Breast cancer (BC) is the most common cancer in women and, despite the undeniable improvements in the outcome of these patients obtained in the last decade, the discovery and the validation of new ...actionable molecular targets represent a priority. ESCAT permits to rank molecular alterations in different classes according to their evidence of actionability in a specific cancer type, assisting clinicians in their therapeutical decisions.
ERBB2, PIK3CA and germline BRCA1/2 alterations are biomarkers prospectively validated in BC, driving the selection of targeted therapies, and are therefore classified in the highest level of evidence (Ia). Agnostic biomarkers, namely microsatellite instability, NTRK fusions and high tumor mutational burden, demonstrated similar activity across different tumor types and are consequently ranked in tier Ic. In tier II are classified alterations that still need confirmatory prospective studies but for which evidence of efficacy is available. Somatic BRCA1/2 mutations, germline PALB2 mutations, HER2-low expression, ERBB2 mutations, PTEN deletions, AKT1 mutations, ESR1 resistance mutations satisfy the requirements to be classified in this tier. In tier III are ranked various molecular alterations for which there is evidence of actionability in other tumors (IIIa) or that have similar functional impact in the same gene or pathway of a tier I alteration, without clinical data (IIIb). In tier IV are listed the molecular alterations for which only preclinical studies are available.
In this review we report the most relevant molecular targets in BC, ordered pursuant to their pathway and classified in concordance with ESCAT.
Solid tumors adopt multiple mechanisms to grow, evade immune responses, and to withstand therapeutic approaches. A major breakthrough in the armamentarium of anti-cancer agents has been the ...introduction of monoclonal antibodies (mAbs), able to inhibit aberrantly activated pathways and/or to unleash antigen (Ag)-specific immune responses. Nonetheless, mAb-mediated targeted pressure often fails due to escape mechanisms, mainly Ag loss/downregulation, ultimately providing therapy resistance. Hence, in order to target multiple Ag at the same time, and to facilitate cancer-immune cells interactions, bispecific antibodies (bsAbs) have been developed and are being tested in clinical trials, yielding variable safety/efficacy results based on target selection and their structure. While in hematologic cancers the bsAb blinatumomab recently reached the Food and Drug Administration (FDA)-approval for B Cell Acute Lymphoblastic Leukemia, bsAbs use in solid tumors faces considerable challenges, such as target Ag selection, biodistribution, and the presence of an immune-suppressive tumor microenvironment (TME). This review will focus on the state-of-the art, the design, and the exploitation of bsAbs against solid malignancies, delineating their mechanisms of action, major pitfalls, and future directions.
Modern business is increasingly adopting fully-digital workflows composed of complementary services (in terms of infrastructures, software, networks, data and devices) from different domains, hence ...giving rise to complex and heterogeneous digital chains. The substantial fragmentation in service operation and ownership between these domains impacts cybersecurity operations, by hindering a coherent and cooperative defense strategy for the entire chain. As a result, this situation gives attackers more opportunity to move laterally within the chain once they have found and compromised the weakest link.
A ground-breaking evolution of legacy cybersecurity processes is necessary towards collaborative and adaptive models that fit the dynamic, agile, and heterogeneous nature of federated environments. In this paper, we elaborate on the necessary convergence between complementary workflows for response, analysis, and intelligence, by considering the peculiarity of these operations and the relevant threat scenario. Our analysis points out the main research challenges to fill the existing gap between management and protection practice for digital service chains. Moreover, we outline a reference architecture that combines such workflows. The objective is to foster researchers to broaden the scope of their work, in order to address open security issues for modern business and computing paradigms.
alterations, such as fusions or mutations, drive the growth of multiple tumor types. These alterations are found in canonical (lung and thyroid) and non-canonical (e.g., gastrointestinal, breast, ...gynecological, genitourinary, histiocytic) cancers.
alterations are best identified via comprehensive next-generation sequencing, preferably with DNA and RNA interrogation for fusions. Targeted therapies for
-dependent cancers have evolved from older multikinase inhibitors to selective inhibitors of RET such as selpercatinib and pralsetinib. Prospective basket trials and retrospective reports have demonstrated the activity of these drugs in a wide variety of
-altered cancers, notably those with
fusions. This paved the way for the first tumor-agnostic selective RET inhibitor US FDA approval in 2022. Acquired resistance to RET kinase inhibitors can take the form of acquired resistance mutations (e.g., RET G810X) or bypass alterations.
Cancers are composed of transformed cells, characterized by aberrant growth and invasiveness, in close relationship with non-transformed healthy cells and stromal tissue. The latter two comprise the ...so-called tumor microenvironment (TME), which plays a key role in tumorigenesis, cancer progression, metastatic seeding, and therapy resistance. In these regards, cancer-TME interactions are complex and dynamic, with malignant cells actively imposing an immune-suppressive and tumor-promoting state on surrounding, non-transformed, cells. Immune cells (both lymphoid and myeloid) can be recruited from the circulation and/or bone marrow by means of chemotactic signals, and their functionality is hijacked upon arrival at tumor sites. Molecular characterization of tumor-TME interactions led to the introduction of novel anti-cancer therapies targeting specific components of the TME, such as immune checkpoint blockers (ICB) (i.e., anti-programmed death 1, anti-PD1; anti-Cytotoxic T-Lymphocyte Antigen 4, anti-CTLA4). However, ICB resistance often develops and, despite the introduction of newer technologies able to study the TME at the single-cell level, a detailed understanding of all tumor-TME connections is still largely lacking. In this work, we highlight the main cellular and extracellular components of the TME, discuss their dynamics and functionality, and provide an outlook on the most relevant clinical data obtained with novel TME-targeting agents, with a focus on T lymphocytes, macrophages, and cancer-associated fibroblasts.
Considering the rapid improvement of cancer drugs’ efficacy and the discovery of new molecular targets, the formulation of therapeutical indications based on the multidisciplinary approach of MTB is ...becoming increasingly important for attributing the correct salience to the targets identified in a single patient. Nevertheless, one of the biggest stumbling blocks faced by MTBs is not the bare indication, but its implementation in the clinical practice. Indeed, administering the drug suggested by MTB deals with some relevant difficulties: the economical affordability and geographical accessibility represent some of the major limits in the patient’s view, while bureaucracy and regulatory procedures are often a disincentive for the physicians. In this review, we explore the current literature reporting MTB experiences and precision medicine clinical trials, focusing on the challenges that authors face in applying their therapeutical indications. Furthermore, we analyze and discuss some of the solutions devised to overcome these difficulties to support the MTBs in finding the most suitable solution for their specific situation. In conclusion, we strongly encourage regulatory agencies and pharmaceutical companies to develop effective strategies with medical centers implementing MTBs to facilitate access to innovative drugs and thereby allow broader therapeutical opportunities to patients.
This open access book presents the main scientific results from the H2020 GUARD project. The GUARD project aims at filling the current technological gap between software management paradigms and ...cybersecurity models, the latter still lacking orchestration and agility to effectively address the dynamicity of the former. This book provides a comprehensive review of the main concepts, architectures, algorithms, and non-technical aspects developed during three years of investigation; the description of the Smart Mobility use case developed at the end of the project gives a practical example of how the GUARD platform and related technologies can be deployed in practical scenarios. We expect the book to be interesting for the broad group of researchers, engineers, and professionals daily experiencing the inadequacy of outdated cybersecurity models for modern computing environments and cyber-physical systems.
Today, the digital economy is pushing new business models, based on the creation of value chains for data processing, through the interconnection of processes, products, services, software, and ...things across different domains and organizations. Despite the growing availability of communication infrastructures, computing paradigms, and software architectures that already effectively support the implementation of distributed multi-domain value chains, a comprehensive architecture is still missing that effectively fulfills all related security issues: mutual trustworthiness of entities in partially unknown topologies, identification and mitigation of advanced multi-vector threats, identity management and access control, management and propagation of sensitive data. In order to fill this gap, this work proposes a new methodological approach to design and implement heterogeneous security services for distributed systems that combine together digital resources and components from multiple domains. The framework is designed to support both existing and new security services, and focuses on three novel aspects: (i) full automation of the processes that manage the whole system, i.e., threat detection, collection of information and reaction to attacks and system anomalies; (ii) dynamic adaptation of operations and security tasks to newest attack patterns, and (iii) real-time adjustment of the level of detail of inspection and monitoring processes. The overall architecture as well as the functions and relationships of its logical components are described in detail, presenting also a concrete use case as an example of application of the proposed framework.
In this paper, starting from the measurements available for a 2000 cm3 turbocharged diesel engine, an analytical model of the turbocharger is proposed and validated. The model is then used to ...extrapolate the efficiency of a power unit with a diesel engine combined with a turbocompound system. The obtained efficiency map is used to evaluate the fuel economy of a supercapacitor-based series hybrid vehicle equipped with the turbocompound power unit. The turbocompound model, in accordance with the studies available in the technical literature, shows that the advantages (in terms of efficiency increase) are significant at high loads. For this reason, turbocompound introduction allows a significant efficiency improvement in a series hybrid vehicle, where the engine always works at high-load. The fuel economy of the proposed vehicle is compared with other hybrid and conventional vehicle configurations.
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