Dissemination and clinical impact of minimal metastatic disease in gastrointestinal cancer

In this thesis, we assess whether gastric and colorectal cancer (CRC) patients with minimal metastatic disease at the time of surgery who are at risk for disease recurrence, can be identified by detection of occult tumor cells (OTC) in lymph nodes or bone marrow or by analyzing the primary tumor for angiogenic and lymphangiogenic markers. Results show that the mere presence of OTC-positive lymph nodes in gastric cancer patients did not predict disease recurrence but the number of examined lymph nodes and the percentage of OTC-positive lymph nodes were independent risk factors for locoregional disease recurrence and distant disease recurrence, respectively. Automated microscopy was essential in identifying patients with OTC-positive lymph nodes. Automated microscopy was also found to be a promising tool for the detection of OTC in lymph nodes, potentially more sensitive but less specific for detecting recurrence of disease in CRC than conventional histopathology or RT-PCR. Lymph node analysis of two levels and immunohistochemical staining add to the detection of macrometastases and micrometastases in CRC. Micrometastases were found to be an independent predictor of disease recurrence but isolated tumor cells were of no prognostic significance. Disseminated tumor cells in bone marrow of patients with colorectal liver metastases detected by CK20 RT-PCR is associated with a worse clinical outcome. Sialyl Lewis X expression (sLeX) and high lymphatic microvessel density (LMVD) of the primary tumor were independent factors predicting disease recurrence in CRC. Expression of sLeX correlated with liver metastases and a high LMVD was related to regional intra-abdominal or intrapelvic lymph node metastases and distant metastases. High blood microvessel density correlated with lung metastases. These results are consistent with the notion that both lymphatic and hematogenous metastasis play a role in colorectal cancer. We conclude that patients treated for gastric or colorectal cancer who are at risk for disease recurrence can be identified through OTC detection in lymph nodes, disseminated tumor cell detection in bone marrow and analysis of angiogenic and lymphangiogenic features of the primary tumor. These findings can be implemented in new strategies for identification of high risk patients, leading to individualized therapy preventing over- and undertreatment.Dutch Cancer Society, AstraZeneca, Novartis Oncology, Greiner Bio-OneUBL - phd migration 201

Vaccine protein stabilization in silica

Successful eradication or control of prevailing infectious diseases is linked to vaccine efficacy, stability and distribution. The majority of protein based vaccines are transported at fridge temperatures (‘cold-chain’) to maintain their potency. However, this has been shown to be problematic. Proteins are inherently susceptible to thermal fluctuations, occurring during transportation, causing them to denature. This leads to ineffective vaccines and an increase in vaccine preventable diseases, especially in low-income countries. Our research utilizes silica to preserve and eventually distribute vaccines at room temperature, thereby decreasing the load on ‘cold-chain’ logistics. The methodology is based upon sol-gel chemistry where soluble silica is employed to encapsulate, ensilicate, vaccine proteins1. This yields protein-loaded silica nanoparticles in the form of a dry powder (figure 1). The material is stored at room temperature and stress tested (heating, 80°C, 2 hours). Subsequently, ensilicated protein is released using a fast chemical process. Silica, silicon dioxide, is an inert biocompatible material with certain ceramic properties that is beneficial in this scenario. The proof-of-concept work was done with a common vaccine antigen: tetanus toxin C fragment2. This protein is the immunogenic part of the full tetanus neurotoxin. Analysis of TTCF protein before and after stabilization in silica revealed full retention of protein structure at various levels. Additionally, specific antibody binding indicated retention of immunogenic epitopes (figure 2). These finding suggest that this methodology could reduce or perhaps eliminate vaccine waste. More work will be undertaken to verify protein stabilization and functional retention in vivo. Please click Additional Files below to see the full abstract

Dimensions of desistance : a qualitative longitudinal analysis of different dimensions of the desistance process among long-term prisoners in the Netherlands

In the past decades a growing body of literature has been dedicated to explain desistance from offending behaviour, or to answer the question why some offenders quit crime and others do not. Currently, more psychological explanations infuse a prominent line of research emphasizing the importance of subjective, individual factors coming from within the offender, such as developing a new sense of self-identity. The aim of this study was to gain more insight into different dimensions of desistance, focusing on two aspects of identity: future expectations and conventional aspirations, and investigated how these related to (non-)criminal behaviour over time. Furthermore, this study examined how the parole experience interacted with the different dimensions of desistance. This qualitative, longitudinal study followed 28 male prisoners serving a long-term sentence in the Netherlands during their transition from prison to society. Findings illustrated the importance of individual factors such as believing in one’s own abilities in the context of pre-release expectations, the lack of conventional scripts and role models, and the contribution of parole supervision to the desistance process. Yet, it also revealed the pain of failure for men attempting to refrain from crime, mostly relating to structural support such as employment or housing issues. Dit proefschrift is onderdeel van het Prison Project. Dit project is financieel ondersteund door de Universiteit Leiden, het Nederlands Studiecentrum voor Criminaliteit en Rechtshandhaving (NSCR), de Nederlandse Organisatie voor Wetenschappelijk onderzoek (NWO) en de Universiteit van Utrecht.Criminal Justice: Legitimacy, accountability, and effectivit

Ensilication Improves the Thermal Stability of the Tuberculosis Antigen Ag85b and an Sbi-Ag85b Vaccine Conjugate

There is an urgent need for the development of vaccine thermostabilisation methodologies as the maintenance of a continuous and reliable cold chain remains a major hurdle to the global distribution of safe and effective vaccines. Ensilication, a method that encases proteins in a resistant silica cage has been shown to physically prevent the thermal denaturation of a number of model proteins. In this study we investigate the utility of this promising approach in improving the thermal stability of antigens and vaccine conjugates highly relevant to the development of candidate tuberculosis vaccines, including antigen 85b conjugated with the Staphylococcus aureus-protein based adjuvant Sbi. Here we analyse the sensitivity of these constructs to thermal denaturation and demonstrate for the first time the benefits of ensilication in conferring these vaccine-relevant proteins with protection against temperature-induced loss of structure and function without the need for refrigeration. Our results reveal the potential of ensilication in facilitating the storage and transport of vaccines at ambient temperatures in the future and therefore in delivering life-saving vaccines globally, and in particular to remote areas of developing countries where disease rates are often highest

Interventions to improve team effectiveness within health care

Background: A high variety of team interventions aims to improve team performance outcomes. In 2008, we conducted a systematic review to provide an overview of the scientific studies focused on these interventions. However, over the past decade, the literature on team interventions has rapidly evolved. An updated overview is therefore required, and it will focus on all possible team interventions without restrictions to a type of intervention, setting, or research design. Objectives: To review the literature from the past decade on interventions with the goal of improving team effectiveness within healthcare organizations and identify the "evidence base" levels of the research. Methods: Seven major databases were systematically searched for relevant articles published between 2008 and July 2018. Of the original search yield of 6025 studies, 297 studies met the inclusion criteria according to three independent authors and were subsequently included for analysis. The Grading of Recommendations, Assessment, Development, and Evaluation Scale was used to assess the level of empirical evidence. Results: Three types of interventions were distinguished: (1) Training, which is sub-divided into training that is based on predefined principles (i.e. CRM: crew resource management and TeamSTEPPS: Team Strategies and Tools to Enhance Performance and Patient Safety), on a specific method (i.e. simulation), or on general team training. (2) Tools covers tools that structure (i.e. SBAR: Situation, Background, Assessment, and Recommendation, (de)briefing checklists, and rounds), facilitate (through communication technology), or trigger (through monitoring and feedback) teamwork. (3) Organizational (re)design is about (re)designing structures to stimulate team processes and team functioning. (4) A programme is a combination of the previous types. The majority of studies evaluated a training focused on the (acute) hospital care setting. Most of the evaluated interventions focused on improving non-technical skills and provided evidence of improvements. Conclusion: Over the last decade, the number of studies on team interventions has increased exponentially. At the same time, research t

Assignment of the evidential value of a fingermark general pattern using a Bayesian network

Abstract: When visible on a fingermark, the general pattern maintains its importance in the fingerprint examination procedure, since the difference between the general pattern of a fingermark and a fingerprint is sufficient for exclusion. In the current work, the importance of the general pattern is extended by evaluating the strength of evidence of a match given corresponding general pattern. In current practice (due to the lack of statistical support for the general pattern evidence) the fingerprint examiners assign personal probabilities to the general pattern evidence based on their knowledge and experience, while in this work the probabilities are calculated using a Bayesian Network which is fed by empirical data. 1

Elderly patients' decision-making embedded in the social context

BACKGROUND: Older patients are increasingly encouraged to be actively involved but how they perceive their role in the decision-making process varies according to their health care providers and their health situation. Their role could be influenced by their social context but more specifically by subjective norms (i.e. patients' view of the role that significant others expect them to play in the decision-making process) and perceived soc