ALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates.... Show moreALK-positive NSCLC patients demonstrate initial responses to ALK tyrosine kinase inhibitor (TKI) treatments, but eventually develop resistance, causing rapid tumor relapse and poor survival rates. Growing evidence suggests that the combination of drug and immune therapies greatly improves patient survival; however, due to the low immunogenicity of the tumors, ALK-positive patients do not respond to currently available immunotherapies. Tumor-associated macrophages (TAMs) play a crucial role in facilitating lung cancer growth by suppressing tumoricidal immune activation and absorbing chemotherapeutics. However, they can also be programmed toward a pro-inflammatory tumor suppressive phenotype, which represents a highly active area of therapy development. Iron loading of TAMs can achieve such reprogramming correlating with an improved prognosis in lung cancer patients. We previously showed that superparamagnetic iron oxide nanoparticles containing core-cross-linked polymer micelles (SPION-CCPMs) target macrophages and stimulate pro-inflammatory activation. Here, we show that SPION-CCPMs stimulate TAMs to secrete reactive nitrogen species and cytokines that exert tumoricidal activity. We further show that SPION-CCPMs reshape the immunosuppressive Eml4-Alk lung tumor microenvironment (TME) toward a cytotoxic profile hallmarked by the recruitment of CD8+ T cells, suggesting a multifactorial benefit of SPION-CCPM application. When intratracheally instilled into lung cancer-bearing mice, SPION-CCPMs delay tumor growth and, after first line therapy with a TKI, halt the regrowth of relapsing tumors. These findings identify SPIONs-CCPMs as an adjuvant therapy, which remodels the TME, resulting in a delay in the appearance of resistant tumors. Show less
This thesis explores ancient Egyptian descriptions of sicknesses of the inner body, the concepts used to understand them, and the trends in associated therapeutic applications for healing. It... Show moreThis thesis explores ancient Egyptian descriptions of sicknesses of the inner body, the concepts used to understand them, and the trends in associated therapeutic applications for healing. It concludes that the ancient Egyptian system of understanding recorded in writings—while somewhat obscured as the surviving texts were never intended to be descriptive of ideas—can be compared to other ways of thinking and categorising sickness experiences as found in other written cultures. Especially in terms of how such ideas are constructed and how therapies are associated with such concepts. Similarities can be observed in terms of core concepts and associated therapeutic applications recorded in cuneiform compendia of comparable age from Mesopotamia. Rather than using these observations as evidence of an influence of one culture over another, it is argued that these writings include practices and ideas which can instead be considered common to this region of the world, rather than as exclusive and invariably peculiar either the Egyptian and/or Mesopotamian cultures. Show less
Dijk, B.T. van; Boeren, A.M.P.; Khidir, S.J.H.; Hollander, N.K. den; Helm-van Mil, A.H.M. van der 2024
Objectives Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently... Show moreObjectives Rheumatoid arthritis (RA) mainly affects small joints. Despite the mechanical function of joints, the role of mechanical stress in the development of arthritis is insufficiently understood. We hypothesised that mechanical stress/physical strain is a risk factor for joint inflammation in RA. Therefore, we studied work-related physical strain in subjects with clinically suspected arthralgia (CSA) as a risk factor for the presence of imaging-detected subclinical joint inflammation and the development of clinical arthritis/RA. Methods In 501 CSA patients and 155 symptom-free persons’ occupation-related physical strain was quantified using the International Standard Classification of Occupations. Contrastenhanced hand-MRIs were made and evaluated for joint inflammation (sum of synovitis/tenosynovitis/osteitis). CSA patients were followed on RA development. Age relationship was studied using an interaction term of physical strain with age. Results The degree of physical strain in CSA is associated with the severity of joint inflammation, independent of educational-level/BMI/smoking (interaction physical strain-age p=0.007; indicating a stronger association with increasing age). Physical strain is associated with higher tenosynovitis scores, in particular. In symptom-free persons, physical strain was not associated with imaging-detected joint inflammation. Higher degrees of physical strain also associated with higher risks for RA development in an age-dependent manner (HR=1.20 (1.06–1.37)/10-year increase in age), independent of educational-level/BMI/smoking. This association was partly mediated by an effect via subclinical joint inflammation. Conclusions Work-related physical strain increases the risk of subclinical joint inflammation and of developing RA. The age relationship suggests an effect of long-term stress or that tenosynovium is more sensitive to stress at older age. Together, the data indicate that mechanical stress contributes to the development of arthritis in RA. Show less
Self-employed workers face numerous demands, including high uncertainty, workload, and personal responsibility for business success, that have the potential to jeopardize their well-being. This... Show moreSelf-employed workers face numerous demands, including high uncertainty, workload, and personal responsibility for business success, that have the potential to jeopardize their well-being. This study integrates aspects of the conservation of resources (COR) theory, the theory of planned behavior (TPB), and the literature on intention–behavior gaps to offer insights into how self-employed workers can influence their well-being. We propose that their intention to adopt self-care practices acts as a motivational element that links assumptions about the well-being-protecting and -enhancing effects of self-care practices to the enactment of such practices. Moreover, we investigate the role of entrepreneurial stressors as potential hindering factors in the translation of self-care practice intentions into actual behavior. In a sample of 290 self-employed workers and employing a two-wave study design with a one-month time lag, we found that frequently practicing self-care was positively associated with workers’ vitality, negatively associated with mental health complaints, and unrelated to somatic health complaints. Among the various types of self-care, physical exercise was most consistently associated with well-being outcomes. Self-care intentions significantly predicted the engagement in self-care practices. Entrepreneurial stressors did not act as barriers to the adoption of self-care practices. By underscoring the utility of selfcare practices for self-employed workers’ well-being and the key role of self-care practice intentions, this study responds to the call for a research focus shift towards identifying practices that protect well-being among self-employed workers. Show less
Oratie uitgesproken door Prof. mr. dr. drs. Mirjam P. Sombroek-van Doorm bij de aanvaarding van het ambt van hoogleraar Recht en Gezondheid aan de Universiteit Leiden op vrijdag 26 april 2024.
By the early eighteenth century Edo (present-day Tokyo) was one of the largest cities in the world. Sex and erotic allure could be found in many guises in this commercialized urban setting, both in... Show moreBy the early eighteenth century Edo (present-day Tokyo) was one of the largest cities in the world. Sex and erotic allure could be found in many guises in this commercialized urban setting, both in the city’s streets and in print. This chapter sets out to argue that sex assumed a multiplicity of meanings in this context that ranged from pleasure and procreation to potential pathology. To this purpose, it begins by tracing various discourses surrounding the three phenomena that have arguably received the most sustained attention in research to date, namely the sex trade, male same-sex desire, and the erotically explicit materials known as ‘spring pictures’ (Japanese shunga 春画/ shunpon 春本). The final sections aim to move beyond the standard narrative of the Edo period’s flourishing erotic culture by focusing on the female reproductive body, as well as medical and health discourses, thus aspiring to unsettle the paradigmatic character of this (male) pleasure-centred mode of sex and repudiate the monolithic view of early modern Japanese sexuality as unregulated. Show less
Triple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis... Show moreTriple-negative breast cancer (TNBC) is a subtype of breast cancer characterized by limited treatment options and unfavorable clinical outcomes. Therefore, the research described in this thesis focused on the exploration of novel targeted therapies for TNBC. Through high-throughput screening, we assessed the responsiveness of TNBC cells to kinase inhibitors, which indicated a notable sensitivity to cyclin-dependent kinase (CDK) inhibitors. Building upon these findings, this thesis systematically compares the efficacy of targeting various transcription-associated CDKs, with CDK9 and CDK12 emerging as highly potent targets for disrupting TNBC cell proliferation. Transcription-associated CDKs play multiple roles in regulating mRNA transcription. Yet, inhibitors of these CDK’s induced selective, rather than global, changes in gene expression. This provides insights into their mechanisms of action and suggesting potential opportunities for combination therapy. Furthermore, our research elucidated the mechanism underlying the synergistic effects of combining kinase inhibitors with transcriptional CDK inhibitors, by demonstrating that this is mediated through the inhibition of cellular drug efflux by ABCG2. In conclusion, this thesis highlights the potential of transcription-associated CDK inhibitors as a promising avenue for treating TNBC. The insights from this thesis will help to further steer the (pre)clinical development and strategy of using transcription-associated CDK inhibitors for the treatment of TNBC. Show less
Accurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have... Show moreAccurate prediction of the unbound drug concentration-time profile at the CNS target site is crucial for the assessment of the right drug concentration-effect relationship. PBPK models have supported the PK prediction of the CNS target sites and the translation of PK data between species and between populations, given their mechanistic, physiology-based structure. In this thesis, we have developed a CNS PBPK model which could predict adequately the brainECF, brainICF, and CSF unbound PK profiles and provide important insights into the brain unbound pharmacokinetics of patients with CNS diseases. Early prediction of the brain target site pharmacokinetics of the right patient population can prioritize drugs with the favored brain PK profiles, which might optimize and accelerate the CNS drug development process. Show less
This thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined... Show moreThis thesis aims at identifying the conducive conditions of coercive diplomacy in the context of nuclear proliferation. Drawing on the US experience with Iran, Libya, and South Africa, we examined the driving factors behind US coercive diplomacy’s divergent and paradoxical results or outcomes in these countries. We chose our case studies based on two factors: the different stages or levels of their nuclear programs when confronted by the US and the nature of the demands formulated by the coercer in relation to the bilateral relations of the parties involved. We hypothesized that two conditions could compel a target subjected to coercive diplomacy to abandon its nuclear (weapons) program: if the coercer’s strategy exploits the target’s vulnerabilities and if the coercer demonstrates the motivation to have a sustained campaign to compel its target to abandon its nuclear weapons program. The interactions between the US and each of the targets mentioned above provide insights into improving coercive diplomacy, both theoretically and practically. The interplay between domestic politics and international pressures theoretically inspires our approach. We emphasized the critical role of domestic actors in alleviating or increasing systemic pressure related to the targets’ nuclear programs. We used neoclassical realism and process tracing to describe these dynamics and unravel the causal relationships between the coercer’s demands and the targets’ responses. Using the structured-focused comparative methodology, we reinforced our findings’ relevance and triangulated our primary and secondary sources. Our findings support the hypothesis of the driving effect of domestic variables in relation to external pressures. Hence, we identified similar and diverse mechanisms in our three cases, which helped us verify the validity of our initial hypotheses and confirmed the relevance of our research strategy regarding the complexity of coercion dynamics in the non-proliferation domain. Show less
Betrokken burgers vormden de ruggengraat van de Republiek. Het dagelijks leven draaide voor een groot deel op buurtorganisaties, gilden en schutterijen – en dat waren juist de stedelijke... Show moreBetrokken burgers vormden de ruggengraat van de Republiek. Het dagelijks leven draaide voor een groot deel op buurtorganisaties, gilden en schutterijen – en dat waren juist de stedelijke instituties waar zij deel van uitmaakten. In 1796 kondigden de Bataafse revolutionairen het einde van sommige van deze instellingen af en introduceerden zij het staatsburgerschap. Maar was daarmee de rol van de stedelijke burger ook uitgespeeld?Dat komen we te weten als we luisteren naar de stadsbewoners zelf. Aan de hand van de levens van Haarlemmers en Groningers tussen 1747 en 1848 illustreert dit boek het voortbestaan van lokaal burgerschap. Zij komen aan het woord via verzoekschriften, kronieken, gelegenheidsgedichten, vergadernotulen en mondelinge klachten op de burgemeesterskamer. Hoe zag de ideale stedelijke gemeenschap er volgens hen uit? Welke rechten en plichten had een burger in hun ogen? En wat waren de dure plichten van een stadsbestuurder? Voor dit burgerschap putten stadsbewoners met souplesse uit traditionele én revolutionaire idealen en praktijken. Show less
This book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how... Show moreThis book examines the issuance of mining licenses in Indonesia from an environmental perspective. It shows how mining licensing has directly contributed to environmental degradation and how consecutive governments have failed to take effective action addressing this problem. The main cause is the low quality of the relevant laws and policies, which is mostly a result of the priority law- and policymakers accord to mining development and a lack of interest in and knowledge about solving environmental problems. This situation has been exacerbated by a lack of public participation and bureaucratic “siloism”: government agencies often develop their own policies and regulations without efforts at co-ordination with other relevant government agencies. Only in a few cases have there been better results, when government agencies developing a policy had a strong interest in its implementation, when their officials disposed of adequate expertise, and when there was a favourable national political situation. Unfortunately, these conditions have rarely been present in Indonesia. Show less
The application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in... Show moreThe application of nanomaterials in industrial processes and consumer products provides many societal benefits, but can also lead to the release of nanomaterials into the environment. The work in this dissertation aims to provide insights into the potential environmental impacts that may follow from this, with specific reference to populations and communities of freshwater invertebrates. Based on experimental studies conducted under conditions reflecting those in natural ecosystems, this dissertation shows that commonly applied methodological approaches can lead to an underestimation of the long-term impacts of nanomaterials on freshwater organisms, particularly at the level of populations and communities. In doing so, this dissertation provides perspective on the role of relevance and realism in ecotoxicological assessments, and shows that impact assessments at higher ecological levels can provide sensitive and reliable insights that can serve as a basis for regulation, and guide the development of safer and more sustainable chemicals, substances and materials. Show less
Innovation plays an essential role in firms' competitiveness and long-term success. It varies from different types, ranging from run-of-the-mill innovation that brings incremental changes to... Show moreInnovation plays an essential role in firms' competitiveness and long-term success. It varies from different types, ranging from run-of-the-mill innovation that brings incremental changes to existing technologies to radical innovation that breaks from existing trajectories. The aim of this PhD dissertation is to integrate radical innovation and social network literature to broaden theoretical understanding, especially contribute to the literature on social networks, creativity, and innovation, and inform innovation management by unpacking the drivers and effects of radical innovation. Focusing on the long-standing debates in the social network literature regarding which types of networks are more advantageous for innovation, this dissertation starts with investigating how tie strength and structural holes collectively affect innovation radicalness at a location within an innovating firm. Then this dissertation investigates how social structure for producing a creative idea influences the adoption and future use of its innovations and makes a novel contribution by exploring how this effect is contingent on the radical nature of the creative idea. In addition to contributing to this long-standing debate, this dissertation also investigates how radicalness affects the private value for the innovating firm. Show less
Antibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses... Show moreAntibody features vary with tuberculosis (TB) disease state. Whether clinical variables, such as age or sex, influence associations between Mycobacterium tuberculosis-specific antibody responses and disease state is not well explored. Here we profiled Mycobacterium tuberculosis-specific antibody responses in 140 TB-exposed South African individuals from the Adolescent Cohort Study. We identified distinct response features in individuals progressing to active TB from non-progressing, matched controls. A multivariate antibody score differentially associated with progression (SeroScore) identified progressors up to 2 years before TB diagnosis, earlier than that achieved with the RISK6 transcriptional signature of progression. We validated these antibody response features in the Grand Challenges 6–74 cohort. Both the SeroScore and RISK6 correlated better with risk of TB progression in adolescents compared with adults, and in males compared with females. This suggests that age and sex are important, underappreciated modifiers of antibody responses associated with TB progression. Show less
This research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et... Show moreThis research investigates tensions associated with positive organizational change (POC) that prioritizes strengths-based dialogue over talk about organizational problems or deficits (Fitzgerald et al., 2010) by bridging the concept of organizational shadow (Bowles, 1991; Fitzgerald et al., 2010; Jung, 1968) with dialectical tension theory (Baxter & Simon, 1993). A recent flurry of studies suggests toxic positivity results in the marginalizing of individuals for expressing their emotions that may not always be positive (Collins, 2022; Cross, 2022; Tufvesson, 2020). A key question this research addresses is what do with the "elephants in the room" that represent what people think is undiscussable in a POC context? Interviews with 41 organizational development practitioners, with more than 600 cumulative years of experience leading POC initiatives using the Appreciative Inquiry (AI) methodology, identified the contexts in which tensions are likely to arise, the theoretical implications of tensions, and practical strategies to navigate tensions in a POC context. This study’s findings advance scholarship on positive organizing by naming the voice, leadership, and temporal shadows. These shadows emerge as three dialectical tensions: free expression and limited expression of what is discussible in the change process, hierarchical and collaborative leadership, and short-term orientation versus long-term orientation. The results of this study demonstrate experienced POC practitioners navigate tensions underlying the voice, leadership, and temporal shadows by using nuanced strategies, such as creating space to hear divergent perspectives, coaching leaders to demonstrate agility in support of collaborative initiatives, and reframing tension such that one pole does not negate the other. Show less
This dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded... Show moreThis dissertation showed that physicians must be aware of the constraints that allow them to identify or obviate (un)desirable effects most notably if they evaluate these effects in a blinded matter. Unblinding might partially mitigate the limitation, but current measurement methods have gaps that we should remain aware of. Detailed measurements of subintervals with characterization of ion channel profiles, concentration QTc modelling, or machine learning might help physicians in their decision making in the future. Show less
AI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services... Show moreAI-powered emotion recognition, typing with thoughts or eavesdropping virtual assistants: three non-fictional examples illustrate how AI may impact society. AI-related products and services increasingly find their way into daily life. Are the EU's fundamental rights to privacy and data protection equipped to protect individuals effectively? In addressing this question, the dissertation concludes that no new legal framework is needed. Instead, adjustments are required. First, the extent of adjustments depends on the AI discipline. There is nothing like 'the AI'. AI covers various concepts, including the disciplines machine learning, natural language processing, computer vision, affective computing and automated reasoning. Second, the extent of adjustments depends on the type of legal problem: legal provisions are violated (type 1), cannot be enforced (type 2) or are not fit for purpose (type 3). Type 2 and 3 problems require either adjustments of current provisions or new judicial interpretations. Two instruments might be helpful for more effective legislation: rebuttable presumptions and reversal of proof. In some cases, the solution is technical, not legal. Research in AI should solve reasoning deficiencies in AI systems and their lack of common sense. Show less
