An update of the mechanisms of resistance to EGFR-tyrosine kinase inhibitors in breast cancer: gefitinib (Iressatrade mark)-induced changes in the expression and nucleo-cytoplasmic trafficking of HER-ligands (Review)

Intrinsic resistance to the epidermal growth factor receptor (EGFR; HER1) tyrosine kinase inhibitor (TKI) gefitinib, and more generally to EGFR TKIs, is a common phenomenon in breast cancer. The availability of molecular criteria for predicting sensitivity to EGFR-TKIs is, therefore, the most relevant issue for their correct use and for planning future research. Though it appears that in non-small-cell lung cancer (NSCLC) response to gefitinib is directly related to the occurrence of specific mutations in the EGFR TK domain, breast cancer patients cannot be selected for treatment with gefitinib on the same basis as such EGFR mutations have been reported neither in primary breast carcinomas nor in several breast cancer cell lines. Alternatively, there is a general agreement on the hypothesis that the occurrence of molecular alterations that activate transduction pathways downstream of EGFR (i.e., MEK1/MEK2 - ERK1/2 MAPK and PI-3'K - AKT growth/survival signaling cascades) significantly affect the response to EGFR TKIs in breast carcinomas. However, there are no studies so far addressing a role of EGF-related ligands as intrinsic breast cancer cell modulators of EGFR TKI efficacy. We recently monitored gene expression profiles and sub-cellular localization of HER-1/-2/-3/-4 related ligands (i.e., EGF, amphiregulin, transforming growth factor-α, ß-cellulin, epiregulin and neuregulins) prior to and after gefitinib treatment in a panel of human breast cancer cell lines. First, gefitinibinduced changes in the endogenous levels of EGF-related ligands correlated with the natural degree of breast cancer cell sensitivity to gefitinib. While breast cancer cells intrinsically resistant to gefitinib (IC50 ≥15 μM) markedly up-regulated (up to 600 times) the expression of genes codifying for HERspecific ligands, a significant down-regulation (up to 106 times) of HER ligand gene transcription was found in breast cancer cells intrinsically sensitive to gefitinib (IC50 ≤1 μM). Second, loss of HER1 function differentially regulated the nuclear trafficking of HER-related ligands. While gefitinib treatment induced an active import and nuclear accumulation of the HER ligand NRG in intrinsically gefitinib-resistant breast cancer cells, an active export and nuclear loss of NRG was observed in intrinsically gefitinib-sensitive breast cancer cells. In summary, through in vitro and pharmacodynamic studies we have learned that, besides mutations in the HER1 gene, oncogenic changes downstream of HER1 are the key players regulating gefitinib efficacy in breast cancer cells. It now appears that pharmacological inhibition of HER1 function also leads to striking changes in both the gene expression and the nucleo-cytoplasmic trafficking of HER-specific ligands, and that this response correlates with the intrinsic degree of breast cancer sensitivity to the EGFR TKI gefitinib. The relevance of this previously unrecognized intracrine feedback to gefitinib warrants further studies as cancer cells could bypass the antiproliferative effects of HER1-targeted therapeutics without a need for the overexpression and/or activation of other HER family members and/or the activation of HER-driven downstream signaling cascades

Prediction of glucose excursions under uncertain parameters and food intake in intensive insulin therapy for type 1 diabetes mellitus

Considering the difficulty in the insulin dosage selection and the problem of hyper- and hypoglycaemia episodes in type 1 diabetes, dosage-aid systems appear as tremendously helpful for these patients. A model-based approach to this problem must unavoidably consider uncertainty sources such as the large intra-patient variability and food intake. This work addresses the prediction of glycaemia for a given insulin therapy face to parametric and input uncertainty, by means of modal interval analysis. As result, a band containing all possible glucose excursions suffered by the patient for the given uncertainty is obtained. From it, a safer prediction of possible hyper- and hypoglycaemia episodes can be calculated

Solució mental i solució motriu en la iniciació als esports col·lectius en l'Educació Primària

The adjustment of the teaching learning contents in Physical Education, requires of a rigorous analysis that permits to adjust them to the maximum with the educational needs of the student body. It has been approached an investigation study in the one which have intervened pupils, boys and girls, of two different populations, Girona and Madrid in order to prove and analyse the motor and mental components of the student body in the real situation of the game. The hypothesis that we have treated are:if it exists differences between the boys and girls of the educational levels studied in the motor and mental solution in the sports initiation, additionally, the differences that they can exist between the courses and what distance is verified between the study ages to approach a physical activity that implies an initial step to the hour of teaching the collective sports in the classes of Physical education. They have been employed three measure instruments: the first permits to analyse the mental solution without need of practice employing situation photographs of the real game with those which the pupils must choose to who to happen; the second is a pass test that permits to prove the technical dominance to use in a collective sport and the third is a real game situation that permits to put in manifesto the relationship between the mental behaviour and the motor of the pupil. This real game situation is ‘the game of ten pass’ (Blázquez,1986; Torres,1993). The results demonstrate that it do not exist differences between the two sexes in the study ages. In the case of the technical execution level, there is a considerable increase with the age and it is slightly greater in the kids that in the girls. In the case of the real game, we find ourselves with a great variability in the results and we cannot conclude that there are relative differences to the sex in none of the three courses. Respect at participation level during the game is confirmed that the pupils that more participate are not the pupils than more balls lose, what permits to guarantee the idea of the fact that it is convenient to use the real game practice as direct learning element. Finally, there is no a high correlation between the execution level measured in the test of technical execution and the decision execution during the game

Subsurface drip irrigation emitter spacing effects on soil water redistribution, corn yield and water productivity

Emitter spacings of 0.3 to 0.6 m are commonly used for subsurface drip irrigation (SDI) of corn on the deep, silt loam soils of the U.S. Great Plains. Subsurface drip irrigation emitter spacings of 0.3, 0.6, 0.9 and 1.2 m were examined for the resulting differences in soil water redistribution, corn grain yield, yield components, seasonal water use, and water productivity in a 4‐year field study (2005 through 2008) at the Kansas State University Northwest Research‐Extension Center, Colby, Kansas. The results indicate that there is increased preferential water movement along the dripline (parallel) as compared to perpendicular to the dripline and that this phenomenon partially compensates for wider emitter spacings in terms of soil water redistribution. Corn yield and water productivity (WP) were not significantly affected by the emitter spacing with application of a full irrigation regime

Un projecte didàctic que ensenya a mirar: 'Ciutat, territori i paisatge' s'ha experimentat en onze instituts de Catalunya

‘Ciutat, territori i paisatge’ consta d’uns materials didàctics, formats per unes làmines de paisatges, un conjunt d’activitats didàctiques i un web interactiu, elaborats pel Departament de Política Territorial i Obres Públiques conjuntament amb el Departament d’ Educació i l’ Observatori del Paisatge i adreçat a estudiants d’educació secundària. Aquests materials poden tenir interès, també, per als educadors en el lleure i per a totes les persones preocupades pel deteriorament que estan patint alguns paisatges que considerem tradicionals i emblemàtics, especialment els dels entorns de les ciutats o els propers a les grans infraestructures

El gènere Kallymenia (Kallymeniaceae, Rhodophyta) a la Península Ibèrica i Illes Balears

L'objectiu d'aquest treball ha estat l'estudi del gènere Kallymenia a la Península Ibèrica i a les Illes Balears, el qual es troba representat per les espècies següents: K. reniformis (Turner) J. Agardh, K. feldmannii Codomier, K. lacerata Feldmann, K. requienii (J. Agardh) J. Agardh, K. patens (J. Agardh) P.G. Parkinson i K. spathulata (J. Agardh) P.G. Parkinson. En aquesta monografia es descriuen les principals característiques morfològiques i vegetatives i també els tetrasporangis de totes les espècies de la Península Ibèrica i de les Illes Balears. També es descriuen les estructures reproductores i els estadis de postfertilització de totes, excepte de K. patens i K. spathulata, espècies més rares que les altres i per a les quals no hem pogut aportar aquesta informació. Les dades s'acompanyen amb una iconografia original a base de dibuixos i fotografies i amb una clau de determinació pels tàxons estudiats. També es detalla la corologia de les diferents espècies, el seu hàbitat i la seva fenologia.

Manuel Brunet i Solà (1889-1956). El periodisme d'idees al servei de la "veritat personal"

This doctoral thesis deals with the intellectual biography of the writer and journalist Manuel Brunet (Vic, 1889, Figueres, 1956). It reconstructs the life and professional studies of the author, and the most important facets of his literature and journalism. In addition, it examines his literary texts. A special emphasis has been placed on the study of journalistic production of Brunet and on the analysis of the professional profile of the author. Examination and assessment of its production has been accurate, including a classification of the items and a comparison of his journalistic style with that of other contemporary authors, both Catalan (Josep Pla and Joseph M. de Sagarra), French (Charles Maurras and Léon Daudet) and English (GK Chesterton and Hilaire Belloc). The latter part of the work analysises the condition of "victor won" of Manuel Brunet after the Spanish Civil War, and how this author is an example of a whole generation of conservative Catalan nationalist witers who lived a difficult situation after the conflict.