Combining cellular and gene therapy approaches for treatment of intracranial tumors.

New treatments are needed for brain metastasis, which is associated with high morbidity and mortality. Two novel cellular and gene therapy modalities were evaluated in xenograft models for human breast cancer. The individual and especially the combined treatments with alloreactive cytotoxic T lymphocytes and replicating retroviral vectors coding for prodrug activating enzymes followed later with nontoxic prodrug demonstrated efficacy without off-target effects

Soil salinization in marshes : study case: Samborombón Bay wetland, Argentina

En el sector sur de la Bahía de Samborombón (Buenos Aires, Argentina) se desarrolla una extensa marisma que forma un humedal intermareal. En ella se realizaron distintas obras de ingeniería con el fin de evitar el ingreso del flujo mareal y lograr una mayor extensión del área de pastoreo. El objetivo del trabajo es evaluar si la regulación de los flujos mareales ocasiona una modificación en el contenido de cloruros en los sedimentos superficiales, afectando la salinidad de los suelos del humedal. Se realizaron interpretaciones de imágenes satelitales, relevamientos de campo, muestreos de sedimentos y mediciones de niveles y conductividad eléctrica del agua superficial y subterránea. Los resultados obtenidos permitieron reconocer cómo las obras de ingeniería (terraplenes de contención y caminos internos) alteran el comportamiento hidrológico natural y en consecuencia el contenido de cloruros en el sedimento. Problemas de salinización de suelos se reconocen en sectores donde el agua mareal se acumula y luego se evapora formando precipitados de halita. Las futuras obras deberán planificarse de forma tal de minimizar la alteración de los flujos de agua con el fin de lograr un manejo sustentable de los recursos naturales en el humedal.The southern sector of the Samborombón Bay (Buenos Aires, Argentina) is an extensive marsh that is associated with an intertidal wetland environment. Different engineering works were built to avoid tidal inflow and to increase the livestock grazing areas. The objective of this work is to assess if the regulation of tidal inflow causes a chloride content change in the surface sediments, affecting the soil salinity of the wetland. Interpretation of satellite images, field surveys, sampling of sediments, and electrical conductivity and levels measurements of surface and groundwater were carried out. The results allowed us to recognize how engineering works (embankments and internal roads) alter the natural hydrological behavior, and, therefore the chloride content in the sediment. Soil salinization problems are recognized in areas where the tidal water accumulates and then evaporates forming halite precipitates. Future engineering works should be planned so as to minimize the alteration of the water flow in order to achieve a sustainable management of natural resources in the wetland.Fil: Carol, Eleonora S.. Universidad Nacional de La PlataFil: Kruse, Eduardo E.. Universidad Nacional de La PlataFil: Cellone, Francisco A.. Universidad Nacional de La Plat

Salinización de suelos en marismas

En el sector sur de la Bahía de Samborombón (Buenos Aires, Argentina) se desarrolla una extensa marisma que forma un humedal intermareal. En ella se realizaron distintas obras de ingeniería con el fin de evitar el ingreso del flujo mareal y lograr una mayor extensión del área de pastoreo. El objetivo del trabajo es evaluar si la regulación de los flujos mareales ocasiona una modificación en el contenido de cloruros en los sedimentos superficiales, afectando la salinidad de los suelos del humedal. Se realizaron interpre- taciones de imágenes satelitales, relevamientos de campo, muestreos de sedimentos y mediciones de niveles y conductividad eléctrica del agua superficial y subterránea. Los resultados obtenidos permitieron reconocer cómo las obras de ingeniería (terraplenes de contención y caminos internos) alteran el comportamiento hidrológico natural y en consecuencia el contenido de cloruros en el sedimento. Problemas de salinización de suelos se reconocen en sectores donde el agua mareal se acumula y luego se evapora formando precipitados de halita. Las futuras obras deberán planificarse de forma tal de minimizar la alteración de los flujos de agua con el fin de lograr un manejo sustentable de los recursos naturales en el humedal.The southern sector of the Samborombón Bay (Buenos Aires, Argentina) is an extensive marsh that is associated with an intertidal wetland environment. Different engineering works were built to avoid tidal inflow and to increase the livestock grazing areas. The objective of this work is to assess if the regulation of tidal inflow causes a chloride content change in the surface sediments, affecting the soil salinity of the wetland. Interpretation of satellite images, field surveys, sampling of sediments, and electrical conductivity and levels measurements of surface and groundwater were carried out. The results allowed us to recognize how engineering works (embankments and internal roads) alter the natural hydrological behavior, and, therefore the chloride content in the sediment. Soil salinization problems are recognized in areas where the tidal water accumulates and then evaporates forming halite precipitates. Future engineering works should be planned so as to minimize the alteration of the water flow in order to achieve a sustainable management of natural resources in the wetland

Salinización de suelos en marismas. Caso de estudio: Humedal de la Bahía Samborombón, Argentina

The southern sector of the Samborombón Bay (Buenos Aires, Argentina) is an extensive marsh that is associated with an intertidal wetland environment. Different engineering works were built to avoid tidal inflow and to increase the livestock grazing areas. The objective of this work is to assess if the regulation of tidal inflow causes a chloride content change in the surface sediments, affecting the soil salinity of the wetland. Interpretation of satellite images, field surveys, sampling of sediments, and electrical conductivity and levels measurements of surface and groundwater were carried out. The results allowed us to recognize how engineering works (embankments and internal roads) alter the natural hydrological behavior, and, therefore the chloride content in the sediment. Soil salinization problems are recognized in areas where the tidal water accumulates and then evaporates forming halite precipitates. Future engineering works should be planned so as to minimize the alteration of the water flow in order to achieve a sustainable management of natural resources in the wetland.En el sector sur de la Bahía de Samborombón (Buenos Aires, Argentina) se desarrolla una extensa marisma que forma un humedal intermareal. En ella se realizaron distintas obras de ingeniería con el fin de evitar el ingreso del flujo mareal y lograr una mayor extensión del área de pastoreo. El objetivo del trabajo es evaluar si la regulación de los flujos mareales ocasiona una modificación en el contenido de cloruros en los sedimentos superficiales, afectando la salinidad de los suelos del humedal. Se realizaron interpretaciones de imágenes satelitales, relevamientos de campo, muestreos de sedimentos y mediciones de niveles y conductividad eléctrica del agua superficial y subterránea. Los resultados obtenidos permitieron reconocer cómo las obras de ingeniería (terraplenes de contención y caminos internos) alteran el comportamiento hidrológico natural y en consecuencia el contenido de cloruros en el sedimento. Problemas de salinización de suelos se reconocen en sectores donde el agua mareal se acumula y luego se evapora formando precipitados de halita. Las futuras obras deberán planificarse de forma tal de minimizar la alteración de los flujos de agua con el fin de lograr un manejo sustentable de los recursos naturales en el humedal

Retroviral replicating vector-mediated gene therapy achieves long-term control of tumor recurrence and leads to durable anticancer immunity.

BackgroundProdrug-activator gene therapy with Toca 511, a tumor-selective retroviral replicating vector (RRV) encoding yeast cytosine deaminase, is being evaluated in recurrent high-grade glioma patients. Nonlytic retroviral infection leads to permanent integration of RRV into the cancer cell genome, converting infected cancer cell and progeny into stable vector producer cells, enabling ongoing transduction and viral persistence within tumors. Cytosine deaminase in infected tumor cells converts the antifungal prodrug 5-fluorocytosine into the anticancer drug 5-fluorouracil, mediating local tumor destruction without significant systemic adverse effects.MethodsHere we investigated mechanisms underlying the therapeutic efficacy of this approach in orthotopic brain tumor models, employing both human glioma xenografts in immunodeficient hosts and syngeneic murine gliomas in immunocompetent hosts.ResultsIn both models, a single injection of replicating vector followed by prodrug administration achieved long-term survival benefit. In the immunodeficient model, tumors recurred repeatedly, but bioluminescence imaging of tumors enabled tailored scheduling of multicycle prodrug administration, continued control of disease burden, and long-term survival. In the immunocompetent model, complete loss of tumor signal was observed after only 1-2 cycles of prodrug, followed by long-term survival without recurrence for >300 days despite discontinuation of prodrug. Long-term survivors rejected challenge with uninfected glioma cells, indicating immunological responses against native tumor antigens, and immune cell depletion showed a critical role for CD4+ T cells.ConclusionThese results support dual mechanisms of action contributing to the efficacy of RRV-mediated prodrug-activator gene therapy: long-term tumor control by prodrug conversion-mediated cytoreduction, and induction of antitumor immunity

Expressions 1993-1994

https://openspace.dmacc.edu/expressions/1015/thumbnail.jp

Assessing associations between the AURKAHMMR-TPX2-TUBG1 functional module and breast cancer risk in BRCA1/2 mutation carriers

While interplay between BRCA1 and AURKA-RHAMM-TPX2-TUBG1 regulates mammary epithelial polarization, common genetic variation in HMMR (gene product RHAMM) may be associated with risk of breast cancer in BRCA1 mutation carriers. Following on these observations, we further assessed the link between the AURKA-HMMR-TPX2-TUBG1 functional module and risk of breast cancer in BRCA1 or BRCA2 mutation carriers. Forty-one single nucleotide polymorphisms (SNPs) were genotyped in 15,252 BRCA1 and 8,211 BRCA2 mutation carriers and subsequently analyzed using a retrospective likelihood appr

Oxidative discolouration in whole-head and cut lettuce: biochemical and environmental influences on a complex phenotype and potential breeding strategies to improve shelf-life

Lettuce discolouration is a key post-harvest trait. The major enzyme controlling oxidative discolouration has long been considered to be polyphenol oxidase (PPO) however, levels of PPO and subsequent development of discolouration symptoms have not always correlated. The predominance of a latent state of the enzyme in plant tissues combined with substrate activation and contemporaneous suicide inactivation mechanisms are considered as potential explanations for this phenomenon. Leaf tissue physical properties have been associated with subsequent discolouration and these may be influenced by variation in nutrient availability, especially excess nitrogen and head maturity at harvest. Mild calcium and irrigation stress has also been associated with a reduction in subsequent discolouration, although excess irrigation has been linked to increased discolouration potentially through leaf physical properties. These environmental factors, including high temperature and UV light intensities, often have impacts on levels of phenolic compounds linking the environmental responses to the biochemistry of the PPO pathway. Breeding strategies targeting the PALand PPOpathway biochemistry and environmental response genes are discussed as a more cost-effective method of mitigating oxidative discolouration then either modified atmosphere packaging or post-harvest treatments, although current understanding of the biochemistry means that such programs are likely to be limited in nature and it is likely that they will need to be deployed alongside other methods for the foreseeable future

Identification of six new susceptibility loci for invasive epithelial ovarian cancer.

Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.COGS project is funded through a European Commission's Seventh Framework Programme grant (agreement number 223175 ] HEALTH ]F2 ]2009 ]223175). The CIMBA data management and data analysis were supported by Cancer Research.UK grants 12292/A11174 and C1287/A10118. The Ovarian Cancer Association Consortium is supported by a grant from the Ovarian Cancer Research Fund thanks to donations by the family and friends of Kathryn Sladek Smith (PPD/RPCI.07). The scientific development and funding for this project were in part supported by the US National Cancer Institute GAME ]ON Post ]GWAS Initiative (U19 ]CA148112). This study made use of data generated by the Wellcome Trust Case Control consortium. Funding for the project was provided by the Wellcome Trust under award 076113. The results published here are in part based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancer Institute and National Human Genome Research Institute (dbGap accession number phs000178.v8.p7). The cBio portal is developed and maintained by the Computational Biology Center at Memorial Sloan ] Kettering Cancer Center. SH is supported by an NHMRC Program Grant to GCT. Details of the funding of individual investigators and studies are provided in the Supplementary Note. This study made use of data generated by the Wellcome Trust Case Control consortium, funding for which was provided by the Wellcome Trust under award 076113. The results published here are, in part, based upon data generated by The Cancer Genome Atlas Pilot Project established by the National Cancerhttp://dx.doi.org/10.1038/ng.3185This is the Author Accepted Manuscript of 'Identification of six new susceptibility loci for invasive epithelial ovarian cancer' which was published in Nature Genetics 47, 164–171 (2015) © Nature Publishing Group - content may only be used for academic research