Unraveling the role of fibroblasts, FGF5 and FGFR2 in HER2-targeted therapies resistance and tumor progression

The majority of women with HER2-positive breast cancer will initially respond to trastuzumab and/or other HER2-targeted therapies such as pertuzumab, lapatinib, neratinib and trastuzumab emtansine (T-DM1). However [...]

Comportamiento del Hidroximetilfurfural y de la actividad diastásica en mieles monoflorales españolas

[ES] El hidroximetilfurfural (HMF) y la actividad diastásica son parámetros reconocidos internacionalmente como indicadores de la perdida de frescura de la miel, por ello sus niveles están establecidos en la legislación española (BOE, Real Decreto 1049/2003). Las mieles frescas, recién recolectadas y no procesadas tienen valores altos de actividad diastásica y bajos de HMF. El origen botánico de las plantas de las que proceden las mieles podría influir en los valores de estos parámetros de calidad. En este sentido, el objetivo de este trabajo es evaluar la influencia del tipo de miel monofloral española en los niveles de actividad diastásica y HMF de mieles frescas. El presente trabajo forma una parte de la segunda anualidad de un estudio que LABMIEL (laboratorio de la miel y los productos apícolas de la UPV) está realizando con el MAPA (Ministerio de Agricultura Pesca y Alimentación) (BOE núm.150, 2018). El HMF se ha evaluado por el método oficial (espectrofotometría) y por cromatografía líquida (HPLC) mientras que la actividad diastásica se ha analizado mediante el método Phadebas. Los resultados de HMF solo han mostrado diferencias significativas entre ambos métodos en el caso de la miel de tomillo. Solo para esta variedad se obtuvieron datos anómalos mediante el método espectrofotométrico. Este hecho cuestiona la validez del método oficial para evaluar el HMF en esta variedad de miel. Los valores de actividad diastásica se han encontrado, en general, en el rango de lo que cabría esperar para las mieles estudiadas, mostrando mayores valores en las mieles de girasol seguido de las de cantueso, romero y azahar. Teniendo en cuenta las dos campañas comparadas (2018 y 2019), en general en la de 2019 se observaron mejores valores medios para los dos parámetros estudiados. Este hecho se podría explicar por un mejor manejo en las prácticas apícolas en la cosecha de 2019.[EN] Hydroxymethylfurfural (HMF) and diastatic activity are internationally recognized parameters as indicators of the loss of freshness of honey and their levels are established in the Spanish legislation (BOE, Royal Decree 1049/2003). Raw honey has high values of diastatic activity and low HMF. The botanical origin of the plants visited by beehoneys could influence the values of these quality parameters. In this sense, the objective of this work is to evaluate the influence of the Spanish monofloral type of honey on the levels of diastatic activity and HMF of raw honey. This work is part of the second year of a study that LABMIEL (laboratory of honey and bee products of the UPV) is carrying out together with the MAPA (Ministerio de Agricultura Pesca y Alimentación) (BOE No. 150, 2018). The HMF was evaluated by the official method (spectrophotometry) and by liquid chromatography (HPLC), while the diastase activity was analyzed using the Phadebas method. HMF showed only significant differences between both methods in the case of thyme honey. Only for this variety, anomalous data were obtained using the spectrophotometric method. This fact questions the validity of the official method to evaluate the HMF in this type of honey. Generally speaking, the values of diastatic activity were found in the range of what would be expected for the different types of honey studied, showing higher values in sunflower honey followed by cantueso, rosemary and orange blossom. Taking into account the two years studies compared (2018 and 2019), 2019 showed in general terms better average values for the two parameters studied. This fact could be explained by a better management of beekeeping practices in the 2019 harvest.Burguillo Carbó, N. (2019). Comportamiento del Hidroximetilfurfural y de la actividad diastásica en mieles monoflorales españolas. http://hdl.handle.net/10251/133681TFG

Verifying the biocontrol activity of novel film‐forming formulations of Candida sake CPA‐1: resilience in relation to environmental factors, rainfall episodes, and control of Botrytis cinerea on different hosts

BACKGROUND The efficacy of Candida sake CPA‐1 as a biocontrol agent against several diseases has been studied since it was isolated 20 years ago. However, it was only recently that two suitable and effective film‐forming formulations based on potato starch and maltodextrins were developed using the fluidized‐bed spray‐drying system. The present work aimed to confirm the capability of both novel formulations by testing their resilience on grapes at different temperatures (0, 22, and 30 °C), relative humidities (40% and 85%), and simulated rainfall levels. Another objective was to examine the control of Botrytis cinerea in different hosts. RESULTS The CPA‐1 cells from both dried formulations survived better than the liquid formulation on grapes stored at 0 and 22 °C regardless of the relative humidity. After simulated rainfall, potato starch formulation achieved significantly higher populations than maltodextrin formulation, although the highest reduction was −1.6 log N N0−1. A positive effect of cell establishment prior to the simulated rainfall was shown, and recovered cells from the potato starch formulation were significantly higher after 72 h of cell establishment. Finally, both formulations reduced the incidence and severity of B. cinerea on pears, apples, and tomatoes. CONCLUSION The potential of these novel film‐forming formulations of C. sake CPA‐1 was verified. The resilience of formulated C. sake was better than the commercialized liquid formulation, the adherence of the formulations to the grapes improved after an establishment period prior to rain exposure, and the control of B. cinerea was verified in a wider range of hosts. © 2019 Society of Chemical Industryinfo:eu-repo/semantics/acceptedVersio

In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cance

Muscle protein waste in tumor-bearing rats is effectively antagonized by a beta 2-adrenergic agonist (clenbuterol). Role of the ATP-ubiquitin-dependent proteolytic pathway.

Tissue protein hypercatabolism (TPH) is a most important feature in cancer cachexia, particularly with regard to the skeletal muscle. The rat ascites hepatoma Yoshida AH-130 is a very suitable model system for studying the mechanisms involved in the processes that lead to tissue depletion, since it induces in the host a rapid and progressive muscle waste mainly due to TPH (Tessitore, L., G. Bonelli, and F. M. Baccino. 1987. Biochem. J. 241:153-159). Detectable plasma levels of tumor necrosis factor-alpha associated with marked perturbations in the hormonal homeostasis have been shown to concur in forcing metabolism into a catabolic setting (Tessitore, L., P. Costelli, and F. M. Baccino. 1993. Br. J. Cancer. 67:15-23). The present study was directed to investigate if beta 2-adrenergic agonists, which are known to favor skeletal muscle hypertrophy, could effectively antagonize the enhanced muscle protein breakdown in this cancer cachexia model. One such agent, i.e., clenbuterol, indeed largely prevented skeletal muscle waste in AH-130-bearing rats by restoring protein degradative rates close to control values. This normalization of protein breakdown rates was achieved through a decrease of the hyperactivation of the ATP-ubiquitin-dependent proteolytic pathway, as previously demonstrated in our laboratory (Llovera, M., C. García-Martínez, N. Agell, M. Marzábal, F. J. López-Soriano, and J. M. Argilés. 1994. FEBS (Fed. Eur. Biochem. Soc.) Lett. 338:311-318). By contrast, the drug did not exert any measurable effect on various parenchymal organs, nor did it modify the plasma level of corticosterone and insulin, which were increased and decreased, respectively, in the tumor hosts. The present data give new insights into the mechanisms by which clenbuterol exerts its preventive effect on muscle protein waste and seem to warrant the implementation of experimental protocols involving the use of clenbuterol or alike drugs in the treatment of pathological states involving TPH, particularly in skeletal muscle and heart, such as in the present model of cancer cachexia

Novel film‐forming formulations of the biocontrol agent Candida sake CPA‐1: biocontrol efficacy and performance at field conditions in organic wine grapes

BACKGROUND: The biocontrol agent (BCA)Candida sakeCPA-1 has previously effectively reducedBotrytisbunch rot (BBR) andit was also suggested as a promising strategy to control sour rot in grapes under field conditions. However, biocontrol efficacyof solid formulations of CPA-1 has never been tested in field trials. The present study aims to confirm the efficacy against BBRand sour rot in grapes under field conditions of two novel formulations recently developed by the addition of biodegradablecoatings using a fluidized-bed spray-drying system.RESULTS: Novel film-forming formulations of the BCAC. sakeCPA-1 controlledB. cinereaas well as liquid formulation. Sour rotcontrol resulted better in the second season and severity reductions were more satisfactory than incidence control. Visual andcryoSEM observations revealed that film-forming treatments were uniformly distributed on plant surfaces. CPA-1 coating couldbe observed on grapes at harvest time.CONCLUSION: The results of this work suggest that solid formulations would be a competitive alternative to conventionalfungicides because they were easy to package and transport, and cell viability could be maintained for a long period of time.© 2018 Society of Chemical Industryinfo:eu-repo/semantics/acceptedVersio

Breast mammographic Density: stromal implications on breast cancer detection and therapy

Current evidences state clear that both normal development of breast tissue as well as its malignant progression need many-sided local and systemic communications between epithelial cells and stromal components. During development, the stroma, through remarkably regulated contextual signals, affects the fate of the different mammary cells regarding their specification and differentiation. Likewise, the stroma can generate tumour environments that facilitate the neoplastic growth of the breast carcinoma. Mammographic density has been described as a risk factor in the development of breast cancer and is ascribed to modifications in the composition of breast tissue, including both stromal and glandular compartments. Thus, stroma composition can dramatically affect the progression of breast cancer but also its early detection since it is mainly responsible for the differences in mammographic density among individuals. This review highlights both the pathological and biological evidences for a pivotal role of the breast stroma in mammographic density, with particular emphasis on dense and malignant stromas, their clinical meaning and potential therapeutic implications for breast cancer patients

Novel film-forming formulations of the biocontrol agent Candida sake CPA-1: biocontrol efficacy and performance at field conditions in organic wine grapes

This is the peer reviewed version of the following article: Carbó, A., Torres, R., Usall, J., Marín, A., Chiralt, A. and Teixidó, N. (2019), Novel film¿forming formulations of the biocontrol agent Candida sake CPA¿1: biocontrol efficacy and performance at field conditions in organic wine grapes. Pest. Manag. Sci., 75: 959-968, which has been published in final form at https://doi.org/10.1002/ps.5200. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.[EN] BACKGROUND The biocontrol agent (BCA) Candida sake CPA-1 has previously effectively reduced Botrytis bunch rot (BBR) and it was also suggested as a promising strategy to control sour rot in grapes under field conditions. However, biocontrol efficacy of solid formulations of CPA-1 has never been tested in field trials. The present study aims to confirm the efficacy against BBR and sour rot in grapes under field conditions of two novel formulations recently developed by the addition of biodegradable coatings using a fluidized-bed spray-drying system. RESULTS Novel film-forming formulations of the BCA C. sake CPA-1 controlled B. cinerea as well as liquid formulation. Sour rot control resulted better in the second season and severity reductions were more satisfactory than incidence control. Visual and cryoSEM observations revealed that film-forming treatments were uniformly distributed on plant surfaces. CPA-1 coating could be observed on grapes at harvest time. CONCLUSION The results of this work suggest that solid formulations would be a competitive alternative to conventional fungicides because they were easy to package and transport, and cell viability could be maintained for a long period of time.The authors thank Cristina Solsona, Celia Sanchez, Andrea Berge and Dani Lastrada for their technical assistance. The authors are grateful to INIA (Instituto Nacional de Investigacion y Tecnologia Agraria y Alimentaria) and FEDER (Fondo Europeo de Desarrollo Regional) for financial support through national project RTA2012-00067-C02-01. The authors are also grateful to INIA and FSE (Fondo Social Europeo) for the PhD grant awarded to A. Carbo. They are also grateful to the CERCA Programme/Generalitat de Catalunya.Carbó, A.; Torres, R.; Usall, J.; Marín, A.; Chiralt Boix, MA.; Teixidó, N. (2019). Novel film-forming formulations of the biocontrol agent Candida sake CPA-1: biocontrol efficacy and performance at field conditions in organic wine grapes. Pest Management Science. 75(4):959-968. https://doi.org/10.1002/ps.5200S95996875

Dehydration of Ampelomyces quisqualis CPA-9 conidia by adding biodegradable coatings: Biocontrol activity against powdery mildew and physical characterization of the formulated product

Ampelomyces quisqualis CPA-9 was reported as a promising biocontrol fungus against powdery mildew on cucurbits, although its formulation had not been developed. The present work aimed to develop a fluidised-bed spray-dried formulation of CPA-9 that included film-forming compounds, which could improve the behaviour of the microorganism under practical conditions. Film forming compounds, efficacy, shelf life, physical stability as a function of aw, and solubility in water were determined. A film-forming formulation based on native potato starch and pregelatinised potato starch as carrier and binder was obtained, and sucrose plus skimmed milk were used as protective compounds. Dehydrated conidia maintained the efficacy of fresh cells against Podosphaera xanthii on zucchini leaves, and powdery mildew was significantly reduced compared with control treatment. Despite of results obtained for the glassy state guaranteed the stability of the powder against sticking and caking processes, the shelf life of the product was limited to 4 months of storage at 4 °C. On the other hand, the formulation was mainly dispersible, due to the high concentration of native potato starch which reduces the solubility of the product. Results obtained in this work, such as the high efficacy of the developed product, the low cost of the employed substances, the film-forming ability of the rehydrated powder, and finally the effectiveness of the dehydration process, confirmed the potential of the product. Further studies to verify the improvement of CPA-9 behaviour under practical conditions or to improve the storage conditions to enlarge the shelf life of the BCA should be done to consider the developed product as a biocontrol-based product for cucurbits against powdery mildew.info:eu-repo/semantics/acceptedVersio

Dry formulations of the biocontrol agent Candida sakeCPA‐1 using fluidised bed drying to control the main postharvest diseases on fruits

BACKGROUND: The biocontrol agent Candida sake CPA‐1 is effective against several diseases. Consequently, the optimisation of a dry formulation of C. sake to improve its shelf life and manipulability is essential for increasing its potential with respect to future commercial applications. The present study aimed to optimise the conditions for making a dry formulation of C. sake using a fluidised bed drying system and then to determine the shelf life of the optimised formulation and its efficacy against Penicillium expansum on apples. RESULTS: The optimal conditions for the drying process were found to be 40 °C for 45 min and the use of potato starch as the carrier significantly enhanced the viability. However, none of the protective compounds tested increased the viability of the dried cells. A temperature of 25 °C for 10 min in phosphate buffer was considered as the optimum condition to recover the dried formulations. The dried formulations should be stored at 4 °C and air‐packaged; moreover, shelf life assays indicated good results after 12 months of storage. The formulated products maintained their biocontrol efficacy. CONCLUSION: A fluidised bed drying system is a suitable process for dehydrating C. sake cells; moreover, the C. sake formulation is easy to pack, store and transport, and is a cost‐effective process.We are grateful to the INIA (Instituto Nacional de Investigación y Tecnología Agraria y Alimentaria) and the FEDER (Fondo Europeo de Desarrollo Regional) for financial support via national project RTA2012‐00067‐C02‐01. In addition, we are also grateful to the INIA and FSE (Fondo Social Europeo) for the PhD grant to A. Carbó and CERCA Programme/Generalitat de Catalunya