In baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68–1.00) for patient response prediction.
Conclusions
The clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.
Journal Article