28. Intravenous Administration of Lentiviral Vectors Expressing Hyperactive Factor IX Converts Severe Into Mild Hemophilia B in a Canine Model

Lentiviral vectors (LVs) are attractive vehicles for liver-directed gene therapy by virtue of their ability to stably integrate in the genome of target cells and the lack of pre-existing immunity against vector components in most humans. Over the past years, we have developed a LV platform that can achieve stable transgene expression in the liver, induce transgene-specific immune tolerance and establish correction of hemophilia in mouse models upon systemic administration. This LV is designed to stringently target transgene expression to hepatocytes through transcriptional and microRNA-mediated regulation. We then investigated the efficacy and safety profile of portal vein administration of LVs expressing wild-type, codon-optimized (c.o.) or c.o. and hyperactive factor IX (FIX) in a canine model of hemophilia B. We produced large-scale batches of LVs qualified for in vivo administration and treated adult hemophilia B dog by portal vein administration. We observed long-term stable reconstitution of canine FIX activity up to 1% of normal and significant amelioration of the clinical phenotype in 3 treated dogs (>9 years cumulative follow up). LV infusion was associated with transient signs of inflammation and mild hepatotoxicity, which could be abrogated by pretreatment with anti-inflammatory drugs. There was no detectable long-term toxicity or development of FIX inhibitors. In the perspective of clinical translation and to increase therapeutic efficacy, we next treated an 11-kg, hemophilia B dog by peripheral vein administration of LVs expressing the c.o. and hyperactive canine FIX at a 5-fold higher dose than those previously administered. At the current follow-up (3 months after gene therapy) FIX activity is 6-9% of normal. Intravenous LV administration, coupled with a 1-day anti-inflammatory and anti-histamine pre-treatment, induced mild and selflimiting leukopenia and elevation of aminotransferases. Treatment of more hemophilia B dogs is underway to confirm and extend these results. Overall, our studies, which suggest comparable efficacy of LV by both portal and peripheral vein administration, position LV-mediated liver gene therapy for further pre-clinical development and clinical translation. LVs may thus complement other available vectors to address some of the outstanding challenges posed by liver gene therapy of hemophilia and conceivably other diseases

Paleopatología del sacro en cazadores recolectores de Patagonia Austral

El sacro es importante para la estabilidad corporal, la fijación de las extremidades inferiores y la protección de los órganos pélvicos. Este hueso puede verse afectado por patologías de índole congénito, degenerativo o multifactorial. El objetivo del presente estudio es analizar lesiones sacrales en una muestra bien preservada de cazadores-recolectores de Patagonia Austral y la posible influencia de los factores temporo-espaciales y el estilo de vida, con especial atención al momento de contacto nativo-europeo. Se analizaron 56 sacros adultos de ambos sexos fechados en un amplio rango cronológico (5.200 años AP - s. XX), siguiendo la metodología propuesta por Campo (2003, 2015). Las patologías analizadas mostraron que los individuos originarios que habitaron espacios misionales presentaron mayores niveles de prevalencia que sujetos pre-contacto y post-contacto fuera de la misión, excepto en el caso de los nódulos de Schmörl. Los efectos de la edad y el sexo mostraron un patrón similar al observado en otras poblaciones. Se apreció una alta prevalencia de espondilolisis, similar a la observada en Inuits. Debido a la carencia de una metodología estandarizada en la clasificación de la Espina Bífida Oculta -SBO-, este trabajo propone el uso de la propuesta por Kumar y Tubbs (2011).Sacrum is important for body stability, lowerlimbs attachment and pelvic organs protection. This bone could be affected bycongenital, degenerative or multifactorial pathologies. The aim of thepresent study is to analyse sacral lesions in a sample well preserved remainsfrom Southern Patagonian hunter-gatherers and the possible influences oftemporal-spatial and lifestyle variables, with special attention to theNative-European contact effect. Pathological signs from 56 adult sacral bonesfrom both sexes and comprising a wide chronology range (5200 years BP- 20thcentury), were analyzed following the methodology proposed by Campo (2003,2015). Pathologies analysed showed that native individualswho lived at missionary places presented higher lesion prevalence thanpre-contact and post-contact out of mission samples, except for Schmörl nodes. Ageand sex effect showed similar patterns with respect to other populations. Highprevalence of spondylolysis was observed, similarly to Inuit samples.Fil: D'angelo del Campo, Manuel Domingo. Universidad Autónoma de Madrid; EspañaFil: Medialdea, Laura. Universidad Autónoma de Madrid; EspañaFil: García Laborde, Pamela. Universidad Nacional del Centro de la Provincia de Buenos Aires; ArgentinaFil: Salemme, Monica Cira. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Santiago, Fernando Carlos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Austral de Investigaciones Científicas; ArgentinaFil: Campo Martín, Manuel. Universidad Autónoma de Madrid; EspañaFil: González Martín, Armando. Universidad Autónoma de Madrid; EspañaFil: Guichón, Ricardo Anibal. Universidad Nacional del Centro de la Provincia de Buenos Aires; Argentin

Base de Información Bioantropológica de Patagonia Austral (B.I.B.P.A)

The human skeletal remains of Southern Patagonia are scattered throughout numerous European and American institutions. Currently there are more than 1150 individuals in those institutions. Information about the remains and the peer-reviewed published bioanthropological information about each of them have been compiled in the Base de Información Bioantropológica de Patagonia Austral (Southern Patagonian Bioanthropological Information Base). This platform is conceived as a tool that seeks to facilitate and streamline the work of the community of bioanthropologists and other scientists. The database is public and open source, and it is available to both the scientific community and the wider public. It will be updated periodically, with the information that the community generates and makes available to its peers by meansof the various formats that scientists employ to publish their scientific work.Los restos óseos humanos de Patagonia Austral se encuentran dispersos en numerosas instituciones europeas y americanas. Actualmente se contabilizan más de 1150 individuos. Esos sujetos y la información de orden bioantropológica publicada acerca de cada uno de ellos ha sido compilada en la Base de Información Bioantropológica de Patagonia Austral. Esta plataforma se concibe como una herramienta que busca facilitar y agilizar la labor de la comunidad de antropólogos biólogos y afines, de la región. Es de carácter público y código abierto, y se encuentra a disposición tanto de la comunidad científica como de la sociedad. Se actualizará de manera periódica, con la información que la comunidad genere y ponga a disposición de sus pares a través de los diversos formatos que los científicos tienen para difundir su labor científica

Soluble CD154 plasma levels in patients with systemic lupus erythematosus: Modulation by antiphospholipid antibodies

[No abstract available

Early detection, prevention and management of cutaneous adverse events due to sorafenib: Recommendations from the Sorafenib Working Group

Cutaneous adverse events commonly reported with tyrosine kinase inhibitors (TKIs) in the treatment of malignancies, represent an important clinical concern since they can limit the optimal use of these novel drugs. Although there are numerous reports in the literature of these events there are no practical guidelines on how they should be managed. The Sorafenib Working Group (SWG) was established with the objective of developing recommendations to allow the early detection, prevention and management of cutaneous adverse events in everyday clinical practice. The SWG was a multidisciplinary team made up of experts in the field who were closely involved in the sorafenib clinical development program. This review provides an overview of the nature and incidence of cutaneous adverse events which manifest with sorafenib treatment and provides recommendations for their early detection and effective management in clinical practice. (c) 2011 Elsevier Ireland Ltd. All rights reserved