Reversion of epigenetically mediated BIM silencing overcomes chemoresistance in Burkitt lymphoma

In Burkitt lymphoma/leukemia (BL), achievement of complete remission with first-line chemotherapy remains a challenging issue, as most patients who respond remain disease-free, whereas those refractory have few options of being rescued with salvage therapies. The mechanisms underlying BL chemoresistance and how it can be circumvented remain undetermined. We previously reported the frequent inactivation of the proapoptotic BIM gene in B-cell lymphomas. Here we show that BIM epigenetic silencing by concurrent promoter hypermethylation and deacetylation occurs frequently in primary BL samples and BL-derived cell lines. Remarkably, patients with BL with hypermethylated BIM presented lower complete remission rate (24% vs 79%; P = .002) and shorter overall survival (P = .007) than those with BIM-expressing lymphomas, indicating that BIM transcriptional repression may mediate tumor chemoresistance. Accordingly, by combining in vitro and in vivo studies of human BL-xenografts grown in immunodeficient RAG2(-/-)γc(-/-) mice and of murine B220(+)IgM(+) B-cell lymphomas generated in Eμ-MYC and Eμ-MYC-BIM(+/-) transgenes, we demonstrate that lymphoma chemoresistance is dictated by BIM gene dosage and is reversible on BIM reactivation by genetic manipulation or after treatment with histone-deacetylase inhibitors. We suggest that the combination of histone-deacetylase inhibitors and high-dose chemotherapy may overcome chemoresistance, achieve durable remission, and improve survival of patients with BL

Growth and nutrient absorption of Cape Gooseberry (Physalis Peruviana L.) in soilless culture

"This is an Author's Accepted Manuscript of an article published in [include the complete citation information for the final version of the article as published in the Journal of Plant Nutrition 2015 March, available online at: http://www.tandfonline.com/10.1080/01904167.2014.934474."Cape gooseberry (Physalis peruviana L.) is a solanaceous plant. The growth and time-course of nutrient accumulation of the plant and its partitioning between roots, stems, leaves, and fruits were examined. The study was conducted analyzing two nutrient solutions in soilless culture under greenhouse conditions during two consecutive seasons. The macronutrient contents were analyzed. On average, the yield was 8.9 t.ha(-1). Growth of the plant until 90 d after transplanting obeys an exponential function of time and the relative growth rate for this period was determined. Nitrogen (N) was the element that showed the highest concentration, corresponding to leaves (4.67%), followed by potassium (K) in stems (4.46%). The highest accumulations of N, phosphorous (P), calcium (Ca), and magnesium (Mg) were found in leaves and of K in the stems. Potassium showed the highest nutrient accumulation (29 g.plant(-1)) and the highest specific uptake rate.Torres Rubio, JF.; Pascual Seva, N.; San Bautista Primo, A.; Pascual España, B.; López Galarza, SV.; Alagarda Pardo, J.; Maroto Borrego, JV. (2015). Growth and nutrient absorption of Cape Gooseberry (Physalis Peruviana L.) in soilless culture. Journal of Plant Nutrition. 38(4):485-496. doi:10.1080/01904167.2014.934474S485496384Bellaloui, N., & Brown, P. H. (1998). Plant and Soil, 198(2), 153-158. doi:10.1023/a:1004343031242Bennett, J. P., Oshima, R. J., & Lippert, L. F. (1979). Effects of ozone on injury and dry matter partitioning in pepper plants. Environmental and Experimental Botany, 19(1), 33-39. doi:10.1016/0098-8472(79)90022-4CAUSTON, D. R. (1991). Plant Growth Analysis: The Variability of Relative Growth Rate Within a Sample. Annals of Botany, 67(2), 137-144. doi:10.1093/oxfordjournals.aob.a088112Convenio MAG-IICA (Ministerio de Agricultura y Ganadería. Institución Interamericana de Cooperación para la Agricultura). 2001. The cape gooseberry (Physalis peruvianaL.Physalis edulis). Subprograma de Cooperación Técnica, Ecuador. Available at: http://www.sica.gov.ec/agronegocios/Biblioteca/Convenio%20MAG%20IICA/productos/uvilla_mag.pdf (Accessed July 2007, in Spanish).El-Tohamy, W. A., El-Abagy, H. M., Abou-Hussein, S. D., & Gruda, N. (2009). Response of Cape gooseberry (Physalis peruviana L.) to nitrogen application under sandy soil conditions. Gesunde Pflanzen, 61(3-4), 123-127. doi:10.1007/s10343-009-0211-0Fresquet, J., Pascual, B., López-Galarza, S., Bautista, S., Baixauli, C., Gisbert, J. M., & Maroto, J. V. (2001). Nutrient uptake of pepino plants in soilless cultivation. The Journal of Horticultural Science and Biotechnology, 76(3), 338-343. doi:10.1080/14620316.2001.11511373Heuvelink, E., Bakker, M. J., Elings, A., Kaarsemaker, R. C., & Marcelis, L. F. M. (2005). EFFECT OF LEAF AREA ON TOMATO YIELD. Acta Horticulturae, (691), 43-50. doi:10.17660/actahortic.2005.691.2Leskovar, D. I., & Cantliffe, D. J. (1993). Comparison of Plant Establishment Method, Transplant, or Direct Seeding on Growth and Yield of Bell Pepper. Journal of the American Society for Horticultural Science, 118(1), 17-22. doi:10.21273/jashs.118.1.17Marcelis, L. F. M. (1993). Fruit growth and biomass allocation to the fruits in cucumber. 1. Effect of fruit load and temperature. Scientia Horticulturae, 54(2), 107-121. doi:10.1016/0304-4238(93)90059-yPuente, L. A., Pinto-Muñoz, C. A., Castro, E. S., & Cortés, M. (2011). Physalis peruviana Linnaeus, the multiple properties of a highly functional fruit: A review. Food Research International, 44(7), 1733-1740. doi:10.1016/j.foodres.2010.09.034Radford, P. J. (1967). Growth Analysis Formulae - Their Use and Abuse1. Crop Science, 7(3), 171. doi:10.2135/cropsci1967.0011183x000700030001xRamadan, M. F., & Moersel, J. T. (2007). Impact of enzymatic treatment on chemical composition, physicochemical properties and radical scavenging activity of goldenberry (Physalis peruviana L.) juice. Journal of the Science of Food and Agriculture, 87(3), 452-460. doi:10.1002/jsfa.2728Ramadan, M. F., & Moersel, J.-T. (2009). Oil extractability from enzymatically treated goldenberry (Physalis peruvianaL.) pomace: range of operational variables. International Journal of Food Science & Technology, 44(3), 435-444. doi:10.1111/j.1365-2621.2006.01511.xSalazar, M. R., Jones, J. W., Chaves, B., & Cooman, A. (2008). A model for the potential production and dry matter distribution of Cape gooseberry (Physalis peruviana L.). Scientia Horticulturae, 115(2), 142-148. doi:10.1016/j.scienta.2007.08.015Scholberg, J., McNeal, B. L., Jones, J. W., Boote, K. J., Stanley, C. D., & Obreza, T. A. (2000). Growth and Canopy Characteristics of Field-Grown Tomato. Agronomy Journal, 92(1), 152. doi:10.2134/agronj2000.921152xTrinchero, G. D., Sozzi, G. O., Cerri, A. M., Vilella, F., & Fraschina, A. A. (1999). Ripening-related changes in ethylene production, respiration rate and cell-wall enzyme activity in goldenberry (Physalis peruviana L.), a solanaceous species. Postharvest Biology and Technology, 16(2), 139-145. doi:10.1016/s0925-5214(99)00011-3Turner, A. (1994). Dry Matter Assimilation and Partitioning in Pepper Cultivars Differing in Susceptibility to Stress-induced Bud and Flower Abscission. Annals of Botany, 73(6), 617-622. doi:10.1006/anbo.1994.1077WILLIAMS, R. F. (1946). The Physiology of Plant Growth with Special Reference to the Concept of Net Assimilation Rate. Annals of Botany, 10(1), 41-72. doi:10.1093/oxfordjournals.aob.a083119Zapata, J.L., A. Saldarriaga, M. Londoño, and C. Díaz. 2002. Cape gooseberry Management in Colombia. Antioquia, Colombia: Rionegro, Programa Nacional de Transferencia de Tecnología Agropecuaria - Corpoica Regional Cuatro (in Spanish).Zerihun, A. (2000). Compensatory Roles of Nitrogen Uptake and Photosynthetic N-use Efficiency in Determining Plant Growth Response to Elevated CO2: Evaluation Using a Functional Balance Model. Annals of Botany, 86(4), 723-730. doi:10.1006/anbo.2000.123

Homozygous deletions localize novel tumor suppressor genes in B-cell lymphomas

Integrative genomic and gene-expression analyses have identified amplified oncogenes in B-cell non-Hodgkin lymphoma (B-NHL), but the capability of such technologies to localize tumor suppressor genes within homozygous deletions remains unexplored. Array-based comparative genomic hybridization (CGH) and gene-expression microarray analysis of 48 cell lines derived from patients with different B-NHLs delineated 20 homozygous deletions at 7 chromosome areas, all of which contained tumor suppressor gene targets. Further investigation revealed that only a fraction of primary biopsies presented inactivation of these genes by point mutation or intragenic deletion, but instead some of them were frequently silenced by epigenetic mechanisms. Notably, the pattern of genetic and epigenetic inactivation differed among B-NHL subtypes. Thus, the P53-inducible PIG7/LITAF was silenced by homozygous deletion in primary mediastinal B-cell lymphoma and by promoter hypermethylation in germinal center lymphoma, the proapoptotic BIM gene presented homozygous deletion in mantle cell lymphoma and promoter hypermethylation in Burkitt lymphoma, the proapoptotic BH3-only NOXA was mutated and preferentially silenced in diffuse large B-cell lymphoma, and INK4c/P18 was silenced by biallelic mutation in mantle-cell lymphoma. Our microarray strategy has identified novel candidate tumor suppressor genes inactivated by genetic and epigenetic mechanisms that substantially vary among the B-NHL subtypes

Metabolic engineering to simultaneously activate anthocyanin and proanthocyanidin biosynthetic pathways in Nicotiana spp

[EN] Proanthocyanidins (PAs), or condensed tannins, are powerful antioxidants that remove harmful free oxygen radicals from cells. To engineer the anthocyanin and proanthocyanidin biosynthetic pathways to de novo produce PAs in two Nicotiana species, we incorporated four transgenes to the plant chassis. We opted to perform a simultaneous transformation of the genes linked in a multigenic construct rather than classical breeding or retransformation approaches. We generated a GoldenBraid 2.0 multigenic construct containing two Antirrhinum majus transcription factors (AmRosea1 and AmDelila) to upregulate the anthocyanin pathway in combination with two Medicago truncatula genes (MtLAR and MtANR) to produce the enzymes that will derivate the biosynthetic pathway to PAs production. Transient and stable transformation of Nicotiana benthamiana and Nicotiana tabacum with the multigenic construct were respectively performed. Transient expression experiments in N. benthamiana showed the activation of the anthocyanin pathway producing a purple color in the agroinfiltrated leaves and also the effective production of 208.5 nmol (-) catechin/g FW and 228.5 nmol (-) epicatechin/g FW measured by the p-dimethylaminocinnamaldehyde (DMACA) method. The integration capacity of the four transgenes, their respective expression levels and their heritability in the second generation were analyzed in stably transformed N. tabacum plants. DMACA and phoroglucinolysis/HPLC-MS analyses corroborated the activation of both pathways and the effective production of PAs in T0 and T1 transgenic tobacco plants up to a maximum of 3.48 mg/g DW. The possible biotechnological applications of the GB2.0 multigenic approach in forage legumes to produce "bloatsafe" plants and to improve the efficiency of conversion of plant protein into animal protein (ruminal protein bypass) are discussed.This work was supported by grants BIO2012-39849-C02-01 and BIO2016-75485-R from the Spanish Ministry of Economy and Competitiveness (MINECO) (http://www.idi.mineco.gob.es/portal/site/MICINN) to LAC and a fellowship of the JAE-CSIC program to SF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Fresquet-Corrales, S.; Roque Mesa, EM.; Sarrión-Perdigones, A.; Rochina, M.; López-Gresa, MP.; Díaz-Mula, HM.; Belles Albert, JM.... (2017). Metabolic engineering to simultaneously activate anthocyanin and proanthocyanidin biosynthetic pathways in Nicotiana spp. PLoS ONE. 12(9). https://doi.org/10.1371/journal.pone.0184839Se018483912

Receptor Complementation and Mutagenesis Reveal SR-BI as an Essential HCV Entry Factor and Functionally Imply Its Intra- and Extra-Cellular Domains

HCV entry into cells is a multi-step and slow process. It is believed that the initial capture of HCV particles by glycosaminoglycans and/or lipoprotein receptors is followed by coordinated interactions with the scavenger receptor class B type I (SR-BI), a major receptor of high-density lipoprotein (HDL), the CD81 tetraspanin, and the tight junction protein Claudin-1, ultimately leading to uptake and cellular penetration of HCV via low-pH endosomes. Several reports have indicated that HDL promotes HCV entry through interaction with SR-BI. This pathway remains largely elusive, although it was shown that HDL neither associates with HCV particles nor modulates HCV binding to SR-BI. In contrast to CD81 and Claudin-1, the importance of SR-BI has only been addressed indirectly because of lack of cells in which functional complementation assays with mutant receptors could be performed. Here we identified for the first time two cell types that supported HCVpp and HCVcc entry upon ectopic SR-BI expression. Remarkably, the undetectable expression of SR-BI in rat hepatoma cells allowed unambiguous investigation of human SR-BI functions during HCV entry. By expressing different SR-BI mutants in either cell line, our results revealed features of SR-BI intracellular domains that influence HCV infectivity without affecting receptor binding and stimulation of HCV entry induced by HDL/SR-BI interaction. Conversely, we identified positions of SR-BI ectodomain that, by altering HCV binding, inhibit entry. Finally, we characterized alternative ectodomain determinants that, by reducing SR-BI cholesterol uptake and efflux functions, abolish HDL-mediated infection-enhancement. Altogether, we demonstrate that SR-BI is an essential HCV entry factor. Moreover, our results highlight specific SR-BI determinants required during HCV entry and physiological lipid transfer functions hijacked by HCV to favor infection

The unfolded protein response and its relevance to connective tissue diseases

The unfolded protein response (UPR) has evolved to counter the stresses that occur in the endoplasmic reticulum (ER) as a result of misfolded proteins. This sophisticated quality control system attempts to restore homeostasis through the action of a number of different pathways that are coordinated in the first instance by the ER stress-senor proteins IRE1, ATF6 and PERK. However, prolonged ER-stress-related UPR can have detrimental effects on cell function and, in the longer term, may induce apoptosis. Connective tissue cells such as fibroblasts, osteoblasts and chondrocytes synthesise and secrete large quantities of proteins and mutations in many of these gene products give rise to heritable disorders of connective tissues. Until recently, these mutant gene products were thought to exert their effect through the assembly of a defective extracellular matrix that ultimately disrupted tissue structure and function. However, it is now becoming clear that ER stress and UPR, because of the expression of a mutant gene product, is not only a feature of, but may be a key mediator in the initiation and progression of a whole range of different connective tissue diseases. This review focuses on ER stress and the UPR that characterises an increasing number of connective tissue diseases and highlights novel therapeutic opportunities that may arise

Orius : un auxiliaire efficace contre le thrips en culture de poivron

National audienc

Médicaments et aliments : approche ethnopharmacologique = Medicines and foods : ethnopharmacological approach

This paper presents the first results of a long-term project of research about the folkmedicine of Spanish Comunidad Valenciana. The project aims to develop one of the fields of long tradition - both in research and medical education - at the Departamento de Historia de la Ciencia y Documentacion de Valencia : Valencia's folkmedicine. After 10 years of systematic data collecting, we are now elaborating ethnographic studies as a basis for future comparative ones in order both to complete knowledge about folkmedicine and explore its applications to Spanish health system. Contents of the present paper concern one of the aspects of popular medical practices : the healing herbals people traditionally use to prevent and fight diseases, and they refer to one valencian region, La Ribera Alta. Data about healing plants have been collected through opened-structurated interviews to the population between 1985 and 1991, the sample being 3 per thousand. The paper presents the 34 most frequently used botanical species, out of a total of 127 identified ones belonging to 20 different botanical families. Under each of the species information about frequency, popular names, parts employed, way of preparing and administration, and popular medical uses - mostly empiric ones, but also magic - can be found. These popular medical practices are discussed briefly in the light of La Ribera Alta culture and history. (Résumé d'auteur