334 research outputs found
Posture normalisation of 3D body scans
No full textFor product developers that design near-body products, virtual mannequins that represent realistic body shapes, are valuable tools. With statistical shape modelling, the variability of such body shapes can be described. Shape variation captured by statistical shape models (SSMs) is often polluted by posture variations, leading to less compact models. In this paper, we propose a framework that has low computational complexity to build a posture invariant SSM, by capturing and correcting the posture of an instance. The posture-normalised SSM is shown to be substantially more compact than the non-posture-normalised SSM. Practitioner summary: Statistical shape modelling is a technique to map out the variability of (body) shapes. This variability is often polluted by variations in posture. In this paper, we propose a framework to build a posture invariant statistical shape model. Abbreviations: SSM: statistical shape model; 1D: one-dimensional; 3D: three-dimensional; DHM: digital human model; LBS: linear blend skinning; PCA: princial component analysis; PC: principal component; TTR: thumb tip reach.Accepted author manuscriptApplied Ergonomics and Desig
Antibody-based approaches to modulate immune response
Get PDFIn context of an increasing interest in immunotherapeutic treatments, the work described in this thesis expands the current knowledge of several potential antibody-based therapeutic approaches. A new development is the use of bispecific antibodies (BsAb). To introduce BsAb, chapter 2 describes the different platforms currently used to generate IgG-like and non-IgG-like BsAbs, as well as the strategies to gain clinical approval for the different BsAbs. A highly selective binding, as can be achieved with BsAbs, could be beneficial to ‘target’ certain cell populations, such as Tregs, against which current treatments appear to be insufficiently specific. Focusing on BsAb-based therapeutic approaches, in chapter 3 we investigate a novel strategy to optimize a T-cell redirecting bispecific antibody. Two Fab x sdAb-Fc, directed against CD3 and EGFR, with different lengths of the hinge region, were compared. The results show that a shorter hinge design improves BsAb-induced anti-tumor activity, induces more effector cell/target cell clustering and activates T cells more efficiently. In addition, we show (chapter 4) how important it is to select the right isotype antibody. In a mouse tumor model, only IgG2a antibodies were found to exert anti-tumor function, achieving a survival rate of approximately 50%. None of the isotypes tested showed a synergistic effect with adoptive T-cell therapy. An increasing interest in the costimulatory receptor TNFR2 in cancer has prompted us to design, generate and produce novel anti-mTNFR2 antibodies (chapter 5). The characterization and different features of these antibodies are described in this chapter, and they could be used as tools in follow-up studies to further investigate i) the role of TNFR2 in cancer, and ii) how TNFR2 targeting with different antibody candidates that either block or activate this receptor could improve immunotherapy. In chapter 6, two anti-mTNFR2 antibodies were selected for assessment of their application in vitro, ex vivo and in vivo, which revealed their capacity to bind to Tregs but also to CD4+ effector T cells. Taken together, the results presented in this thesis highlight the progress achieved in immunotherapy approaches, with focus on BsAbs and novel strategies to improve cancer treatments. Furthermore, novel anti-mTNFR2 antibodies were developed and featured as useful tools to unravel the role of this receptor in tumor growth
Predicting User’s Measurements without Manual Measuring: A Case on Sports Garment Applications
Get PDFAs sports garments are stretchable, different sizing tables are used than for retail clothing. However, customers measuring themselves leads to errors and unsatisfaction, since these customized branded garments cannot be returned. Using fitting sets avoids this, but this is not always feasible, especially in an online retail environment. Therefore, this research aims to use descriptive measures—parameters that do not require manual measuring because they are readily known by heart by almost any customer—to predict users’ body measurements, which can, thus, be used by customers to determine the size of their sports garment from a sizing chart. To validate if these input measures are sufficient to predict the correct size, three prediction methods are used and compared with baseline manual measurements. The methods are: (i) clothing size predictions from shape models with descriptive measures as inputs, (ii) clothing size predictions from a regression analysis, and (iii) clothing size predictions from a shape model based on extensive 3D scanned measurements as input. The conclusion is that a regression algorithm with, as input variables, the straightforward demographics of age, gender, stature, and weight is more accurate than the algorithm with the same inputs but with a shape model behind it. Moreover, chest and hip circumferences have an intraclass correlation coefficient rating above 0.9 and are, thus, suited for online retail of stretchable garments, such as cycling clothes. As validated by end-users, the regression predictions are shown to agree with preferred garment sizes of the participants, within the natural variation of personal preferences
Engineered bispecific antibodies as cancer therapy
No full textBispecific antibodies (BsAbs) are a class of monoclonal antibodies that can target two different antigens/epitopes simultaneously. BsAbs can be roughly divided into two classes: IgG-like BsAbs and fragment-based BsAbs. Fragment-based BsAbs have a much shorter serum half-life due to the absence of the Fc fragment, which has limited their application in the clinic. In contrast, IgG-like BsAbs have relatively long serum half-lives, however, generating pure IgG-like BsAbs and improving their yield is still challenging due to chain association issues. The production of a BsAb in one expression cell line is very difficult and unfavourable due to challenges in extracting the desired BsAb from the lysates and the inherently low yield (Chapter 1, Figure 2). Thus, the aim of the research described in chapter 3 was to design a novel format to improve the purity and yield of BsAb during production. We have combined a conventional antigen-binding fragment with a single-domain antibody and generated BsAbs in a Fab x sdAb-Fc format. Our data show that this format can avoid potential heavy-light chain mis-pairing during the production of BsAbs, and increases the purity of BsAbs to above 95%. Further characterization assays showed that the BsAbs in this configuration nevertheless maintained the ability of binding to two distinct antigens concurrently. During the design of this novel BsAb format, we found that the hinge region can be adapted for different application scenarios. There are already several studies indicating that enhanced T-cell mediated tumor cell elimination can be achieved by decreasing the distance between T cells and tumor cells. In our case, the distance between tumor cells and T cells can be modulated by different hinge designs. Thus, we modulated the hinge region in T-cell redirecting bispecific antibodies (TRBAs) and studied their anti-tumor activity in in vitro assays. Our data show that with less space separating the two arms of the TRBA, tumor cells and effector T cells can bridge more tightly, which strengthens T cell activation and, in turn, increases tumor cell death. Therefore, our data indicate that the modulation of the ‘hinge region length’ parameter can possibly contribute to future design of similar molecules (Chapter 4). Since the antibody Fc-tail activates specific immune effector mechanisms, antibody isotype plays an important role in cancer therapy. Previous studies in a mouse tumor model showed the efficacy of prophylactic application of mIgG2a isotype antibodies. However, human cancer patients usually receive antibodies in a therapeutic setting. Thus, in the last study, we developed a panel of anti-Thy1.1 antibodies with various isotypes (mIgG1, mIgG2a, mIgE and Fc-silenced) and evaluated their effectiveness in a therapeutic setting in mouse tumor models. Our data demonstrated that mIgG2a is the most effective isotype in treating cancer in a therapeutic setting in mice. Therefore, isotype selection is a critical parameter determining the efficacy of tumor-targeting antibody therapy. We believe future research in tumor immunotherapy may benefit from the knowledge we gained in designing tumor antigen targeting antibodies for cancer therapy (Chapter 5)
Bidirectional regulation between B cells and T cells
No full textB cells were often thought of as simple precursors of end-stage effector cells that are merely in charge of antibody production. Research in the last decades has shown that B cells possess important other roles as well, including their involvement in the regulation and functioning of T cell-mediated (autoimmune) diseases and host-protective immune responses. This thesis aimed to get a better understanding of the variety of roles B cell subsets play in immune regulation, and how the reciprocal interplay between B- and T cells shapes the outcome of an immune response. Knowledge on how specific B cell subsets influence other players of the immune network provides valuable information that can be used to develop and improve therapies aimed to restore the balance in dysregulated immune systems such as during autoimmunity. Chapter 2 describes research investigating an experimental tolerogenic vaccination strategy. An immunodominant peptide of proteoglycan (PG) was recombinantly fused to a DEC205 endocytic receptor-specific antibody (anti-DEC205-PG). Administration of anti-DEC205-PG delivers PG-peptide to tolerogenic steady-state dendritic cells, and mice prophylactically treated with anti-DEC205-PG do not develop experimental arthritis. Our investigations showed that the DEC205-mediated tolerogenic vaccination resulted in a reduced availability of arthritic PG-specific (follicular) helper T-cells and (temporarily) increased numbers of FoxP3+ regulatory T cells. The amount of B cells participating in germinal centers was subsequently lower as well. Our data suggests that the reduced availability in germinal center-supporting follicular helper T cells eventually limits the production of autoantibodies required for the pathogenesis of arthritis. Chapter 3 and 4 describe research in the immune-regulatory roles of murine peritoneal cavity-derived innate-like B- and B-1a cells when they act either as antigen-presenting cells (APCs) or secrete immunoregulatory cytokines. Chapter 3 shows that peritoneal cavity (PerC) B cells acting as APCs, when compared to splenic B cells, differently activate CD4+ helper T (Th) cells in vitro. Higher percentages of the Th cells activated by PerC B-1a cells possess the ability to secrete the cytokines interferon-γ (IFN-γ), interleukin (IL)-10 and IL-4. This new immunological pathway may be of relevance in vivo, since adoptive transfer experiments showed that peripheral Th cells could be activated locally in the PerC by B-1a cells. Chapter 4 shows that activated PerC B cells produce large amounts of the anti-inflammatory cytokine IL-10. These activated PerC B cells can subsequently function as regulatory B cells (Bregs), since they reduce the amount of Th cells that can produce the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and IFN-γ in an in vitro Breg-suppression assay. The activation status of PerC B cells turned out to be crucial in this matter, since non-activated PerC B cells increased the amount of TNF-α-producing Th cells instead. Chapter 5 describes an investigation towards the B-cell epitopes on the G1 domain of the joint-derived self-antigen proteoglycan. Our research shows that both proteoglycan-induced arthritic mice and some rheumatoid arthritic patients possess certain antibodies directed against G1-specific B cell epitopes. This knowledge may be useful for the development of new diagnostic tools, e.g., to differentiate clinical subsets of arthritis patients
Engineered bispecific antibodies as cancer therapy
Get PDFBispecific antibodies (BsAbs) are a class of monoclonal antibodies that can target two different antigens/epitopes simultaneously. BsAbs can be roughly divided into two classes: IgG-like BsAbs and fragment-based BsAbs. Fragment-based BsAbs have a much shorter serum half-life due to the absence of the Fc fragment, which has limited their application in the clinic. In contrast, IgG-like BsAbs have relatively long serum half-lives, however, generating pure IgG-like BsAbs and improving their yield is still challenging due to chain association issues. The production of a BsAb in one expression cell line is very difficult and unfavourable due to challenges in extracting the desired BsAb from the lysates and the inherently low yield (Chapter 1, Figure 2). Thus, the aim of the research described in chapter 3 was to design a novel format to improve the purity and yield of BsAb during production. We have combined a conventional antigen-binding fragment with a single-domain antibody and generated BsAbs in a Fab x sdAb-Fc format. Our data show that this format can avoid potential heavy-light chain mis-pairing during the production of BsAbs, and increases the purity of BsAbs to above 95%. Further characterization assays showed that the BsAbs in this configuration nevertheless maintained the ability of binding to two distinct antigens concurrently. During the design of this novel BsAb format, we found that the hinge region can be adapted for different application scenarios. There are already several studies indicating that enhanced T-cell mediated tumor cell elimination can be achieved by decreasing the distance between T cells and tumor cells. In our case, the distance between tumor cells and T cells can be modulated by different hinge designs. Thus, we modulated the hinge region in T-cell redirecting bispecific antibodies (TRBAs) and studied their anti-tumor activity in in vitro assays. Our data show that with less space separating the two arms of the TRBA, tumor cells and effector T cells can bridge more tightly, which strengthens T cell activation and, in turn, increases tumor cell death. Therefore, our data indicate that the modulation of the ‘hinge region length’ parameter can possibly contribute to future design of similar molecules (Chapter 4). Since the antibody Fc-tail activates specific immune effector mechanisms, antibody isotype plays an important role in cancer therapy. Previous studies in a mouse tumor model showed the efficacy of prophylactic application of mIgG2a isotype antibodies. However, human cancer patients usually receive antibodies in a therapeutic setting. Thus, in the last study, we developed a panel of anti-Thy1.1 antibodies with various isotypes (mIgG1, mIgG2a, mIgE and Fc-silenced) and evaluated their effectiveness in a therapeutic setting in mouse tumor models. Our data demonstrated that mIgG2a is the most effective isotype in treating cancer in a therapeutic setting in mice. Therefore, isotype selection is a critical parameter determining the efficacy of tumor-targeting antibody therapy. We believe future research in tumor immunotherapy may benefit from the knowledge we gained in designing tumor antigen targeting antibodies for cancer therapy (Chapter 5)
Antibody-based approaches to modulate immune response
No full textIn context of an increasing interest in immunotherapeutic treatments, the work described in this thesis expands the current knowledge of several potential antibody-based therapeutic approaches. A new development is the use of bispecific antibodies (BsAb). To introduce BsAb, chapter 2 describes the different platforms currently used to generate IgG-like and non-IgG-like BsAbs, as well as the strategies to gain clinical approval for the different BsAbs. A highly selective binding, as can be achieved with BsAbs, could be beneficial to ‘target’ certain cell populations, such as Tregs, against which current treatments appear to be insufficiently specific. Focusing on BsAb-based therapeutic approaches, in chapter 3 we investigate a novel strategy to optimize a T-cell redirecting bispecific antibody. Two Fab x sdAb-Fc, directed against CD3 and EGFR, with different lengths of the hinge region, were compared. The results show that a shorter hinge design improves BsAb-induced anti-tumor activity, induces more effector cell/target cell clustering and activates T cells more efficiently. In addition, we show (chapter 4) how important it is to select the right isotype antibody. In a mouse tumor model, only IgG2a antibodies were found to exert anti-tumor function, achieving a survival rate of approximately 50%. None of the isotypes tested showed a synergistic effect with adoptive T-cell therapy. An increasing interest in the costimulatory receptor TNFR2 in cancer has prompted us to design, generate and produce novel anti-mTNFR2 antibodies (chapter 5). The characterization and different features of these antibodies are described in this chapter, and they could be used as tools in follow-up studies to further investigate i) the role of TNFR2 in cancer, and ii) how TNFR2 targeting with different antibody candidates that either block or activate this receptor could improve immunotherapy. In chapter 6, two anti-mTNFR2 antibodies were selected for assessment of their application in vitro, ex vivo and in vivo, which revealed their capacity to bind to Tregs but also to CD4+ effector T cells. Taken together, the results presented in this thesis highlight the progress achieved in immunotherapy approaches, with focus on BsAbs and novel strategies to improve cancer treatments. Furthermore, novel anti-mTNFR2 antibodies were developed and featured as useful tools to unravel the role of this receptor in tumor growth
The installation effects of screwed displacement piles: Testing and numerical modelling
No full textDuring construction in urban areas often noise and vibrations are not tolerated. For the installation of the foundation piles in these cases there is often chosen for screwed displacement piles. These piles can be installed without nuisance for the vicinity, but do induce large soil displacements during installation. The soil displacements can cause increased soil pressure on adjacent structures. Because urban areas are getting more densely built, these problems will occur more often in the future. The effects can be minimilized when they are known in advanced. This research looks into the possibility of predicting the installation effects of screwed displacements piles on adjacent structures. This is divided in the prediction of the soil displacement in a finite element analysis and in the effect of the soil displacement on adjacent piles. This is done with two case studies. First data from tests in Shanghai is used to create a finite element model. After this measurements are done in Rotterdam to verify this model for Dutch cases.Combining all the analysis of the measured and modelled displacements showed that the displacement is depended on the stiffness of the soil layers, the initial displacement at the edge of the pile and the distance from the pile. The soil parameters influence the initial displacements in each soil layers. When the initial displacements are correctly determined with tests, it is possible to predict the soil displacement due to the installation of a screw pile with a finite element model. No conclusion could be made on the effect of the soil displacements on adjacent structures.Geo-Engineerin
Exploring the Immunomodulatory Potential of Pectins and Polysaccharides as Feed Additives for Poultry: In Vitro Insights and Gut Model Development
Get PDFAntimicrobial resistance in poultry has become a global public health threat, hence the need for alternatives in poultry production is warranted. Carbohydrate compounds have shown promising effects in promoting gut health in poultry as they escape enzymatic digestion in the upper gastrointestinal tract (GIT) and reach the colon to promote growth of beneficial gut microbiota and produce short chain fatty acids (SCFA). In addition to altering the gut microbiota composition, carbohydrate compounds can directly interact with immune cells such as NK cells, a major intraepithelial lymphocyte (IEL) population, and macrophages that are present in the lamina propria and modulate the immune response. This way carbohydrate compounds can promote gut health and thereby reduce the required use of antimicrobials in poultry production. In this thesis we have determined the direct interaction of several pectins and polysaccharides, that may be used as feed additives in poultry production, with chicken macrophages and NK cells and describe their immunomodulatory properties. In addition, an in vitro chicken gut model “chicken intestinal organoids” was also developed. This in vitro model can be used for large screening of several drugs, carbohydrate compounds, and for disease modeling
- …
