The Controversial History of Hormone Replacement Therapy

The history of hormone replacement therapy (HRT) started in the 1960s, with very high popularity in the 1990s. The first clinical trials on HRT and chronic postmenopausal conditions were started in the USA in the late 1990s. After the announcement of the first results of the Women's Health Initiative (WHI) in 2002, which showed that HRT had more detrimental than beneficial effects, HRT use dropped. The negative results of the study received wide publicity, creating panic among some users and new guidance for doctors on prescribing HRT. The clear message from the media was that HRT had more risks than benefits for all women. In the following years, a reanalysis of the WHI trial was performed, and new studies showed that the use of HRT in younger women or in early postmenopausal women had a beneficial effect on the cardiovascular system, reducing coronary disease and all-cause mortality. Notwithstanding this, the public opinion on HRT has not changed yet, leading to important negative consequences for women's health and quality of life

Ospemifene in the management of vulvar and vaginal atrophy: Focus on the assessment of patient acceptability and ease of use

Endocrinological changes that occur with menopause lead to a chronic and progressive condition named vulvar and vaginal atrophy (VVA). This disease is characterized by symptoms such as dryness, dyspareunia, itching, burning, and dysuria. According to recent epidemiological studies, VVA has a high prevalence and can also occur in younger women prior to the menopause, negatively affecting quality of life, sexual function, intimacy and relationship with the partner. Accordingly, therapy should be effective, initiated early and continued for as long as possible. Up to recent years, available therapeutic options have included over-the-counter lubricants and moisturizers, vaginal oestrogens and systemic hormones. These products are not indicated for all women. Hormones are mostly contraindicated in women with a history of hormone-sensitive cancer and are frequently not accepted even by women without contraindications. Local therapies are frequently considered uncomfortable, difficult to apply, and messy. Indeed, these treatments have a high spontaneous discontinuation rate, mostly due to dissatisfaction, safety concern, side effects and difficulty in vaginal placement. Recently, ospemifene, a new non-hormonal systemic remedy, was approved by FDA (Food and Drug Administration) and EMA (European Medicines Agency) for the treatment of the two most bothersome symptoms of VVA: dryness and dyspareunia. Because ospemifene is a selective estrogen receptor modulator (SERM), it can be administered also in women with a history of breast cancer, and this makes it more acceptable by any woman. In addition, its route of administration minimizes those bothersome side effects intrinsic to the vaginal route of administration. Available data indicate that women using ospemifene have higher adherence to treatment, higher persistence and lower discontinuation rate. Satisfaction is higher than with other local therapies and overall health care cost is lower

El estudio del vulcanismo subsecuente y plutonismo intercedente en los geosinclinales de ámbito andino

En esIe trabajo se analizan las características generales de los procesos magmáticos de tipo intercedente-subsecuente, su distribución, alcance, particularidades y sn importancia geotectóuica. Se indican, además, las áreas de movilidad geosinclinal andiua donde este fenómeno ma.smático ha sido diferenciado de los de tipos sinorogénicos, señalando las particularidades de cada una y las conclusiones generales alcanzadas en la adecuación del esquema geomagmático que se analiza

The use of dynamic landscape metapopulation models for forest management: a case study of the red-backed salamander

Spatial models of population dynamics have been proposed as a useful method for predicting the impacts of environmental change on biodiversity. Here, we demonstrate advances in dynamic landscape metapopulation modelling and its use as a decision support tool for evaluating the impacts of forest management scenarios. This novel modelling framework incorporates both landscape and metapopulation model stochasticity and allows their relative contributions to model output variance to be characterized. It includes a detailed sensitivity analysis, allowing defensible uncertainty bounds and the prioritization of future data gathering to reduce model uncertainties. We demonstrate this framework by modelling the landscape-level impacts of eight forest management scenarios on the red-backed salamander (Plethodon cinereus (Green, 1818)) in the boreal forest of Ontario, Canada, using the RAMAS Landscape package. The 100 year forest management scenarios ranged in intensity of timber harvesting and fire suppression. All scenarios including harvesting predicted decreases in salamander population size and the current style of forest management is predicted to produce a 9%-17% decrease in expected minimum population size compared with scenarios without harvesting. This method is amenable to incorporating many forms of environmental change and allows a meaningful treatment of uncertainty

Impacto del cambio climático sobre la distribución de Prosopis Hassleri y P.alba en la región chaqueña

El algarrobo, principalmente Prosopis alba y P. hassleri son las especies nativas de mayor uso para madera de aserrío en nuestro país, registrándose en los últimos años un aumento constante en la tasa de consumo. Dado que la totalidad de la madera de algarrobo consumida proviene de bosques nativos, la explotación del recurso es insostenible no sólo desde el punto de vista ambiental sino también económico. A esta situación crítica se le agregan además problemáticas que están afectando a los bosques a escala global como es la expansión de la frontera agrícola sobre áreas de bosque nativo, forestación con especies exóticas de crecimiento rápido, y la interacción de estos factores con el cambio climático actual. En este trabajo indagamos sobre el posible impacto del cambio climático sobre la distribución de P. hassleri (Algarrobo paraguayo) y de tres morfotipos de P. alba (santiagueño, chaqueño y chaqueño sur) en el norte de Argentina, para proveer información útil en la planificación de estrategias de conservación y manejo de los recursos genéticos nativos. Para ello, se utilizaron modelos predictivos de nicho que permitieron estimar la distribución potencial de ambas especies bajo un escenario actual y de cambio climático futuro. De esta manera se pudieron establecer áreas de alto y bajo impacto, y nuevas áreas adecuadas para la persistencia de las respectivas especies. Se utilizaron datos georreferenciados de 30-77 individuos de poblaciones naturales de cada una de las especies y morfotipos, y los 19 parámetros bioclimáticos disponibles en la base de datos mundial WorldClim. Los análisis de modelado de nicho actual y futuro se realizaron mediante el algoritmo de máxima entropía implementado en el programa Maxent; posteriormente los modelados resultantes fueron procesados en el programa DIVA-GIS. Los resultados indican que todas las especies/morfotipos tienden a desplazar su área de distribución hacia el sur, excepto el morfotipo P. alba chaqueño sur que se expandiría hacia el norte. Prosopis hassleri sería la especie que perdería la mayor proporción de superficie de su distribución actual. Sin embargo, en un escenario futuro surgirían áreas favorables para su persistencia cuya superficie duplicaría la distribución actual. Contrariamente, el morfotipo santiagueño de P. alba conservaría casi la totalidad de su área de distribución actual, y es la que menos ampliaría su rango de distribución en un escenario futuro. A partir de los resultados obtenidos se sugieren estrategias de manejo y conservación para estas especies, a través de la identificación y protección de refugios climáticos y del establecimiento de corredores biológicos que favorezcan la dispersión natural de las especies hacia nuevas áreas adecuadas. (Nuestro agradecimiento al Proyecto Específico INTA PNFOR044341 y al Banco Nacional de Germoplasma de Prosopis, FCA-UNC, por facilitar la información básica para este trabajo).Fil: Venier, Maria Paula. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Cosacov Martinez, Andrea. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: López Lauenstein, D.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias; ArgentinaFil: Vega, C.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias; ArgentinaFil: Verga, A.. Instituto Nacional de Tecnología Agropecuaria. Centro de Investigaciones Agropecuarias; Argentin

PI3K/AKT/mTOR inhibition in combination with doxorubicin is an effective therapy for leiomyosarcoma.

BackgroundLeiomyosarcoma (LMS) is a common type of soft tissue sarcoma that responds poorly to standard chemotherapy. Thus the goal of this study was to identify novel selective therapies that may be effective in leiomyosarcoma by screening cell lines with a small molecule library comprised of 480 kinase inhibitors to functionally determine which signalling pathways may be critical for LMS growth.MethodsLMS cell lines were screened with the OICR kinase library and a cell viability assay was used to identify potentially effective compounds. The top 10 % of hits underwent secondary validation to determine their EC50 and immunoblots were performed to confirm selective drug action. The efficacy of combination drug therapy with doxorubicin (Dox) in vitro was analyzed using the Calcusyn program after treatment with one of three dosing schedules: concurrent treatment, initial treatment with a selective compound followed by Dox, or initial treatment with Dox followed by the selective compound. Single and combination drug therapy were then validated in vivo using LMS xenografts.ResultsCompounds that targeted PI3K/AKT/mTOR pathways (52 %) were most effective. EC50s were determined to validate these initial hits, and of the 11 confirmed hits, 10 targeted PI3K and/or mTOR pathways with EC50 values <1 μM. We therefore examined if BEZ235 and BKM120, two selective compounds in these pathways, would inhibit leiomyosarcoma growth in vitro. Immunoblots confirmed on-target effects of these compounds in the PI3K and/or mTOR pathways. We next investigated if there was synergy with these agents and first line chemotherapy doxorubicin (Dox), which would allow for earlier introduction into patient care. Only combined treatment of BEZ235 and Dox was synergistic in vitro. To validate these findings in pre-clinical models, leiomyosarcoma xenografts were treated with single agent and combination therapy. BEZ235 treated xenografts (n = 8) demonstrated a decrease in tumor volume of 42 % whereas combining BEZ235 with Dox (n = 8) decreased tumor volume 68 % compared to vehicle alone.ConclusionsIn summary, this study supports further investigation into the use of PI3K and mTOR inhibitors alone and in combination with standard treatment in leiomyosarcoma patients