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Francis Arena Clinical Research Alliance, Lake Success, New York, NY, USAAbstract: Breast cancer is a leading cause of cancer-related death worldwide. Approximately 75% of breast cancer is hormone receptor-positive (HR+) and is managed with endocrine therapies. However, relapse or disease progression caused by primary or acquired endocrine resistance is frequent. Phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR)-mediated signaling is one of the molecular mechanisms leading to endocrine resistance. mTOR inhibitors that target the PI3K/Akt/mTOR pathway are the first of the targeted therapies to be evaluated in clinical trials to overcome endocrine resistance. Although the clinical trial with temsirolimus, an mTOR inhibitor, did not show any benefit when compared with endocrine therapy alone, a Phase II clinical trial with sirolimus has been promising. Recently, everolimus was approved in combination with exemestane by the US Food and Drug Administration for treating postmenopausal women with advanced HR+ breast cancer, based on the results of a Phase III trial. Therefore, everolimus represents the first and only targeted agent approved for combating endocrine resistance.Keywords: advanced breast cancer, hormone receptor-positive, endocrine resistance, mTOR inhibitors

Antecedentes: Los síntomas que afectan la esfera sexual durante el climaterio son altamente prevalentes. Objetivos: Describir los aspectos fundamentales de la respuesta sexual humana en un sentido integral, analizando las modificaciones que el climaterio le imprime, y analizar la inferencia de la terapia hormonal de reemplazo sobre la respuesta y el comportamiento sexual humano. Metodología: Se realizó una revisión de la bibliografía de las bases de dato MEDLINE y LILACS, encontrando un total de 465 artículos sobre el tema. Se seleccionaron aquellos estudios que presentaban un mayor rigor científico. Resultados: El climaterio repercute en forma variable en la respuesta sexual femenina. Generando una afectación tanto en la esfera biológica como psicológica y comportamental de la misma. Existen factores endocrinos y tróficos sobre los distintos tejidos que modifican el factor coital de esta respuesta. El deseo sexual y el orgasmo se afectan en forma más variable, no dependiendo exclusivamente de parámetros biológicos. Conclusión: El uso de terapia de reemplazo hormonal disminuye el deterioro de la respuesta sexual en el climaterioBackground: The symptoms that affect the sexual sphere in women's during climacteric are of high prevalence. Aims: To describe the fundamental aspects of human sexual response during the climacteric and to analyze the effect of climacteric replacement hormone therapy. Methodology: a revision of existing bibliography was done, from MEDLINE and LILACS databases, finding a total of 465 articles. From that group, those which presented the highest scientific rigor were selected. Results: It was found that climacteric affects in a variable way the female sexual response, affecting not only her biological sphere, but her psychological and behavioral spheres. It can be seen that there are endocrine and trophic factors acting upon the different tissues which modify the coital factor of this response. It was also found that sexual desire and orgasm are affected in a more variable way, the affection not exclusively depending on biological parameters. Conclusion: The use of hormone replacement lower it the deterioration of the human sexual response during the climacterium

Objetivo: analizar los factores que afectan y/o determinan el inicio y cumplimiento de la terapia hormonal en el climaterio, y el efecto de como el estudio WHI y los trabajos vinculados a éste han impactado sobre esta terapéutica. Metodología: Se realizó una búsqueda de la información que hace referencia al tema en cuestión en las bases de datos MEDLINE y LILACS, seleccionando los trabajos para el análisis que presentaran mayor rigor científico, que fueran publicados en revistas arbitradas que no generaran conflicto de intereses según el financiamiento presentado, y que analizaran casuísticas significativas o que por su metodología original incorporan un aporte valioso al análisis del tema. Resultados: Encontramos en primer lugar que hay factores tales como la presencia de síndrome climatérico, la información que los pacientes tuvieran precedentemente en el tema, el seguimiento estrecho por parte del equipo de salud, y una mayor predisposición a la incorporación de intervenciones de prevención primaria en salud cumplían un rol favorecedor de la incorporación y mantenimiento de la terapia hormonal de reemplazo en el climaterio femenino. Por el contrario son factores negativos en la resiliencia a dicha intervención la mala tolerancia a dicha terapéutica, el sedentarismo, la obesidad, la no concomitancia de pareja, el inicio a edades más tardía, y la no presencia de síndrome climatérico. Conclusiones: Si bien la bibliografía no abunda aún al respecto, el impacto del estudio del WHI indudablemente que ejerció una fuerte retracción en la incorporación de esta terapéutica así como una menor compliance y una mayor tasa de abandono de la mismaObjective: The present bibliographic revision was done aiming at analyzing the factors which affect and/or determine the beginning and accomplishment of hormone therapy in climacterics, and the effect of the impact of studies on WHI and related papers on this therapy. Methodology: Searching in MEDLINE and LILACS databases looking for information referred to the topic in question, selecting papers for analysis which presented the highest scientific rigor, which were published in arbitrated magazines, did not generate interest conflicts according to the presented financing, and which analyzed significant casuistry or because of their original methodology they add value to the analysis of the topic. Result: In the first place we found that there are factors such as the presence of climacteric syndrome, the information that patients already have about the topic, the close monitoring by the health team, and a higher predisposition to add primary intervention in health, have a facilitating role in adding and maintaining replacement hormone therapy in female climacteric. On the contrary, negative factors in resiliency to such intervention are the bad resistance to the therapy, sedentary habits, obesity, no concomitance of partner, starting at later ages, and no climacteric syndrome presence. Conclusion: Even though there is no abundant bibliography on the matter, the impact of the study of WHI undoubtedly did not exert a strong retraction to incorporating the therapy as well as a smaller compliance and a larger rate of giving it up

In this paper some non-linear effects for the mechanics of sea wave groups with large waves are investigated, either for waves in an undisturbed field or for waves in front of a vertical wall. To the first-order in a Stokes expansion, Boccotti's quasi-determinism theory enables us to foresee the mechanics of wave groups, either in undisturbed or in diffracted fields, when a large wave occurs. The first formulation of this theory shows the random group mechanics when a large crest height occurs ('New wave'); the second theory formulation gives the random group mechanics when a large crest-to-trough wave height occurs. The quasi-determinism theory in both formulations, for undisturbed fields, was extended recently to the second-order by the author. In this paper the procedure to derive the second-order solution is analyzed and is applied to random wave groups in front of a vertical wall. The non-linear effects are then investigated in space-time domain, and it is obtained a good agreement of analytical predictions with both field data and data from numerical simulation.