nactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability and cancer. Importantly, BRCA1/2... Show morenactivating mutations in the BRCA1 and BRCA2 genes impair DNA double-strand break (DSB) repair by homologous recombination (HR), leading to chromosomal instability and cancer. Importantly, BRCA1/2 deficiency also causes therapeutically targetable vulnerabilities. Here, we identify the dependency on the end resection factor EXO1 as a key vulnerability of BRCA1-deficient cells. EXO1 deficiency generates poly(ADP-ribose)-decorated DNA lesions during S phase that associate with unresolved DSBs and genomic instability in BRCA1-deficient but not in wild-type or BRCA2-deficient cells. Our data indicate that BRCA1/ EXO1 double-deficient cells accumulate DSBs due to impaired repair by single-strand annealing (SSA) on top of their HR defect. In contrast, BRCA2-deficient cells retain SSA activity in the absence of EXO1 and hence tolerate EXO1 loss. Consistent with a dependency on EXO1-mediated SSA, we find that BRCA1- mutated tumors show elevated EXO1 expression and increased SSA-associated genomic scars compared with BRCA1-proficient tumors. Overall, our findings uncover EXO1 as a promising therapeutic target for BRCA1-deficient tumors. Show less
Hoes, L.R.; Henegouwen, J.M.V.; Wijngaart, H. van der; Zeverijn, L.J.; Velden, D.L. van der; Haar, J. van de; ... ; Voest, E.E. 2023
Background Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The... Show moreBackground Glioblastoma (GBM), the most common glial primary brain tumour, is without exception lethal. Every year approximately 600 patients are diagnosed with this heterogeneous disease in The Netherlands. Despite neurosurgery, chemo -and radiation therapy, these tumours inevitably recur. Currently, there is no gold standard at time of recurrence and treatment options are limited. Unfortunately, the results of dedicated trials with new drugs have been very disappointing. The goal of the project is to obtain the evidence for changing standard of care (SOC) procedures to include whole genome sequencing (WGS) and consequently adapt care guidelines for this specific patient group with very poor prognosis by offering optimal and timely benefit from novel therapies, even in the absence of traditional registration trials for this small volume cancer indication. Methods The GLOW study is a prospective diagnostic cohort study executed through collaboration of the Hartwig Medical Foundation (Hartwig, a non-profit organisation) and twelve Dutch centers that perform neurosurgery and/or treat GBM patients. A total of 200 patients with a first recurrence of a glioblastoma will be included. Dual primary endpoint is the percentage of patients who receive targeted therapy based on the WGS report and overall survival. Secondary endpoints include WGS report success rate and number of targeted treatments available based on WGS reports and number of patients starting a treatment in presence of an actionable variant. At recurrence, study participants will undergo SOC neurosurgical resection. Tumour material will then, together with a blood sample, be sent to Hartwig where it will be analysed by WGS. A diagnostic report with therapy guidance, including potential matching off-label drugs and available clinical trials will then be sent back to the treating physician for discussing of the results in molecular tumour boards and targeted treatment decision making. Discussion The GLOW study aims to provide the scientific evidence for changing the SOC diagnostics for patients with a recurrent glioblastoma by investigating complete genome diagnostics to maximize treatment options for this patient group. Trial registration: ClinicalTrials.gov Identifier: NCT05186064. Show less
Hoes, L.R.; Henegouwen, J.M.V.; Wijngaart, H. van der; Zeverijn, L.J.; Velden, D.L. van der; Haar, J. van de; ... ; Voest, E.E. 2022
Purpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We... Show morePurpose: Patients with rare cancers (incidence less than 6 cases per 100,000 persons per year) commonly have less treatment opportunities and are understudied at the level of genomic targets. We hypothesized that patients with rare cancer benefit from approved anticancer drugs outside their label similar to common cancers. Experimental Design: In the Drug Rediscovery Protocol (DRUP), patients with therapy-refractory metastatic cancers harboring an actionable molecular profile are matched to FDA/European Medicines Agency-approved targeted therapy or immunotherapy. Patients are enrolled in parallel cohorts based on the histologic tumor type, molecular profile and study drug. Primary endpoint is clinical benefit (complete response, partial response, stable disease >= 16 weeks). Results: Of 1,145 submitted cases, 500 patients, including 164 patients with rare cancers, started one of the 25 available drugs and were evaluable for treatment outcome. The overall clinical benefit rate was 33% in both the rare cancer and nonrare cancer subgroup. Inactivating alterations of CDKN2A and activating BRAF aberrations were overrepresented in patients with rare cancer compared with nonrare cancers, resulting in more matches to CDK4/6 inhibitors (14% vs. 4%; P <= 0.001) or BRAF inhibitors (9% vs. 1%; P <= 0.001). Patients with rare cancer treated with small-molecule inhibitors targeting BRAF experienced higher rates of clinical benefit (75%) than the nonrare cancer subgroup. Conclusions: Comprehensive molecular testing in patients with rare cancers may identify treatment opportunities and clinical benefit similar to patients with common cancers. Our findings highlight the importance of access to broad molecular diagnostics to ensure equal treatment opportunities for all patients with cancer. Show less
Genomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the... Show moreGenomic profiling is critical for the identification of treatment options for patients with metastatic cancer, but it remains unclear how frequently this procedure should be repeated during the course of the disease. To address this, we analyzed whole-genome sequencing (WGS) data of 250 biopsy pairs, longitudinally collected over the treatment course of 231 adult patients with a representative variety of metastatic solid malignancies. Within the biopsy interval (median, 6.4 months), patients received one or multiple lines of (mostly) standard-of-care (SOC) treatments, with all major treatment modalities being broadly represented. SOC biomarkers and biomarkers for clinical trial enrollment could be identified in 23% and 72% of biopsies, respectively. For SOC genomic biomarkers, we observed full concordance between the first and the second biopsy in 99% of pairs. Of the 219 biomarkers for clinical trial enrollment that were identified in the first biopsies, we recovered 94% in the follow-up biopsies. Furthermore, a second WGS analysis did not identify additional biomarkers for clinical trial enrollment in 91% of patients. More-frequent genomic evolution was observed when considering specific genes targeted by small-molecule inhibitors or hormonal therapies (21% and 22% of cases, respectively). Together, our data demonstrate that there is limited evolution of the actionable genome of treated metastases. A single WGS analysis of a metastatic biopsy is generally sufficient to identify SOC genomic biomarkers and to identify investigational treatment opportunities.Whole-genome sequencing of metastatic biopsies longitudinally sampled during the course of anticancer treatment reveals that the actionable metastatic cancer genome remains relatively stable over time. Show less
Nieuwenhuis, E.; Cuppen, E.; Langeveld, J.; Bruijn, H. de 2020
Climate change and urbanization, as well as growing environmental and economic concerns, highlight the limitations of traditional wastewater practices and thereby challenge the management of urban... Show moreClimate change and urbanization, as well as growing environmental and economic concerns, highlight the limitations of traditional wastewater practices and thereby challenge the management of urban water systems. Both in theory and in practice, it has been widely acknowledged that the challenges of the twenty-first century require solutions that address problems in a more integrated way. Although the demand for integration is obvious, implementation has proved challenging because of the complexity and uncertainty involved. In addition, the urban water literature contains a wide diversity of approaches to integration, each contribution having its own understanding of the term, as well as how to deal with the complexity that comes with it. In this article, we take a first step in supporting both decision-making and decision-makers in urban water systems integration. First, we work towards a more comprehensive perspective on integration in urban water management; one that uses and structures the variety of existing approaches. In so doing, we introduce a typology of urban water systems integration that distinguishes between geographical, physical, informational, and project-based forms. Second, we explore the implications that such integrated solutions bring for decision-makers. They will be faced with additional uncertainty arising (1) at the interfaces of previously unconnected systems and (2) from the social and institutional changes that systems integration requires. Finally, we draft three decision-making challenges that come with integration and provide some possibilities for dealing with them. Show less
Cuppen, E.; Nikolic, I.; Kwakkel, J.; Quist, J. 2020
Finding leverage points for sustainability transformation of industrial and infrastructure systems is challenging, given that transformation is emergent from the complex interactions among socio... Show moreFinding leverage points for sustainability transformation of industrial and infrastructure systems is challenging, given that transformation is emergent from the complex interactions among socio-technical system elements over time within a specific social, technical and geographical context. Participatory multi-modelling, in which modellers and stakeholders collaborate to develop multiple interacting models to support a shared understanding of systems, is a promising approach to support sustainability transformations. The participatory process of modeling can serve as a leverage point by facilitating social learning amongst stakeholders, in which models can function as boundary objects that facilitate dialogue between stakeholders from different social worlds. We propose that participatory multi-modeling allows for the creation of a boundary object ecology, which involves a set of interacting and co-evolving boundary objects emerging throughout the modeling process. To explore this, we analyse the participatory multi-modelling process in the Windmaster project in the Rotterdam Port industrial cluster to understand which design choices were key to the creation of boundary objects. Our analysis shows that two types of design choices were key: design choices that enabled translations between participants, and those between participants and their organisation. We conclude that conceptualising participatory multi-modelling as a process of an evolving boundary object ecology, creating and adapting multiple interacting boundary objects provides a novel perspective that is useful for analysis and design of future participatory multi-modeling processes. Show less
Cuppen, E.; Ejderyan , O.; Pesch, U.; Spruit, S,.; van de Grift, E.; Correlje, A.; Taebi, B 2020
Energy controversies have been widely studied. Such studies are, however, generally based on either single case studies, providing rich and in-depth understanding of (local) dynamics of planning... Show moreEnergy controversies have been widely studied. Such studies are, however, generally based on either single case studies, providing rich and in-depth understanding of (local) dynamics of planning and implementation processes, or they focus on understanding responses to a specific technology (not bound to a location). Therefore these studies tend to overlook a key dynamic in controversy, namely that publics respond to projects by drawing on earlier experiences with a similar technology elsewhere, or with earlier experiences with other technologies in their vicinity. We refer to this dynamic as controversy spillover. The notion of controversy spillover helps to understand how the discursive space of controversy changes over time. In case studies, other controversies are usually considered as context, i.e. as an external condition. However, in order to understand the temporal dynamics of public engagement with energy projects, spillover from other controversies deserves to be investigated more as an object of interest, rather than as an external condition. The aim of this paper is to conceptualize controversy spillover as an important dynamic in controversies and to develop a research agenda. We identify three different types of spillover: 1) geographical (i.e. between the same energy technology in different locations), 2) historical (i.e. with respect to earlier experiences at the same location), 3) technology (i.e. between different technologies). Three empirical examples serve to illustrate the three types of spillover. We finalize the paper with a research agenda for further conceptualization and empirical analysis of the notion of controversy spillover. Show less
Clinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >... Show moreClinical implementation of tumor organoids for personalized medicine requires that pure tumor organoids can be reliably established. Here, we present our experience with organoid cultures from >70 non-small cell lung cancer (NSCLC) samples. We systematically evaluate several methods to identify tumor purity of organoids established from intrapulmonary tumors. Eighty percent of organoids from intrapulmonary lesions have a normal copy number profile, suggesting overgrowth by normal airway organoids (AOs). This is further supported by the failure to detect mutations found in the original tumor in organoids. Histomorphology alone is insufficient to determine tumor purity, but when combined with p63 immunostaining, tumor and normal AOs can be distinguished. Taking into account overgrowth by normal AOs, the establishment rate of pure NSCLC organoids is 17%. Therefore, current methods are insufficient to establish pure NSCLC organoids from intrapulmonary lesions. We discourage their use unless steps are taken to prevent overgrowth by normal AOs. Show less
The agency of incumbents has gained increasing attention in the study of transitions. Recent studies show that besides being inert and resistant to change, incumbents can also support transitions.... Show moreThe agency of incumbents has gained increasing attention in the study of transitions. Recent studies show that besides being inert and resistant to change, incumbents can also support transitions. We focus on the agency of a particular type of incumbent, grid operators. In several countries, these actors play an active role in institutional change in the energy domain. At the same time, they are engaging in activities to maintain the regime. This paper examines the actions of grid operators when performing institutional work, i.e. when creating, maintaining and disrupting institutions. We conducted a qualitative content analysis of Dutch media to analyze the actions of grid operators while engaging with decentralized energy innovations. We conclude that grid operators are both subject and object of institutional work as part of a distributed, collective process of institutional change. Furthermore, our analysis reflects on their paradoxical position as embedded actors engaging in institutional change. Show less
Velden, D.L. van der; Hoes, L.R.; Wijngaart, H. van der; Henegouwen, J.M.V.; Werkhoven, E. van; Roepman, P.; ... ; Voest, E.E. 2019
The crowd increasingly plays a key role in facilitating innovations in a variety of sectors, spurred on by IT-developments and the concomitant increase in connectivity. Initiatives in this... Show moreThe crowd increasingly plays a key role in facilitating innovations in a variety of sectors, spurred on by IT-developments and the concomitant increase in connectivity. Initiatives in this direction, captured under the umbrella-term ‘crowd-based innovations’ (CBI), offer novel opportunities in all domains of society by increasing the access, reach and speed of services and goods. At the same time, they signify important challenges because these innovations occur in a context of traditional, well-established institutionalarrangements. CBI create an ‘institutional void’: existing rules, standards and practices are challenged and renegotiated. This raises questions about the safeguarding of public values such as quality, legitimacy, efficiency and governance of crowd-based innovations. The objective of this perspective piece is to presentan interdisciplinary research agenda to address normative challenges for governing CBI. We will argue that such an agenda needs an integrated empirical-normative approach. We will detail three lines of empirical-normative research that together build up towards an interdisciplinary agenda. Show less
Baldassarre, B.; Schepers, M.; Bocken, N.; Cuppen, E.; Korevaar, G.; Calabretta, G. 2019
Industrial Symbiosis (IS) is a collective approach to competitive advantage in which separate industries create a cooperative network to exchange materials, energy, water and/or by-products. By... Show moreIndustrial Symbiosis (IS) is a collective approach to competitive advantage in which separate industries create a cooperative network to exchange materials, energy, water and/or by-products. By addressing issues related to resource depletion, waste management and pollution, IS plays an important role in the transition towards sustainable development. In the literature, two conceptual perspectives on IS can be identified: the Industrial Ecology (IE) and the Circular Economy (CE) perspective. Despite the recognition of these two perspectives, their relationship remains unclear and explicit attempts to develop an integrated perspective have not been made yet. Consequently, the goal of this research is to highlight and start addressing this critical gap of knowledge in order to support future research and practice geared towards the design of new IS clusters. We pose the following research question: How can the IE and CE perspectives on IS be combined in order to support the design of IS clusters? To this end, we first investigate the two perspectives more in depth and compare them in terms of nature, features and relevance for the study of IS. This is done by applying them as conceptual lenses for the analysis of the same case study, an existing IS cluster. The comparative analysis provides insights into how the two perspectives differ, ultimately demonstrating that they are complimentary and both necessary to fully describe an IS cluster. While the CE perspective is more suitable to explain how a cluster functions from a business standpoint in the operating phase, the IE perspective is more suitable to explain its development over time and its impacts on the environment, the economy and society. Building upon the outcomes of the comparative analysis, we leverage on the discipline of Strategic Design and integrate the two perspectives into a process for designing new IS clusters. We suggest two directions for future research. First, improving our comparative analysis of the two perspectives by looking at a wider sample of IS clusters of different sizes and in different contexts. Second, focusing with more specificity on the issue of how IS clusters can be designed, potentially by trying to apply the process we propose on a real case aimed at designing a new IS cluster. Show less
Drost, J.; Boxtel, R. van; Blokzijl, F.; Mizutani, T.; Sasaki, N.; Sasselli, V.; ... ; Clevers, H. 2017
This paper aims to contribute to understanding the dynamics of industrial symbiosis. More specifically, we focus on the dynamics of anchoring as they can be observed in the Chinese context of eco... Show moreThis paper aims to contribute to understanding the dynamics of industrial symbiosis. More specifically, we focus on the dynamics of anchoring as they can be observed in the Chinese context of eco-industrial development. We define anchoring as those activities that (typically local) actors perform to create local physical and institutional conditions conducive to the emergence and further development of industrial symbiosis in a specific regional industrial system. We argue that, in the study of industrial symbiosis dynamics, it is conceptually more useful to focus on anchoring as an activity, rather than anchor tenants as actors. Based on a systematic literature review, we distinguish two types of anchoring activities: institutional and physical. We analyze anchoring dynamics in the case of Qijiang Industrial Symbiosis (Chongqing Municipality) in China. We have identified the physical and institutional anchoring activities, the actors responsible for these activities, and how different anchoring activities build on each other over time. Our case study shows that the attempt to bring about industrial symbiosis in the Qijiang industrial park can be described in a richer way than just 'governmental planning'. Show less
Middelkamp, S.; Heesch, S. van; Braat, A.K.; Ligt, J. de; Iterson, M. van; Simonis, M.; ... ; Cuppen, E. 2017
The crowd increasingly plays a key role in facilitating innovations in a variety of sectors, spurred on by IT developments and the concomitant increase in connectivity. Initiatives in this... Show moreThe crowd increasingly plays a key role in facilitating innovations in a variety of sectors, spurred on by IT developments and the concomitant increase in connectivity. Initiatives in this direction, captured under the umbrella term ‘crowd-based innovations’, offer novel opportunities in socio-technical systems by increasing the access, reach and speed of services. At the same time, they signify important challenges because these innovations occur in a context of traditional, well-established institutional and governance structures and practices. This dynamic is captured in the idea of the ‘institutional void’: the tension between traditional structures and (radically) new initiatives. Existing rules, standards and practices are challenged, which raises questions about the safeguarding of public values such as quality, legitimacy, efficiency and governance of crowd-based innovations. This article argues that understanding these tensions requires supplementing empirical research with an explicitly normative dimension to reach thorough and balanced conclusions to facilitate innovation while protecting the valuable elements in existing rules and regulations. Illustrated by a number of short examples, we propose a multidisciplinary research agenda towards formulating appropriate governance structures. Show less
