Landscape of germline BRCA1/BRCA2 variants in breast and ovarian cancer in Peru

BackgroundThere is an increasing amount of data from Latin America on the characterization of BRCA variants; however, there is limited information from Peru. We conducted a retrospective study to describe germline pathogenic/likely pathogenic(P/LP) variants and variants of uncertain/unknown significance (VUS) in the BRCA1 and BRCA2 genes in Peru, in patients with breast and ovarian cancer, candidates for treatment with poly (adenosine diphosphate–ribose) polymerase (PARP) inhibitors.MethodsThe patients were evaluated during the period 2019-2021. Genomic DNA was isolated from peripheral blood samples and targeted sequencing was performed using the Ampliseq BRCA panel. Genetic variant interpretation was carried out in accordance with the recommendations of the American College of Medical Genetics and ClinVar. During this period, 525 patients (143 with breast cancer and 382 with ovarian cancer) were studied. ResultsWe found that 14.7% (21/143) of breast cancer patients and 20.7% (79/382) of ovarian cancer patients were carriers of P/LP variants in BRCA1/2. The most frequent pathogenic variants detected in BRCA1 were c.2105dupT (BIC: 2224insT, n=12, 18.75%), c.68_69delAG (BIC: 185delAG, n=6, 9.38%), c.140G>T and c.815_824dupAGCCATGTGG (n=5, 7.81%), while in BRCA2 were c.8023A>G (n=6, 16.67%), c.6024dupG (BIC: 6252insG, n=4, 11.11%), and c.9235delG (BIC: 9463delG, n=3, 8.33%). Regarding VUS, we found that 6.99% (10/143) of breast cancer patients and 7.33% (28/382) of ovarian cancer patients were carriers of a VUS in BRCA1/2. For BRCA1, the most frequent VUS was c.93C>G (n=2), and for BRCA2, c.5465A>T (n=4), c.3101T>C (n=3), c.205C>A and c.437T>C (n=2). ConclusionWe found a frequency of 14.7% germline mutations in breast cancer patients and 20.7% in ovarian cancer patients. The most recurrent mutations were BRCA1 c.2105dupT and BRCA2 c.8023A>G. We found that BRCA2 c.8023A>G, c.6024dupG, and c.9235delG were not previously reported in Peruvian patients. BRCA1 c.2344dupA is a novel mutation that has not been previously reported in any database. The frequency of VUS in our cohort was 7.2%

Mesenchymal Stem Cells Delivery in Individuals with Different Pathologies: Multimodal Tracking, Safety and Future Applications

Due to their ease of isolation and their properties, mesenchymal stem cells (MSCs) have been widely investigated. MSCs have been proved capable of migration towards areas of inflammation, including tumors. Therefore, they have been suggested as vectors to carry therapies, specifically to neoplasias. As most of the individuals joining clinical trials that use MSCs for cancer and other pathologies are carefully recruited and do not suffer from other diseases, here we decided to study the safety and application of iv-injected MSCs in animals simultaneously induced with different inflammatory pathologies (diabetes, wound healing and tumors). We studied this by in vitro and in vivo approaches using different gene reporters (GFP, hNIS, and f-Luc) and non-invasive techniques (PET, BLI, or fluorescence). Our results found that MSCs reached different organs depending on the previously induced pathology. Moreover, we evaluated the property of MSCs to target tumors as vectors to deliver adenoviruses, including the interaction between tumor microenvironment and MSCs on their arrival. Mechanisms such as transdifferentiation, MSC fusion with cells, or paracrine processes after MSCs homing were studied, increasing the knowledge and safety of this new therapy for cancer.This research was supported by Instituto de Salud Carlos III (ISCIII) (PI19/01007 and DTS21/00130) and by Fondo Europeo de Desarrollo Regional (Feder) “Una manera de hacer Europa”. We also thank CIBER-BBN and CIBERONC an initiative funded by the VI National R&D&i Plan 2008–2011 financed by the Instituto de Salud Carlos III (ISCIII) with the assistance of the European Regional Development Fund. This study was also partially funded by the Aragon Government (Ph.D. Grant No.r B054/12) and cofounded by Aragon/FEDER 2014–2020 “Building Europe from Aragon”. This research was funded by Spanish Ministerio de Economía y Competitividad and European Regional Development Fund (FEDER) SAF2015-69964-R, RTI2018-099343-B-100 and from the CiberOnc by Instituto de Salud Carlos III (to ADlV).S

Dinámica espacial y temporal de las ocupaciones prehispánicas en la cuenca hidrográfica del rio Limari (30° Lat. S.).

Este trabajo discute la secuencia de desarrollo histórico prehispánico en el Norte Semiárido de Chile a partir del estudio de las dinámicas espaciales y temporales de las ocupaciones humanas en la cuenca hidrográfica del río Limarí. A partir del estudio de asentamientos, materiales depositados en colecciones y arte rupestre se observa una secuencia de transformaciones y desarrollo desde el Arcaico Temprano hasta el período Incaico que diverge de lo tradicionalmente planteado para la región, reconociéndose ritmos de cambios sociales diferenciales dentro de la misma zona, especialmente en relación con la tradicional asociación entre incorporación de cerámica y la constitución de un modo de vida agrícola. La incorporación del arte rupestre permite articular sus características espaciales y representacionales con procesos más amplios, discutiéndose las relaciones establecidas entre dinámicas y cambios sociales con los flujos de información que producen las representaciones rupestres y sus respectivas audiencias.This paper discusses the pre-Hispanic sequence of historical development in the semiarid north of Chile through the study of spatial and temporal dynamics of human occupation in the Limari valley. Based on the study of settlements, museum collections and rock art, a sequence of transformations and development between the Early Archaic and Inca Period is observed that differs from what is traditionally known of the area. In this time frame, social changes such as the adoption of pottery and the constitution of an agrarian way of life, occur at different paces in both time and space within the same Limari valley. We discuss spatial and representational characteristics of rock art in relation to pre-hispanic social processes, emphasizing the links between audiences, flows of information and the dynamics of social life.Fil: Troncoso, Andrés. Universidad de Chile; ChileFil: Vergara, Francisco. No especifica;Fil: Pavlovic, Daniel. Universidad de Chile; ChileFil: González, Paola. No especifica;Fil: Pino, Mariela. No especifica;Fil: Larach, Pablo. No especifica;Fil: Escudero, Antonia. No especifica;Fil: La Mura, Natalia. No especifica;Fil: Moya, Francisca. No especifica;Fil: Pérez, Isidora. No especifica;Fil: Gutiérrez, Renata. No especifica;Fil: Pascual, Daniel. No especifica;Fil: Belmar, Carolina. No especifica;Fil: Basile, Mara Valeria. Universidad de Buenos Aires. Facultad de Filosofía y Letras. Museo Etnográfico "Juan B. Ambrosetti"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: López, Patricio. Universidad de Chile; ChileFil: Dávila, Cristian. No especifica;Fil: Vásquez, María José. No especifica;Fil: Urzúa, Paula. No especifica

Estudio de células troncales mesenquimales para su empleo como vectores en terapias antitumorales: Visualización mediante técnicas de imagen molecular

El cáncer es la enfermedad con mayor tasa de mortalidad en nuestros días, causando una muerte de cada cuatro casos, en USA en el año 2010 (Jemal et al, 2010). A pesar de los avances, muchos tipos de tumores siguen sin posibilidad de un tratamiento eficaz, por lo que la investigación en nuevas terapias es necesario. Las células malignas o tumorales no se encuentran solas, si no que conviven en un complejo microambiente denominado como estroma tumoral (Albini et al, 2007) y que pueden ser caracterizados como ¿heridas que nunca se cierran¿ donde se producen de manera constante una gran cantidad de citoquinas, quimioquinas y otros mediadores inflamatorios que sirven de señales para el reclutamiento de otros tipos celulares, incluidas las células madre mesenquimales (MSCs) y proveyendo los componentes necesarios para la supervivencia del mismo, incluyendo soporte estructural, vascularización y matrices extracelulares (Dvorak et al, 1986). Los esfuerzos actuales para generar una terapia eficaz contra el cáncer consisten en ser capaces de desarrollar estrategias dirigidas a las células tumorales y a cualquier otro elemento del estroma tumoral, en el que se combinen el uso de genes específicos antitumorales y el empleo de vehículos o vectores que se dirijan e incorporen directamente en el tumor (Dai et al, 2011). Las células troncales mesenquimales (MSCs), han generado un gran interés biomédico desde que se descubrieron sus propiedades, constituyéndolas así en una atractiva elección como agentes terapéuticos. Las MSCs son sencillas de obtener, pueden expandirse rápidamente y son fácilmente transfectables, lo que permite su modificación ex vivo. Las MSCs representan un tipo celular inmunologícamente privilegiado debido a que expresan niveles muy bajos del complejo de histocompatibilidad tipo I (MHC I) y no expresan el tipo II (MHC II). Esto permite reducir el riesgo de rechazo en transplantes alogénicos, generando ventajas en el tratamiento de enfermedades donde existe daño o perdida celular como infartos de miocardio, Parkinson, diabetes tipo 1, y enfermedades hepáticas (Loebinger et al, 2011). Recientemente se ha demostrado en diferentes ensayos pre-clínicos, el potencial que tienen las MSCs para migrar de forma específica a zonas tumorales constituyéndose así como una herramienta ideal para su utilización como vehículos de genes y fármacos antitumorales, en una terapia génica y celular combinada (Dwyer and Kerin, 2010). Las condiciones que han de darse para que ocurra este fenómeno, son la producción de moléculas quimio-atrayentes por parte del tumor y la expresión de los receptores correspondientes en las MSCs. Con estos antecedentes establecidos, la presente tesis doctoral tiene como objetivo principal la caracterización y el estudio de la capacidad de migración de las MSCs en diversas patologías, así como las diferencias y colaboración en el estroma tumoral de las MSCs de distintos orígenes para su utilización como vehículos de una posible terapia antitumoral. Se analizará la utilidad del empleo del simporter de yodo y sodio (NIS) como herramienta de visualización y como herramienta terapéutica y las estrategias de mejora en la transferencia génica a las MSCs. Para la consecución de estos objetivos principales, se establecieron los siguientes objetivos específicos: 1. Análisis de la capacidad de migración de las MSCs de forma simultánea, aisladas de un mismo conjunto de animales, a sitios de daños o inflamatorios establecidos en diferentes modelos de patologías. 2. Evaluación del potencial multipotente de cinco líneas de MSCs aisladas de diferentes tejidos (médula ósea, tejido adiposo, epitelio y estroma de endometrio y placenta) bajo los criterios de adherencia a la placa, expresión de un patrón de marcadores y capacidad para diferenciarse in vitro bajo condiciones específicas. 3. Estudiar las diferencias en la capacidad de migración entre las líneas de MSCs en un modelo de tumor mediante visualización con dos técnicas de imagen molecular no invasivas: (i) nanoSPECT/CT; y (ii) MRI. Incluyendo por primera vez MSCs aisladas tanto de epitelio como de estroma de endometrio. 4. Estudiar el efecto generado el microambiente tumoral tras la migración y el injerto de las MSCs, mediante la monitorización del tamaño, análisis histológico de los tumores, efecto en un patrón de genes relacionados con migración y análisis del destino de las MSCs en el microambiente tumoral. 5. Comparación de la capacidad migratoria de las líneas de MSCs con hiPSCs y análisis de los genes típicos de pluripotencia. 6. Ensayar el potencial terapéutico en la reducción del tamaño de los tumores mediante el empleo de MSCs expresando NIS en un protocolo de I131. 7. Evaluar el aumento en los niveles de la tranferencia génica mediada por infección adenoviral en las MSCs mediante el empleo de un compuesto derivado de poletilenimina conjugado con el péptido RGD (PEI-RGD)

Tissue-derived mesenchymal stromal cells used as vehicles for anti-tumor therapy exert different in vivo effects on migration capacity and tumor growth

This is an Open Access article distributed under the terms of the Creative Commons Attribution License.-- et al.[Background]: Mesenchymal stem cells (MSCs) have been promoted as an attractive option to use as cellular delivery vehicles to carry anti-tumor agents, owing to their ability to home into tumor sites and secrete cytokines. Multiple isolated populations have been described as MSCs, but despite extensive in vitro characterization, little is known about their in vivo behavior.The aim of this study was to investigate the efficacy and efficiency of different MSC lineages derived from five different sources (bone marrow, adipose tissue, epithelial endometrium, stroma endometrium, and amniotic membrane), in order to assess their adequacy for cell-based anti-tumor therapies. Our study shows the crucial importance of understanding the interaction between MSCs and tumor cells, and provides both information and a methodological approach, which could be used to develop safer and more accurate targeted therapeutic applications. [Methods]: We first measured the in vivo migration capacity and effect on tumor growth of the different MSCs using two imaging techniques: (i) single-photon emission computed tomography combined with computed tomography (SPECT-CT), using the human sodium iodine symporter gene (hNIS) and (ii) magnetic resonance imaging using superparamagnetic iron oxide. We then sought correlations between these parameters and expression of pluripotency-related or migration-related genes. [Results]: Our results show that migration of human bone marrow-derived MSCs was significantly reduced and slower than that obtained with the other MSCs assayed and also with human induced pluripotent stem cells (hiPSCs). The qPCR data clearly show that MSCs and hiPSCs exert a very different pluripotency pattern, which correlates with the differences observed in their engraftment capacity and with their effects on tumor growth. [Conclusion]: This study reveals differences in MSC recruitment/migration toward the tumor site and the corresponding effects on tumor growth. Three observations stand out: 1) tracking of the stem cell is essential to check the safety and efficacy of cell therapies; 2) the MSC lineage to be used in the cell therapy needs to be carefully chosen to balance efficacy and safety for a particular tumor type; and 3) different pluripotency and mobility patterns can be linked to the engraftment capacity of the MSCs, and should be checked as part of the clinical characterization of the lineage.This work was supported by FIS (PI080750), DGA (PI041/08, B84, PI086/09), MMA Fund (ICS/08/0050), PROMETEO/2008/163; CTQ-2010-20960-C02-02; S2010/BMD-2349, PIPAMER-0912, and PIPAMER-1214. CB-L was funded by fellowships ICS/08/0050 and DGA PI-086/09, GM by PIPAMER-0912, and PMD by the Araid Fund.Peer Reviewe

The initial peopling of Central Western Patagonia (southernmost South America): Late Pleistocene through Holocene site context and archaeological assemblages from Cueva de la Vieja site

This article discusses new data on the initial peopling of Central Western Patagonia based on research conducted at the Cueva de la Vieja site (45°16′27″ S; 71°32′24″ W, 718 masl), contextualizing this event it in the broader Pleistocene human dispersal of southernmost South America. Archaeological excavations and analyses at this cave site were undertaken to address the chronology of the initial settlement of the region, characteristics of the first human presence and subsequent site redundancy. This paper includes a description of the site context based on macro- and microscopic stratigraphy of the excavated section, the characterization of anthropogenic features and a comprehensive radiocarbon-dating program. Archaeological assemblages (i.e., lithics, bones and charred seeds) are used to explain the variations in the human occupation of this venue, with particular emphasis on the earliest materials and occupational surfaces as well as post-depositional processes. The occupation events at Cueva de la Vieja span the last 12,000 calibrated years and indicate, at this point, the earliest securely dated human presence in Central-Western Patagonia, at least one millennium after other thoroughly-dated sites toward the east. This suggests that the initial settlers must have occupied the eastern flank of the Andes at this latitude only after glaciers and other glaciogenetic features retreated and viable ecosystems emerged.Fil: Méndez, César. Centro de Investigación En Ecosistemas de la Patagonia; ChileFil: Nuevo Delaunay, Amalia. Centro de Investigación En Ecosistemas de la Patagonia; ChileFil: Reyes, Omar. Universidad de Magallanes; ChileFil: Ozán, Ivana Laura. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Geociencias Básicas, Aplicadas y Ambientales de Buenos Aires; ArgentinaFil: Belmar, Carolina. Universidad de Chile; ChileFil: López, Patricio. Sociedad Chilena de Arqueología; Chil

Small tombs on the hill: contributions to the knowledge of the early pottery period in the valley of mauro (31 degrees s) from the funebria

MAU085 is an important settlement in the southern section of the Chilean northern semi-arid. Amongst the occupations identified at the site, an Early Ceramic component dated between 1110-740 BP stands out; this component is characterised by the use and production of pottery, structures made of quincha, consumption of wild plants and limited camelid exploitation. New excavations in the site MAU085 identified four funerary contexts, far from the domestic settlement. The burials comprise of structures composed of rocks and fractured grinding stones, bones and lithics. The four individuals buried here were infants, associated to offerings such as pottery, a necklace and a metallic ring. The analyses of these burials and its offerings suggest that the Early Ceramic communities were highly mobile and used non-local technologies

Pequeñas tumbas en la colina: Aportes al conocimiento del período alfarero temprano en El valle de Mauro (31° s) desde la funebria

MAU085 is an important settlement in the southern section of the Chilean northern semi-arid. Amongst the occupations identified at the site, an Early Ceramic component dated between 1110-740 BP stands out; this component is characterised by the use and production of pottery, structures made of quincha, consumption of wild plants and limited camelid exploitation. New excavations in the site MAU085 identified four funerary contexts, far from the domestic settlement. The burials comprise of structures composed of rocks and fractured grinding stones, bones and lithics. The four individuals buried here were infants, associated to offerings such as pottery, a necklace and a metallic ring. The analyses of these burials and its offerings suggest that the Early Ceramic communities were highly mobile and used non-local technologies.El sitio MAU085 corresponde a un asentamiento de gran relevancia para el extremo meridional del Norte Semiárido de Chile. Dentro de las ocupaciones identificadas en el sitio, destaca un componente del Alfarero Temprano datado entre los 1110 hasta los 740 años AP, caracterizado por la utilización de quincha en la elaboración de vasijas y construcción de estructuras, junto a la recolección de plantas silvestres, una escasa explotación de camélidos y uso de vasijas de tamaño pequeño. A partir de nuevas excavaciones realizadas en MAU085, se identificaron cuatro contextos funerarios distantes del área habitacional, carac-terizados por estructuras elaboradas con clastos y soportes de molienda fractu-rados, restos óseos y líticos, junto a piedras sin alteraciones. Estos materiales se encuentran dispuestos sobre los restos de cuatro lactantes y perinatos asociados a ofrendas cerámicas y ajuares como collar y anillo metálico. El análisis de los con-textos, ofrendas y del ajuar respaldan los nuevos antecedentes de grupos alfareros tempranos altamente móviles y con presencia de tecnologías no locale

Increased induction of de novo serum ANCA and ANCA-associated vasculitis after mass vaccination against SARS-CoV-2

Different immune-mediated diseases have been described after SARS-CoV-2 vaccination, with antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV) being one of the possible side effects. In this study, a total of 35 patients presented ANCA for the first time during 2021, with the number during 2019 being 15. Twenty-seven out of thirty-five patients developed ANCA after vaccination. Two of them developed these antibodies after receiving the first dose (7.4%), and 25 patients developed ANCA after the second dose of the vaccine (92.6%), with BNT162b2 being the main vaccine received by these patients. In 97.1% of the patients who developed ANCA during 2021, the positivity of ANCA was accompanied by systemic involvement, with renal and respiratory tracts being the main organs affected. Therefore, an increase in the development of AAV has been observed during 2021 in comparison with 2019, which could be due to the administration of SARS-CoV-2 vaccine.Clinical findingDiseaseHealth science

The E1a Adenoviral Gene Upregulates the Yamanaka Factors to Induce Partial Cellular Reprogramming

The induction of pluripotency by enforced expression of different sets of genes in somatic cells has been achieved with reprogramming technologies first described by Yamanaka’s group. Methodologies for generating induced pluripotent stem cells are as varied as the combinations of genes used. It has previously been reported that the adenoviral E1a gene can induce the expression of two of the Yamanaka factors (c-Myc and Oct-4) and epigenetic changes. Here, we demonstrate that the E1a-12S over-expression is sufficient to induce pluripotent-like characteristics closely to epiblast stem cells in mouse embryonic fibroblasts through the activation of the pluripotency gene regulatory network. These findings provide not only empirical evidence that the expression of one single factor is sufficient for partial reprogramming but also a potential mechanistic explanation for how viral infection could lead to neoplasia if they are surrounded by the appropriate environment or the right medium, as happens with the tumorogenic niche