Evaluating a Targeted Cancer Therapy Approach Mediated by RNA

Conventional anti-cancer therapies based on chemo- and/or radiotherapy represent highly effective means to kill cancer cells but lack tumor specificity and, therefore, result in a wide range of iatrogenic effects. A promising approach to overcome this obstacle is spliceosome-mediated RNA trans-splicing (SMaRT), which can be leveraged to target tumor cells while leaving normal cells unharmed. Notably, a previously established RNA trans-splicing molecule (RTM44) showed efficacy and specificity in exchanging the coding sequence of a cancer target gene (Ct-SLCO1B3) with the suicide gene HSV1-thymidine kinase in a colorectal cancer model, thereby rendering tumor cells sensitive to the prodrug ganciclovir (GCV). In the present work, we expand the application of this approach, using the same RTM44 in aggressive skin cancer arising in the rare genetic skin disease recessive dystrophic epidermolysis bullosa (RDEB). Stable expression of RTM44, but not a splicing-deficient control (NC), in RDEB-SCC cells resulted in expression of the expected fusion product at the mRNA and protein level. Importantly, systemic GCV treatment of mice bearing RTM44-expressing cancer cells resulted in a significant reduction in tumor volume and weight compared with controls. Thus, our results demonstrate the applicability of RTM44-mediated targeting of the cancer gene Ct-SLCO1B3 in a different malignancy

Dig Deep: Conflict Prevention through Protection of Vital Human Water Needs

Deadly disputes over access to boreholes and wells are not uncommon in drought stricken or water scarce regions. Where livelihoods are at stake, human despair can become a cause of violent conflict. The case of Darfur has demonstrated that conflicts that emanate from situations of severe shortages of water do not always remain within local or national boundaries, but can spread across borders. This paper analyzes the contribution of international water law (IWL) to the prevention of conflicts caused at least in part by water scarcity. In line with the topic of the conference, the focus is on recent developments in international groundwater law; particular attention is accorded to recent improvements of legal mechanisms promoting conflict prevention that have been introduced by the 2008 Draft Articles on the Law of Transboundary Aquifers. Where water scarcity constitutes a potential cause for inter-state conflict, the principle of equitable and reasonable utilization of transboundary water resources and associated cooperation obligations can serve as useful means to anticipate conflicts. The 2008 Draft Articles have developed the traditional conception of this principle a step further and have recast it into an increasingly forward-looking principle by putting additional emphasis on future uses and intergenerational equity. The paper argues that these small alterations as well as the special weight the Draft Articles accord to vital human water needs in determining equitable and reasonable utilization mark an important contribution to the preventive qualities of IWL. In contrast to the 1997 UN Watercourses Convention, the provisions of the Draft Articles establish legal mechanisms by which the emergence of situations that could lead to conflict is already considered before disputes between users occur. It is argued that such techniques of shaping normative content should be kept in mind in order to anticipate future conflicts when negotiating new groundwater agreements

Peut-on résoudre les conflits transfrontaliers par des règles de préférence dans les utilisations de l’eau ?

L’eau est une ressource essentielle à la vie humaine. Plusieurs auteurs et organisations ont démontré que la disponibilité, mais aussi et surtout la pénurie, de ressources naturelles peuvent être une source potentielle de conflit. Cet article établi un bilan de la contribution du droit à la prévention des conflits par le biais d’une analyse des règles internationales concernant la satisfaction des besoins humains essentiels dans le contexte des systèmes hydrographiques transfrontaliers. L'analyse se penche avant tout, sur l’étude des règles de droit international de ressources en eau transfrontalières, instruments juridiques de base pour la réalisation d’une gestion pacifique des ressources en eau partagées entre États

Cooperation in the law of transboundary water resources

La thèse porte sur les droits et obligations en matière de coopération internationale dans le domaine des ressources en eau transfrontalières. La nature juridique de l'obligation générale de coopérer est mise en lumière à travers l'analyse approfondie d'obligations spécifiques relatives à la coopération, notamment les obligations d'échange d'informations, de notification et de négociation. Cette analyse démontre que l'obligation générale est une règle qui contient des éléments procéduraux ainsi que des éléments substantiels. Elle interagit avec les autres principes généraux de droit international de ressources en eau transfrontalières et facilite leur mise en œuvre. Face à une population mondiale en nombre croissant et aux risques de changements climatiques, la gestion de ressources en eau partagées doit faire face à de nouveaux enjeux. On constate un élargissement des obligations de coopérer qui inclut progressivement les droits et intérêts des individus et reconnaît l'interdépendance internationale créée par le cycle de l'eau

International Legal Frameworks for Adaptation on Transboundary Rivers

Water is the primary medium through which the effects of climate change will be noticed in the human environment. In consequence, impacts will also be felt in international river basins. Water balance and timing of river flow are likely to change considerably in some regions of the world. These changes are likely to alter conventional methods of transboundary water resources management. Some regulatory frameworks that govern joint management and development of international water resources might require adjustment are may be no longer applicable due to changes in underlying hydrologic circumstances. This will create legal uncertainty in relations between riparian States and can become the cause of friction. Despite the high probability that some of the world's largest river basins will undergo considerable hydrologic change over the coming decades, efforts to adjust agreements and to develop an international legal framework that provides for adequate adaptation in transboundary water basins lag behind. Water does not feature as a separate topic in international climate change negotiations; it is rarely mentioned in preparatory documents. Yet, the demand for principles and guidance on how to address climate change in transboundary water cooperation is increasing. The paper analyzes the contours of the existing legal framework; including universal rules captured in the UNFCCC and UN1997, regional efforts such as the UNECE Guidance Note and instruments adopted by the European Union, as well as the flexibility of basin treaties in dealing with hydrologic change

Cooperation in the law of transboundary water resources /

"Climate change, population growth and the increasing demand for water are all capable of leading to disputes over transboundary water systems. Dealing with these challenges will require the enhancing of adaptive capacity, the improving of the quality of water-resources management and a reduction in the risk of conflict between riparian states. Such changes can only be brought about through significant international cooperation. Christina Leb's analysis of the duty to cooperate and the related rights and obligations highlights the interlinkages between this duty and the principles of equitable and reasonable utilisation and the prevention of transboundary harm. In doing so, she considers the law applicable to both international watercourses and transboundary aquifers, and explores the complementarities and interaction between the rules of international water law and the related obligations of climate change and human rights law"--"Climate change, population growth and the increasing demand for water are all capable of leading to disputes over transboundary water systems. Dealing with these challenges will require the enhancing of adaptive capacity, the improving of the quality of water-resources management and a reduction in the risk of conflict between riparian states. Such changes can only be brought about through significant international cooperation. Christina Leb's analysis of the duty to cooperate and the related rights and obligations highlights the interlinkages between this duty and the principles of equitable and reasonable utilisation and the prevention of transboundary harm. In doing so, she considers the law applicable to both international watercourses and transboundary aquifers, and explores the complementarities and interaction between the rules of international water law and the related obligations of climate change and human rights law"--Includes bibliographical references and index