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Telomerase deficiency leads to age-related diseases and shorter lifespans. Inhibition of the mechanistic target of rapamycin (mTOR) delays aging and age-related pathologies. Here, we show that telomerase deficient mice with short telomeres (G2-Terc−/−) have an hyper-activated mTOR pathway with increased levels of phosphorylated ribosomal S6 protein in liver, skeletal muscle and heart, a target of mTORC1. Transcriptional profiling confirms mTOR activation in G2-Terc−/− livers. Treatment of G2-Terc−/− mice with rapamycin, an inhibitor of mTORC1, decreases survival, in contrast to lifespan extension in wild-type controls. Deletion of mTORC1 downstream S6 kinase 1 in G3-Terc−/− mice also decreases longevity, in contrast to lifespan extension in single S6K1−/− female mice. These findings demonstrate that mTOR is important for survival in the context of short telomeres, and that its inhibition is deleterious in this setting. These results are of clinical interest in the case of human syndromes characterized by critically short telomeres., Telomerase deficiency leads to age-related diseases and shortened lifespan, while inhibition of the mTOR pathway delays aging. Here, the authors show that inhibition of mTORC1 signaling shortens the lifespan of telomerase deficient mice.

Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6) approved for the treatment of some cancers. The main mechanism of action of palbociclib is to induce cell cycle arrest and senescence on responsive cells. Here, we report that palbociclib concentrates in intracellular acidic vesicles, where it can be readily observed due to its intrinsic fluorescence, and it is released from these vesicles upon dilution or washing out of the extracellular medium. This reversible storage of drugs into acidic vesicles is generally known as lysosomal trapping and, based on this, we uncover novel properties of palbociclib. In particular, a short exposure of cells to palbociclib is sufficient to produce a stable cell-cycle arrest and long-term senescence. Moreover, after washing out the drug, palbociclib-treated cells release the drug to the medium and this conditioned medium is active on susceptible cells. Interestingly, cancer cells resistant to palbociclib also accumulate and release the drug producing paracrine senescence on susceptible cells. Finally, other lysosomotropic drugs, such as chloroquine, interfere with the accumulation of palbociclib into lysosomes, thereby reducing the minimal dose of palbociclib required for cell-cycle arrest and senescence. In summary, lysosomal trapping explains the prolonged temporal activity of palbociclib, the paracrine activity of exposed cells, and the cooperation with lysosomotropic drugs. These are important features that may help to improve the therapeutic dosing and efficacy of palbociclib. Finally, two other clinically approved CDK4/6 inhibitors, ribociclib and abemaciclib, present a similar behavior as palbociclib, suggesting that lysosomal trapping is a property common to all three clinically-approved CDK4/6 inhibitors.

Exclusion of brain metastases from clinical trials is a major cause of the limited therapeutic options for this growing population of cancer patients. Here, we report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to brain metastasis, we identified several hits from a library of FDA approved inhibitors and others being tested in clinical trials. A blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to organotypic cultures with metastases treated with the chaperone inhibitor revealed novel biomarkers in human brain metastasis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is fully compatible with human samples. We envision that METPlatform could be established as a clinically relevant strategy to personalize the management of metastatic disease in the brain and elsewhere.SummarySystemic spread of cancer continues to be the key aspect associated with lethality. In this publication, Zhu et al. describes a drug-screening platform specifically designed to study vulnerabilities of metastasis when colonizing secondary organs and demonstrates its value in difficult-to-treat brain metastasis using new models and patient-derived samples.

El objetivo de la presente investigación es identificar el comportamiento de algunas variables de la Mezcla de Mercadotecnia, que son utilizadas por los directivos de las micro y pequeñas empresas, (MyPES) en el Municipio de Cajeme y el impacto que ejercen estas en las ventas de productos y servicios, así mismo se utilizó un cuestionario de 47 reactivos, de los cuales se tomaron las variables de mezcla de marketing y ventas. El método que se utilizo fue el método cuantitativo con un alcance descriptivo, ya que el estudio tiene como finalidad conocer si algunas de las variables de la mezcla de mercadotecnia, son determinantes en las ventas, teniendo como resultado que la variable mezcla de mercadotecnia tiene una buena correlación con la variable ventas, con una puntuación de 0.789 y 0.779, en la pruebas de Pearson y Spearman respectivamente, en la presente investigación se concluye que la prueba más adecuada es Spearman ya que las variables tienen relaciones monótonas; es decir, no cambian al mismo ritmo; pero si al mismo tiempo. Lo anterior reafirma que el comportamiento de las variables de la mezcla de mercadotecnia tiene una buena correlación con las ventas. Abstract The objective of this research is to identify the behavior of some Marketing Mix variables, which are used by the managers of micro and small companies (MyPES) in the Municipality of Cajeme and the impact they have on sales of products and services. Likewise, a 47-item questionnaire was used, from which the marketing and sales mix variables were taken. The method that was used was the quantitative method with a descriptive scope, since the study has as purpose to know if some of the variables of the marketing mix are determining in the sales, having as a result that the mixed variable of marketing has a good correlation with the sales variable, with a score of 0.789 and 0.779, in the Pearson and Spearman tests, respectively, in the present investigation it is concluded that the most adequate test is that of Spearman since the variables have monotonous relationships; That is, they do not change at the same pace; but at the same time. The above reaffirms that the behavior of the variables of the marketing mix has a good correlation with sales.

A scaffold hopping strategy, including intellectual property availability assessment, was successfully applied for the discovery of novel PI3K inhibitors. Compounds were designed based on the chemical structure of the lead compound ETP-46321, a potent PI3K inhibitor, previously reported by our group. The new generated compounds showed good in vitro potency and selectivity, proved to inhibit potently the phosphorylation of AKTSer473 in cells and demonstrated to be orally bioavailable, thus becoming potential back-up candidates for ETP-46321.

Despite significant efforts to improve pancreatic ductal adenocarcinoma (PDAC) clinical outcomes, overall survival remains dismal. The poor response to current therapies is partly due to the existence of pancreatic cancer stem cells (PaCSCs), which are efficient drivers of PDAC tumorigenesis, metastasis and relapse. To find new therapeutic agents that could efficiently kill PaCSCs, we screened a chemical library of 680 compounds for candidate small molecules with anti-CSC activity, and identified two compounds of a specific chemical series with potent activity in vitro and in vivo against patient-derived xenograft (PDX) cultures. The anti-CSC mechanism of action of this specific chemical series was found to rely on induction of lysosomal membrane permeabilization (LMP), which is likely associated with the increased lysosomal mass observed in PaCSCs. Using the well characterized LMP-inducer siramesine as a tool molecule, we show elimination of the PaCSC population in mice implanted with tumors from two PDX models. Collectively, our approach identified lysosomal disruption as a promising anti-CSC therapeutic strategy for PDAC., This study was financially supported by a Ramón y Cajal Merit Award (RYC-2012-12104) from the Ministerio de Economía y Competitividad, Spain (B.S.Jr.); funding fromThe Fero Foundation (B.S.Jr.); a Coordinated grant from the Fundación Asociación Española Contra el Cáncer (AECC) GC16173694BARB (B.S.,Jr.); Fondo de Investigaciones Sanitarias (FIS) grant PI15/01507 and PI18/00757 (B.S.,Jr.), (cofinanced through Fondo Europeo de Desarrollo Regional (FEDER) “Una manera de hacer Europa”). ETP activities were supported by funds of The Spanish National Cancer Research Centre (CNIO).Work in the laboratory of M.S. was funded by the CNIO, the IRB and “laCaixa” Foundation, and by grants from the Spanish Ministry of Economy co-funded by the European Regional Development Fund (ERDF) (SAF2017-82613-R), the European Research Council (ERC-2014-AdG/669622) and, Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixement of Catalonia (Grup de Recerca consolidat 2017 SGR 282).

El objetivo de la presente investigación es identificar el comportamiento de algunas variables de la Mezcla de Mercadotecnia, que son utilizadas por los directivos de las micro y pequeñas empresas, (MyPES) en el Municipio de Cajeme y el impacto que ejercen estas en las ventas de productos y servicios, así mismo se utilizó un cuestionario de 47 reactivos, de los cuales se tomaron las variables de mezcla de marketing y ventas. El método que se utilizo fue el método cuantitativo con un alcance descriptivo, ya que el estudio tiene como finalidad conocer si algunas de las variables de la mezcla de mercadotecnia, son determinantes en las ventas, teniendo como resultado que la variable mezcla de mercadotecnia tiene una buena correlación con la variable ventas, con una puntuación de 0.789 y 0.779, en la pruebas de Pearson y Spearman respectivamente, en la presente investigación se concluye que la prueba más adecuada es Spearman ya que las variables tienen relaciones monótonas; es decir, no cambian al mismo ritmo; pero si al mismo tiempo. Lo anterior reafirma que el comportamiento de las variables de la mezcla de mercadotecnia tiene una buena correlación con las ventas. Abstract The objective of this research is to identify the behavior of some Marketing Mix variables, which are used by the managers of micro and small companies (MyPES) in the Municipality of Cajeme and the impact they have on sales of products and services. Likewise, a 47-item questionnaire was used, from which the marketing and sales mix variables were taken. The method that was used was the quantitative method with a descriptive scope, since the study has as purpose to know if some of the variables of the marketing mix are determining in the sales, having as a result that the mixed variable of marketing has a good correlation with the sales variable, with a score of 0.789 and 0.779, in the Pearson and Spearman tests, respectively, in the present investigation it is concluded that the most adequate test is that of Spearman since the variables have monotonous relationships; That is, they do not change at the same pace; but at the same time. The above reaffirms that the behavior of the variables of the marketing mix has a good correlation with sales.

The brain microenvironment imposes a particularly intense selective pressure on metastasis-initiating cells, but successful metastases bypass this control through mechanisms that are poorly understood. Reactive astrocytes are key components of this microenvironment that confine brain metastasis without infiltrating the lesion. Here, we describe that brain metastatic cells induce and maintain the co-option of a pro-metastatic program driven by signal transducer and activator of transcription 3 (STAT3) in a subpopulation of reactive astrocytes surrounding metastatic lesions. These reactive astrocytes benefit metastatic cells by their modulatory effect on the innate and acquired immune system. In patients, active STAT3 in reactive astrocytes correlates with reduced survival from diagnosis of intracranial metastases. Blocking STAT3 signaling in reactive astrocytes reduces experimental brain metastasis from different primary tumor sources, even at advanced stages of colonization. We also show that a safe and orally bioavailable treatment that inhibits STAT3 exhibits significant antitumor effects in patients with advanced systemic disease that included brain metastasis. Responses to this therapy were notable in the central nervous system, where several complete responses were achieved. Given that brain metastasis causes substantial morbidity and mortality, our results identify a novel treatment for increasing survival in patients with secondary brain tumors. Reactive astrocytes expressing STAT3 support the metastatic growth of tumor cells colonizing the brain and can be pharmacologically targeted to improve the clinical management of patients with secondary brain tumors.

In the version of this article originally published, the names of three authors were incorrect. The authors were listed as “Coral Fustero-Torres”, “Elena Pineiro” and “Melchor Sanchez-Martinez”. Their respective names are “Coral Fustero-Torre”, “Elena Pineiro-Yanez” and “Melchor Sanchez-Martinez”. The errors have been corrected in the print, HTML and PDF versions of this article.