Abstract en Concreet

Abstract en concreet, laat ik zo concreet mogelijk beginnen. Twee jaar geleden werd meneer Vere naar onze polikliniek verwezen. Zijn naam heb ik aangepast om herkenning te voorkomen. Zijn huisarts had hem verwezen i.v.m. moeheidsklachten en een afwijkend aantal witte bloedcellen. Aanvullend onderzoek van bloed en beenmerg in ons laboratorium toonde inderdaad een hoog aantal witte bloedcellen zowel in bloed als in het beenmerg. Het bleken echter geen volwassen, uitgerijpte cellen te zijn, maar voorlopers daarvan, zeer jonge cellen, misschien zelfs wel stamcellen (Figuur 1). Links kijkt u met mij door de microscoop naar normaal beenmerg met alle verschillende bloed- en beenmerg-celtypen en rechts ziet u dat de normale cellen zijn verdrongen door een agressieve woekering van leukemiecellen. De diagnose werd gesteld op een acute leukemie en meneer Vere kreeg een intensieve behandeling aangeboden bestaande uit een combinatie van meerdere celdodende middelen (cytostatica). Dit leidde weliswaar tot het terugdringen van de leukemie, maar met fi jngevoelige technieken konden we nog steeds activiteit van de leukemie aantonen. Het was duidelijk dat aanvullende behandeling noodzakelijk zou zijn om tot definitieve genezing te komen. De mogelijkheden van een bloedstamceltransplantatie werden overwogen, maar er bleek geen passende donor in de familie en ook een passende, vrijwillige volwassen donor uit de wereldwijde donorbank bleek niet te vinden. Uiteindelijk vonden wij in de bloedbank van New York een navelstrengbloed-transplantaat, dat wel bleek te passen en ook voldoende bloedvormende stamcellen leek te bevatten.Rede, uitgesproken ter gelegenheid van het aanvaarden van het ambt van Hoogleraar in de Haematopoietische Stamceltransplantatie aan het Erasmus MC, faculteit van de Erasmus Universiteit Rotterdam, op 1 september 200

Development of a cell encapsulation technology for the production of functional, micro-encapsulated pancreatic islets for transplantation

Previously held under moratorium from 8 August 2019 until 9 December 2021Diabetes type 1 is an autoimmune disease in which the patient’s own immune system destroys the insulin producing β-cells, located in the pancreatic islets. Without enough insulin production, the blood glucose levels of the patient rise, which can lead to damages of blood vessels and nerves, blindness or even seizures and comas. For some patients that have trouble maintaining normoglycaemia allogeneic islet transplantation has become an alternative treatment option. Patients with these transplanted islets are no longer prone to hypoglycaemic episodes and can sometimes become completely insulin independent. However, this success is not long-lived. The life span of the transplanted islets is limited due to the host’s immune responses and the toxicity of modern immunosuppressive agents. In this thesis, islet encapsulation for clinical transplantation is investigated and further developed. Islet encapsulation can protect the islets from the immune system, without the aid of the immunosuppressants. The construction and optimization of a micro-encapsulator that can be used to create encapsulations is described, as well as the multiple parameters to create small, uniform encapsulations. To further enhance the biocompatibility and immunoprotective properties of alginate hydrogel, alginate was purified to eliminate most of the impurities and tested for its permeability. Encapsulating pancreatic islets in this purified alginate showed encouraging results, with the islets remaining viable and functional longer than their control counterparts. Larger islets can develop necrotic cores within encapsulations, due to the lack of vascularization. To create smaller islets out of dissociated larger islets, a single-step encapsulation and aggregation method was developed, that unfortunately was not suitable for islet cells, but was capable of developing functional hepatic organoids out of HepaRG cells, that could be used for drug testing. Finally, a proof of principle was given for the creation of pancreatic islet patches using 3D bioprinting methods.Diabetes type 1 is an autoimmune disease in which the patient’s own immune system destroys the insulin producing β-cells, located in the pancreatic islets. Without enough insulin production, the blood glucose levels of the patient rise, which can lead to damages of blood vessels and nerves, blindness or even seizures and comas. For some patients that have trouble maintaining normoglycaemia allogeneic islet transplantation has become an alternative treatment option. Patients with these transplanted islets are no longer prone to hypoglycaemic episodes and can sometimes become completely insulin independent. However, this success is not long-lived. The life span of the transplanted islets is limited due to the host’s immune responses and the toxicity of modern immunosuppressive agents. In this thesis, islet encapsulation for clinical transplantation is investigated and further developed. Islet encapsulation can protect the islets from the immune system, without the aid of the immunosuppressants. The construction and optimization of a micro-encapsulator that can be used to create encapsulations is described, as well as the multiple parameters to create small, uniform encapsulations. To further enhance the biocompatibility and immunoprotective properties of alginate hydrogel, alginate was purified to eliminate most of the impurities and tested for its permeability. Encapsulating pancreatic islets in this purified alginate showed encouraging results, with the islets remaining viable and functional longer than their control counterparts. Larger islets can develop necrotic cores within encapsulations, due to the lack of vascularization. To create smaller islets out of dissociated larger islets, a single-step encapsulation and aggregation method was developed, that unfortunately was not suitable for islet cells, but was capable of developing functional hepatic organoids out of HepaRG cells, that could be used for drug testing. Finally, a proof of principle was given for the creation of pancreatic islet patches using 3D bioprinting methods

“How do you know someone's vegan?” They won't always tell you. An empirical test of the do-gooder's dilemma

A growing number of people (privately) endorse the benefits associated with adopting a meat-free diet. Yet, the societal transition to a more plant-based diet is taking place rather slowly. Why do people's private meat-free preferences fail to materialize in their daily food choices? One potential explanation is that vegetarians and vegans, at this time still a minority group, are worried about eliciting stigma and thus may not feel comfortable expressing their meat-free preferences during social interactions with meat-eaters. Their self-silencing could reinforce the notion that adopting a meat-free diet is nothing more than a niche phenomenon, and in turn discourage others from eliminating meat from their diet as well, thus perpetuating the non-vegetarian norm. Adapting the classic conformity paradigm by Asch, we found that vegetarian and vegan participants were hesitant to express their meat-free preferences. Vegan and vegetarian participants avoided signing a petition that promoted veg*an food options after a majority of confederates had declined to do so. When the experimenter endorsed veg*an food options, however, participants went against the majority, and did sign the petition. Together, these findings point to a pivotal role for exemplars and institutions: by signaling that there are allies who endorse a meat-free diet, they may liberate vegetarians and vegans to publicly express their deviant, meat-free preferences, and thus speed up wider societal change

Toxoplasma gondii Infection in Animal-Friendly Pig Production Systems

PURPOSE. Consumption of undercooked pork meat products has been considered a major risk factor for contracting toxoplasmosis in humans. Indoor farming and improved hygiene have drastically reduced Toxoplasma infections in pigs over the past decades. Whether introduction of animal-friendly production systems will lead to a reemergence of Toxoplasma infections in pigs is not yet known. Investigating this possibility was the purpose of this study. METHODS. Blood was obtained from pigs raised for slaughter and tested for Toxoplasma antibodies by using latex agglutination and indirect immunofluorescence testing, with confirmation by immunoblotting. RESULTS. None of the slaughter pigs (n = 621) from conventional farms (n = 30) were positive, whereas 38 (2.9%) of 1295 animals from animal-friendly systems tested positive (n = 33 farms; 13 [39%] farms positive). CONCLUSIONS. The following conclusions may be derived from this study: Conventionally (indoors) raised pigs are free from Toxoplasma infection, and (2) animal-friendly production systems may lead to a reemergence of Toxoplasma infections, although many of these farms remain Toxoplasma free. Slaughterhouse monitoring of pigs from animal-friendly production systems combined with on-farm prevention strategies should be applied to ensure safety for consumers of the meat products obtained from these animals

The role of rodents and shrews in the transmission of Toxoplasma gondii to pigs

Inadequate rodent control is considered to play a role in Toxoplasma gondii infection of pigs. This issue was addressed in the current study by combining a 4-month rodent control campaign and a 7-month longitudinal analysis of T. gondii seroprevalence in slaughter pigs. Three organic pig farms with known rodent infestation were included in the study. On these farms, presence of T. gondii in trapped rodents was evaluated by real-time PCR. All rodent species and shrews investigated had T. gondii DNA in brain or heart tissue. Prevalence was 10.3% in Rattus norvegicus, 6.5% in Mus musculus, 14.3% in Apodemus sylvaticus and 13.6% in Crocidura russula. Initial T. gondii seroprevalence in the slaughter pigs ranged between 8% and 17% and dropped on the three farms during the rodent control campaign to 0–10%, respectively. After 4 months of rodent control, T. gondii infection was absent from pigs from two of the three farms investigated and appeared again in one of those two farms after the rodent control campaign had stopped. This study emphasizes the role of rodents and shrews in the transmission of T. gondii to pigs and the importance of rodent control towards production of T. gondii-free pig meat

Communication strategies for moral rebels:How to talk about change in order to inspire self-efficacy in others

Current carbon-intensive lifestyles are unsustainable and drastic social changes are required to combat climate change. To achieve such change, moral rebels (i.e., individuals who deviate from current behavioral norms based on ethical considerations) may be crucial catalyzers. However, the current literature holds that moral rebels may do more harm than good. By deviating from what most people do, based on a moral concern, moral rebels pose a threat to the moral self-view of their observers who share but fail to uphold that concern. Those observers may realize that their behavior does not live up to their moral values, and feel morally inadequate as a result. Work on “do-gooder derogation” demonstrates that rebel-induced threat can elicit defensive reactance among observers, resulting in the rejection of moral rebels and their behavioral choices. Such findings suggest that advocates for social change should avoid triggering moral threat by, for example, presenting nonmoral justifications for their choices. We challenge this view by arguing that moral threat may be a necessary ingredient to achieve social change precisely because it triggers ethical dissonance. Thus, instead of avoiding moral justifications, it may be more effective to harness that threat. Ethical dissonance may offer the fuel needed for observers to engage in self-improvement after being exposed to moral rebels, provided that observers feel capable of changing. Whether or not observers feel capable of changing, however, depends on how rebels communicate their moral choices to others—how they talk about change. This article is categorized under: Perceptions, Behaviour and Communication of Climate Change > Behaviour Change and Responses

Attitudes of healthcare professionals and drug regulators about progression-free survival as endpoint in the advanced cancer setting

Purpose: To describe the attitudes of healthcare professionals and drug regulators about progression-free survival (PFS) as efficacy endpoint in clinical trials with patients with advanced cancer and to explore to what extent these attitudes influence the willingness to trade between PFS and toxicity. Methods: Cross-sectional survey with regulators from the European Medicines Agency (EMA), and healthcare professionals (HCP) from the “Stichting Hemato-Oncologie voor Volwassenen Nederland” (HOVON) collaborative group and the European Organisation for Research and Treatment of Cancer (EORTC). Attitudes towards PFS were elicited using 5-point Likert items. The respondents’ willingness to trade between PFS and grade 3 or 4 (G34) toxicity was assessed using the threshold technique and quantified in terms of their maximum acceptable risk (MAR). Results: Responses were collected from 287 HCPs and 64 regulators with mainly clinical expertise. Attitudes towards PFS were often spread out in both groups and related to beliefs about PFS being a likely surrogate for clinical benefit, being an intrinsic benefit to be distinguished from OS, or on the importance given to OS. Being a regulator or holding stronger beliefs about PFS being a likely surrogate or an intrinsic benefit were associated with a higher MAR. Presence of a supportive trend in OS was stated as important but was not associated with MAR. There was agreement on the need to address bias in the adjudication of PFS and the need for improving communication to patients about meaning, strengths, and limitations of improvements in PFS. Conclusion: Attitudes towards PFS were spread out and were associated with individual differences in the willingness to trade between toxicity and PFS. There was agreement on the need to address bias in the adjudication of PFS and improving communication to patients.</p

Design and fabrication of a low cost implantable bladder pressure monitor

In the frame of the Flemish Community funded project Bioflex we developed and fabricated an implant for short term (< 7 days) bladder pressure monitoring, and diagnosis of incontinence. This implant is soft and flexible to prevent damaging the bladder's inner wall. It contains a standard flexible electronic circuit connected to a battery, which are embedded in surface treated silicone to enhance the biocompatibility and prevent salt deposition. This article describes the fabrication of the pill and the results of preliminary cytotoxicity tests. The electronic design and its tests, implantation and the result of the in-vivo experimentation will be presented in other articles

Monitoring and control of reproducibility in quasi-continuous integrated production processes of Active Pharmaceutical Ingredients

The development of integrated production processes include the combination and transformation of current batch oriented unit operations into linked sequential/parallel production strategies. The presented process starts with a two-stage upstream consisting of cell cultivation and subsequent protein production, which in turn results in a five step downstream process, consisting of cell clarification via a separator, retention of cellular debris using microfiltration, concentration of the secreted product by ultrafiltration with subsequent buffer exchange through diafiltration, followed by a final purification using column chromatography. The three main operations cell breeding, protein production and the complete downstream line are running in series, but also in parallel with a one-day-offset each. Such strategies were developed at HAW Hamburg [Luttmann et al., 2015]. To achieve reproducible process conditions, the process development was done in accordance with the known industry guidelines from FDA and ICH regarding QbD and PAT. In this context the identification of optimal Design Spaces and Control Spaces was in the foreground. The in-line measurement of important media components and cell physiological parameters as well as the on-line evaluation of process reproducibility, are remaining unsolved problems in industrial biotechnology - irrespective of whether a process is operated batch wise or continuously. A way out of this dilemma can be found by on-line MVDA data processing. This paper describes a comprehensive application of MVDA in process monitoring and control using the example of an integrated production of potential Malaria vaccines with Pichia pastoris. Cell mass, glycerol and secreted target proteins as well as cell internal AOX content are measured with NIR-, Raman- and 2D-Fluorescence-spectrometry. Here, intensive off-line analysis of the concerned process variables form the foundation for the training of spectral observations as well as for the evaluation of cell specific reaction rates from routinely measured on-line variables with MVDA-investigations. The main approach of MVDA was an on-line monitoring of reproducibility of involved unit operations. This was achieved by off-line modeling of Golden Batch tunnels and on-line evaluation of the process trajectories using SIPAT® and SIMCA® software tools. On top of this, on-line process prediction and on-line Golden Batch control were implemented. The prediction is based on IBR-Imputation by Regression (SIMCA® Q) and the control of processes evolving outside their Golden Batch limitations is based on BOBYQA-Bound Optimization by Quadratic Approximation (SIMCA® online). Such methods for process monitoring and control of quasi continuous pharmaceutical production pave the way for Real Time Release of APIs. All approaches have been approved and tested in real industrial-like production processes which have been performed over several weeks