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Plain English Summary Currently, more and more collaborations exist between patients and researchers in scientific research projects. Patient-research partnerships give patients the opportunity to add value to research by sharing their own experiences. Besides, patients themselves feel heard in their needs and are empowered. However, inclusion of young patients, like young adults with a cancer diagnosis, remains limited in research itself and specifically in the form of active involvement and collaboration initiatives. Thereby little is known about their age-specific problems and needs. This seems especially the case in young patient populations like adolescents and young adults (AYAs) with cancer who have a poor or uncertain prognosis. By analyzing the experiences of AYAs and researchers, this study aimed to unravel if collaboration within research projects is possible, and what defines the added value of such collaboration. Our study shows that researchers, as well as AYAs, think positively about collaborating during most phases of scientific research projects, even for challenging populations like AYAs with an uncertain and/or poor prognosis. Creating awareness of the possibilities of AYA involvement might increase involvement initiatives in future projects. This can be done using the Involvement Matrix. This is an existing tool which we further expanded according to our findings. Researchers and AYAs can fill in this tool (a table) together to plan, structure and discuss their collaboration. Our findings can be validated and might serve as a starting point for other patient groups.

IntroductionAdolescents and young adults with an uncertain or poor cancer prognosis (UPCP) are confronted with ongoing and unique age-specific challenges, which forms an enormous burden. To date, little is known about the way AYAs living with a UPCP cope with their situation. Therefore, this study explores how AYAs with a UPCP cope with the daily challenges of their disease.MethodWe conducted semi-structured in-depth interviews among AYAs with a UPCP. Patients of the three AYA subgroups were interviewed (traditional survivors, new survivors, low-grade glioma survivors), since we expected different coping strategies among these subgroups. Interviews were analyzed using elements of the Grounded Theory by Corbin and Strauss. AYA patients were actively involved as research partners.ResultsIn total 46 AYAs with UPCP participated, they were on average 33.4 years old (age range 23–44) and most of them were woman (63%). Most common tumor types were low-grade gliomas (16), sarcomas (7), breast cancers (6) and lung cancers (6). We identified seven coping strategies in order to reduce the suffering from the experienced challenges: (1) minimizing impact of cancer, (2) taking and seeking control, (3) coming to terms, (4) being positive, (5) seeking and receiving support, (6) carpe diem and (7) being consciously alive.ConclusionThis study found seven coping strategies around the concept of ‘double awareness’ and showcases that AYAs are able to actively cope with their disease but prefer to actively choose life over illness. The findings call for CALM therapy and informal AYA support meetings to support this group to cope well with their disease.

IntroductionIncreasingly more adolescent and young adult (AYA, aged 18–39 years) patients with an uncertain and/or poor cancer prognosis (UPCP) are gaining life-years because of novel treatments or refinement of established therapies, and sometimes even face the prospect of long-term disease control. This study aims to examine the challenges of AYAs with a UPCP in daily life to inform the development of AYA care programs.MethodsSemi-structured in-depth interviews were conducted among AYAs with a UPCP. Since we expected differences in experiences between three AYA subgroups, we interviewed patients of these subgroups (1): traditional survivors (2), low-grade glioma survivors, and (3) new survivors. Interviews were analyzed using elements of grounded theory. AYA patients were actively involved as research partners.ResultsIn total 46 AYAs with UPCP participated and shared their challenges in daily life. They were on average 33.4 years old (age range 23–44) and most of them were women (63%). The most common tumor types were low-grade gliomas (16), sarcomas (7), breast cancers (6), and lung cancers (6). We identified five primary themes: (1) feeling inferior to previous self and others (e.g. feeling useless, who wants me in a relationship), (2) feeling of being alone (e.g. lonely thoughts, nobody really gets me), (3) ongoing confrontation (e.g. it is always there, own decline), (4) grief about life (e.g. grief about life I did not get, grief about old life), and (5) loss of control over the future (e.g. not able to make future plans, waiting for growth). Although all of the challenges were identified in the three AYA subgroups, the perceived intensity of the challenges differed slightly between the subgroups.DiscussionAYAs living with a UPCP experience challenges associated to their sense of altered identity, their position in the social network, and the future uncertainties. This study highlights the importance to recognize and acknowledge the unique challenges of this group. To provide age-specific care, it is important to embed acceptance and commitment therapy and AYA peer support within the healthcare system and other care programs to support AYAs to live well with their disease.

The efficacy of thrombolysis is inversely correlated with thrombus age. During early thrombogenesis, activated factor XIII (FXIIIa) cross-links α2-AP to fibrin to protect it from early lysis. This was exploited to develop an α2-AP-based imaging agent to detect early clot formation likely susceptible to thrombolysis treatment. In this study, this imaging probe was improved and validated using 111In SPECT/CT in a mouse thrombosis model. In vitro fluorescent- and 111In-labelled imaging probe-to-fibrin cross-linking assays were performed. Thrombus formation was induced in C57Bl/6 mice by endothelial damage (FeCl3) or by ligation (stenosis) of the infrarenal vena cava (IVC). Two or six hours post-surgery, mice were injected with 111In-DTPA-A16 and ExiTron Nano 12000, and binding of the imaging tracer to thrombi was assessed by SPECT/CT. Subsequently, ex vivo IVCs were subjected to autoradiography and histochemical analysis for platelets and fibrin. Efficient in vitro cross-linking of A16 imaging probe to fibrin was obtained. In vivo IVC thrombosis models yielded stable platelet-rich thrombi with FeCl3 and fibrin and red cell-rich thrombi with stenosis. In the stenosis model, clot formation in the vena cava corresponded with a SPECT hotspot using an A16 imaging probe as a molecular tracer. The fibrin-targeting A16 probe showed specific binding to mouse thrombi in in vitro assays and the in vivo DVT model. The use of specific and covalent fibrin-binding probes might enable the clinical non-invasive imaging of early and active thrombosis.

Galectin-1 (gal-1) is a carbohydrate-binding lectin with important functions in angiogenesis, immune response, hemostasis and inflammation. Comparable functions are exerted by platelet factor 4 (CXCL4), a chemokine stored in the α-granules of platelets. Previously, gal-1 was found to activate platelets through integrin αIIbβ3. Both gal-1 and CXCL4 have high affinities for polysaccharides, and thus may mutually influence their functions. The aim of this study was to investigate a possible synergism of gal-1 and CXCL4 in platelet activation. Platelets were treated with increasing concentrations of gal-1, CXCL4 or both, and aggregation, integrin activation, P-selectin and phosphatidyl serine (PS) exposure were determined by light transmission aggregometry and by flow cytometry. To investigate the influence of cell surface sialic acid, platelets were treated with neuraminidase prior to stimulation. Gal-1 and CXCL4 were found to colocalize on the platelet surface. Stimulation with gal-1 led to integrin αIIbβ3 activation and to robust platelet aggregation, while CXCL4 weakly triggered aggregation and primarily induced P-selectin expression. Co-incubation of gal-1 and CXCL4 potentiated platelet aggregation compared with gal-1 alone. Whereas neither gal-1 and CXCL4 induced PS-exposure on platelets, prior removal of surface sialic acid strongly potentiated PS exposure. In addition, neuraminidase treatment increased the binding of gal-1 to platelets and lowered the activation threshold for gal-1. However, CXCL4 did not affect binding of gal-1 to platelets. Taken together, stimulation of platelets with gal-1 and CXCL4 led to distinct and complementary activation profiles, with additive rather than synergistic effects.

The chemokines CCL5 and CXCL4 are deposited by platelets onto endothelial cells, inducing monocyte arrest. Here, the fate of CCL5 and CXCL4 after endothelial deposition was investigated. Human umbilical vein endothelial cells (HUVECs) and EA.hy926 cells were incubated with CCL5 or CXCL4 for up to 120 min, and chemokine uptake was analyzed by microscopy and by ELISA. Intracellular calcium signaling was visualized upon chemokine treatment, and monocyte arrest was evaluated under laminar flow. Whereas CXCL4 remained partly on the cell surface, all of the CCL5 was internalized into endothelial cells. Endocytosis of CCL5 and CXCL4 was shown as a rapid and active process that primarily depended on dynamin, clathrin, and G protein-coupled receptors (GPCRs), but not on surface proteoglycans. Intracellular calcium signals were increased after chemokine treatment. Confocal microscopy and ELISA measurements in cell organelle fractions indicated that both chemokines accumulated in the nucleus. Internalization did not affect leukocyte arrest, as pretreatment of chemokines and subsequent washing did not alter monocyte adhesion to endothelial cells. Endothelial cells rapidly and actively internalize CCL5 and CXCL4 by clathrin and dynamin-dependent endocytosis, where the chemokines appear to be directed to the nucleus. These findings expand our knowledge of how chemokines attract leukocytes to sites of inflammation.

The field of extracellular vesicles (EV) is rapidly expanding, also within cardiovascular diseases. Besides their exciting roles in cell-to-cell communication, EV have the potential to serve as excellent biomarkers, since their counts, content, and origin might provide useful information about the pathophysiology of cardiovascular disorders. Various studies have already indicated associations of EV counts and content with cardiovascular diseases. However, EV research is complicated by several factors, most notably the small size of EV. In this review, the advantages and drawbacks of EV-related methods and applications as biomarkers are highlighted.