In order to facilitate implementation of precision medicine in clinical management of cancer, there is a need to harmonise and standardise the reporting and interpretation of clinically relevant ...genomics data.
The European Society for Medical Oncology (ESMO) Translational Research and Precision Medicine Working Group (TR and PM WG) launched a collaborative project to propose a classification system for molecular aberrations based on the evidence available supporting their value as clinical targets. A group of experts from several institutions was assembled to review available evidence, reach a consensus on grading criteria and present a classification system. This was then reviewed, amended and finally approved by the ESMO TR and PM WG and the ESMO leadership.
This first version of the ESMO Scale of Clinical Actionability for molecular Targets (ESCAT) defines six levels of clinical evidence for molecular targets according to the implications for patient management: tier I, targets ready for implementation in routine clinical decisions; tier II, investigational targets that likely define a patient population that benefits from a targeted drug but additional data are needed; tier III, clinical benefit previously demonstrated in other tumour types or for similar molecular targets; tier IV, preclinical evidence of actionability; tier V, evidence supporting co-targeting approaches; and tier X, lack of evidence for actionability.
The ESCAT defines clinical evidence-based criteria to prioritise genomic alterations as markers to select patients for targeted therapies. This classification system aims to offer a common language for all the relevant stakeholders in cancer medicine and drug development.
The spatial organization of chromatin is pivotal for regulating genome functions. We report an imaging method for tracing chromatin organization with kilobase- and nanometer-scale resolution, ...unveiling chromatin conformation across topologically associating domains (TADs) in thousands of individual cells. Our imaging data revealed TAD-like structures with globular conformation and sharp domain boundaries in single cells. The boundaries varied from cell to cell, occurring with nonzero probabilities at all genomic positions but preferentially at CCCTC-binding factor (CTCF)- and cohesin-binding sites. Notably, cohesin depletion, which abolished TADs at the population-average level, did not diminish TAD-like structures in single cells but eliminated preferential domain boundary positions. Moreover, we observed widespread, cooperative, multiway chromatin interactions, which remained after cohesin depletion. These results provide critical insight into the mechanisms underlying chromatin domain and hub formation.
The establishment of cell types during development requires precise interactions between genes and distal regulatory sequences. We have a limited understanding of how these interactions look in three ...dimensions, vary across cell types in complex tissue, and relate to transcription. Here we describe optical reconstruction of chromatin architecture (ORCA), a method that can trace the DNA path in single cells with nanoscale accuracy and genomic resolution reaching two kilobases. We used ORCA to study a Hox gene cluster in cryosectioned Drosophila embryos and labelled around 30 RNA species in parallel. We identified cell-type-specific physical borders between active and Polycomb-repressed DNA, and unexpected Polycomb-independent borders. Deletion of Polycomb-independent borders led to ectopic enhancer-promoter contacts, aberrant gene expression, and developmental defects. Together, these results illustrate an approach for high-resolution, single-cell DNA domain analysis in vivo, identify domain structures that change with cell identity, and show that border elements contribute to the formation of physical domains in Drosophila.
Genomic instability is a hallmark of cancer, and often is the result of altered DNA repair capacities in tumour cells. DNA damage repair defects are common in different cancer types; these ...alterations can also induce tumour-specific vulnerabilities that can be exploited therapeutically. In 2009, a first-in-man clinical trial of the poly(ADP-ribose) polymerase (PARP) inhibitor olaparib clinically validated the synthetic lethal interaction between inhibition of PARP1, a key sensor of DNA damage, and BRCA1/BRCA2 deficiency. In this review, we summarize a decade of PARP inhibitor clinical development, a work that has resulted in the registration of several PARP inhibitors in breast (olaparib and talazoparib) and ovarian cancer (olaparib, niraparib and rucaparib, either alone or following platinum chemotherapy as maintenance therapy). Over the past 10 years, our knowledge on the mechanism of action of PARP inhibitor as well as how tumours become resistant has been extended, and we summarise this work here. We also discuss opportunities for expanding the precision medicine approach with PARP inhibitors, identifying a wider population who could benefit from this drug class. This includes developing and validating better predictive biomarkers for patient stratification, mainly based on homologous recombination defects beyond BRCA1/BRCA2 mutations, identifying DNA repair deficient tumours in other cancer types such as prostate or pancreatic cancer, or by designing combination therapies with PARP inhibitors.
Next-generation sequencing (NGS) allows sequencing of a high number of nucleotides in a short time frame at an affordable cost. While this technology has been widely implemented, there are no ...recommendations from scientific societies about its use in oncology practice. The European Society for Medical Oncology (ESMO) is proposing three levels of recommendations for the use of NGS. Based on the current evidence, ESMO recommends routine use of NGS on tumour samples in advanced non-squamous non-small-cell lung cancer (NSCLC), prostate cancers, ovarian cancers and cholangiocarcinoma. In these tumours, large multigene panels could be used if they add acceptable extra cost compared with small panels. In colon cancers, NGS could be an alternative to PCR. In addition, based on the KN158 trial and considering that patients with endometrial and small-cell lung cancers should have broad access to anti-programmed cell death 1 (anti-PD1) antibodies, it is recommended to test tumour mutational burden (TMB) in cervical cancers, well- and moderately-differentiated neuroendocrine tumours, salivary cancers, thyroid cancers and vulvar cancers, as TMB-high predicted response to pembrolizumab in these cancers.
Outside the indications of multigene panels, and considering that the use of large panels of genes could lead to few clinically meaningful responders, ESMO acknowledges that a patient and a doctor could decide together to order a large panel of genes, pending no extra cost for the public health care system and if the patient is informed about the low likelihood of benefit. ESMO recommends that the use of off-label drugs matched to genomics is done only if an access programme and a procedure of decision has been developed at the national or regional level. Finally, ESMO recommends that clinical research centres develop multigene sequencing as a tool to screen patients eligible for clinical trials and to accelerate drug development, and prospectively capture the data that could further inform how to optimise the use of this technology.
•ESMO recommends the use of tumour multigene NGS in NSCLC, cholangiocarcinoma, prostate and ovarian cancers.•It is recommended to test TMB in well- and moderately-differentiated neuroendocrine tumours (NETs), cervical, salivary, thyroid and vulvar cancers.•Academic research centres should perform multigene NGS as part of their missions to enable access to innovative treatments.•A large panel of genes could be ordered, considering the benefit for the patient and the cost for the public health care system.
Voluntary corporate environmental disclosure has increased significantly in the last decade. However, the increase in environmental disclosure has also been accompanied by the social questioning of ...its veracity. Previous studies have mainly focused on the determinant factors behind corporate decisions to disclose environmental data, with only limited consideration of both carbon performance and the veracity of the information disclosed. Based on an international sample of firms from 12 countries, this paper analyzes the impact of regulative pressures related to climate change on the likelihood of companies engaging in greenwashing. The results show that the number of regulations related to climate change negatively influences the propensity of firms to engage in greenwashing. Furthermore, firms in countries with stringent climate-related regulations are less likely to participate in greenwashing practices. This paper adds to the existing literature concerning greenwashing by demonstrating that institutional theory can deliver further insights into the explanation of corporate greenwashing behavior. This is the first study to incorporate international climate-related regulations into the analysis of corporate greenwashing. It also provides a new method for identifying greenwashing firms, based on their carbon performance and disclosure.
•Countries' climate-related laws negatively influence corporate greenwashing.•Stricter climate-related regulations reduce greenwashing practices of firms.•The study provides a new method for the identification of greenwashing firms.
In recent years, there has been a remarkable development in the technology and legislation related to electric and autonomous vehicles (i.e., EVs/AVs). This technological advancement requires the ...deployment of the most up-to-date supporting infrastructure to achieve safe operation. Further infrastructure is needed for Level 5 vehicles, namely the introduction of super-fast wireless 5G technology. To achieve harmony between the rapid technological advancement of EVs/AVs and environmental preservation, enacting legislation related to their sustainable use is vital. Thus, this manuscript provides a review of the technological development of EVs/AVs, with a special focus on carbon footprints and the implementation of additive manufacturing using recycled materials. While EVs have a 12.13% increased carbon footprint compared to conventional vehicles, AVs with basic and advanced intelligence features have an increased carbon footprint of 41.43% and 99.65%, respectively. This article emphasizes that the integration of 3D-printed components has the potential to offset this impact with a substantial 60% reduction. As a result, custom-made solutions involving 3D printing are explored, leading to greater speed, customization, and cost-effectiveness for EVs/AVs. This article also lists the advantages and disadvantages of the existing legislation in Spain, the United Kingdom, and the western Balkans, demonstrating various approaches to promoting electric mobility and the development of autonomous vehicles. In Spain, initiatives like the MOVES program incentivize EV adoption, while the UK focuses on expanding the EV market and addressing concerns about EVs’ quiet operation. In the western Balkans, the adoption of legislation lags behind, with limited incentives and infrastructure for EVs. To boost sales, legal mechanisms are necessary to reduce costs and improve accessibility, in addition to offering subsidies for the purchase of EVs. To this end, an analysis of the incentive measures proposed for the development and use of renewable power sources for the supply of energy for EVs/AVs is presented.
Quantum Key Distribution (QKD) is maturing quickly. However, the current approaches to its application in optical networks make it an expensive technology. QKD networks deployed to date are designed ...as a collection of point-to-point, dedicated QKD links where non-neighboring nodes communicate using the trusted repeater paradigm. We propose a novel optical network model in which QKD systems share the communication infrastructure by wavelength multiplexing their quantum and classical signals. The routing is done using optical components within a metropolitan area which allows for a dynamically any-to-any communication scheme. Moreover, it resembles a commercial telecom network, takes advantage of existing infrastructure and utilizes commercial components, allowing for an easy, cost-effective and reliable deployment.
Abstract
New SARS-CoV-2 may pose problems in controlling the COVID-19 pandemic for public health. We aimed to assess and compare the symptoms and severity of cases due to the Alpha and Delta variant ...dominance periods, taking into account the effect of COVID-19 vaccination. A prospective epidemiological study of SARS-CoV-2 in Lleida was made to determine differences between Alpha and Delta variants periods. We assessed symptoms, specific comorbidities, sociodemographic information and vaccination status. Bivariate and logistic regression analyses were used to estimate the adjusted odds ratio (aOR) and 95% confidence intervals (CI) to investigate the relationship between symptoms and severity and the variants. Alpha variant period compared to the Delta showed an increased risk of ICU admission (aOR 2.0; 95% CI 1.2–2.3) and death (aOR 2.6; 95% CI 1.8–3.9) and cases were associated with people aged > 85 years (aOR 2.1; 95% CI 1.7–2.6) and partially vaccinated (aOR 5.6; 95% CI 3.2–9.9) and unvaccinated people (aOR 27.8; 95% CI 19.7–40.5). Fever, cough and vomiting were significantly associated with the Alpha variant compared to the Delta (aOR 1.6 (95% CI 1.5–1.7), 2.0 (95% CI 1.9–2.2) and 2.5 (95% CI 2.2–2.9, respectively). Our results show that the severity and profile of clinical symptoms varied according to the variant. The risk of ICU admission and death was higher in the Alpha period compared to the Delta as it affected the elderly and cases were less vaccinated.
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