Determinantes de la osteoporosis posmenopáusica: aspectos genéticos e inmunológicos y modulación por diferentes tratamientos

La pérdida ósea acelerada puede desencadenar en osteoporosis, una enfermedad esquelética caracterizada por una menor resistencia ósea y riesgo aumentado de fractura. Es la enfermedad metabólica más prevalente entre la población femenina ya que afecta al 35% de las mujeres españolas mayores de 50 años, y por lo tanto es un problema de salud pública muy importante. El tipo de osteoporosis más frecuente es la osteoporosis posmenopáusica, una enfermedad multigénica que se inicia con la retirada de la protección estrogénica. No obstante, a pesar de que todas las mujeres aceleran su tasa de pérdida ósea con la menopausia, no todas desarrollarán osteoporosis en el futuro. La causa hay que buscarla en el pico de masa ósea alcanzado por cada mujer y que está determinado principalmente por factores genéticos. Históricamente, los factores genéticos se han buscado en genes que regulan el metabolismo óseo y en genes de diversas citoquinas. Recientemente, se ha descrito la relación que existe entre el sistema inmune con la pérdida ósea, debida a la deficiencia estrogénica, y con la regulación ósea basal. De hecho, se ha relacionado la participación de células T, células B, monocitos, incluso de células dendríticas, con la osteoporosis. En este trabajo de Tesis Doctoral se ha estudiado la asociación a masa ósea de genes importantes en el metabolismo óseo, como RUNX2, y otros genes relacionados con el sistema inmune, como OCIL, CD40 y CD40L, en una población de mujeres posmenopáusicas. Debido a que la principal causa de la osteoporosis es la deficiencia estrogénica, el tratamiento más utilizado para esta patología ha sido la terapia hormonal sustitutiva (THS) mediante la administración de estrógenos. Pese a los efectos beneficiosos de la THS en el hueso, se ha descrito diversos efectos adversos, como el aumento en el riesgo de cáncer de mama o alteraciones cardiovasculares, que han llevado a la búsqueda de alternativas terapéuticas a la THS. Entre las alternativas terapéuticas utilizadas actualmente, encontramos compuestos agonistas del receptor de estrógenos, como los moduladores selectivos del receptor de estrógenos (raloxifeno) y fitoestrógenos (genisteina), y también extractos vegetales (Cimicífuga racemosa). En el presente trabajo de Tesis Doctoral se ha estudiado, comparativamente, el efecto sobre la pérdida de hueso y microestructura ósea, mediante micro-TC, de la administración del estradiol, el raloxifeno y la genisteina en el ratón ovariectomizado como modelo animal de pérdida ósea. Asimismo, también se ha evaluado en una población pequeña de mujeres posmenopáusicas, el efecto sobre el metabolismo óseo de un extracto isopropanólico vegetal de Cimicífuga racemosa (Remifemin).Osteoporosis is a disease characterized by the progressive loss of bone mineral density (BMD) that may compromise bone strength leading to an increased risk of fracture. Although osteoporosis affects an elevated percentage not only of women but also of men, the most frequent form of the disease is the postmenopausal osteoporosis associated with the estrogenic deficiency that occurs in the menopause. Genetic factors have been recognized as playing an important role in the pathogenesis of osteoporosis, although, as a multifactorial disease, it is influenced by other parameters such diet, physical activity, medication use and lifestyle. Twin and family studies have demonstrated a high heritability of BMD. Most of the genetic studies have been focused on genes than regulated the bone metabolism and on several citoquines. Recently, the immune system have been associated with the posmenopausal osteoporosis. In fact, the participation of T cells, B cells, monocytes and dendritic cells have been related with osteoporosis. In this doctoral thesis work we have analyzed the association with BMD of polymorphisms in bone metabolism genes, as RUNX2, and other genes related with the immune system, as OCIL, CD40 and CD40L. The hormone replacement (HRT), with the estrogen administration, has been the main treatment used in the postmenopausal osteoporosis to prevent bone loss. However, there were some studies that have demonstrated some adverse effects in the HRT as cancer and cardiovascular risk. Therefore, attention has been centered on other therapeutic possibilities with lesser side-effects. Among the alternative treatments we can list the estrogen receptor agonist, as the selective estrogen receptor modulators (raloxifene) and phytoestrogens (genistein), as well as vegetable extracts (Cimicífuca racemosa). In this work, we also have studied the effect of estradiol, raloxifene and genistein administration on bone loss and bone microarchitecture in an animal model of accelerated bone loss by using ovariectomized young female mice. Likewise, we studied the effect of an isopropanolic extract of Cimicífiga racemosa on the bone metabolism in a group of postmenopausal women

Percepción de problemas ambientales por las administraciones locales. Comunidad Autónoma de Madrid

Depto. de Biodiversidad, Ecología y EvoluciónFac. de Ciencias BiológicasTRUEpu

Production of engineered long-life and male sterile Pelargonium plants

[EN] Background: Pelargonium is one of the most popular garden plants in the world. Moreover, it has a considerable economic importance in the ornamental plant market. Conventional cross-breeding strategies have generated a range of cultivars with excellent traits. However, gene transfer via Agrobacterium tumefaciens could be a helpful tool to further improve Pelargonium by enabling the introduction of new genes/traits. We report a simple and reliable protocol for the genetic transformation of Pelargonium spp. and the production of engineered long-life and male sterile Pelargonium zonale plants, using the pSAG12::ipt and PsEND1::barnase chimaeric genes respectively. Results: The pSAG12::ipt transgenic plants showed delayed leaf senescence, increased branching and reduced internodal length, as compared to control plants. Leaves and flowers of the pSAG12::ipt plants were reduced in size and displayed a more intense coloration. In the transgenic lines carrying the PsEND1::barnase construct no pollen grains were observed in the modified anther structures, which developed instead of normal anthers. The locules of sterile anthers collapsed 3¿4 days prior to floral anthesis and, in most cases, the undeveloped anther tissues underwent necrosis. Conclusion: The chimaeric construct pSAG12::ipt can be useful in Pelargonium spp. to delay the senescence process and to modify plant architecture. In addition, the use of engineered male sterile plants would be especially useful to produce environmentally friendly transgenic plants carrying new traits by preventing gene flow between the genetically modified ornamentals and related plant species. These characteristics could be of interest, from a commercial point of view, both for pelargonium producers and consumers.This work was funded by grants AGL2009-13388-C03-01 and BIO2009-08134 from the Spanish Ministry of Science and Innovation (MICINN). We acknowledge support of the publication fee by the CSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI). In the past five years we have received funding from the Spanish Ministry of Science and Innovation (MICINN) and the article-processing charge will be pay with funds from two granted projects. The authors received salaries from two different institutions: The Polytechnic University of Valencia (UPV) or the High Spanish Council of Scientific Research (CSIC). We are not currently applying for a patent related with the content of this manuscript. All the mentioned organisms/institutions do not gain or lose financially from the publication of this manuscript either now or in the future.García Sogo, B.; Pineda Chaza, BJ.; Roque Mesa, EM.; Antón Martínez, MT.; Atarés Huerta, A.; Borja, M.; Beltran Porter, JP.... (2012). Production of engineered long-life and male sterile Pelargonium plants. BMC Plant Biology. 12:156-171. https://doi.org/10.1186/1471-2229-12-1561561711

Phylogenetic relationships and genetic diversity among Orobanche cumana Wallr. and O. cernua L. (Orobanchaceae) populations in the Iberian Peninsula

Orobanche cumana is found in the Iberian Peninsula as an allochthonous species parasitizing exclusively sunflower, in contrast to the closely related species Orobanche cernua, which is an autochthonous species that only parasitizes wild Asteraceae hosts. Ten O. cumana populations were collected in the two traditional areas of sunflower broomrape occurrence, the Guadalquivir Valley, Southern Spain (six populations) and Cuenca province, Central Spain (four populations). Twelve O. cernua populations were collected on wild hosts across its natural distribution area in Southeastern Spain. Genetic relationships within and between both sets of populations were studied using a set of 50 robust and co-dominant SSR markers from O. cumana. The results supported the taxonomic separation of the two species and the existence of two distant genetic groups for O. cumana, one in Guadalquivir Valley and another one in Cuenca province. The inter- and intra-population variability was extremely low for O. cumana, whereas the overall genetic diversity was much higher for O. cernua. The genetic structure of O. cumana populations probably reflects a founder effect, with the two genetically distant groups deriving from separate introduction events. The high degree of genetic differentiation observed in O. cernua is mainly explained on the basis of restricted gene flow due to ecological barriers together with the occurrence of a predominantly self-pollinating mating system. Complementary diversity studies on both species in its current distribution area are required for understanding global genetic variability and evolutionary characteristics of the parasitism.The study was partially funded by Fundación Ramón Areces, Madrid, Spain. R. Pineda-Martos was the recipient of a Ph.D. fellowship from the Spanish National Research Council (CSIC) (JAEPre_08_00370).Peer Reviewe

Nuevo cultivar con frutos y sépalos convertidos en frutos de alto interés para su consumo fresco y procesado industrial

Número de publicación: 2 341 527 21 Número de solicitud: 200900003 51 Int. Cl.: C12N 15/82 (2006.01) A01H 5/00 (2006.01Nuevo cultivar con frutos y sépalos convertidos en frutos de alto interés para su consumo fresco y procesado industrial. En la presente invención se describen secuencias de nucleótidos capaces de incrementar la expresión de un gen de desarrollo reproductivo lo que tiene como resultado la generación de cultivares con un fruto de alto interés para su consumo fresco y procesado industrial caracterizado por poseer características mejoradas respecto de los cultivares conocidos de variedades comerciales. Estos nuevos cultivares tienen el cáliz de la flor carnoso y convertido en fruto. El fruto verdadero y el cáliz tienen mayores niveles de azúcares y licopeno y un mayor contenido en grados Brix. Además, exhiben una mayor tasa de cuajado de fruto y tienen inhibida la zona de abscisión del fruto, lo que facilita la recolección mecánica.Universidad de Almerí

Genetic studies in sunflower broomrape

Much research has been conducted to identify sources of genetic resistance to sunflower broomrape (Orobanche cumana Wallr.) and to study their mode of inheritance. However, studies on the parasite have been scarce. This manuscript reviews three genetic studies in sunflower broomrape. First, the inheritance of the absence of pigmentation in a natural mutant of this species with yellow plant color phenotype was studied. In a first stage, lines from the unpigmented mutant and a normally pigmented population were developed by several generations of self-pollination. Plants of both lines were crossed and the F1, F2, and F3 generations were evaluated. The results indicated that plant pigmentation is controlled by a partially dominant allele at a single locus. Second, the unpigmented mutant was used to evaluate outcrossing potential of the species. Two experiments in which single unpigmented plants were surrounded by normally pigmented plants were conducted under pot and field conditions. The cross-fertilization rate was estimated as the percentage of F1 hybrids in the progenies of unpigmented plants, which averaged 21.5% in the pot and 28.8% in the field experiment. The results indicated that, under the conditions of this study, the species was not strictly self-pollinated. Finally, the inheritance of avirulence was studied in crosses of plants from lines of O. cumana races E and F, developed by several generations of self-pollination. The F1 and F3 generations were evaluated on the differential line P-1380 carrying the race-E resistance gene Or5. The results suggested that race E avirulence and race F virulence on P-1380 are allelic and controlled by a single locus, which confirmed the gene-for-gene theory for the O. cumana-sunflower interaction.The manuscript reviews research partially funded by Fundación Ramón Areces, Madrid. The contribution of Dr. Enrique Quesada Moraga, entomologist from the University of Córdoba, Spain, to taxonomic classification of pollinators is gratefully acknowledged. R. Pineda-Martos was the recipient of a PhD fellowship from the Spanish National Research Council (CSIC) (JAEPre_08_00370)Peer Reviewe

SEOM clinical guideline on heritable TP53-related cancer syndrome (2022)

Li-Fraumeni syndrome; Cancer; Pathogenic variantsSíndrome de Li-Fraumeni; Cáncer; Variantes patogénicasSíndrome de Li-Fraumeni; Càncer; Variants patogèniquesLi-Fraumeni syndrome is caused by heterozygous germline pathogenic variants in the TP53 gene. It involves a high risk of a variety of malignant tumors in childhood and adulthood, the main ones being premenopausal breast cancer, soft tissue sarcomas and osteosarcomas, central nervous system tumors, and adrenocortical carcinomas. The variability of the associated clinical manifestations, which do not always fit the classic criteria of Li-Fraumeni syndrome, has led the concept of SLF to extend to a more overarching cancer predisposition syndrome, termed hereditable TP53-related cancer syndrome (hTP53rc). However, prospective studies are needed to assess genotype–phenotype characteristics, as well as to evaluate and validate risk-adjusted recommendations. This guideline aims to establish the basis for interpreting pathogenic variants in the TP53 gene and provide recommendations for effective screening and prevention of associated cancers in carrier individuals

A two-gene epigenetic signature for the prediction of response to neoadjuvant chemotherapy in triple-negative breast cancer patients

Background: pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature. Methods: epigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines. Results: twenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805-1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative. Conclusions: these results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted

Alq mutation increases fruit set rate and allows the maintenance of fruit yield under moderate saline conditions

[EN] Arlequin (Alq) is a gain-of-function mutant whose most relevant feature is that sepals are able to become fruit-like organs due to the ectopic expression of the ALQ-TAGL1 gene. The role of this gene in tomato fruit ripening was previously demonstrated. To discover new functional roles for ALQ-TAGL1, and most particularly its involvement in the fruit set process, a detailed characterization of Alq yield-related traits was performed. Under standard conditions, the Alq mutant showed a much higher fruit set rate than the wild type. A significant percentage of Alq fruits were seedless. The results showed that pollination-independent fruit set in Alq is due to early transition from flower to fruit. Analysis of endogenous hormones in Alq suggests that increased content of cytokinins and decreased level of abscisic acid may account for precocious fruit set. Comparative expression analysis showed relevant changes of several genes involved in cell division, gibberellin metabolism, and the auxin signalling pathway. Since pollination-independent fruit set may be a very useful strategy for maintaining fruit production under adverse conditions, fruit set and yield in Alq plants under moderate salinity were assessed. Interestingly, Alq mutant plants showed a high yield under saline conditions, similar to that of Alq and the wild type under unstressed conditions.This work was supported by the research grants AGL2015-64991-C3-3-R and AGL2015-64991-C3-1-R from the Spanish Ministry of Economy and Competitiveness (MINECO/FEDER). The PhD grant to CRA (BES-2013-063778) was funded by the Spanish Ministry of Economy and Competitiveness.The authors thank Dr Isabel Lopez-Diaz and Dr Esther Carrera for their help in hormone quantification carried out at the Plant Hormone Quantification Service, IBMCP,Valencia, Spain. The authors thank David Harry Rhead for reviewing the manuscript in the English language.Ribelles Alfonso, C.; García Sogo, B.; Yuste-Lisbona, FJ.; Atarés Huerta, A.; Castañeda, L.; Capel, C.; Lozano, R.... (2019). Alq mutation increases fruit set rate and allows the maintenance of fruit yield under moderate saline conditions. Journal of Experimental Botany. 70(20):5731-5744. https://doi.org/10.1093/jxb/erz342S57315744702

Relationship of sclerostin and secreted frizzled protein polymorphisms with bone mineral density: an association study with replication in postmenopausal women

Objectives.- Secreted frizzled-related protein and sclerostin, encoded by FRZB and SOST genes, respectively, are extracellular Wnt inhibitors that tend to decrease bone formation. The purpose of this study was to explore the association of sets of polymorphisms capturing common variations of these genes with bone mineral density (BMD). Methods.- Twelve polymorphic loci of the FRZB gene and 7 of the SOST gene were genotyped in postmenopausal women from two Spanish regions (Cantabria, n=1043, and Valencia, n=342). The polymorphisms included tagging SNPs and SNPs with possible functional consequences assessed in silico. Results.-The rs4666865 polymorphism of the FRZB gene was associated with spine BMD in the Cantabria cohort in the single-locus (p=0.008) and the haplotypic analysis. However, the results were not replicated in the Valencia cohort. Several polymorphisms at the 5´region of the SOST gene, and particularly rs851056, were associated with BMD in women from both cohorts (p=0.002 in Cantabria and 0.005 in Valencia). When the results of both cohorts were combined, the mean BMD difference across rs851056 genotypes was 47 mg/cm2 or 0.31 standard deviations (p<0.001). No differences in FRZB and SOST expression was detected across genotypes. Conclusions.- Polymorphisms in the 5’ region of SOST gene are associated with BMD in postmenopausal women, and consequently contribute to explain in part the hereditary influence on bone mass