Search

We study a fewF ¼ 2 andF ¼ 1 flavor-changing neutral current processes in the minimal 3-3-1 model by considering, besides the neutral vector bosons Z 0 , the effects due to one CP-even and one CP-odd scalar. We find that there are processes in which the interference among all the neutral bosons is constructive or destructive and in others the interference is negligible. We first obtain numerical values for all the unitary matrices that rotate the left- and right-handed quarks and give the correct mass of all the quarks in each charge sector and the Cabibbo-Kobayashi-Maskawa (CKM) mixing matrix. The so-called 3-3-1 models with gauge symmetry SUð3ÞCSUð3ÞLUð1ÞX are interesting extensions of the standard model (SM). The main feature of these models is that, by choosing appropriately the representation con- tent, the triangle anomalies cancel out, and the number of families has to be a multiple of three. Moreover, because of the asymptotic freedom, this number is just three (1-3). In particular, the minimal version of this class of models (m3- 3-1 for short) (1) has other interesting predictions: It ex- plains why sin 2 � W < 1=4 is observed, and at the same time, when sin 2 � W ¼ 1=4, it implies the existence of a Landau-like pole at energies of the order of a few TeVs (4). The existence of this Landau-like pole also stabilizes the electroweak scale avoiding the hierarchy problem (5), and the model allows the quantization of electric charge inde- pendently of the nature of the massive neutrinos (6,7). It also has an almost automatic Peccei-Quinn symmetry if the trilinear term in the scalar potential becomes a dynamical degree of freedom (8), there are also new sources of CP violations which allow to obtainand � 0 =� even without the Cabibbo-Kobayashi-Maskawa (CKM) phase; i.e., if we put � ¼ 0 (9). And, probably, it could explain CPviolation in the B � B mesons as well. One important feature that distinguishes the model from any other one is the predic- tion of extra singly charged and doubly charged gauge boson bileptons (10) and also exotic charged quarks, while the lepton sector is the same as that of the SM. Right- handed neutrinos are optional in the model. They are not needed to generate light active neutrinos or the Pontecorvo-Maki-Nakagawa-Sakata (PMNS) mixing ma- trix. Those exotic charged particles may have an effect on the two photon decay of the SM-like Higgs scalar (11). A common feature of all 3-3-1 models is that two of the quark triplets transform differently from the third one, and this implies flavor-changing neutral currents (FCNC) at tree level mediated by the extra neutral vector boson, Z 0

The neuregulins (NRGs) are a family of EGF-like factors that activate receptor tyrosine kinases of the ErbB/HER type. Some NRGs are membrane anchored and are released upon cleavage of the ectodomain. Here we have investigated the characteristics of the cleavage of different transmembrane NRG isoforms (proNRG) that diverge in domains that have been implicated in the regulation of the cleavage of other membrane-anchored growth factors. We show that cleavage of proNRGs is complex and generates several cell-bound truncated fragments. Comparison of the resting generation of these truncated fragments between proNRG forms that diverge in the linker region that connects the EGF-like module to the transmembrane domain revealed that proNRGβ2a was relatively resistant to processing compared to proNRGβ4a which was processed more efficiently than proNRGα2a. An important role for this linker in proNRG cleavage was supported by deletion analysis of this region that prevented NRG solubilization. Studies aimed at the identification of the proteolytic machinery responsible for proNRG processing indicated that metalloproteases were involved in proNRG processing. This was further supported by the fact that cleavage of proNRGα2c was defective in fibroblasts derived from TACE(-/-) animals that express an inactive form of the metalloprotease TACE., We thank the funding from the European Community, the Fundación Ramón Areces, and the Spanish Ministry of Education and Culture. A.E.-O. was supported by a psotdoctoral contract from the Spanish Ministry of Education and Culture. E.D.-R. and L.Y were supported by a predoctoral fellowship from the same Ministry.

Work in our lab was supported by grant PB94–0075 from the Spanish Ministry of Science and Education; by the BIOTECH Program (BIO4-CT96–0058) from the European Community; and by the Fundacion Ramon Areces. E.D.-R. was supported by a predoctoral fellowship from the Spanish Ministry of Science and Education; and N.C. holds a fellowship from the Scientific Foundation of the Spanish Association Against Cancer (AECC). A.E-O holds a postdoctoral contract from the Spanish Ministry of Education and Science.

Daily mortality displays a seasonal pattern linked to weather, air pollution, photoperiod length, influenza incidence and diet, among which temperature ranks as a leading cause. This study thus sought to assess the relationship between temperature, relative humidity, wind speed and mortality in the Madrid Autonomous Region (Spain) for the period January 1986–December 1992, controlling for the effects of air pollution and influenza incidence. Daily data on maximum, minimum and 24-hour mean temperature, relative humidity and wind speed were matched against daily mortality. Transfer function was identified using the Box–Jenkins pre-whitening method. Multivariate time series regression models were used to control for the confounding effects of air pollution and influenza incidence. Separate seasonal analyses were carried out for winter and summer periods. A J-shaped relationship between outdoor temperature, relative humidity and daily mortality was found. Mortality proved to be inversely related to cold temperature (4- to 11-day lag) and directly related to warm temperature (1-day lag). High relative humidity during summer periods was negatively related to mortality. Thermal variation ascribable to Madrid's mesothermal Mediterranean climate was strongly related to daily mortality, even where air pollution and influenza incidence were controlled for.

We apply a multiple-time version of the reductive perturbation method to study long waves as governed by the shallow water wave model equation. As a consequence of the requirement of a secularity-free perturbation theory, we show that the well known N-soliton dynamics of the shallow water wave equation, in the particular case of α=2β, can be reduced to the N-soliton solution that satisfies simultaneously all equations of the Korteweg-de Vries hierarchy.

Introduction Recent decades have seen a major international effort to inventory tree communities in the Amazon Basin and Guiana Shield (Amazonia), but the vast extent and record diversity of these forests have hampered an understanding of basinwide patterns. To overcome this obstacle, we compiled and standardized species-level data on more than half a million trees in 1170 plots sampling all major lowland forest types to explore patterns of commonness, rarity, and richness. Methods The ~6-million-km 2 Amazonian lowlands were divided into 1° cells, and mean tree density was estimated for each cell by using a loess regression model that included no environmental data but had its basis exclusively in the geographic location of tree plots. A similar model, allied with a bootstrapping exercise to quantify sampling error, was used to generate estimated Amazon-wide abundances of the 4962 valid species in the data set. We estimated the total number of tree species in the Amazon by fitting the mean rank-abundance data to Fisher’s log-series distribution. Results Our analyses suggest that lowland Amazonia harbors 3.9 × 10 11 trees and ~16,000 tree species. We found 227 “hyperdominant” species (1.4% of the total) to be so common that together they account for half of all trees in Amazonia, whereas the rarest 11,000 species account for just 0.12% of trees. Most hyperdominants are habitat specialists that have large geographic ranges but are only dominant in one or two regions of the basin, and a median of 41% of trees in individual plots belong to hyperdominants. A disproportionate number of hyperdominants are palms, Myristicaceae, and Lecythidaceae. Discussion The finding that Amazonia is dominated by just 227 tree species implies that most biogeochemical cycling in the world’s largest tropical forest is performed by a tiny sliver of its diversity. The causes underlying hyperdominance in these species remain unknown. Both competitive superiority and widespread pre-1492 cultivation by humans are compelling hypotheses that deserve testing. Although the data suggest that spatial models can effectively forecast tree community composition and structure of unstudied sites in Amazonia, incorporating environmental data may yield substantial improvements. An appreciation of how thoroughly common species dominate the basin has the potential to simplify research in Amazonian biogeochemistry, ecology, and vegetation mapping. Such advances are urgently needed in light of the >10,000 rare, poorly known, and potentially threatened tree species in the Amazon.

We analyze the capability of the next generation of linear electron-positron colliders to unravel the spin and couplings of excited leptons predicted by composite models. Assuming that these machines will be able to operate both in the {ital e}{sup +}{ital e}{sup {minus}} and {ital e}{sup {minus}}{gamma} modes, we study the effects of the excited electrons of spin 1/2 and 3/2 in the reactions {ital e}{sup {minus}}{gamma}{r_arrow}{ital e}{sup {minus}}{gamma} and {ital e}{sup +}{ital e}{sup {minus}}{r_arrow}{gamma}{gamma}. We show how the use of polarized beams is able not only to increase the reach of these machines, but also to determine the spin and couplings of the excited states. {copyright} {ital 1996 The American Physical Society.}

There can be no question that in any area of science it is important to establish methodologies and criteria which enable universally comparable and applicable results to be obtained. In this regar...

Selective acid-promoted cyclization of lapachols (I) affords the α- (III) and β-lapachones (II), respectively.

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 seen in the metastatic setting. Therefore, identification of new therapeutic targets is required. With this aim, we have profiled the activation status of 44 receptor tyrosine kinases (RTKs) and their major signaling pathways in patient-derived TNBC tumors. Frequent co-activation of several RTKs as well as the extracellular signal-regulated protein kinases 1 and 2 (Erk1/2) and mammalian target of rapamycin (mTOR) routes was found. Pharmacologic targeting of the activated kinases indicated that agents that attack the mTOR route are more potent and efficient antitumoral treatments than agents targeting RTKs. mTOR signals through two multiprotein complexes, mTORC1 and mTORC2. We used a genetic approach to explore the contribution of each of the two mTOR branches to the regulation of cell number of TNBC cells. RNA interference experiments indicated that mTORC1 predominated over mTORC2 in the control of TNBC cell proliferation. Moreover, RNA interference of mTOR had a superior antiproliferative action than separately acting on mTORC1 or mTORC2. To analyze the relevance of mTOR targeting in vivo, we used mice with TNBC. Treatment of these mice with BEZ235, a drug that targets mTOR, slowed tumor growth. Mechanistically, BEZ235 delayed cell cycle progression without affecting cell viability. Our results show that TNBCs are particularly sensitive to inhibition of the mTOR pathway, and indicate that mTOR targeting may be a more efficient anti-TNBC therapy than exclusively acting on the mTORC1 branch of the pathway. This is relevant as most mTOR inhibitors used in the clinic act on mTORC1. Collectively with the fact that BEZ235 synergized with drugs commonly used in the treatment of TNBC, our data support the clinical development of agents that act on mTOR as a therapy for this disease., This work was supported by grants from the Ministry of Science and Innovation of Spain (BFU2009–07728/BMC to AP, and PS09/00868 to AE-O). JCM and SS were supported by the Cancer Center Network Program from the ISCIII (RD06/0020/0041). The Cancer Research Institute, and the work carried out at AP and AE-O laboratories, receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces. AO receives research support from the FISCAM (Grant PI2010/017) and from the ISCIII (Grant PS09/02144).

Resumen Objetivo Analizar las implicaciones del uso de receta electrónica sobre el gasto farmacéutico (GF) así como explorar factores determinantes de su utilización. Métodos Construcción de 2 modelos de regresión múltiple, tomando en uno de ellos como variable dependiente el GF y en el otro el porcentaje de prescripción mediante receta electrónica, incluyendo datos referidos a 9 centros de atención primaria de Andalucía. Resultados Cada incremento en un punto de prescripción por principio activo (PPA) se relacionó con una reducción media del GF de 2.079 €/año, mientras que cada incremento porcentual en el uso de receta electrónica se relacionó con un aumento de 1.027 € anuales. También se relacionaron con un mayor GF cada tarjeta ajustada por edad y tipo de farmacia (TAFE) asignada (36,71 €/año), la presión asistencial (2.585 €/año) y la frecuentación (2.17.148 €/año).Los factores que se relacionaron con un mayor uso de receta electrónica fueron un menor índice de ruralidad, una mayor distancia a la capital, una mayor PPA y una menor frecuentación. Conclusiones La prescripción mediante receta electrónica parece ser una variable predictora del gasto farmacéutico, relacionándose cada incremento porcentual con un incremento medio anual de 1.027 euros. Esta variable, junto con la prescripción mediante principio activo, el número de TAFE asignadas, la frecuentación y la presión asistencial media, contribuyen a explicar más del 65% de la variabilidad en el GF entre facultativos. El incremento del gasto relacionado con la receta electrónica parece producirse a expensas del aumento en el número de prescripciones por paciente.

Legionellosis is an uncommon cause of pneumonia in children and even more exceptionally in healthy children. The purpose of this study is to describe the procedure which led to the identification of an unusual source of legionella infection, in a healthy girl, and highlight the need to adopt preventive measures.A 4-year old girl without any risk factors was diagnosed of pneumonia caused by Legionella pneumophila serogroup 1. After investigating the environment, it was found that the source of the transmission was a home humidifier.Despite the fact that this equipment is classified with a low probability of spreading legionella, a lack of cleanliness and maintenance of these machines can increase the risk of transmission of the bacteria. Therefore, healthcare professionals must give adequate advice to their patients about the care of this equipment and how to use these machines properly.

Reseña del libro de Diego Enrique Osorno González (selección e introducción) et al., País de muertos. Crítica contra la impunidad, México, Debate, 2011, 328 pp.

La malformación es una de las enfermedades más importantes del mango en el ámbito mundial. Varias especies de Fusarium han sido identificadas como agentes causales de esta enfermedad. Recientemente, una nueva especie, F. mexicanum, fue descrita causando malformación en huertas de mango de la región centro occidente de México; sin embargo, esta especie no ha sido detectada en áreas productoras del Golfo de México. Durante los últimos años, se ha presentado un incremento en las huertas de mango que presentan malformación en Jalisco, un estado localizado al norte del área donde F. mexicanum ha sido detectado. El objetivo de este trabajo fue identificar el patógeno causante de la malformación floral y vegetativa en Jalisco. Análisis morfológico y genético de los genes ß tubulina, EF-1á, e histona H3, mostró que todos los aislados estudiados fueron F. mexicanum. Se confirmó que este patógeno es la especie principal causante de la malformación del mango en los estados localizados en la región del Pacífico central. Análisis filogenéticos mostraron que F. mexicanum pudiera estar presente como poblaciones clonales cuya dispersión pudo haber ocurrido por medio de la comercialización de plantas de vivero contaminadas. F. mangiferae, F. sterilihyphosum y tipo F. subglutinans, especies causantes de la malformación en otros países, no fueron detectadas en este estudio.

El artículo constituye una propuesta para definir con claridad el significado de gobernabilidad. Para ello, se propone considerarla como una categoría conceptual para el análisis político incorporando elementos tanto del régimen político como del de políticas públicas. La propuesta relaciona y diferencia la definición de gobernabilidad con conceptos como estabilidad, orden, crisis, gobernanza y buen gobierno., The article builds a proposal to define the governability's meaning. We propose to consider governability as a conceptual category for political analysis that may allow incorporating elements from the political regime and the policy regimes. Relating and differentiating the governability´s definition with concepts as stability, order, crisis, governance and good governance develops the proposal of the article.

mTOR is a serine/threonine kinase that acts by binding different sets of proteins forming two complexes, termed mTORC1 and mTORC2. mTOR is deregulated in a substantial proportion of ovarian tumors. Despite the use of drugs directed to mTOR in ongoing clinical trials, the functional relevance of the individual mTORC branches in ovarian cancer is not known. Here, we show that mTORC1 and mTORC2 were constitutively active in ovarian cancer cell lines. Knockdown of raptor or rictor, proteins required for the function of mTORC1 or mTORC2, respectively, resulted in profound inhibition of ovarian cancer cell proliferation. The knockdown of raptor had a more important inhibitory effect than the knockdown of rictor, indicating mTORC1 had a predominant role over mTORC2 in the control of ovarian cancer cell proliferation. Rapamycin decreased the proliferation of ovarian cancer cells, and this was accompanied by inhibition of the phosphorylation of S6, a protein used as readout of mTORC1 function. However, rapamycin had only amarginal effect on the phosphorylation status of 4E-BP1, anothermTORC1 substrate. Therefore, mTORC1 probably controls p4E-BP1 along two distinct pathways, one of them sensitive to rapamycin and another insensitive. The dual PI3K/mTOR inhibitor BEZ235 was more efficient than rapamycin in its inhibitory action on ovarian cancer cell proliferation. Biochemically, BEZ235 completely inhibited pS6, p4E-BP1, and pAkt. Our results suggest that broad-spectrum mTOR inhibitors that block mTORC1 and mTORC2 are more desirable for their clinical development in ovarian cancer than agents exclusively targeting one of the mTOR branches. ©2012 AACR., This work was supported by grants from the Ministry of Science and Innovation of Spain (BFU2009-07728/BMC; A. Pandiella) and by the Consejería de Sanidad de la Junta de Castilla y León (SAN196/SA03/ 07; J.C. Montero). X. Chen is supported by the Cancer Center Network Program from the Instituto de Salud Carlos III (RD06/0020/0041). Our Cancer Research Institute and the work carried out at our laboratory received support from the European Community through the Regional Development Funding Program(FEDER) and from the Fundación Ramón Areces.

In this study, we describe the synthesis of a series of α- and β-lapachone containing hydroxyl or methoxyl groups on the benzene ring, by means of the selective acid promoted cyclization of the appropriate lapachol analog. The evaluation of the antiproliferative activity in human solid tumor cell lines provided 7-hydroxy-β-lapachone as lead with enhanced activity over the parent drug β-lapachone. Cell cycle studies, protein expression experiments, and reactive oxygen species analysis revealed that, similarly to β-lapachone, ROS formation and DNA damage are critical factors in the cellular toxicity of 7-hydroxy-β-lapachone., Co-financed by the European Social Fund (FEDER), the Spanish Instituto de Salud Carlos III (PI11/00840), the Spanish MSC (RTICC RD06/0020/1046 and RD06/0020/0041), the Canary Islands ACIISI (PI 2007/021), the Canary Islands FUNCIS (PI 43/ 09), and by the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET PIP 0447), and Universidad de Buenos Aires (UBACyT 20020090200697). E.L.B. thanks CONICET for a fellowship. L.G.L. thanks ACIISI for a postdoctoral contract (SE- 10/19).

Made available in DSpace on 2022-04-29T01:01:57Z (GMT). No. of bitstreams: 0 Previous issue date: 2011-09-22 In the framework of a 3-3-1 model with a minimal scalar sector we make a detailed study concerning the implementation of the Peccei-Quinn symmetry in order to solve the strong CP problem. For the original version of the model, with only two scalar triplets, we show that the entire Lagrangian is invariant under a Peccei-Quinn-like symmetry but no axion is produced since a U(1) subgroup remains unbroken. Although in this case the strong CP problem can still be solved, the solution is largely disfavored since three quark states are left massless to all orders in perturbation theory. The addition of a third scalar triplet removes the massless quark states but the resulting axion is visible. In order to become realistic the model must be extended to account for massive quarks and an invisible axion. We show that the addition of a scalar singlet together with a ZN discrete gauge symmetry can successfully accomplish these tasks and protect the axion field against quantum gravitational effects. To make sure that the protecting discrete gauge symmetry is anomaly-free we use a discrete version of the Green-Schwarz mechanism. © 2011 American Physical Society. Instituto de Física Teórica Universidade Estadual Paulista, R. Dr. Bento Teobaldo Ferraz 271, Barra Funda, São Paulo-SP, 01140-070 Instituto de Física Teórica Universidade Estadual Paulista, R. Dr. Bento Teobaldo Ferraz 271, Barra Funda, São Paulo-SP, 01140-070

Introduction All the climate-change studies undertaken to date agree that one of the principal consequences of this phenomenon is the increase in heat waves, which, without exception, are linked to marked rises in mortality. The characteristics that modulate and determine the relationship between high temperatures and health must therefore be ascertained in the greatest possible detail, so that really effective prevention plans can be designed to address temperature extremes. Methods We examined the effect of heat waves on daily non-accidental-cause mortality across all age groups in the Castile-La Mancha region (Spain) from 1975 to 2003. Quantitative analyses were performed using autoregressive integrated moving average (ARIMA) models, with other covariates, such as pressure trends, relative humidity, and duration and chronological number of heat waves. Results Mortality increased significantly with respect to the mean, when temperatures exceeded the designated provincial thresholds in Castile-La Mancha. For each degree centigrade that temperatures exceeded these thresholds, the percentage increase in mortality amounted to increases of approximately 12% over the daily mean, albeit with clear provincial variations. The longest heat waves were associated with daily mortality, with those at the end of summer causing the lowest mortality. Meteorological situations most closely associated with increases in mortality were cyclonic conditions accompanied by low humidity. Conclusions Spatio-temporal variability in the temperature–mortality relationship must be studied in order to enable really effective heat-wave prevention plans to be drawn up. The influence of variables, such as heat-wave duration or time of appearance, is important in the total increase in mortality during temperature extremes. Since parameters, such as humidity or pressure trends, can play very different roles in different geographical settings, they should be analysed separately from temperature.

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The Neuregulins and their receptors, the ErbB/HER subfamily of receptor tyrosine kinases, have critical roles in animal physiology, and their deregulation is frequent in cancer. Here we report the identification of the guanine nucleotide exchange factor, phosphatidylinositol 3,4,5-triphosphate-dependent Rac exchanger 1 (P-Rex1), as a novel mediator in signalling by ErbB/HER receptors. P-Rex1 was formerly described as a phosphoinositide 3-kinase and G beta gamma activated protein that regulates Rac function. We define how ErbB/HER receptors regulate P-Rex1 function, which involves dephosphorylation of inhibitory residues, and phosphorylation of activating residues of P-Rex. The net balance resulting from activation of this phosphorylation/dephosphorylation cycle of P-Rex1 favours Rac activation. Molecular and biological studies indicated that P-Rex1 phosphorylation regulated the proliferation of breast cancer cells, and P-Rex1 knockdown affected their migration or invasiveness, as well as their in vivo tumourigenic potential. Moreover, as we found correlation between high P-Rex1 expression and poor patient outcome in breast cancer, P-Rex1 targeting may be therapeutically relevant in cancer., This work was supported by grants from the Ministry of Science and Innovation of Spain (BFU2006-01813/BMC and BFU2009-07728/BMC) and by the Consejería de Sanidad de la JCYL. 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.

Las crisis son eventos inesperados que detonan y permiten el cambio en los regímenes de políticas públicas. Para analizar cómo cambia el paradigma de políticas públicas, el artículo ofrece una exposición de tres diferentes crisis: la argentina en el periodo 2000-2003, la española en 2008-2011, y la mexicana en 1994-1996. Se busca responder a la pregunta: ¿cómo las crisis impulsan el cambio de régimen de políticas? Se responde con la identificación de que las crisis destruyen las coaliciones gobernantes previas a la crisis, obligan a la formación de una nueva coalición para enfrentarla, pero que es sustituida por otra que consolida el nuevo paradigma.

The neuregulins (NRGs) play important roles in animal development and homeostasis, and their deregulation has been linked to diseases such as cancer and schizophrenia. The NRGs belong to the epidermal growth factor (EGF) family of transmembrane growth factors. Although NRGs may be synthesized as transmembrane proteins (the pro-NRGs), some of them lack an N-terminal signal sequence, raising the question of how these pro-NRGs are directed to the plasma membrane. Here we have explored the domains of pro-NRGs that are required for their membrane anchoring, cell surface exposure, and biological activity. We show that an internal hydrophobic region acts as a membrane-anchoring domain, but other regions of pro-NRG are required for proper sorting to the plasma membrane. Using mutants that are located in different subcellular compartments, we show that only plasma membrane-exposed pro-NRG is biologically active. At this location, the pro-NRGs may act as transautocrine molecules (i.e. as membrane factors able to activate receptors present in cells that are in physical contact with the pro-NRG-producing cells (in trans) or capable of activating receptors present in the pro-NRG-producing cells (in cis))., This work was supported in part by Ministry of Science and Technology of Spain Grants BMC2003-01192, BFU2006-01813/BMC, and BFU2009-07728/BMC. Our Cancer Research Institute receives support from the European Community through the regional development funding program (FEDER/ERDF) and the Fundación Ramón Areces. Supported by the Scientific Foundation of the Spanish Association for Cancer Research. Supported by the Cancer Center Network Program from the Instituto de Salud Carlos III (RD06/0020/0041). RRB Recipient of a fellowship from the Spanish Ministry of Education.

Breast cancer is the most commonly diagnosed tumor in women. While important advances in this field led to progressive increases in survival, in the metastatic setting the disease remains incurable. Because of this, important efforts are being carried out to define the molecular alterations that drive the oncogenic properties of the disease, to therapeutically act on them. In an attempt to better categorize patients to act on their disease more efficiently, several genetic studies have classified breast tumors into different subgroups, according to their gene expression profiles (Curtis et al. Nature 2012; 486:346-52; Perou et al. Nature 2000; 406:747-52). However, gene expression profiling is still not widely used to define treatment of breast cancer, which is mostly guided by anatomopathological criteria (Dawson et al. EMBO J 2013; 32:617-28). Using this approach, breast tumors can be classified into three subgroups: hormone receptor positive (HR+), HER2 positive, or triple negative breast tumors (TNBC). Hormone positive tumors express estrogen and progesterone receptors and are highly sensitive to antihormonal therapies. HER2+ tumors are characterized by overexpression of the transmembrane tyrosine kinase and receive agents against HER2 such as antibodies or small molecule kinase inhibitors. TNBC are characterized by the lack of hormone receptors, and no overexpression of HER2. In contrast to the other two subtypes, no available target is known for patients with TNBC, and their actual treatment is based on classical chemotherapeutics. This fact very much limits successful therapy of TNBC, and for this reason major research efforts aimed at identifying etiopathogenic targets are being carried out (Turner and Reis-Filho, Clin Cancer Res 2013; 19:6380-8). Genomic studies have revealed deficiencies in DNA repair mechanisms in TNBC (Shah et al. Nature 2012; 486:395-9). As a consequence, agents targeting proteins involved in such mechanisms are under clinical evaluation (Juvekar et al. Cancer Discov 2012; 2:1048-63). How can we identify additional therapeutic vulnerabilities in this type of breast cancer? Phosphokinase profiling has recently been used to analyze the activation status of several oncogenically relevant kinases in TNBC (Montero et al. Oncogene 2014; 33:148-56). Using patient samples as well as representative TNBC cell lines, these studies indicated frequent activation of components of the PI3K/mTOR pathway as well as the ERK1/2 route in this type of tumors. Genetic as well as pharmacological studies indicated an important role of the PI3K/mTOR pathway in the control of the proliferation of TNBC cells both in vitro and in vivo. In contrast, targeting of the ERK1/2 route failed to substantially affect proliferation of TNBC cells. mTOR controls cellular functions through formation of multiprotein complexes, termed mTORC1 and mTORC2. When dissecting the importance of either complex in TNBC, mTORC1 seemed to have a more relevant role than mTORC2 in the control of cellular proliferation. However, when mTOR was neutralized, by either knock down or pharmacological inhibition, the effect on cell proliferation was greater than targeting of mTORC1 or mTORC2 individually. This is therapeutically relevant, since most agents being developed with clinical purposes, i.e. rapamycin and analogues, act mainly on mTORC1. The fact that targeting mTOR was more efficient than exclusively targeting mTORC1, should stimulate an effort to clinically develop mTOR inhibitors instead of mTORC1-directed rapalogs. The precise mechanisms by which the PI3K/mTOR route is frequently active in TNBC are still unclear. Interestingly, recent massive genomic studies identified certain genetic events which may activate this pathway, including PTEN mutation/deletion in 10%, and PIK3CA mutation in 8% of the tumors. Other genomic alterations which may impinge on this route include EGFR or FGFR amplification (4%) or HER2 mutations (2%) (Shah et al. Nature 2012; 486:395-9; Curtis et al. Nature 2012; 486: 346-52). Therapeutic inhibition of the PI3K/mTOR pathway in breast cancer is currently an active area of research. Indeed, at this moment several ongoing studies are evaluating PI3K/mTOR inhibitors in TNBC alone or in combination with chemotherapy. However the incorporation of PI3K/mTOR inhibitors into the clinic raises several questions: should PI3K inhibitors be given alone? Can/should they be combined with chemotherapy or targeted agents? How can we select responsive patients? The preclinical data suggest that combinations with chemotherapy should be a preferred option (Montero et al. 2014). In fact, combination with other targeted agents including PARP inhibitors is under clinical evaluation (Juvekar et al. 2012). Preclinical evidence indicates that PI3K/mTOR targeting in TNBC and other solid tumors causes a cytostatic effect, rather than cytotoxic (Montero et al. 2014). Therefore, full exploitation of the antitumoral effect of the PI3K/mTOR inhibitors probably would require their combination with agents that cause cell death. A relevant concept is how to identify patients responsive to PI3K/mTOR inhibitors. Some studies have selected patients based on mutations at the PI3KCA gene and/or loss of PTEN. However, recent data suggest that PI3KCA mutations do not predict response to agents against this route (Dillon and Miller. Curr Drug Targets 2014; 15:65-79). This suggests that the best approach to identify a targetable route may be to evaluate its activation status, rather than an analysis of mutational or expression data. In the case of the PI3K/mTOR route, assessment of phosphorylated proteins that can be used as readouts of the activity of the pathway may represent the best method to predict sensitivity to PI3K/mTOR targeting compounds. In conclusion evaluation of cancer vulnerabilities in triple negative tumors discovered the PI3K/mTOR pathway as a key druggable element. Identification of potential responsive patients and the best partner drug to be combined will be required to optimize the efficacy of these agents in TNBCs.

Many extensions of the standard model predict the existence of extra neutral vector bosons, generically referred as ${Z}^{\ensuremath{'}}$. This boson may be discovered at the LHC but in this case it will be necessary to study the respective parameters in order to discriminate to which model it belongs to. This is a task for a much clean lepton linear collider as the future International Linear Collinear. In this paper we develop an exemplary study of the capability of several asymmetries on and off ${Z}^{\ensuremath{'}}$ peak in discriminating among those extensions with (almost) no ambiguities.

We worked out in detail the three-Higgs-doublet extension of the standard model when the $A_4$ symmetry, which is imposed to solve the flavor problem, is extended to the scalar sector. The three doublets may be related to the fermion mass generation and, in particular, they may be the unique responsible for the generation of the neutrino masses. If this is the case, the respective VEVs have to be quite smaller than the electroweak scale if no fine tuning in the Yukawa couplings is assumed. We consider here the mass spectra in the scalar sector in three different situations. In one of them there are no light scalars at all, but in the other ones a light or two massless scalars, at the tree level, may survive. The later fields are safe, from the phenomenological point of view, since it couples mainly with neutrinos and/or becomes enough massive at the tree level if there exist trilinear interactions. Quantum effects may be important too., 11 pages, no figures, new references added

[Background]: The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits. [Methods]: We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided. [Results]: Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm3, difference = 2.1 cm3, 95% confidence interval = 0.76 to 3.51 cm3, P = .01) and total regression of tumors by day 36 with no later relapse. [Conclusions]: Results showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancer patients., Ministry of Science and Innovation of Spain (BFU2006-01813/BMC-FEDER), the Instituto de Salud Carlos III through the Spanish Cancer Centers Network Program (RD06/0020/0041), and an Acción transversal en cancer to A.P. S.S. and J.C.M. were supported by Juan de la Cierva and Scientific Foundation of the Spanish Association Against Cancer (AECC) contracts, respectively. This work was partially sponsored by a research contract to AP from Bristol-Myers Squibb, S.A., Madrid, Spain.

In the summer of 2003 the temperatures reached were responsible for a large number of deaths in Europe. A year after this fact, many countries had implemented some sort of plan of prevention against excessive temperatures. Plans that had already shown its ability to prevent a large proportion of avoidable mortality in other latitudes. Since then, a lot of papers have been published providing new data on health effects of a heat wave, which can help increase the efficiency of these prevention plans. Knowing the weather conditions at risk, defining "heat wave" or to take into account the time that the plan should be active from the study of the relationship between temperature and their effects on health, to identify weather patterns that modulate the relationship between temperature and mortality, locate the profile of people at risk or to develop protocols for action as accurately as possible and based on scientific knowledge are elements drawn from studies carried on in recent years that should be taken into account.

Introduction As is known, the effects of extreme temperatures on mortality are characterised by an annual periodicity, with a rise centred in the winter months. The most recent epidemiological studies show that mortality caused by cold waves is, in many cases, comparable to that caused by the severest heat waves. This study sought to quantify the rise in mortality due to extreme cold and the factors that determine the relationship between these variables in Castile-La Mancha (Spain). Methods We examined the effect of extreme winter temperature on daily non accidental cause mortality in Castile — La Mancha from 1975 to 2003, for all ages. Quantitative analyses were performed using ARIMA models, with other covariates, such as influenza, pressure trends, relative humidity, and cold wave duration and chronological number. Results There were two mortality peaks: a short-term peak (with a lag of 3 to 7 days); and a longer term peak (of under two weeks). Excess mortality during cold waves was around 10% per degree centigrade below the threshold temperature for all the provinces except Guadalajara, where an increase of only 4.61% was detected. Mortality increased in response to rises in cold-wave duration and relative humidity. Cold waves occurring at the end of the “winter” season caused the greatest mortality. Conclusions This study confirms that daily mortality in Castile — La Mancha increases during cold waves. Efficient cold-wave prevention plans must therefore be implemented. Such plans should be based on in-depth knowledge of the causes that underlie and modulate the relationship between low temperatures and health effects.

A small structure-focused library of propargylic enol ethers was prepared by means of a modular and efficient chemodifferentiating organocatalyzed multicomponent reaction. The most active compound (GI50 0.25 μM) against solid tumor cells was selected as lead. Cell cycle analysis and immunoblotting demonstrated arrest at the metaphase, pointing out human topoisomerase II as plausible molecular target. In vitro assays were carried out, showing that the lead behaves as a catalytic inhibitor of the enzyme., Financial support cofinanced by the EU-FEDER: the Spanish MICIIN (CTQ2008-06806-C02-01/BQU, CTQ2008-06806-C02-02/BQU, and BFU2006-01813/BMC), MSC (RTICC RD06/0020/1046 and RD06/0020/0041); Canary Islands’ ACIISI (PI 2007/021) and FUNCIS (REDESFAC PI 01/06 and 35/06). L.G.L and E.P.R.: Spanish MSC-FIS Sara Borrell contracts. J.M.P.: SpanishMEC-FSE Ramón y Cajal contract.

To determine time trends and the geographical distribution of mortality trigger temperature thresholds due to extreme temperatures in Castile-La Mancha (central Spain) between 1975 and 2003. The analysis was divided into three periods (1975-1984, 1985-1994 and 1995-2003) for each province of the region. Daily mortality due to organic causes (dependent variable) was modelled using autoregressive integrated moving average (ARIMA) procedures. The resulting residual series was related to the maximum temperature series grouped in 2 degrees C intervals to obtain a threshold temperature for cold or heat when the residuals rose significantly (p

We consider quantum electrodynamics in the quenched approximation including a four-fermion interaction with coupling constantg. The effective potential at stationary points is computed as a function of the coupling constants α andg and an ultraviolet cutoff Λ, showing a minimum of energy in the (α,g) plane for α=αc=π/3 andg=∞. When we go to the continuum limit (Λ→∞), keeping finite the dynamical mass, the minimum of energy moves to (α=0,g=1), which correspond to a point where the theory is trivial.

Two iridoid scaffolds were synthesized enantioselectively using as key step an l-proline-catalyzed α-formyl oxidation. The in vitro antiproliferative activities were evaluated against a representative panel of human solid tumor cell lines. Both iridoids induced considerably growth inhibition in the range 0.38–1.86 μM. Cell cycle studies for these compounds showed the induction of cell cycle arrest at the G1 phase. This result was consistent with a decrease in the expression of cyclin D1. Damaged cells underwent apoptosis as indicated by specific Annexin V staining.

To determine time trends and the geographical distribution of mortality trigger temperature thresholds due to extreme temperatures in Castile-La Mancha (central Spain) between 1975 and 2003.The analysis was divided into three periods (1975-1984, 1985-1994 and 1995-2003) for each province of the region. Daily mortality due to organic causes (dependent variable) was modelled using autoregressive integrated moving average (ARIMA) procedures. The resulting residual series was related to the maximum temperature series grouped in 2 degrees C intervals to obtain a threshold temperature for cold or heat when the residuals rose significantly (p0,05) above the mean residual mortality value of the corresponding study period.Mortality trigger temperature thresholds decreased over time in Castile- La Mancha. In Toledo, the trigger temperature diminished from 40 degrees C to 38 degrees C. In Cuenca and Guadalajara, threshold temperatures for heat events were obtained in the last few decades but not in the first. These thresholds varied from the 92nd percentile in Cuenca to the 98th percentile in Albacete in the last decade. No threshold temperatures for cold spells were observed in any province or period.Castile-La Mancha registered an upward trend in the relationship between high temperatures and mortality, probably due to population aging. This trend could have been influenced by the increased frequency of extremely hot days. Prevention plans should be periodically reviewed.

Background Breast cancer is the most common neoplasia in women. Even though advances in its treatment have improved disease outcome, some patients relapse. Therefore, attempts to better define the molecular determinants that drive breast cancer cell proliferation may help in defining potential therapeutic targets. Mitogen-activated protein kinases (MAPK) play important roles in tumorigenesis. One of them, Erk5, has been linked to the proliferation of breast cancer cells in vitro. Here we have investigated the expression and prognostic value of Erk5 in human breast cancer. Methodology/Principal Findings Animal and cellular models were used to study Erk5 expression and function in breast cancer. In 84 human breast tumours the expression of Erk5 was analyzed by immunohistochemistry. Active Erk5 (pErk5) was studied by Western blotting. Correlation of Erk5 with clinicopathological parameters and with disease-free survival in early stage breast cancer patients was analyzed. Expression of Erk5 was detected in most patients, and overexpression was found in 20%. Active Erk5 was present in a substantial number of samples, as well as in tumours from an animal breast cancer model. Overexpression of Erk5 was associated with a decrease in disease-free survival time, which was independent of other clinicopathological parameters of prognosis. Transient transfection of a short hairpin RNA (shRNA) targeting Erk5, and a stable cell line expressing a dominant negative form of Erk5 (Erk5AEF), were used to investigate the influence of Erk5 on drugs used in the clinic to treat breast tumours. We found that inhibition of Erk5 decreased cancer cell proliferation and also sensitized these cells to the action of anti-HER2 therapies. Conclusions/Significance Overexpression of Erk5 is an independent predictor of disease-free survival in breast cancer, and may represent a future therapeutic target.

Multiple myeloma (MM) remains incurable, and new drugs with novel mechanisms of action are still needed. In this report, we have analyzed the action of Zalypsis, an alkaloid analogous to certain natural marine compounds, in MM. Zalypsis turned out to be the most potent antimyeloma agent we have tested so far, with IC50 values from picomolar to low nanomolar ranges. It also showed remarkable ex vivo potency in plasma cells from patients and in MM cells in vivo xenografted in mice. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double-strand breaks (DSBs), evidenced by an increase in phospho-histone-H2AX and phospho-CHK2, followed by a striking overexpression of p53 in p53 wild-type cell lines. In addition, in those cell lines in which p53 was mutated, Zalypsis also provoked DSBs and induced cell death, although higher concentrations were required. Immunohistochemical studies in tumors also demonstrated histone-H2AX phosphorylation and p53 overexpression. Gene expression profile studies were concordant with these results, revealing an important deregulation of genes involved in DNA damage response. The potent in vitro and in vivo antimyeloma activity of Zalypsis uncovers the high sensitivity of tumor plasma cells to DSBs and strongly supports the use of this compound in MM patients.

Background c-Kit is expressed in the plasma cells from 30% of patients with multiple myeloma. Two different isoforms of c-Kit, characterized by the presence or absence of the tetrapeptide sequence GNNK in the extracellular domain, have been described. However, their expression and function in myeloma cells are unknown.We explored the function and expression of these c-Kit isoforms in myeloma cells.Design and Methods Expression of c-Kit isoforms was investigated by reverse transcriptase polymerase chain reaction in fresh plasma cells from patients and cell lines. The function of these c-Kit isoforms was analyzed upon expression in myeloma cells. Signaling was investigated by western blotting using antibodies specific for activated forms of several signaling proteins. The impact of c-Kit on the action of drugs commonly used in the treatment of multiple myeloma was investigated by MTT proliferation assays.Results Fresh plasma cells from patients as well as myeloma cell lines expressed the two isoforms of c-Kit. Retroviral infection of myeloma cells with vectors that code for c-Kit-GNNK+ or c-Kit-GNNK− forms demonstrated differences in the kinetics of phosphorylation between these isoforms. Stem cell factor-induced activation of the GNNK− form was faster and more pronounced than that of the GNNK+ form, whose activation, however, lasted for longer. The c-Kit receptors weakly activated the Erk1/2 and Erk5 pathways. Both receptors, however, efficiently coupled to the PI3K/Akt pathway, and stimulated p70S6K activation. The latter was sensitive to the mTOR inhibitor, rapamycin. Studies of drug sensitivity indicated that cells expressing the GNNK− form were more resistant to the anti-myeloma action of bortezomib and melphalan.Conclusions Our data indicate that c-Kit expression in multiple myeloma cells is functional, and coupled to survival pathways that may modulate cell death in response to therapeutic compounds used in the treatment of this disease.

RESUMENSe presenta el caso clinico de una mujer de 33 anos con una leiomiomatosis peritoneal diseminada (LPD) diagnosticada durante cirugia por tumor anexial. Al siguiente ano se embaraza. Durante la cesarea efec-tuada a las 38 semanas, se observa una exacerbacion de la enfermedad con sospecha de malignizacion por lo que se efectua una histerectomia total mas salpingooforectomia bilateral y reseccion de solo algunos nodulos de la cavidad abdominal. La biopsia diferida confirma el diagnostico de LPD. A la fecha completo 8 anos de seguimiento sin evidencias clinicas ni imagenes de persistencia.PALABRAS CLAVE: Leiomiomatosis peritoneal diseminadaSUMMARYWe report the clinical case of 33 years-old woman with leiomyomatosis peritonealis disseminata (LPD) who-se diagnosis becomes evident during a surgery for adnexal tumor. The next year she gets pregnant. During the cesarean section performed at 38 weeks’ gestation, it is observed a disease exacerbation with malignant characteristics. Because of that, a total hysterectomy takes place. It is performed a bilateral salpingo-oopho-rectomy and resection of only some nodules of the abdominal cavity. The deferred biopsy confirms the LPD diagnosis. By this time she has completed 8 years of clinical follow-up without clinical evidences or images of persistence.KEY WORDS: Leiomyomatosis peritonealis disseminataINTRODUCCIONLa leiomiomatosis peritoneal diseminada (LPD) es una enfermedad poco frecuente con no mas de 100 casos reportados en la literatura mundial. Se caracteriza por el desarrollo de multiples leio-miomas en la cavidad peritoneal que semejan una enfermedad maligna. Se presenta en mujeres en edad fertil, y la sospecha preoperatoria es dificil. Generalmente el diagnostico se hace durante la cirugia por un tumor abdominal. El diagnostico defi-nitivo es histologico. El objetivo de esta comunicacion es presentar el manejo de un caso clinico de LPD y una revision de la literatura.CASO CLINICOMujer de 33 anos, multipara de 2 partos vagina-les, referida a la Unidad de Oncologia Ginecologica del Hospital San Juan de Dios, en julio de 1998, con diagnostico de tumor ovarico izquierdo. En octubre de 1998 se efectuo una laparotomia exploradora en la que se describe: ovario izquierdo con tumor

The neuregulins represent the largest subclass of polypeptide factors of the epidermal growth factor family of ligands. These molecules are synthesized as membrane-bound, biologically active growth factors that act by binding to the HER/ErbB receptor tyrosine kinases. Preclinical data have indicated that increased expression and function of neuregulins may provoke cancer. Furthermore, neuregulin expression has been detected in several neoplasias, and their presence may correlate with response to treatments that target the HER receptors such as trastuzumab. In addition, the neuregulins have also been implicated in resistance to anti-HER therapies. Therefore, targeting of the neuregulins may be helpful in neoplastic diseases in which these polypeptide factors contribute to tumor generation and/or maintenance. © 2008 American Association for Cancer Research., Grant support: Ministry of Science and Education of Spain (BFU2006-01813/ BMC) and an Institutional Cancer Center Network program from the ISCIII (RD06/ 0020/0041), the Scientific Foundation of the Spanish Association for Cancer Research (J.C. Montero), a fellowship from the Ministry of Science and Education (R. Rodríguez-Barrueco), the Instituto de Salud Carlos III (A. Esparís-Ogando), and the I3PProgramfrom the CSIC (E. Díaz-Rodríguez). Our Cancer Research Institute, and the work carried out at our laboratory, receives support from the European Community through the regional development funding program (FEDER).

Non-lineal temperature-mortality relationship varies depending on the characteristics of the designated study geographic zone. In given places, a growing level of economic development has led to lesser influence of environmental variables on mortality. This paper analyzes trends in the association between maximum temperatures and organic-cause mortality from 1975 to 2003 in Castile-La Mancha (Spain).Daily maximum temperatures and organic-cause mortality data were divided into 3 time period: 1975-1984, 1985-1994 and 1995-2003. After data pre-whitening by applying ARIMA model estimated for the daily maximum temperature series, we calculate cross-correlation functions between residuals of temperature and mortality, 7 days lagged for summer, 15 for cold months, and comparing its correlation coefficients.We observe an increasing number of significant lags during the warm season (p0.05) between first and second decades studied in regional overall but with some provincial differences. In the third study period the number of significant lags varies slightly, although cross correlation coefficients were significantly upward (p0.05) at lag 3 in the entire region and Toledo in particular.Maximum temperature and mortality by organic cause association became more extensive and intense since 1975-1984 decade in Castile-La Mancha. The aging of regional population could offset the probable beneficial effect of economic growth on this relationship. No appreciable time trends are found in cold months.

Fundamento: La relación no lineal temperatura- mortalidad varía según las características de la zona geográfica estudiada. En determinados lugares un incremento en el nivel de desarrollo ha conducido a una menor influencia de las variables ambientales sobre la mortalidad. Se analiza la evolución entre 1975 y 2003 de la asociación de las temperaturas máximas con la mortalidad por causas orgánicas en Castilla-La Mancha. Métodos: Los datos diarios de temperaturas máximas y de mortalidad por causas orgánicas se dividen en tres periodos: 1975-1984, 1985-1994 y 1995-2003. Tras un preblanqueo de los datos aplicando el modelo ARIMA ajustado para las series de temperaturas, se calculan las funciones de correlación cruzada entre los residuos de las series de temperaturas y de mortalidad con 7 desfases en verano y 15 en invierno, comparándose los coeficientes de correlación. Resultados: Se observa en los meses calurosos un incremento del número de retardos significativos (p

Purpose Human epidermal growth factor receptor 2 (HER-2) overexpression has been associated with the genesis and progression of a subset of breast cancers. The function of HER-2 may be upregulated by overexpression or by the availability of neuregulins (NRGs), a group of transmembrane growth factors. Transmembrane NRGs strongly activated HER-2 and cell proliferation in breast cancer cells that did not overexpress HER-2, and treatment with trastuzumab prevented the proliferative action of transmembrane NRG. This raised the relevant clinical question of whether patients considered as HER-2 negative, but expressing transmembrane NRG, may benefit from treatment with trastuzumab. Patients and Methods MCF7 cells expressing transmembrane NRG (MCF7-NRGα2c) were injected into mice, and their sensitivity to trastuzumab was assessed. A retrospective study of 124 patients with early-stage or metastatic breast cancer was conducted. Expression of transmembrane NRG was evaluated by immunohistochemistry. In 11 patients, Western blot for NRGs was also carried out. Statistics were performed to analyze possible correlations between NRG expression and response to trastuzumab-based therapies, event-free survival, and overall survival (OS). Results Trastuzumab inhibited tumor growth in mice injected with MCF7-NRGα2c cells. Transmembrane NRG was frequently expressed in breast cancer patients. Overexpression of transmembrane NRG significantly correlated with a longer event-free survival and OS in patients with low or normal HER-2 expression who were treated with trastuzumab-based therapies but not in patients with HER-2 overexpression. Conclusion We suggest that the spectrum of patients who may benefit from trastuzumab-based therapies may be widened to include patients with metastatic breast cancer without HER-2 amplification but who express transmembrane NRGs.

The relationship between air temperature and human mortality is described as non-linear, with mortality tending to rise in response to increasingly hot or cold ambient temperatures from a given minimum mortality or optimal comfort temperature, which varies from some areas to others according to their climatic and socio-demographic characteristics. Changes in these characteristics within any specific region could modify this relationship. This study sought to examine the time trend in the maximum temperature of minimum organic-cause mortality in Castile-La Mancha, from 1975 to 2003. The analysis was performed by using daily series of maximum temperatures and organic-cause mortality rates grouped into three decades (1975-1984, 1985-1994, 1995-2003) to compare confidence intervals (p

Erk5 is a recently discovered MAPK claimed to be responsible for some of the roles attributed to Erk1/2; here we report that it is activated in mitosis in comparison to G1/S. When Erk5 is inactivated pharmacologically or largely ablated by RNAi, cell survival in mitosis is diminished. We have previously shown Bim, a BH3-only protein of the Bcl-2 family, to be phosphorylated in mitosis, in a MEK-dependent manner (M. Grãos, A. D. Almeida, S. Chatterjee, Biochem. J. 388 (2005) 185). Inactivation of Erk5 in mitosis causes dephosphorylation of Bim. Bim is in the mitochondria in mitosis and when dephosphorylated interacts with Bax, inducing caspase activation. We also show that in mitosis Bim co-immunoprecipitates with Erk5 and Erk5 phosphorylates GST-Bim in in vitro kinase reaction. Taken together, our results identify a new target of the still largely mysterious Erk5 and suggest that Erk5 in mitosis may be a decisive step for the survival of proliferating cells. © 2007 Elsevier Inc. All rights reserved., This work was funded by a research grant (BCI/ 42249/01) from Fundação para a Ciência e a Tecnologia (Portugal) to S.C, and Ministry of Education and Science (BFU2006- 01813/BMC) to A.P.. A.G. was funded with a fellowship (SFRH/ BD/8099/2002) from Fundação para a Ciência e a Tecnologia. Our Institutes receive support from the European Community through the regional development funding program.

We show that the extension of the approximate custodial $SU(2)_{L+R}$ global symmetry to all the Yukawa interactions of the standard model Lagrangian implies the introduction of sterile right-handed neutrinos and the seesaw mechanism in this sector. In this framework, the observed quark and lepton masses may be interpreted as an effect of physics beyond the standard model. The mechanism used for breaking this symmetry in the Yukawa sector could be different from the one at work in the vector boson sector. We give three model independent examples of these mechanisms., Comment: RevTex, 12 pages and one eps figure. Extended version to be published in Physical Review D

The neuregulins (NRGs) play important roles in animal physiology, and their disregulation has been linked to diseases such as cancer or schizophrenia. The NRGs may be produced as transmembrane proteins (proNRGs), even though they lack an N-terminal signal sequence. This raises the question of how NRGs are sorted to the plasma membrane. It is also unclear whether in their transmembrane state, the NRGs are biologically active. During studies aimed at solving these questions, we found that deletion of the extracellular juxtamembrane region termed the linker, decreased cell surface exposure of the mutant proNRG ΔLinker, and caused its entrapment at the cis-Golgi. We also found that cell surface-exposed transmembrane NRG forms retain biological activity. Thus, a mutant whose cleavage is impaired but is correctly sorted to the plasma membrane activated ErbB receptors in trans and also stimulated proliferation. Because the linker is implicated in surface sorting and the regulation of the cleavage of transmembrane NRGs, our data indicate that this region exerts multiple important roles in the physiology of NRGs. © 2007 by The American Society for Cell Biology., This work was supported by a grant from the Ministry of Science and Technology of Spain (BMC2003-01192). R.R.-B. and L.Y. were supported by fellowships from the Ministry of Education and Culture, and A.E.O. was initially supported by the Scientific Foundation of the Spanish Association for Cancer Research (AECC), and later by the Instituto de Salud Carlos III. J.B. was supported by a Fundaçcâo para a Ciência e a Tecnologia (FCT/FSEIII), Quadro Comunitario de Apoio III.