Superior antitumoral activity of dimerized targeted single-chain TRAIL fusion proteins under retention of tumor selectivity

Although targeting of the death receptors (DRs) DR4 and DR5 still appears a suitable antitumoral strategy, the limited clinical responses to recombinant soluble TNF-related apoptosis inducing ligand (TRAIL) necessitate novel reagents with improved apoptotic activity/tumor selectivity. Apoptosis induction by a single-chain TRAIL (scTRAIL) molecule could be enhanced >10-fold by generation of epidermal growth factor receptor (EGFR)-specific scFv-scTRAIL fusion proteins. By forcing dimerization of scFv-scTRAIL based on scFv linker modification, we obtained a targeted scTRAIL composed predominantly of dimers (Db-scTRAIL), exceeding the activity of nontargeted scTRAIL ∼100-fold on Huh-7 hepatocellular and Colo205 colon carcinoma cells. Increased activity of Db-scTRAIL was also demonstrated on target-negative cells, suggesting that, in addition to targeting, oligomerization equivalent to an at least dimeric assembly of standard TRAIL per se enhances apoptosis signaling. In the presence of apoptosis sensitizers, such as the proteasomal inhibitor bortezomib, Db-scTRAIL was effective at picomolar concentrations in vitro (EC50 ∼2 × 10−12 M). Importantly, in vivo, Db-scTRAIL was well tolerated and displayed superior antitumoral activity in mouse xenograft (Colo205) tumor models. Our results show that both targeting and controlled dimerization of scTRAIL fusion proteins provides a strategy to enforce apoptosis induction, together with retained tumor selectivity and good in vivo tolerance

Human Dignity and the Principle of Culpability

The paper describes the origins and implications of the principle of culpability in Germany and Israel. The comparison shows that the principle of culpability is more closely related to human dignity in German law and that it carries more weight there than in Israeli law. However, the adoption of the Basic Law: Human Dignity and Liberty and the new General Part of the Israeli Criminal Code in the 1990's have increased the role and impact of the principle of culpability in Israeli law

Human Dignity as a Protected Interest in Criminal Law

This publication is with permission of the rights owner freely accessible due to an Alliance licence and a national licence (funded by the DFG, German Research Foundation) respectively.Human dignity can be a protected interest in criminal law. This paper starts with some reflections about the meaning of human dignity and then examines offense descriptions in the German Penal Code and the Israeli Penal Code. These codes are used as sources for identifying possibly relevant prohibitions. One can indeed find numerous examples of offense descriptions that can be justified by pointing to human dignity, either as a main protected interest or as a protected interest in addition to other interests. The protected interest can be either the individual victim's right to human dignity or human dignity as an objective value. Offense descriptions that can be connected to “protection of human dignity” should, for analytical purposes, be divided into three groups: violations of the dignity of individual human beings through acts other than speech; violations of the human dignity of individuals through speech; and media content that does not contain statements about individuals but shows scenes of severe humiliation (e.g., fictional child pornography). Questions that need further discussion primarily concern the second group (what role should free speech play in cases of human dignity violations?) and the third group (does the acknowledgement of human dignity as an objective value mean to endorse a re-moralization of the criminal law?).Peer Reviewe

Digital Rights and Jurisdiction: The European Approach to Online Defamation and IPRs Infringements

The new media and communication technologies have significantly increased the number of online cross-border disputes involving the security and protection of personal identity as well as of intellectual property creations. The persistent lack of a uniform private international law approach on the matter deter- mines a substantial gap in Internet governance, which results in the application of domestic rules or, where existing, of regional ones. This legal scenario is conducive to conflicts of jurisdiction and, ultimately, to legal uncertainty and instances of forum shopping. The Chapter focuses on the allocation of adjudicative jurisdiction at European level by examining the current EU approach to cross-border online disputes resolution involving the main types of infringements of digital rights (notably, personality rights and IPRs). The absence of EU rules on jurisdiction concern- ing online tort disputes has encouraged the elaboration of a prolific and controversial case law of the CJEU over the interpretation of Article 7(2) of Brussels I-bis Regulation (i.e. eDate, BOÜ/Ilsjan, Wintergeister, Pinckney and Hejduk rulings). The Chapter provides a thorough and critical insight over the characteristics and trends of this development and comes to propose a brand-new “less is more” normative approach, aimed at reducing the range of eligible fora in light of a well-balanced system of assessment of the competing interests involved

Online dispute resolution and models of relational law and justice: a table of ethical principles

Regulatory systems constitute a set of coordinated complex behavior (individual and collective) which can be grasped through rules, values and principles that constitute the social framework of the law. Relational law, relational justice and the design of regulatory models can be linked to emergent agreement technologies and new versions of Online Dispute Resolution (ODR) and Negotiation Support Systems (NSS). We define the notions of public space and information principles, extending the concept of 'second order validity' to the fields of ODR and NSS