The Protomedicato Tribunal and minorities in Castile at the end of the 17th century: the case of surgeon Roldán Solimán

[EN] This note aims to provide a small set of documents which report the vicissitudes of a North-African Muslim surgeon who tried to settle professionally during the late seventeenth century in the Kingdom of Castile. The four letters exchanged between the Royal Palace and the Castilian tribunal of the Protomedicato reveal that the Spanish king Charles II (1661-1700) resoluted supported the surgeon's aspirations, and the Protomedicato's concerted resistence to the royal will. These eloquent documents shed light on the history of the Castilian Protomedicato during the final years of the reign of the last Habsburg king in Spain by providing evidence about the role of this institution in the process of segregation/exclusion of ethnic minorities from the practice of health professions.[ES] El objeto de esta nota es presentar y editar una colección documental muy breve cuyo contenido nos informa sobre las vicisitudes de un cirujano musulmán norteafricano que a finales del siglo XVII busca su asentamiento profesional en la Corona de Castilla. Las cuatro cartas entre el Palacio Real y el Tribunal del Protomedicato, que se conservan en relación a este asunto, revelan tanto el decidido apoyo del Rey Carlos 11 (1665-1700) a las pretensiones del cirujano, como la fuerte resistencia ofrecida por el Protomedicato a la voluntad real. Esta expresiva documentación arroja luz en torno a la historia del Protomedicato en la Corona de Castilla durante los años finales del reinado del último Habsburgo en España, ilustrándonos sobre el papel entonces jugado por esta institución en el proceso de segregación/exclusión de las minorías étnicas, de la práctica de las ocupaciones sanitarias.Peer reviewe

A novel fully-human cytolytic fusion protein based on granzyme B shows in vitro cytotoxicity and ex vivo binding to solid tumors overexpressing the epidermal growth factor receptor

Human cytolytic fusion proteins (hCFPs) offer a promising immunotherapeutic approach for the treatment of solid tumors, avoiding the immunogenicity and undesirable side-effects caused by immunotoxins derived from plants or bacteria. The well-characterized human serine protease granzyme B has already been used as a therapeutic pro-apoptotic effector domain. We therefore developed a novel recombinant hCFP (GbR201K-scFv1711) consisting of an epidermal growth factor receptor-specific human antibody fragment and a granzyme B point mutant (R201K) that is insensitive to serpin B9 (PI9), a natural inhibitor of wild-type granzyme B that is often expressed in solid tumors. We found that GbR201K-scFv1711 selectively bound to epidermoid cancer and rhabdomyosarcoma cells and was rapidly internalized by them. Nanomolar concentrations of GbR201K-scFv1711 achieved the specific killing of epidermoid cancer cells by inducing apoptosis, and similar effects were observed in rhabdomyosarcoma cells when GbR201K-scFv1711 was combined with the endosomolytic substance chloroquine. The novel hCFP was stable in serum and bound to human rhabdomyosarcoma tissue ex vivo. These data confirm that GbR201K-scFv1711 is a promising therapeutic candidate suitable for further clinical investigation

Engineered Versions of Granzyme B and Angiogenin Overcome Intrinsic Resistance to Apoptosis Mediated by Human Cytolytic Fusion Proteins

The use of therapies based on antibody fusion proteins for the selective elimination of tumor cells has increased markedly over the last two decades because the severe side effects associated with conventional chemotherapy and radiotherapy are reduced or even eliminated. However, the initial development of immunotoxins suffered from a number of drawbacks such as nonspecific cytotoxicity and the induction of immune responses because the components were non-human in origin. The most recent iteration of this approach is a new class of targeted human cytolytic fusion proteins (hCFPs) comprising a tumor-specific targeting component such as a human antibody fragment fused to a human effector domain with pro-apoptotic activity. Certain tumors resist the activity of hCFPs by upregulating the intracellular expression of native inhibitors, which rapidly bind and inactivate the human effector domains. Higher doses of the hCFPs are, therefore, required to improve therapeutic efficacy. To circumvent these inhibitory processes, novel isoforms of the enzymes granzyme B and angiogenin have been designed to increase their intrinsic activity and reduce their interactions with native inhibitors resulting in more potent hCFPs that can be applied at lower doses. This chapter summarizes the basic scientific knowledge that can facilitate the rational development of human enzymes with novel and beneficial characteristics, including the ability to avoid neutralization by native inhibitors