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Los bosques de pino-encino de la comunidad de Nuevo San Juan, Michoacan, estan dominados por Pinus pseudostrobus, P. devoniana y P. leiophylla. Los patrones de variacion genetica de estas especies no se conocen lo suficiente, particularmente los de P. leiophylla, lo cual limita la creacion de lineamientos para el movimiento de semillas y plantulas para reforestacion y su adaptacion al cambio climatico. Las especies se recolectaron en cuatro o cinco procedencias a lo largo de un transecto altitudinal (1,650 a 2,500 m) para el establecimiento de un ensayo en vivero, con el objetivo de cuantificar la variacion genetica entre y dentro de las especies. La altura de la planta (tres y cinco meses de edad) fue significativamente diferente (P < 0.0001) entre especies. Entre procedencias hubo diferencias significativas para P. devoniana (P < 0.0001) y P. leiophylla (P = 0.0352). La especie P. devoniana mostro un pronunciado patron de crecimiento asociado con la altitud de origen, donde las plantas con mayor crecimiento procedian de una menor altitud. Las poblaciones de P. leiophylla fueron diferentes solo a los tres meses de edad, sin un patron altitudinal estadisticamente significativo. No se encontraron diferencias significativas entre poblaciones de P. pseudostrobus

Former reports demonstrated that P-Rex, a Rac guanine nucleotide exchange factor (GEF), participated in signaling upon activation of the ErbB receptor tyrosine kinases (RTKs). Activation of ErbB receptors turned on a phosphorylation/dephosphorylation cycle of P-Rex in which stimulation of serine1169 phosphorylation played a critical role in the activation of this GEF. This precedent raised the important question of whether this P-Rex1 activation mechanism was restricted to ErbB receptors or could represent a general signaling event shared by several RTKs. To explore that possibility the effect of activation of distinct RTKs on the phosphorylation of P-Rex1 at serine1169 was analyzed. Here we report that IGF-1 and FGF receptors activate serine1169 phosphorylation of P-Rex1. P-Rex1 phosphorylation was required for IGF-1-induced up-regulation of Rac activity and cell proliferation. Moreover, IGF-1-induced adhesion was impaired in MCF7 breast cancer cells by knocking down P-Rex1. These results demonstrate that phosphorylation P-Rex1 at S1169 represents a mechanism of activation of P-Rex1 common to multiple RTKs. We suggest that P-Rex proteins may act as novel and important transducers of pro-oncogenic signals that emanate from RTKs, and could even participate in other biological responses, such as metabolic control, which are not strictly related to the proliferation effects of RTKs., This work was supported by a grant from the Ministry of Science and Innovation of Spain [BFU2009-07728/BMC]. JCM receives support from the Cancer Center Network Program from the ISCIII [RD06/0020/0041], and SS from the Juan de la Cierva Program. Our Cancer Research Institute, and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces.

Despite important progress on Amazonian floodplain research, the flooded forest of the Negro River “igapo” has been little investigated. In particular, no study has previously focused the linkage between fluvial geomorphology and the floristic variation across the course of the river. In this paper we describe and interpret relations between igapo forest, fluvial geomorphology and the spatial evolution of the igapo forest through the Holocene. Therefore, we investigate the effect of geomorphological units of the floodplain and channel patterns on tree diversity, composition and structural parameters of the late-successional igapo forest. Our results show that sites sharing almost identical flooding regime, exhibit variable tree assemblages, species richness and structural parameters such as basal area, tree density and tree heights, indicating a trend in which the geomorphologic styles seem to partially control the organization of igapo's tree communities. This can be also explained by the high variability of well-developed geomorphologic units in short distances and concentrated in small areas. In this dynamic the inputs from the species pool of tributary rivers play a crucial role, but also the depositional and erosional processes associated with the evolution of the floodplain during the Holocene may control floristic and structural components of the igapo forests. These results suggest that a comprehensive approach integrating floristic and geomorphologic methods is needed to understand the distribution of the complex vegetation patterns in complex floodplains such as the igapo of the Negro River. This combination of approaches may introduce a better comprehension of the temporal and spatial evolutionary analysis and a logic rationale to understand the vegetation distribution and variability in function of major landforms, soil distributions and hydrology. Thus, by integrating the past into macroecological analyses will sharpen our understanding of the underlying forces for contemporary floristic patterns along the inundation forests of the Negro River.

Saharan dust intrusions make a major contribution to levels of particulate matter (PM) present in the atmosphere of large cities. We analysed the impact of different PM fractions during periods with and without Saharan dust intrusions, using time-series analysis with Poisson regression models, based on: concentrations of coarse PM (PM10 and PM10-2.5) and fine PM (PM2.5); and daily all-, circulatory- and respiratory-cause hospital admissions. While periods without Saharan dust intrusions were marked by a statistically significant association between daily mean PM2.5 concentrations and all- and circulatory-cause hospital admissions, periods with such intrusions saw a significant increase in respiratory-cause admissions associated with fractions corresponding to PM10 and PM10-2.5.

Antecedentes: El cancer de endometrio es uno de los canceres ginecologicos mas frecuentes. La incidencia de esta enfermedad pudiera ir en aumento dado los cambios epidemiologicos de la poblacion femenina. Objetivo: Evaluar resultados clinicos y caracteristicas de la poblacion atendida por cancer de endometrio. Metodo: Se analizaron las historia clinicas de 100 pacientes tratadas por cancer de endometrio entre enero de 2000 y diciembre de 2009. En el analisis de los datos se considero como base la etapificacion FIGO 1988. Resultados: La edad promedio fue de 62 anos, el 75% de las pacientes consultaron por hemorragia post menopausica y en el 64% de las pacientes el diagnostico se realizo por dilatacion y curetaje. En el 60% se realizo etapificacion completa. El 60% correspondio a etapa I y el 15% a etapa II. La sobrevida global en etapa I y II fue del 83% y 66%, respectivamente. Conclusion: El cancer de endometrio se presenta preferentemente en pacientes post menopausicas en etapas precoces. La mayoria accede a tratamiento quirurgico con escasas complicaciones y alta sobrevida global.

We inventoried 10 ha of late-successional and seasonally inundated black-water floodplain (igapo) forest along four river sections of the Negro River, Central Amazonia, Brazil. The aim of the study was to test if tree species composition and diversity changes along the river course, and whether these changes reflect the different geological formations of the Negro River. On a continental-wide scale, we assessed alpha-diversity patterns of black-water flooded forests across the Amazon and Orinoco basins. Phytosociological analyses include family and species importance, species similarity, and Fisher’s alpha-diversity, as well as Detrended Correspondence Analysis. A total of 6.126 individuals were recorded, belonging to 243 tree species. Only few tree species occurred in more than one river section, and floristic composition changed abruptly from one section to the other. Tree species richness ranged from 57 to 79 species ha−1, and alpha-diversity was highest (27.24) in the lower river section upon sediments of Pliocene–Pleistocene origin. We found a gradual decrease in species diversity with increasing age of the geological formations. The igapo forest is relatively species-poor, which we interpret to be the result of general low nutrient availability in alluvial substrates of the Negro River.

Receptor tyrosine kinases (RTKs) are a superfamily of transmembrane proteins that mediate intracellular signaling by phosphorylating substrate proteins involved in cell proliferation, survival, differentiation or migration. The Human Epidermal growth factor Receptor (HER) family belongs to the RTKs superfamily, and comprises four members: EGFR (epidermal growth factor receptor), HER2, HER3 and HER4. Physiologically, these receptors are activated by the ligands of the EGF family. In solid tumors other mechanisms of activation, such as overexpression or molecular alterations have been reported, and have been linked to tumour initiation/progression. Because of that, several strategies have been developed to target HER receptors and include i) antibody-based therapies using monoclonal antibodies against the extracellular domain of these receptors, and ii) small molecule tyrosine kinase inhibitors (TKIs) against the intracellular kinase domain. In this review we will provide basic information about biological aspects of HER receptors and their ligands as well as the therapeutic strategies to target them. We also summarize general mechanisms of resistance generated in patients to such anti-HER therapies.

[Background]: Neuregulins (NRG) are a family of epidermal growth factor ligands which act through binding to HER3 and HER4 receptors. NRGs are widely expressed in solid tumors. Their prognostic significance or their role as predictors of benefit from anti-HER3 therapy is not known. [Results]: Of 29 included studies, 7 studies reported the association between NRG and outcome. NRG was most commonly expressed in breast, prostate, colon and bladder cancers. NRG expression was not associated with either OS or PFS (HR: 3.47, 95% CI 0.78-15.47, p = 0.10 and HR: 1.64, 95% CI 0.94-2.86, p = 0.08, respectively). In 4 placebo controlled trials of anti-HER3 therapy, the addition of anti-HER3 antibodies to control therapy in unselected patients was not associated with improved PFS (HR: 0.88, 95% CI 0.75-1.04. p = 0.14). However, in patients with high NRG expression, there was significantly delayed progression (HR: 0.35, 95% CI 0.23-0.52, p < 0.001). Anti-HER3 antibodies were associated with increased risk of diarrhea, nausea and rash. [Methods]: A search of electronically available databases identified studies exploring clinical outcomes based on NRG expression, as well as placebo-controlled trials of HER3- directed therapy reporting results based on NRG expression status. Data were combined in a meta-analysis using generic inverse variance and random effects modeling for studies reporting the hazard ratio (HR) for overall (OS) or progression-free survival (PFS). Mantel-Haenszel random-effect modeling was used for odds ratio (OR) for 3-year and 5-year OS and PFS. [Conclusions]: NRG expression is not associated with either OS or PFS, but is a predictor of benefit from anti-HER3 antibodies., Instituto de Salud Carlos III (PI13/01444), ACEPAIN; Diputación de Albacete and CRIS Foundation (to AO). Ministry of Economy and Competitiveness of Spain (BFU2012–39151), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003), the scientific foundation of the AECC and the CRIS Foundation (to AP). Instituto de Salud Carlos III (PI15/01180) (to AE-O). JCM is a recipient of a Miguel Servet fellowship program (CP12/03073). The work carried out in the EU laboratories receive support from the European Community through the regional development funding program (FEDER).

Triple-negative breast cancer (TNBC) is an incurable disease with poor prognosis. At this moment, therapeutic options are limited to chemotherapy, and no targeted agent has reached the clinical setting. Bromodomain and extraterminal (BET) inhibitors are a new family of compounds that inhibit bromodomain-containing proteins affecting the expression of transcription factors, therefore modifying the expression of relevant oncogenic genes. In the present article, by using an in silico approach, we have identified the expression of upregulated transcription factors in TNBC compared with normal breast. Treatment with JQ1, a well-characterized BET inhibitor, modified some transcription factors, including DEP domain containing 1 (DEPDC), Forkhead box M1 (FOXM1), and Lim domain only 4 (LM04). In cell line models, administration of JQ1 or OTX015, another BET inhibitor, produced a significant antiproliferative effect and synergized with chemotherapies. Biochemical evaluation demonstrated an arrest at G as the main mechanism of action with a clear increase of p27. Addition of these compounds to chemotherapy induced apoptosis compared to each agent given alone. Evaluation of JQ1 in xenografted tumors in nude mice showed a profound antitumoral effect with a reduction of DEPDC, FOXM1, and LM04, in addition to an increase of p27. Globally, our data demonstrate the antitumor effect of this new family of compounds in TNBC, paving the way for its future clinical development., The study was supported by Instituto de Salud Carlos III (PI13/01444), ACEPAIN; AMAC, Diputacion de Albacete and CRIS Cancer Foundation (to A. Ocaña). Ministry of Economy and Competitiveness of Spain (BFU2012-39151and RD12/0036/0003 to A. Pandiella), and the AECC (to A. Pandiella). J.C. Montero is a recipient of a Miguel Servet fellowship program. European FEDER program.

Numerous studies have shown the presence of pharmaceutically active compounds (PhACs) in different environmental compartments, for example, in surface water or wastewater ranging from nanograms per litre to micrograms per litre. Likewise, some recent studies have pointed to seasonal variability, thus indicating that PhAcs concentrations in the aquatic environment may depend on the time of year. This work intended to find out (1) whether Tagus fluvial and drinking water were polluted with different groups of PhACs and (2) if their concentrations differed between winter and summer seasons. From the 58 substances analysed, 41 were found belonging to the main therapeutic groups. Statistical differences were seen for antibacterials, antidepressants, anxiolytics, antiepileptics, and cardiovascular drugs, with higher concentrations being detected in winter than in summer. These results might indicate that the PhACs analysed in this study undergo lower environmental degradation in winter than in summer. In order to confirm these initial results, a continuous monitoring should be performed especially on those PhACs that either because of an elevated consumption or an intrinsic chemical persistence are poorly degraded during winter months due to low temperatures and solar irradiation. It is especially important to identify which of these specific PhACs are in order to recommend their substitution by equally effective and safe substances but also environmentally friendly.

article i nfo The presence of pharmaceuticals in surface and drinking water has been evidenced in numerous studies. Despite representing one of the most common consumption sources, to the best of our knowledge, this is the first report on the presence of pharmaceutical compounds in bottled mineral water. Pollution of these sources not only could pose a serious human health risk, but would also warn about the quality of the water in our aquifers, a vital and vulnerable source of water, essential for the future water supply. Fifty eight pharmaceutically active compounds (PhACs) belonging to the 12 main therapeutic groups were ana- lyzed in 10 bottled mineral water brands produced in Spain. Nicotine was detected in concentrations ranging from 7 ng L �1 to 15 ng L �1 in 5 of 10 bottled mineral waters. Despite the low nicotine concentration mea- sured, the presence of this compound in bottled water still raises concern. Health risk assessment researchers have postulated that the risk to adult healthy humans from oral intake of nicotine at low levels is negligible. However, no studies have been conducted to assess the human health risk of vulnerable populations such as pregnant women and newborns. This population is the target of advertising on the purity and quality char- acteristics of bottled mineral water.

This paper is based on the assumption that the organized crime is a menace for democracy. The article develops an analysis on the fight against organized crime's policy design in the Felipe Calderon's government, questioning if the policy is managed as a police's issue or a national security's issue. The main finding is the identification of the Mexican's government objective in the "war against organized crime" switching the focus from organized crime to the violence created by criminal organizations. To fight violence the government implements a policy based on the use of public force that doesn't consider the cooperation between different governmental agencies.

Welcome to the power and energy theme issue of IEEE Potentials. The following four articles will address highimpact topics in the world of power systems, written by energy experts from both industry and academia. I hope you enjoy reading them and gain a greater insight into this exciting field.

• Mesoamerican arid biomes epitomize neotropical rich and complex biodiversity. To document some of the macroevolutionary processes underlying the vast species richness of Mesoamerican seasonally dry tropical forests (SDTFs), and to evaluate specific predictions about the age, geographical structure and niche conservatism of SDTF-centered woody plant lineages, the diversification of Bursera is reconstructed. • Using a nearly complete Bursera species-level phylogeny from nuclear and plastid genomic markers, we estimate divergence times, test for phylogenetic and temporal diversification heterogeneity, test for geographical structure, and reconstruct habitat shifts. • Bursera became differentiated in the earliest Eocene, but diversified during independent early Miocene consecutive radiations that took place in SDTFs. The late Miocene average age of Bursera species, the presence of phylogenetic geographical structure, and its strong conservatism to SDTFs conform to expectations derived from South American SDTF-centered lineages. • The diversification of Bursera suggests that Mesoamerican SDTF richness derives from high speciation from the Miocene onwards uncoupled from habitat shifts, during a period of enhanced aridity resulting mainly from global cooling and regional rain shadows.

The new species Cestrum sotonunezii Mont.-Castro (Solanaceae) is described from central Mexico. Because of their overall similarity, specimens of the new species have been previously confused with C. flavescens Greenm., C. aurantiacum Lindl., C. oblongifolium Schltdl., and C. thyrsoideum Kunth, all of which also occur in central Mexico. The new species is most similar to C. flavescens, but is clearly separated by several characteristics, mainly differences in the androecium. The new species is described and illustrated, and a key to distinguish morphologically similar species in central Mexico (Guerrero, Michoacan) is provided.

Se revisa la distribución de Cestrum mortonianum y se describe e ilustra una variedad de la Sierra de Manantlán. Se discuten las características que la diferencian de C. mortonianum var. mortonianum, C. tomentosum y C. pacificum, las cuales tienen en común la presencia de pubescencia ramificada. Se proporciona una clave para separar las especies de Cestrum de México con este tipo de indumento.

Studies on temperature–mortality time trends especially address heat, so that any contribution on the subject of cold is necessarily of interest. This study describes the modification of the lagged effects of cold on mortality in Castile-La Mancha from 1975 to 2003, with the novelty of also approaching this aspect in terms of mortality trigger thresholds. Cross-correlation functions (CCFs) were thus established with 15 lags, after application of ARIMA models to the mortality data and minimum daily temperatures (from November to March), and the results for the periods 1975–1984, 1985–1994 and 1995–2003 were then compared. In addition, daily mortality residuals for the periods 1975–1989 and 1990–2003 were related to minimum temperatures grouped in 2°C intervals, with a cold threshold temperature being obtained in cases where such residuals increased significantly (p

Resumen Fundamento y objetivos La legionelosis es una causa infrecuente de neumonia en ninos, y es aun mas excepcional en ninos sanos. El objetivo es presentar las actuaciones que llevaron a la identificacion de una inusual fuente de infeccion de legionela, en una nina sana, y resaltar la necesidad de adoptar medidas preventivas. Metodologia y resultados Una nina de 4 anos, sin factores de riesgo, fue confirmada con el diagnostico de neumonia por Legionella pneumophila serogrupo 1. A partir de la investigacion ambiental se evidencia como fuente de transmision un humidificador domestico. Conclusiones A pesar de que estos equipos son clasificados de baja probabilidad de proliferacion y dispersion de legionela, la falta de limpieza y mantenimiento de los mismos aumenta el riesgo de transmision de la bacteria. Es fundamental que los profesionales de la salud adviertan a los pacientes usuarios de estos equipos de la necesidad de su adecuado uso.

Background: Intracellular signalling pathways associated with the oncogenesis of basal-like breast cancer are relatively unknown. Basal-like breast cancer constitutes 15% of all breast tumors. Although chemotherapy is the only treatment, no data support the use of one agent over others. Furthermore, combinations of chemotherapies with targeted agents against activated signalling pathways have not been explored. Here we have analyzed the action of the dual PI3K-AKT-mTOR pathway inhibitor BEZ235 on a panel of basal-like breast cancer cell lines. Methods: We used several triple negative breast cancer cell lines, and analyzed the action of BEZ235 on their proliferation and cell survival using MTT metabolization and other apoptosis assays. Biochemical experiments were performed to investigate the molecular bases of the action of BEZ235. Experiments in combination with chemotherapies were also performed to identify synergic combinations. Results: PI3K-AKT pathway was activated in most of the cell lines studied. Administration of the dual PI3K-mTOR inhibitor BEZ235 decreased AKT phosphorylation in a dose dependent manner. It also reduced signalling through the mTORC1 and mTORC2 complexes. BEZ235 also decreased proliferation of most cell lines with IC50 values Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-15-19.

Basal-like breast cancer and ovarian cancer are considered as unmet entities as patient outcome in advanced stages is short, even receiving the most appropriate treatment. These tumors are characterized by a high grade of genetic instability and a notable impairment of DNA repair processes. Thus, in response to DNA damage, they depend on checkpoint arrest proteins, such as Chek1, to stop division. Inactivation of Chk1 permits cell cycle progression without a proper DNA repair, therefore increasing genetic instability and aneuploidy and eventually leading to cell death. Chk1 inhibitors are currently in clinical development and, therefore, the identification of chemotherapies that could be used as clinical partners to potentiate their effect is a main goal. OVCAR3 and IGROV ovarian cancer cells as well as the basal-like MDA-MB-231 and HS578T cell lines were used to screen for agents that may increase the antiproliferative properties of Chk1 inhibitors. Combination of DNA-damaging agents, like platinum compounds or gemcitabine, with the Chk1 inhibitors LY2603618 and SAR020106 had a synergistic effect, not observed when combined with agents targeting mitosis, like taxotere, eribulin or vinorelbine. A similar antiproliferative effect was observed for PARP inhibitors such as olaparib, reinforcing the concept that inhibition of Chk1 allows cells to enter apoptosis when a relevant genetic instability is present. Clonogenic assays and 3D colony formation studies confirmed the effect observed on proliferation also on invasion and long-term survival. Analyses of cell cycle, cell death and intracellular mediators were performed by flow cytometry and Western blot. The effect of the association of LY2603618 with cisplatin and gemcitabine did not change the cell cycle. However, combination of both agents produced a marked induction of apoptosis. Experiments evaluating caspase activity demonstrated that the principal mechanism associated with the induction of apoptosis was caspase dependent. We also explored combination of agents that have a clear translation to the clinics including double combinations with chemotherapies like cisplatin and gemcitabine. We observed that these triple combinations were more effective than double or single agents. Finally, we wanted to evaluate the antiproliferative effect when adding LY2603618 to olaparib in addition to a DNA-damaging agent. Of note, we observed a higher effect than single-agent olaparib or the chemotherapy. Interestingly, inhibition of Chk1 also reverted the effect of cisplatin in platinum-resistant cells. Our findings support the clinical development of Chk1 inhibitors in combination with DNA-damaging agents in basal-like and ovarian cancer. Citation Format: Eva M. Galan-Moya, Ana Alcaraz-Sanabria, Cristina Nieto-Jimenez, Veronica Corrales-Sanchez, Miriam Nuncia-Cantarero, Juan C. Montero, Atanasio Pandiella, Alberto Ocaña. Pharmacologic screening identifies synthetic lethality interactions with Chk1 inhibitors in basal-like breast and ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1608.

The type of estrogen and progestin as well as their doses, route and regimens of administration may each affect the benefit-risk profile of postmenopausal hormone therapy. The aim of this study was to evaluate the endometrial effect of progesterone released continuously from a vaginal ring, combined with transdermal estradiol in postmenopausal women.Forty-four postmenopausal women participated in a randomized, double-blind, dose-finding study evaluating two hormonal treatments, combining 50 microg/day of estradiol delivered by transdermal patches and either 0.5-g or 1-g progesterone vaginal rings (PVR) given for 12 weeks. The effect on the endometrium was assessed by histology and the detection of the proliferative marker Ki-67. We also measured the serum concentration of estradiol and progesterone, the tissue concentration of progesterone and the immunolocalization of estradiol and progesterone receptors in the endometrium.Endometrial thickness was increased after both treatments, although endometrial histology appeared atrophic in most biopsies. A circulating dose-response of serum progesterone levels was observed from the first to the 12th week of PVR use. In the high-progesterone-dose group, the scarce presence of Ki-67 and hormone receptors reflected the predominant action of progesterone in endometrial glands and stroma, in parallel with a lower tissue concentration of progesterone in this group.The PVR appears to be a promising method of administering natural progesterone to postmenopausal women treated with estrogen. Estradiol levels corrected the menopausal symptoms, as expected, and the presence of atrophic endometrium in the majority of women indicated that both doses of progesterone oppose the stimulatory estradiol effects, although the percentage of proliferative tissue was not negligible in both groups.

Introduction Following the 2003 heat wave, many European countries implemented heat-wave prevention plans. A number of aspects can prove fundamental in determining the effectiveness of such plans, and of these we sought to analyse the criteria used to define threshold temperatures and trigger a higher level of intervention. Method Retrospective study of the days on which heat-wave thresholds were exceeded during the period 1974–2003 was conducted. We compared when and at what level the heat-wave prevention plan would have been activated using a statistical–meteorological criterion (as applied by the Spanish Ministry of Health & Consumer Affairs) versus a temperature–mortality criterion. Results The number of days on which the threshold was exceeded was far higher when the temperature–mortality criterion was applied. The temperature percentile at which a heat wave occurred was different for each province analysed and was inversely proportional to its respective ageing index. Using both criteria, there was an increase in heat-wave days per decade. Conclusion The establishment of a heat-wave threshold temperature must be based on knowledge of the cause–effect relationship between temperature and the health of a given population. Mortality is an appropriate indicator of population health. The future effects of climate change render it essential for this relationship to be studied on a local scale, so as to enable truly efficient prevention plans to be drawn up.

In this Letter we consider that assuming: (a) that the only left-handed neutral fermions are the active neutrinos, (b) that B − L is a gauge symmetry, and (c) that the L assignment is restricted to the integer numbers, the anomaly cancellation imply that at least three right-handed neutrinos must be added to the minimal representation content of the electroweak standard model. However, two types of models arise: (i) the usual one where each of the three identical right-handed neutrinos has total lepton number L = 1 ; (ii) and the other one in which two of them carry L = 4 while the third one carries L = − 5 .

Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH2-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results. ©2008 American Association for Cancer Research., The Multiple Myeloma Research Foundation (C.S. Mitsiades, N. Mitsiades, and J.F. San-Miguel), The Lauri Strauss Leukemia Foundation (C.S. Mitsiades and N. Mitsiades), The International Waldenstrom’s Macroglobulinemia Foundation (C.S. Mitsiades), The Fund to Cure Myeloma (K.C. Anderson), The Fulbright Commission (C.J. McMullan), Doris Duke Distinguished Clinical Research Scientist Award (K.C. Anderson), Fondo de Investigación Sanitaria and European Commission grants FIS-FEDER 04/0843 (F. Mollinedo) and 06/0813 (C. Gajate), Ministerio de Educación y Ciencia grant SAF2005-04293 (F. Mollinedo), Fundación de Investigación Médica Mutua Madrileña (F. Mollinedo), and Fundación ‘‘la Caixa’’ grant BM05-30-0 (F. Mollinedo). C. Gajate is supported by the Ramón y Cajal Program from the Ministerio de Educación y Ciencia of Spain; E.M. Ocio is supported by Carlos IIIFondo de Investigación Sanitaria-Ministerio de Ciencia y Tecnología grant CM04/0001; This work was supported by a grant from the Ministry of Education and Science of Spain (BFU2006-01813/BMC), and by an Institutional Cancer Center Network program from the ISCIII. The Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER). P. Maiso was supported by the FIS-FEDER through projects to J.F. San-Miguel, and a Spanish Myeloma Network Program (G03/136). M. Garayoa is supported by ‘‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria-Ministerio de Ciencia y Tecnología’’ grant CP 05/0279.

A new species of Brachistus is described from the region of Chiriqui in Panama. Brachistus knappiae morphologically resembles Brachistus stramoniifolius, and has been confused with it in the past. The diagnostic features of Brachistus knappiae are discussed, and the plant is illustrated.

Multiple myeloma (MM) is a B-cell malignancy characterized by accumulation of monoclonal plasma cells in the bone marrow (BM). Despite recent advances in the treatment, MM represents an incurable disease for which development of new therapies is required. We report the antimyeloma effect of NVP-AEW541, a small molecule that belongs to the pyrrolo[2,3-d]pyrimidine class, identified as a selective inhibitor of the insulin-like growth factor-I receptor (IGF-IR) in vitro kinase activity. NVP-AEW541 had a potent cytotoxic effect on fresh cells and in a murine MM model. NVP-AEW541 partially abrogated the proliferative advantage conferred by the coculture with BM stromal cells and the presence of growth factors produced by the BM microenvironment. In addition, NVP-AEW541 potentiated the action of drugs, such as bortezomib, lenalidomide, dexamethasone or melphalan. Moreover the triple combination of NVP-AEW541, dexamethasone and bortezomib resulted in a significant increase in growth inhibition. Mechanistic studies indicated that NVP-AEW541 provoked a marked cell cycle blockade accompanied by pRb downregulation. Interestingly, NVP-AEW541 increased the levels of p27 associated with a reduction in the CDK2 activity. Finally, NVP-AEW541 induced cell death through caspase-dependent and -independent mechanisms. All these data, suggest the potential effect of IGF-IR kinase inhibitors as therapeutic agents for MM patients. © 2008 The Authors., This work was supported by a grant from the Ministry of Education and Science of Spain (BFU2006-01813/BMC), and by an Institutional Cancer Center Network program from the ISCIII. Our Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER). PM was supported by the FISFEDER through projects to JSM, and a Spanish Myeloma Network Program (G03/136). EMO was supported by the ‘Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I)’ and by ‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria’ with expedient no. 400001. MG was supported by the ‘Plan Nacional de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I)’ and by ‘Instituto de Salud Carlos III-Fondo de Investigación Sanitaria’ with expedient no. 05/0279. FH, CGE, JZ are employed by Novartis Pharma AG, Basel, Switzerland, the manufacturer of NVP-AEW541.

[Background]: Proteasome inhibition represents a promising novel anticancer therapy, and bortezomib is a highly selective reversible inhibitor of the proteasome complex. Acute myeloid leukemia (AML) is an immnunophenotypically heterogeneous group of diseases, with CD34+ cases being associated with drug resistance and poor outcome. We investigated the effects of bortezomib on the growth and survival of AML cells. [Design and Methods]: We studied the in vitro activity and mechanism of action of bortezomib on both cell lines and fresh cells from 28 AML patients including CD34+ and CD34- cases. [Results]: Bortezomib showed potent anti-AML activity (IC50 < 50 nM), which was greater than that of conventional agents (doxorubicin, cytarabine and fludarabine). Moreover, synergistic effects were observed when bortezomib was adminstered in combination with doxorubicin and cytarabine. Mechanistically, bortezomib induced accumulation of cells in the G2/M phase, with up-regulation of p27, together with cell death through an increase in the mitochondrial outer membrane permeability involving caspase-dependent and -independent pathways. The apoptotic activity of bortezomib on fresh CD34 + blast cells from patients was similar to that observed on CD34 - blast cells. Importantly, bortezomib was significantly more active than doxorubicin in the immature CD34+ cells, while there were no differences in its action on CD34- cells. [Conclusions]: Bortezomib induces apoptosis in acute myeloid leukemia cells in vitro. Whether this drug might be useful in the treatment of patients with acute myeloid leukemia can be established only in ad hoc clinical trials. ©2008 Ferrata Storti Foundation., We thank Johnson and Johnson Pharmaceutical Research and Development (JJPRD).

Objective The study was conducted to evaluate the effect of Carraguard vaginal gel containing 0.75 mg of levonorgestrel (CARRA/LNG gel) administered in a single dose at different stages of follicle development over subsequent follicle rupture and hormonal levels. Method Randomized, blinded, cross-over study comparing the effects of a single administration of CARRA/LNG gel or Carraguard (CARRA) gel. Twenty-four healthy women were enrolled in two centers. The gels were administered when the follicle had reached diameters of 12–14, 15–17 and ≥18 mm in eight women each. Volunteers were followed for one treatment, one washout cycle and a second treatment cycle. Follicle rupture or nonrupture was assessed by transvaginal ultrasound. Luteinizing hormone, estradiol and progesterone levels were measured daily for 5 days following treatment, and three times per week until menses. Results No follicular rupture within the 5-day period following administration was observed in 74% and 30% of the CARRA/LNG and CARRA gel treatment cycles, respectively, while ovulation was documented in 4% and 61%, respectively. The overall proportion of cycles with lack of follicular rupture or ovulatory dysfunction (follicle rupture preceded by an inadequate LH surge) was 96% for CARRA/LNG and 39% in the CARRA gel cycles. Conclusion Single vaginal administration of 0.75 mg LNG in CARRA gel in the late follicular phase is effective for interfering with the ovulatory process.

Objective The study was conducted to assess levonorgestrel (LNG) serum levels achieved after a single administration of two different doses of Carraguard vaginal gel containing LNG (CARRA/LNG), designed for use as microbicide and contraceptive for potential dual protection. Materials and Methods This was a randomized double-blind pharmacokinetic study conducted in 12 subjects enrolled at two centers. Each subject received a single vaginal administration of CARRA/LNG containing either 0.75 or 1.5 mg LNG per 4 mL of gel on Days 10–12 of the menstrual cycle. LNG serum levels were measured at 0, 1, 2, 4, 8 and 12 h after administration and for the following 7 days. LH and progesterone (for a preliminary evaluation of effect on the ovarian function) as well as SHBG were measured in the daily samples. Results Serum LNG maximum concentrations (Cmax) were 14.1±2.1 and 11.7±2.7 nmol/L and Tmax was 12.0 and 6.0 h for the low and high dose, respectively, with large intersubject variability within the first 48 h. Mean levels at 96 h were 10% of Cmax. Differences in AUC between both doses were not statistically significant. SHBG levels decreased approximately 25% by Day 4 after administration. Luteal activity was observed in 3/6 and 5/6 of the subjects in the low- and high-dose group, respectively. Conclusion This study demonstrates that the CARRA/LNG gel can sustain elevated serum levels of the contraceptive steroid for up to 96 h after a single application. The serum levels attained with the 0.75-mg formulation are in the range expected to perturb the ovulatory process as observed in some subjects. The lack of correlation between the administered dose and serum concentrations of the steroid may be related to a rate-limiting absorption of LNG from the vaginal mucosa. The results reported here suggest that the CARRA/LNG formulation has good potential to become a dual-protection method, possibly preventing conception and sexually transmitted infections.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., Protein kinases play a central role in the oncogenesis of colorectal tumors and are attractive druggable targets. Detection of activated kinases within a tumor could open avenues for drug selection and optimization of new kinase inhibitors. By using a phosphokinase arrays with human colorectal tumors we identified activated kinases, including the Epidermal Growth Factor Receptor (EGFR), components of the PI3K/mTOR pathway (AKT and S6), and STAT, among others. A pharmacological screening with kinase inhibitors against these proteins helped us to identify a new kinase inhibitor, termed EC-70124 that showed the highest anti-proliferative activity in cell lines. EC-70124 also inhibited cell migration and biochemical experiments demonstrated its effect targeting the PI3K/mTOR pathway. This drug also arrested cells at G2/M and induced apoptosis. Experiments in combination with standard chemotherapy used in the clinical setting indicated a synergistic effect. EC-70124 also reduced tumor growth in vivo and inhibited pS6 in the implanted tumors. In conclusion, by studying the kinase profile of colorectal tumors, we identified relevant activated pathways, and a new multi-kinase compound with significant antitumor properties., Ministry of Economy and Competitiveness of Spain (BFU2012-39151 and RD12/0036/0003 to AP), and the AECC (to AP). ISCIII, Fondo de Investigación Sanitaria (PI13/01444), CRIS Cancer Foundation, Diputación Albacete and ACEPAIN (to AO). JCM is a recipient of a Miguel Servet fellowship program. Our translational research laboratory was initially supported by AECC.

[Background] Legionella testing conducted at environmental laboratories plays an essential role in assessing the risk of disease transmission associated with water systems. However, drawbacks of culture-based methodology used for Legionella enumeration can have great impact on the results and interpretation which together can lead to underestimation of the actual risk. Up to 20% of the samples analysed by these laboratories produced inconclusive results, making effective risk management impossible. Overgrowth of competing microbiota was reported as an important factor for culture failure. For quantitative polymerase chain reaction (qPCR), the interpretation of the results from the environmental samples still remains a challenge. Inhibitors may cause up to 10% of inconclusive results. This study compared a quantitative method based on immunomagnetic separation (IMS method) with culture and qPCR, as a new approach to routine monitoring of Legionella., [Results] First, pilot studies evaluated the recovery and detectability of Legionella spp using an IMS method, in the presence of microbiota and biocides. The IMS method results were not affected by microbiota while culture counts were significantly reduced (1.4 log) or negative in the same samples. Damage by biocides of viable Legionella was detected by the IMS method. Secondly, a total of 65 water samples were assayed by all three techniques (culture, qPCR and the IMS method). Of these, 27 (41.5%) were recorded as positive by at least one test. Legionella spp was detected by culture in 7 (25.9%) of the 27 samples. Eighteen (66.7%) of the 27 samples were positive by the IMS method, thirteen of them reporting counts below 103 colony forming units per liter (CFU l−1), six presented interfering microbiota and three presented PCR inhibition. Of the 65 water samples, 24 presented interfering microbiota by culture and 8 presented partial or complete inhibition of the PCR reaction. So the rate of inconclusive results of culture and PCR was 36.9 and 12.3%, respectively, without any inconclusive results reported for the IMS method., [Conclusion] The IMS method generally improved the recovery and detectability of Legionella in environmental matrices, suggesting the possibility to use IMS method as valuable indicator of risk. Thus, this method may significantly improve our knowledge about the exposure risk to these bacteria, allowing us to implement evidence-based monitoring and disinfection strategies., The study was funded by the Valencian Institute of Business Competitiveness (IVACE), I + D PYME project IFIDTA/2014/64.

Advances in the treatment of breast cancer have resulted in increased survival. However, in the metastatic setting, the disease remains incurable. Therefore, understanding of the mechanisms that promote dissemination of breast cancer cells may favor the development of novel therapeutic strategies to fight those tumors. Here, we show that the ErbB ligands, Neuregulins (NRGs), promote metastatic dissemination of breast cancer cells by switching on a kinase-metalloproteinase network. Clinicopathological analyses demonstrated that NRG expression in breast tumors associated to lymph node invasion and poor patient outcome. Preclinical in vivo analyses showed that NRG expression favored in situ tumor growth, local spreading and metastatic dissemination. Genomic, biochemical and functional studies identified matrix metalloproteinases, particularly stromelysin 2 and collagenase 3, as key mediators of the NRG-induced dissemination properties of breast cancer cells. Mechanistic analyses demonstrated that NRG augmented metalloproteinase expression through a route controlled by ERK1/2 kinases. ERK1/2 increased collagenase 3 expression by controlling the activity of an SBF1-related transcription factor. In conclusion, we describe a pathway linked to breast cancer dissemination. The clinical availability of agents that target some of the components of this signalling pathway suggests that patients with tumors fed by NRGs or other factors able to activate the ERK-Collagenase 3 route may benefit from agents that act on that signalling axis., Ministry of Economy and Competitiveness of Spain (BFU2009-07728 and BFU2012- 39151), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD06/0020/0041 and RD12/0036/0003) and the Scientific Foundation of the Spanish Association Against Cancer (AECC). SSR was supported by a Juan de la Cierva contract. JCM is a recipient of a Miguel Servet fellowship program.

The development of resistance to therapy is unavoidable in the history of multiple myeloma patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired resistance. Here we present an in vivo model of acquired resistance based on the continuous treatment of mice bearing subcutaneous MM1S plasmacytomas. Xenografts acquired resistance to two generations of immunomodulatory drugs (IMiDs; lenalidomide and pomalidomide) in combination with dexamethasone, that was reversible after a wash-out period. Furthermore, lenalidomide-dexamethasone (LD) or pomalidomide-dexamethasone (PD) did not display cross-resistance, which could be due to the differential requirements of the key target Cereblon and its substrates Aiolos and Ikaros observed in cells resistant to each combination. Differential gene expression profiles of LD and PD could also explain the absence of cross-resistance. Onset of resistance to both combinations was accompanied by upregulation of the mitogen-activated protein kinaseextracellular signal-regulated kinase (ERK) kinase (MEK)ERK pathway and addition of selumetinib, a small-molecule MEK inhibitor, could resensitize resistant cells. Our results provide insights into the mechanisms of acquired resistance to LD and PD combinations and offer possible therapeutic approaches to addressing IMiD resistance in the clinic.

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al., Disseminated triple negative breast cancer (TNBC) is an incurable disease with limited therapeutic options beyond chemotherapy. Therefore, identification of druggable vulnerabilities is an important aim. Protein kinases play a central role in cancer and particularly in TNBC. They are involved in many oncogenic functions including migration, proliferation, genetic stability or maintenance of stem-cell like properties. In this article we describe a novel multi-kinase inhibitor with antitumor activity in this cancer subtype. EC-70124 is a hybrid indolocarbazole analog obtained by combinatorial biosynthesis of Rebeccamycin and Staurosporine genes that showed antiproliferative effect and in vivo antitumoral activity. Biochemical experiments demonstrated the inhibition of the PI3K/mTOR and JAK/STAT pathways. EC-70124 mediated DNA damage leading to cell cycle arrest at the G2/M phase. Pathway analyses identified several deregulated functions including cell proliferation, migration, DNA damage, regulation of stem cell differentiation and reversion of the epithelial-mesenchymal transition (EMT) phenotype, among others. Combination studies showed a synergistic interaction of EC-70124 with docetaxel, and an enhanced activity in vivo. Furthermore, EC-70124 had a good pharmacokinetic profile. In conclusion these experiments demonstrate the antitumor activity of EC-70124 in TNBC paving the way for the future clinical development of this drug alone or in combination with chemotherapy., Ministry of Economy and Competitiveness of Spain (BFU2012-39151 and RD12/0036/0003 to AP), and the AECC (to AP). Instituto de Salud Carlos III (PI13/01444) ACEPAIN and CRIS Cancer Foundation (to AO). JCM is a recipient of a Miguel Servet fellowship program (CP12/03073).

This is an open-access article distributed under the terms of the Creative Commons Attribution License., Triple negative breast cancer (TNBC) is an aggressive form of breast cancer. Despite response to chemotherapy, relapses are frequent and resistance to available treatments is often observed in the metastatic setting. Therefore, identification of new therapeutic strategies is required. Here we have investigated the effect of the mithramycin analog EC-8042 (demycarosil-3D-β-D-digitoxosyl mithramycin SK) on TNBC. The drug caused a dose-dependent inhibition of proliferation of a set of TNBC cell lines in vitro, and decreased tumor growth in mice xenografted with TNBC cells. Mechanistically, EC-8042 caused an arrest in the G2 phase of the cell cycle, coincident with an increase in pCDK1 and Wee1 levels in cells treated with the drug. In addition, prolonged treatment with the drug also causes apoptosis, mainly through caspaseindependent routes. Importantly, EC-8042 synergized with drugs commonly used in the therapy of TNBC in vitro, and potentiated the antitumoral effect of docetaxel in vivo. Together, these data suggest that the mithralog EC-8042 exerts an antitumoral action on TNBC cells and reinforces the action of standard of care drugs used in the therapy of this disease. These characteristics, together with a better toxicology profile of EC-8042 with respect to mithramycin, open the possibility of its clinical evaluation., The Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces. Ministry of Economy and Competitiveness of Spain (BFU2009-07728 and BFU2012-39151), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD12/0036/0003) and the Scientific Foundation of the Spanish Association Against Cancer (AECC) and the CRIS Foundation to AP. JCM is a recipient of a Miguel Servet fellowship program (CP12/03073). The work carried out by A.O receives support by Instituto de Salud Carlos III; Fondo de Investigación Sanitaria (FIS), PI13/01444.

The high species richness of tropical forests has long been recognized, yet there remains substantial uncertainty regarding the actual number of tropical tree species. Using a pantropical tree inventory database from closed canopy forests, consisting of 657,630 trees belonging to 11,371 species, we use a fitted value of Fisher's alpha and an approximate pantropical stem total to estimate the minimum number of tropical forest tree species to fall between ∼40,000 and ∼53,000, i.e. at the high end of previous estimates. Contrary to common assumption, the Indo-Pacific region was found to be as species-rich as the Neotropics, with both regions having a minimum of ∼19,000-25,000 tree species. Continental Africa is relatively depauperate with a minimum of ∼4,500-6,000 tree species. Very few species are shared among the African, American, and the Indo-Pacific regions. We provide a methodological framework for estimating species richness in trees that may help refine species richness estimates of tree-dependent taxa., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

Phylogenetic analysis of DNA sequences from chloroplast regions and nuclear ribosomal ITS was conducted to test the monophyly of Cestrum sect. Habrothamnus and investigate its relationships with other sections of Cestrum. Molecular divergence was very low among the sampled species, suggesting a rapid diversification in Cestrum. Individual and combined analyses of these molecular data sets using maximum parsimony and Bayesian inference reject the monophyly of the traditionally recognized sections of Cestrum, including sect. Habrothamnus. Infrageneric classifications will require significant revision. Nevertheless, the resolved monophyletic clades in this molecular analysis are geographically structured.

Aim Attention has increasingly been focused on the floristic variation within forests of the Amazon Basin. Variations in species composition and diversity are poorly understood, especially in Amazonian floodplain forests. We investigated tree species composition, richness and a diversity in the Amazonian white-water (varzea) forest, looking particularly at: (1) the flood-level gradient, (2) the successional stage (stand age), and (3) the geographical location of the forests. Location Eastern Amazonia, central Amazonia, equatorial western Amazonia and the southern part of western Amazonia. Methods The data originate from 16 permanent varzea forest plots in the central and western Brazilian Amazon and in the northern Bolivian Amazon. In addition, revised species lists of 28 varzea forest inventories from across the Amazon Basin were used. Most important families and species were determined using importance values. Floristic similarity between plots was calculated to detect similarity variations between forest types and over geographical distances. To check for spatial diversity gradients, a diversity (Fisher) of the plots was correlated with stand age, longitudinal and latitudinal plot location, and flood- level gradient. Results More than 900 flood-tolerant tree species were recorded, which indicates that Amazonian varzea forests are the most species-rich floodplain forests worldwide. The most important plant families recorded also dominate most Neotropical upland forests, and c. 31% of the tree species listed also occur in the uplands. Species distribution and diversity varied: (1) on the flood-level gradient, with a distinct separation between low-varzea forests and high-varzea forests, (2) in relation to natural forest succession, with species-poor forests in early stages of succession and species-rich forests in later stages, and (3) as a function of geographical distance between sites, indicating an increasing a diversity from eastern to western Amazonia, and simultaneously from the southern part of western Amazonia to equatorial western Amazonia. Main conclusions The east-to-west gradient of increasing species diversity in varzea forests reflects the diversity patterns also described for Amazonian terra firme. Despite the fine-scale geomorphological heterogeneity of the floodplains, and despite high disturbance of the different forest types by sedimentation and erosion, varzea forests are dominated by a high proportion of generalistic, widely distributed tree species. In contrast to high-varzea forests, where floristic dissimilarity increases significantly with increasing distance between the sites, low-varzea forests can exhibit high floristic similarity over large geographical distances. The high varzea may be an important transitional zone for lateral immigration of terra firme species to the floodplains, thus contributing to

Aim This study evaluates the performance of extended use of a progesterone (P)-releasing vaginal ring (PVR) in nursing women. Method An open-label, noncomparative study on the safety and contraceptive efficacy of PVR replaced every 4 months of use (instead of 3 months) in 192 PVR acceptors. PVR use was initiated at day 59±2 (mean±SD) postpartum and continued until weaning or completing the use of three PVRs. Results Plasma P levels attained with the ring decreased from 17±1 to 14±1 nmol/L (mean±SE) from the third to the fourth month of use. These levels are still over the critical level of 10 nmol/L required for contraceptive protection. One pregnancy occurred in the third month of use of the second ring in 1998 woman-months of exposure. Extended use of the ring did not appear to affect breast-feeding performance or the rate of infant growth, and lactational amenorrhea was prolonged. No differences in the characteristics of bleeding between the third and fourth month of ring use were observed. Conclusion The results indicate that use of the PVR for 4 months represents a safe and effective contraceptive for nursing women.

Background: Triple negative breast cancer (TNBC) represents around 15% of all breast tumors. Therapeutic strategies in TNBC are mainly based on classical chemotherapeutic agents, with limited success in the metastatic setting. Here we have explored the action of a novel mithramycin analog named EC-8042 in TNBC. Methods: we used a panel of cell lines representative of triple negative tumors including BT549, HBL100, HCC-1037, HS578T, MDA-MB213, HCC-1187, HCC-3153 and HCC-70. Proliferation studies with EC-8042 were measured by MTT assays. Propidium iodide (PI) staining followed by FACS was used for cell cycle analyses and AnnexinV-fluorescein for analysis of apoptosis. Proteins involved in cell cycle control and apoptosis were evaluated by western blot. Mitochondrial membrane potential was assessed by measuring the fluorescence of tetramethylrhodamineethylester (TMRE) dye. Results: The IC50 values obtained were in the nM range, indicating that the drug had a potent effect on these cell lines. Mechanistically, the drug caused accumulation of cells in the S phase of the cell cycle at doses of 100 and 500 nM in MDA-MB231. Biochemically, EC-8042 caused an increase in cyclin E, cyclin A, cyclin D3, cyclin B, and p27, and decreased cyclin D1 and Rb phosphorylation at serine 780. These data are consistent with an action of EC-8042 on the cell cycle. Moreover, the increase in wee1 and pY15-CDK1 are in line with an effect of the drug blocking cell cycle progression through the S phase. Annexin V staining indicated that treatment with 500 nM of EC8042 provoked apoptosis, which was also revealed by PARP processing. The treatment reduced the amounts of MCL1, BCLXL, and XIAP, but did not affect BCL2 levels. Conclusion: our results indicate that EC-8042 has a strong antitumoral action on TNBC cells, which is caused by increased apoptosis and a decrease in cell cycle progression, and opens the possibility for further development of this drug in TNBC. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P4-06-17.

Transforming growth factor-beta (TGF-beta) plays a pivotal role in the extracellular matrix accumulation observed in chronic progressive tissue fibrosis, but the intracellular signaling mechanism by which TGF-beta stimulates this process remains poorly understood. We examined whether mitogen-activated protein kinase (MAPK) routes were involved in TGF-beta1-induced collagen expression in L(6)E(9) myoblasts. TGF-beta1 induced p38 and extracellular signal-regulated kinase (ERK) 1/2 phosphorylation whereas no effect on Jun N-terminal kinase phosphorylation was observed. Biochemical blockade of p38 but not of the ERK MAPK pathway abolished TGF-beta1-induced alpha(2)(I) collagen mRNA expression and accumulation. These data indicate that TGF-beta1-induced p38 activation is involved in TGF-beta1-stimulated collagen synthesis.

We build a supersymmetric version with [Formula: see text] gauge symmetry, where [Formula: see text] is a new charge and [Formula: see text] and [Formula: see text] are the usual baryonic and leptonic numbers. The model has three right-handed neutrinos with identical [Formula: see text] charges, and can accommodate all fermion masses at the tree level. In particular, the type I seesaw mechanism is implemented for the generation of the active neutrino masses. We obtain the mass spectra of all sectors and for the scalar one we also give the flat directions allowed by the model.

e17089 Background: Ovarian cancer is characterized by frequent mutations at TP53. These tumors also harbor germline mutations at homologous recombination repair (HR) genes, so they rely on DNA-damage checkpoint proteins, like the Checkpoint kinase 1 (CHEK1) to induce G2 arrest. In our study, by using an in silico approach, we identified a synthetic lethality interaction between CHEK1 inhibitors and mitotic Aurora Kinase A and B (AURKA/B) inhibitors. Methods: Gene expression analyses were used for the identification of relevant biological functions. OVCAR3, OVCAR8, IGROV1 and SKOV3 were used for proliferation studies. Alisertib was tested as AURKA/B inhibitor and LY2603618 as CHEK1 inhibitor. Analyses of cell cycle and intracellular mediators were performed by flow cytometry and western-blot. Stem cell properties were evaluated with immunofluorescence. Results: Gene expression analyses followed by functional annotation identified cell cycle as a deregulated function. Identified druggable kinases within this function included AURKA/B, TTK kinase and CHEK1. CHEK1 and AURKA/B inhibitors showed a synergistic interaction in different cellular models. Combination of Alisertib and LY2603618 triggered apoptosis, reduced the stem cell population and increased the effect of taxanes and platinum compounds. AURKA and CHEK1 were amplified in 8.7% and 3.9% of ovarian cancers, respectively. Expression of these genes was linked with detrimental clinical outcome. Conclusions: Amplification of AURKA and CHEK1 was observed in more than 12% of ovarian tumors. Our data describes a synthetic lethality interaction between CHEK1 and AURKA/B inhibitors with potential translation to the clinic.

Made available in DSpace on 2022-04-29T07:21:44Z (GMT). No. of bitstreams: 0 Previous issue date: 2014-09-22 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) In this work, we implement a complex scalar dark matter (DM) candidate in a U(1)B-L gauge extension of the Standard Model. The model contains three right-handed neutrinos with different quantum numbers and a rich scalar sector, with extra doublets and singlets. In principle, these extra scalars can have vacuum expectation values (VΦ and Vφ for the extra doublets and singlets, respectively) belonging to different energy scales. In the context of ζ≡VΦVφ1, which allows one to obtain naturally light active neutrino masses and mixing compatible with neutrino experiments, the DM candidate arises by imposing a Z2 symmetry on a given complex singlet, φ2, in order to make it stable. After doing a study of the scalar potential and the gauge sector, we obtain all the DM-dominant processes concerning the relic abundance and direct detection. Then, for a representative set of parameters, we find that a complex DM with mass around 200 GeV, for example, is compatible with the current experimental constraints without resorting to resonances. However, additional compatible solutions with heavier masses can be found in vicinities of resonances. Finally, we address the issue of having a light CP-odd scalar in the model showing that it is safe concerning the Higgs and the Zμ-boson invisible decay widths, and also astrophysical constraints regarding energy loss in stars. HEP Division Argonne National Lab Instituto de Física Teórica Universidade Estadual Paulista, R. Dr. Bento Teobaldo Ferraz 271 Instituto de Física Teórica Universidade Estadual Paulista, R. Dr. Bento Teobaldo Ferraz 271 CAPES: 2264-13-7

in the last years, the presence of new contaminants in water has been rising. There are only few studies which analyze such presence. The aims were to determine the occurrence of drugs of abuse and their metabolites in the influent and effluent of the Sewage Treatment Plant (STP) in Talavera de la Reina, and the River Tagus, as well as to evaluate the STP removal efficiency in the elimination of these substances and to estimate the consumption of drugs in Talavera.whe samples were taken on June 28, 2010. The presence of 5 groups of drugs (10 drugs of abuse and 9 metabolites) was quantified. The efficiency was calculated from the percentage of reduction of the concentration in the influent and effluent of the STP. Drug consumption was calculated from influent concentrations. Using a specific methodology, based on the assumption the drugs after they are consumed and metabolized in the human body are excreted as parent compounds or metabolites. Whose metabolic pathways are known, and the amount of drug or metabolite quantified corresponds to the dose consumed.ten substances were detected. In all sampling points appeared: Benzoiclegonina (BE) (cocaine metabolite), ephedrine, methadone and its metabolite EDDP. The highest concentrations were of BE (239 ng/L), and THC-COOH (35 ng/L), both in influent. In the Tagus River, the highest concentrations were of BE (5.38 ng/L) and EDDP (4.4 ng/L). The STP removal efficiency was up to 80% for all substances except for methadone (which was zero) and EDDP (increasing to leave the STP). The estimated consumption shows that the most consumed substances were cannabis (1.88 grams / day) and cocaine (0.46 grams / day).the presence of drugs of abuse in River Tagus in Talavera demonstrates that these substances are not eliminated completly by STPs. Drug consumption estimate indicates that the population of Talavera mainly consumed cannabis and cocaine. Thus this methodology can complement epidemiological surveys.

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License., [Background]: The androgen receptor (AR) plays a central role in the oncogenesis of different tumors, as is the case in prostate cancer. In triple negative breast cancer (TNBC) a gene expression classification has described different subgroups including a luminal androgen subtype. The AR can be controlled by several mechanisms like the activation of membrane tyrosine kinases and downstream signaling pathways. However little is known in TNBC about how the AR is modulated by these mechanisms and the potential therapeutic strategists to inhibit its expression. [Methods]: We used human samples to evaluate the expression of AR by western-blot and phospho-proteomic kinase arrays that recognize membrane tyrosine kinase receptors and downstream mediators. Western-blots in human cell lines were carried out to analyze the expression and activation of individual proteins. Drugs against these kinases in different conditions were used to measure the expression of the androgen receptor. PCR experiments were performed to assess changes in the AR gene after therapeutic modulation of these pathways. [Results]: AR is present in a subset of TNBC and its expression correlates with activated membrane receptor kinases-EGFR and PDGFRβ in human samples and cell lines. Inhibition of the PI3K/mTOR pathway in TNBC cell lines decreased notably the expression of the AR. Concomitant administration of the anti-androgen bicalutamide with the EGFR, PDGFRβ and Erk1/2 inhibitors, decreased the amount of AR compared to each agent given alone, and had an additive anti-proliferative effect. Administration of dihydrotestosterone augmented the expression of AR that was not modified by the inhibition of the PI3K/mTOR or Erk1/2 pathways. AR expression was posttranscriptionally regulated by PI3K or Erk1/2 inhibition. [Conclusion]: Our results describe the expression of the AR in TNBC as a druggable target and further suggest the combination of bicalutamide with inhibitors of EGFR, PDGFRβ or Erk1/2 for future development., This research is supported by: Fundación Sociosanitaria de Castilla La Mancha (FISCAM) Grant Number. PI/2010/017, Ministerio de Ciencia e Innovación, Grant Number BFU2009-07728/BMC, Fondo de Investigación Sanitaria (FIS), Grant Number PI09/02144, Cancer Center Network Program from the ISCIII (RD06/0020/0041). Fundación Científica AECC.

By considering left-right (L-R) asymmetries we study the capabilities of lepton colliders in searching for new exotic vector bosons. Specifically we study the effect of a doubly charged bilepton boson and an extra neutral vector boson appearing in a 3-3-1 model on the L-R asymmetries for the processes $e^-e^-\to e^-e^-$, $\mu^-\mu^-\to\mu^-\mu^-$ and $e^-\mu^-\to e^-\mu^-$ and show that these asymmetries are very sensitive to these new contributions and that they are in fact powerful tools for discovery this sort of vector bosons., Comment: RevTeX, 22 pages, 12 eps figures

The present paper summarizes a joint effort undertaken by the Instituto Geografico Militar de Chile (IGM) and the Instituto Antartico Chileno (INACH) in order to obtain digital cartography of the Fildes Peninsula, Rey Jorge Island, Antarctica. This peninsula constitutes the prototype project area for the main IGM-INACH project No 153 “Cartographic Survey and Geographic Information System of the South Shetlands Islands”