Extracellular vesicles produced in B cells deliver tumor suppressor miR-335 to breast cancer cells disrupting oncogenic programming in vitro and in vivo.

The successful implementation of miRNA (miR) therapies in humans will ultimately rely on the use of vehicles with improved cellular delivery capability. Here we tested a new system that leverages extracellular vesicles (EVs) laden with a tumor suppressor miRNA (miR-335) produced in B cells by plasmid DNA induction (iEVs). We demonstrate that iEVs-335 efficiently and durably restored the endogenous miR-335 pool in human triple negative breast cancer cells, downregulated the expression of the miR-335 target gene SOX4 transcription factor, and markedly inhibited tumor growth in vivo. Remarkably, iEVs-335 mediated transcriptional effects that persisted in tumors after 60 days post orthotopic implantation. Genome-wide RNASeq analysis of cancer cells treated in vitro with iEVs-335 showed the regulation of a discrete number of genes only, without broad transcriptome perturbations. This new technology may be ideally suited for therapies aimed to restore tumor suppressor miRNAs in cancer cells, disrupting the oncogenic program established after escape from miRNA control

Prostate cancer cells undergoing ER stress in vitro and in vivo activate transcription of pro-inflammatory cytokines

Navin R Mahadevan, Antonio Fernandez, Jeffrey J Rodvold, Gonzalo Almanza, Maurizio ZanettiThe Laboratory of Immunology, Department of Medicine and Moores Cancer Center, University of California, San Diego, USABackground: Several micro-environmental and cell-intrinsic stimuli cause tumor cells to undergo endoplasmic reticulum (ER) stress in vivo. The occurrence of an ER stress response has been associated with tumor progression and angiogenesis. Recently, we found that pharmacological induction of ER stress in B lymphoma cells upregulates the transcription of several pro-inflammatory cytokines.Results: Here, we show that transgenic adenocarcinoma of the mouse prostate (TRAMP) C1 murine prostate cancer cells induced to undergo ER stress in vitro activate the transcription of interleukin 6 (IL-6), interleukin 23p19 (IL-23p19), and tumor necrosis factor a (TNF-a). Furthermore we show that TRAMP C1 tumors growing in vivo spontaneously experience ER stress and that transcription of IL-6, IL-23p19, and TNF-a correlates with the in vivo ER stress response.Conclusions: These results suggest that an ER stress response in prostate cancer cells activates a program of pro-inflammatory cytokine transcription. A possible implication of this finding is that cancer cells may use the ER stress response to modify their microenvironment.Keywords: unfolded protein response, tumorigenesis, inflammatio

Entropy production and fluctuation theorems for monitored quantum systems under imperfect detection

The thermodynamic behavior of Markovian open quantum systems can be described at the level of fluctuations by using continuous monitoring approaches. However, practical applications require assessing imperfect detection schemes, where the definition of main thermodynamic quantities becomes subtle and universal fluctuation relations are unknown. Here we fill this gap by deriving a universal fluctuation relation that links entropy production in ideal and in inefficient monitoring setups. This provides a suitable estimator of dissipation using imperfect detection records that lower bounds the underlying entropy production at the level of single trajectories. We illustrate our findings with a driven-dissipative two-level system following quantum jump trajectories.Comment: 5 + 10 pages, 2 figures. The two first authors contributed equally to this wor

ESTRATEGIA DE SUPERACIÓN PARA EL DESARROLLO DE LA EXPRESIÓN ORAL DE LA LENGUA INGLESA EN LA ENSEÑANZA POSTGRADUADA / TRAINING STRATEGY TO DEVELOP SPEAKING IN ENGLISH LANGUAGE IN THE POSTGRADUATE TEACHING

En este artículo se ofrece el resultado obtenido a través del diagnóstico aplicado a profesores de la Filial de Ciencias Médicas del municipio Morón, Cuba. Se verificó que los profesores que imparten la docencia de las especialidades médicas presentan una inadecuada preparación en idioma inglés lo que les impide la comunicación fluida con estudiantes extranjeros de habla inglesa que allí estudian. A partir de esta problemática es que se elabora una estrategia de superación, sustentada en los postulados del aprendizaje desarrollador, dirigida a desarrollar la expresión oral del idioma inglés de los profesores de dicha Filial Preparatori

Terminal de Ómnibus de Las Breñas (Chaco)

El presente artículo tiene por objetivo exponer los fundamentos y decisiones de diseño de la propuesta del Concurso Provincial de Anteproyecto de la Terminal de Ómnibus de Las Breñas (Chaco), del cual se obtuvo el Primer Premio. Este concurso fue organizado por la Sociedad de Arquitectos del Chaco, y promovido por la Municipalidad de la Ciudad de Las Breñas, del Departamento 9 de Julio, de la provincia del Chaco

Aprendizaje acelerado y desarrollador: alternativa para perfeccionar la expresión oral de la lengua inglesa

En este artículo se presenta uno de los más importantes resultados de una investigación desarrollada en la Universidad de Ciego de Ávila, Cuba, cuya finalidad era perfeccionar el proceso de enseñanza aprendizaje de la lengua inglesa en los estudiantes de primer año de las carreras de Contabilidad y Finanzas, Informática y de Turismo. Partimos de las insuficiencias que presenta este proceso en la referida universidad que dificultan el establecimiento de una comunicación eficiente en este idioma; para su solución se elaboró una Alternativa Metodológica dirigida a perfeccionar la expresión oral en la lengua inglesa, fundamentada en las concepciones actuales del aprendizaje acelerado y en las aportaciones del paradigma histórico cultural acerca del aprendizaje desarrollador que, unidos a diferentes métodos y técnicas participativas, garantizan el cumplimiento de los objetivos propuestos. Esta investigación responde a los postulados de la educación permanente presentada por la UNESCO en el informe «Aprender a Ser». Desde el punto de vista del método científico, la forma en que se realizó la investigación y se recogieron los datos es afín al diseño preexperimental de un grupo con pretest y postest. Para llevar a cabo las indagaciones empíricas y recoger los datos se emplearon diferentes técnicas e instrumentos de investigación, en correspondencia con los indicadores que se establecieron para medir el aprendizaje acelerado y desarrollador del idioma inglés. Entre los principales resultados alcanzados se encuentran la influencia positiva que se logró en la formación integral de los estudiantes y el aumento de la competencia expresiva oral junto al resto de las demás habilidades del idioma.This article presents one of the most important outcomes of a research carried out in the University Of Ciego de Ávila Cuba, with the purpose of improving the English language teaching-learning process in first-academic-year-students of Accounting and Finances, Informatics and Tourism courses. We started from the inadequacies that this process presents in this university which hinder the establishment of a steady communication in that language. In order to solve such problem, a Methodological Alternative was elaborated directed to improve the oral expression in the English language, with its foundations laid on the present day conceptions of the accelerated learning as well as on the contributions of the historical-cultural paradigm about the developing learning, which together with different methods and participative techniques; guarantee the accomplishment of the goals that have been set. The research carried out responds to the permanent education’s postulates presented by UNESCO in the report ‘’Learning to Be’’. From the scientific method point of view, the way used to do the research and to gather data is akin to the pre-experimental design of a group with pre-test and post-test. To carry out the empirical inquiries and to gather the data, several techniques and researching tools were employed according to the indicators established to measure the accelerated learning and to develop English language. The most outstanding results include the achievement of a positive influence on the students’ integral formation and the development of the oral expression as well as of the rest of the language’s skills

Cytokine and microRNA levels during different periods of paradoxical sleep deprivation and sleep recovery in rats

Background Sleep has a fundamental role in the regulation of homeostasis. The aim of this study was to assess the effect of different periods of paradoxical sleep deprivation (PSD) and recovery on serum levels of cytokines and miRNAs related to inflammatory responses. Methods Male Wistar rats were submitted to a PSD of 24, 96, or 192 h, or of 192 h followed by 20 days of recovery (192 h PSD+R). The concentrations of corticosterone, cytokines (IL-6, TNF, IL-10, Adiponectin) and miRNAs (miR-146a, miR-155, miR-223, miR-16, miR-126, miR-21) in serum were evaluated. Results At PSD 24 h a significant increase of IL-6 and decrease of IL-10 were observed. At PSD 96h adiponectin increased. At 192 h of PSD IL-6 increased significantly again, accompanied by a threefold increase of IL-10 and an increase of serum corticosterone. After 20 days of recovery (192 h PSD+R) corticosterone, IL-6 and TNF levels increased significantly, while IL-10 decreased also significantly. Regarding the miRNAs at 24 h of PSD serum miR-146a, miR-155, miR-223, and miR-16 levels all increased. At 96 h of PSD miR-223 decreased. At 192 h of PSD decreases in miR-16 and miR-126 were observed. After recovery serum miR-21 increased and miR-16 decreased. Conclusion PSD induces a dynamic response likely reflecting the induced cellular stress and manifested as variating hormonal and inflammatory responses. Sleep deprivation disturbed corticosterone, cytokine and miRNA levels in serum related to the duration of sleep deprivation, as short-term PSD produced effects similar to those of an acute inflammatory response and long-term PSD induced long-lasting disturbances of biological mediators

ER stress drives Lipocalin 2 upregulation in prostate cancer cells in an NF-κB-dependent manner

<p>Abstract</p> <p>Background</p> <p>Tumor cells adapt to endoplasmic reticulum (ER) stress through a set of conserved intracellular pathways, as part of a process termed the unfolded protein response (UPR). The expression of UPR genes/proteins correlates with increasing progression and poor clinical outcome of several tumor types, including prostate cancer. UPR signaling can activate NF-κB, a master regulator of transcription of pro-inflammatory, tumorigenic cytokines. Previous studies have shown that Lipocalin 2 (Lcn2) is upregulated in several epithelial cancers, including prostate cancer, and recently Lcn2 was implicated as a key mediator of breast cancer progression. Here, we hypothesize that the tumor cell UPR regulates Lcn2 production.</p> <p>Methods</p> <p>We interrogated Lcn2 regulation in murine and human prostate cancer cells undergoing pharmacological and physiological ER stress, and tested UPR and NF-κB dependence by using pharmacological inhibitors of these signaling pathways.</p> <p>Results</p> <p>Induction of ER stress using thapsigargin (Tg), a canonical pharmacologic ER stress inducer, or via glucose deprivation, a physiologic ER stressor present in the tumor microenvironment, upregulates LCN2 production in murine and human prostate cancer cells. Inhibition of the UPR using 4-phenylbutyric acid (PBA) dramatically decreases Lcn2 transcription and translation. Inhibition of NF-κB in prostate cancer cells undergoing Tg-mediated ER stress by BAY 11-7082 abrogates Lcn2 upregulation.</p> <p>Conclusions</p> <p>We conclude that the UPR activates Lcn2 production in prostate cancer cells in an NF-κB-dependent manner. Our results imply that the observed upregulation of Lipocalin 2 in various types of cancer cells may be the direct consequence of concomitant UPR activation, and that the ER stress/Lipocalin 2 axis is a potential new target for intervention in cancer progression.</p

Selected MicroRNAs Define Cell Fate Determination of Murine Central Memory CD8 T Cells

During an immune response T cells enter memory fate determination, a program that divides them into two main populations: effector memory and central memory T cells. Since in many systems protection appears to be preferentially mediated by T cells of the central memory it is important to understand when and how fate determination takes place. To date, cell intrinsic molecular events that determine their differentiation remains unclear. MicroRNAs are a class of small, evolutionarily conserved RNA molecules that negatively regulate gene expression, causing translational repression and/or messenger RNA degradation. Here, using an in vitro system where activated CD8 T cells driven by IL-2 or IL-15 become either effector memory or central memory cells, we assessed the role of microRNAs in memory T cell fate determination. We found that fate determination to central memory T cells is under the balancing effects of a discrete number of microRNAs including miR-150, miR-155 and the let-7 family. Based on miR-150 a new target, KChIP.1 (K + channel interacting protein 1), was uncovered, which is specifically upregulated in developing central memory CD8 T cells. Our studies indicate that cell fate determination such as surface phenotype and self-renewal may be decided at the pre-effector stage on the basis of the balancing effects of a discrete number of microRNAs. These results may have implications for the development of T cell vaccines and T cell-based adoptive therapies

Nurses' perceptions of aids and obstacles to the provision of optimal end of life care in ICU

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