Sharpening the teeth of EU social fundamental rights? The case of state pension age

This article analyzes current EU pension law and policy in light of the case “State Pension Age” (SPA) and considers the implications of this analysis for EU social rights. In examining the applicability of EU pension law, it provides two critical entry point of analysis into the SPA cases: i) Article 21 Charter Fundamental Rights of the European Union, and ii) The Internal Market scenario.publishedVersio

Sharpening the teeth of EU social fundamental rights? The case of state pension age

This article analyzes current EU pension law and policy in light of the case “State Pension Age” (SPA) and considers the implications of this analysis for EU social rights. In examining the applicability of EU pension law, it provides two critical entry point of analysis into the SPA cases: i) Article 21 Charter Fundamental Rights of the European Union, and ii) The Internal Market scenario.publishedVersio

CD47-SIRPα blocking-based immunotherapy:Current and prospective therapeutic strategies

BACKGROUND: The CD47‐signal regulatory protein alpha (SIRPα) ‘don't eat me’ signalling axis is perhaps the most prominent innate immune checkpoint to date. However, from initial clinical trials, it is evident that monotherapy with CD47‐SIRPα blocking has a limited therapeutic effect at the maximum tolerated dose. Furthermore, treatment is associated with severe side effects, most notably anaemia, that are attributable to the ubiquitous expression of CD47. Nevertheless, promising clinical responses have been reported upon combination with the tumour‐targeting antibody rituximab or azacytidine, although toxicity issues still hamper clinical application. MAIN BODY: Here, we discuss the current state of CD47‐SIRPα blocking therapy with a focus on limitations of current strategies, such as depletion of red blood cells. Subsequently, we focus on innovations designed to overcome these limitations. These include novel antibody formats designed to selectively target CD47 on tumour cells as well as tumour‐targeted bispecific antibodies with improved selectivity. In addition, the rationale and outcome of combinatorial approaches to improve the therapeutic effect of CD47 blockade are discussed. Such combinations include those with tumour‐targeted opsonizing antibodies, systemic therapy, epigenetic drugs, other immunomodulatory T‐cell‐targeted therapeutics or dual immunomodulatory CD47 bispecific antibodies. CONCLUSION: With these advances in the design of CD47‐SIRPα‐targeting therapeutic strategies and increasing insight into the mechanism of action of this innate checkpoint, including the role of adaptive immunity, further advances in the clinical application of this checkpoint can be anticipated

An Explorative Dive into Decision Rights and Governance of Blockchain: A Literature Review and Empirical Study

Background: Blockchain technology and accompanying programmed protocols (smart contracts) offer disruptive opportunities for businesses, public institutions, society, and its citizens. However, blockchain is a relatively young research area: the number of publications available regarding blockchain did not begin to rise significantly until 2012, and certain fields of the blockchain domain remain to be explored. A similar situation exists with research into the governance of blockchain solutions focusing on decision rights: the limited number of theoretical and empirical contributions hinders the proper adoption of governance mechanisms in practice. Method: A mixed-method approach was conducted in which 1) a structured literature review, 2) semi-structured interviews, and 3) a focus group discussion were utilized to determine the current situation regarding decision rights in the context of blockchain governance. Results: The structured literature review resulted in a total of 23 relevant contributions. Those contributions were consolidated to serve as input for a total of twelve semi-structured interviews, and for a focus group session with five participants, who were not part of the interviewee pool. Using that approach, an overview of the concepts, relationships and mechanisms pertinent to decision rights was composed. Conclusions: Considered together, the results show that decision rights are often overlooked at the start of a blockchain project, where technical considerations are dominant in the discussion with stakeholders. However, research also points out that the longer it takes to address decision rights in a blockchain consortium, the more complex and costly it becomes to introduce governance mechanisms at a later stage. Another important conclusion is that consensus is currently lacking as to what constitutes blockchain governance and what part decision rights play in governance processes, in both theoretical and practical terms

The Implementation of TNFRSF Co-Stimulatory Domains in CAR-T Cells for Optimal Functional Activity

SIMPLE SUMMARY: Members of the Tumor Necrosis Factor Receptor Superfamily (TNFRSF) provide crucial co-stimulatory signals to many if not all immune effector cells. With distinct and unique functional features on multiple types of immune effector cells, the co-stimulatory activity of TNFRSF members is being implemented in the tailoring of Chimeric Antigen Receptor (CAR) T cell activity for cancer therapy. This integration of intracellular TNFRSF stimulatory domains into a CAR provides a unique signaling output. Here, we highlight the rationale and summarize the current evidence for the application and the unique attributes of co-stimulatory signaling by TNFRSF members (4-1BB; OX40; CD40; CD27; GITR; HVEM) in CAR-T therapy. ABSTRACT: The Tumor Necrosis Factor Receptor Superfamily (TNFRSF) is a large and important immunoregulatory family that provides crucial co-stimulatory signals to many if not all immune effector cells. Each co-stimulatory TNFRSF member has a distinct expression profile and a unique functional impact on various types of cells and at different stages of the immune response. Correspondingly, exploiting TNFRSF-mediated signaling for cancer immunotherapy has been a major field of interest, with various therapeutic TNFRSF-exploiting anti-cancer approaches such as 4-1BB and CD27 agonistic antibodies being evaluated (pre)clinically. A further application of TNFRSF signaling is the incorporation of the intracellular co-stimulatory domain of a TNFRSF into so-called Chimeric Antigen Receptor (CAR) constructs for CAR-T cell therapy, the most prominent example of which is the 4-1BB co-stimulatory domain included in the clinically approved product Kymriah. In fact, CAR-T cell function can be clearly influenced by the unique co-stimulatory features of members of the TNFRSF. Here, we review a select group of TNFRSF members (4-1BB, OX40, CD27, CD40, HVEM, and GITR) that have gained prominence as co-stimulatory domains in CAR-T cell therapy and illustrate the unique features that each confers to CAR-T cells

Chemotherapy and Chemoradiotherapy Studies in Oesophageal Cancer

The aim of this thesis was, first, to explore the use of preoperative chemoradiotherapy and palliative chemotherapy in the treatment of oesophageal cancer. Furthermore, the effects of a chemoradiotherapy regimen on histopathological and psychological and social level were studied. Chapter 2 provides a review of the literature on systemic treatment for oesophageal cancer. An overview is given for preoperative and postoperative chemotherapy, preoperative chemoradiotherapy, definitive chemoradiotherapy, and palliative chemotherapy. In Chapter 3 the efficacy and safety of preoperative chemoradiotherapy consisting of carboplatin and paclitaxel and concurrent radiotherapy for patients with resectable oesophageal cancer is studied. Chapter 4 describes the histopathological effects of the above mentioned chemoradiotherapy regimen and correlates the effect of specific pathologic and clinical findings to overall survival. In Chapter 5 the health related quality of life up to one year after surgery, in patients with oesophageal cancer treated with curative intent with neoadjuvant chemoradiotherapy consisting of the above mentioned regimen followed by oesophagectomy is evaluated. Finally, in Chapter 6 the analysis of a phase II study evaluating the safety and efficacy of the combination of oxaliplatin and capecitabine in patients with metastatic or local-regional unresectable carcinoma of the oesophagus, oesophagogastric junction, and cardia is given. In addition, the effect of this regimen of the patients’ well-being is evaluated by performing a quality of life analysis on these patients during the treatment. The studies described in this thesis are summarized in Chapter 7. Furthermore, potential directions for future studies are addressed