Role of telomere dysfunction, DNA damage response and p53 mutations in tumorigenesis and aging

The ends of eukaryotic chromosomes are protected by specialized ribonucleoprotein structures termed telomeres. Telomeres protect chromosomes from end-to-end fusions, inappropriate repair and degradation. Disruption of this complex activates an ATM/ATR DNA damage response (DDR) pathway. One component of the complex is the Protection Of Telomeres 1 (POT1) protein, an evolutionarily conserved protein which binds single-stranded 3' overhang and is required for both chromosomal end protection and telomere length regulation. The mouse contains two POT1 orthologs, Pot1a and Pot1b. Here we show that both proteins colocalize with telomeres through interaction with the adapter protein TPP1. In addition, compared to Pot1a, the OB-folds of Pot1b possess less sequence specificity for telomeres. Disruption of POT1 proteins result in telomere dysfunction and activation of an ATR-dependent DDR at telomeres, suggesting that this response is normally suppressed by POT1 binding to the single-stranded G-overhang. ^ Telomeres are maintained by telomerase, and its absence in somatic cells results in telomere progressive loss that triggers the activation of p53. Telomere dysfunction initiates genomic instability and induces both p53-dependent replicative senescence and apoptosis to suppress tumorigenesis. In the absence of functional p53, this genomic instability promotes cancer. It was previously not known which aspect of the p53 dependent DNA damage response is important to suppress tumorigenesis initiated by dysfunctional telomeres. The p53R172P knock-in mouse, which is unable to induce apoptosis but retains intact cell cycle arrest/cellular senescence pathways, allowed us to examine whether p53-dependent apoptosis is a major tumor suppression pathway initiated in the setting of telomere dysfunction. Spontaneous tumorigenesis remains potently suppressed in late generation telomerase null mice possessing the p53P/P mutation. These results suggest that suppression of spontaneous tumorigenesis initiated by dysfunctional telomeres requires activation of a p53-dependent senescence pathway. In addition, we used another knock-in mouse model with a p53R172H (p53H) point mutation to test the hypothesis that telomere dysfunction promotes chromosomal instability and accelerates the onset of tumorigenesis in vivo in the setting of this most common gain-of-function mutation in the human Li Fraumeni cancer syndrome. We unexpectedly observed that telomerase null mice possessing dysfunctional telomeres in the setting of the p53H/+ mutation develop significantly fewer tumors, die prematurely and exhibit higher level of cellular senescence, apoptosis and elevated genomic instability compared to telomerase intact p53H/+ and telomerase null p53+/+ mice. These contrasting results thus link cancer and aging to the functional status of telomeres and the integrity of the p53 pathway. ^

The role of beta-arrestin 2 in lysophosphatidic acid-induced NF-kappaB activation

Lysophosphatidic acid (LPA) is a bioactive phospholipid and binds to its receptors, a family of G protein-coupled receptors (GPCR), which initiates multiple signaling cascades and leads to activation of several transcription factors, including NF-κB. NF-κB critically regulates numerous gene expressions, and is persistently active in many diseases. In our previous studies, we have demonstrated that LPA-induced NF-κB activation is dependent on a novel scaffold protein, CARMA3. However, how CARMA3 is recruited to receptor remains unknown. β-Arrestins are a family of proteins involved in desensitization of GPCR signaling. Additionally, β-arrestins function as signaling adaptor proteins, and mediate multiple signaling pathways. Therefore, we have hypothesized that β-arrestins may link CARMA3 to LPA receptors, and facilitate LPA-induced NF-κB activation. ^ Using β-arrestin-deficient MEFs, we found that β-arrestin 2, but not β-arrestin 1, was required for LPA-induced NF-κB activation. Also, we showed that the expression of NF-κB-dependent cytokines, such as interlukin-6, was impaired in β-arrestin 2-deficient MEFs. Mechanistically, we demonstrated the inducible association of endogenous β-arrestin 2 and CARMA3, and we found the CARD domain of CARMA3 interacted with 60-320 residues of β-arrestin 2. To understand why β-arrestin 2, but not β-arrestin 1, mediated NF-κB activation, we generated β-arrestin mutants. However, some mutants degraded quickly, and the rest did not rescue NF-κB activation in β-arrestin-deficient MEFs, though they had similar binding affinities with CARMA3. Therefore, it indicates that slight changes in residues may determine the different functions of β-arrestins. Moreover, we found β-arrestin 2 deficiency impaired LPA-induced IKK kinase activity, while it did not affect LPA-induced IKKα/β phosphorylation. ^ In summary, our results provide the genetic evidence that β-arrestin 2 serves as a positive regulator in NF-κB signaling pathway by connecting CARMA3 to LPA receptors. Additionally, we demonstrate that β-arrestin 2 is required for IKKα/β activation, but not for the inducible phosphorylation of IKKα/β. Because the signaling pathways around the membrane-proximal region of LPA receptors and GPCRs are quite conserved, our results also suggest a possible link between other GPCRs and CARMA3-mediated NF-κB activation. To fully define the role of β-arrestins in LPA-induced NF-κB signaling pathways will help to identify new drug targets for clinical therapeutics.^

The survival role and the potential therapeutic targeting of MET in multiple myeloma

Multiple myeloma (MM) is a debilitating and incurable B-cell malignancy. Previous studies have documented that the hepatocyte growth factor (HGF) plays a role in the pathobiology of MM. The receptor tyrosine kinase MET induced signaling initiates when its ligand HGF binds to the MET receptor. However, the direct importance of MET in MM has not been elucidated. The present work used three different but complementary approaches to reduce MET protein levels or its activity to demonstrate the importance of MET in MM. ^ In the first approach, MET transcript and protein levels were reduced by directly targeting the cellular MET transcripts using shRNA retroviral infection techniques. This direct reduction of MET mRNA leads to a reduction of MET protein levels, which caused an inhibition of growth and induction of cell death. ^ In the second approach, a global transcription inhibitor flavopiridol was used as a potential pharmacological tool to reduce MET levels. MET has a short half-life of 30 min for mRNA and 4 hours for protein; therefore using a RNA pol II inhibitor such as flavopiridol would be a viable option to reduce MET levels. When using flavopiridol in MM cell lines, there was a reduction of MET transcript and protein levels, which was associated with the induction of cell death. ^ Finally in the last strategy, MET kinase activity was suppressed by MP470, a small molecule inhibitor that binds to the ATP binding pocket in the kinase domain. At concentrations where phosphorylation of MET was inhibited there was induction of cell death in MM cell lines and primary cells from patients. In addition, in MM cell lines there was a decrease in phosphorylation of AKT (ser473) and caspase-9 (ser196); downstream of MET, suggesting that the mechanism of action for survival may be through these cascade of events. ^ Overall, this study provides a proof-of-principle that MET is important for the survival of MM cell lines as well as primary plasma cells obtained from patients. Therefore, targeting MET therapeutically may be a possible strategy to treat patients with this debilitating disease of MM. ^

UNDERSTANDING INTERRUPTIONS IN HEALTHCARE: DEVELOPING A MODEL

Developing a Model Interruption is a known human factor that contributes to errors and catastrophic events in healthcare as well as other high-risk industries. The landmark Institute of Medicine (IOM) report, To Err is Human, brought attention to the significance of preventable errors in medicine and suggested that interruptions could be a contributing factor. Previous studies of interruptions in healthcare did not offer a conceptual model by which to study interruptions. As a result of the serious consequences of interruptions investigated in other high-risk industries, there is a need to develop a model to describe, understand, explain, and predict interruptions and their consequences in healthcare. Therefore, the purpose of this study was to develop a model grounded in the literature and to use the model to describe and explain interruptions in healthcare. Specifically, this model would be used to describe and explain interruptions occurring in a Level One Trauma Center. A trauma center was chosen because this environment is characterized as intense, unpredictable, and interrupt-driven. The first step in developing the model began with a review of the literature which revealed that the concept interruption did not have a consistent definition in either the healthcare or non-healthcare literature. Walker and Avant’s method of concept analysis was used to clarify and define the concept. The analysis led to the identification of five defining attributes which include (1) a human experience, (2) an intrusion of a secondary, unplanned, and unexpected task, (3) discontinuity, (4) externally or internally initiated, and (5) situated within a context. However, before an interruption could commence, five conditions known as antecedents must occur. For an interruption to take place (1) an intent to interrupt is formed by the initiator, (2) a physical signal must pass a threshold test of detection by the recipient, (3) the sensory system of the recipient is stimulated to respond to the initiator, (4) an interruption task is presented to recipient, and (5) the interruption task is either accepted or rejected by v the recipient. An interruption was determined to be quantifiable by (1) the frequency of occurrence of an interruption, (2) the number of times the primary task has been suspended to perform an interrupting task, (3) the length of time the primary task has been suspended, and (4) the frequency of returning to the primary task or not returning to the primary task. As a result of the concept analysis, a definition of an interruption was derived from the literature. An interruption is defined as a break in the performance of a human activity initiated internal or external to the recipient and occurring within the context of a setting or location. This break results in the suspension of the initial task by initiating the performance of an unplanned task with the assumption that the initial task will be resumed. The definition is inclusive of all the defining attributes of an interruption. This is a standard definition that can be used by the healthcare industry. From the definition, a visual model of an interruption was developed. The model was used to describe and explain the interruptions recorded for an instrumental case study of physicians and registered nurses (RNs) working in a Level One Trauma Center. Five physicians were observed for a total of 29 hours, 31 minutes. Eight registered nurses were observed for a total of 40 hours 9 minutes. Observations were made on either the 0700–1500 or the 1500-2300 shift using the shadowing technique. Observations were recorded in the field note format. The field notes were analyzed by a hybrid method of categorizing activities and interruptions. The method was developed by using both a deductive a priori classification framework and by the inductive process utilizing line-byline coding and constant comparison as stated in Grounded Theory. The following categories were identified as relative to this study: Intended Recipient - the person to be interrupted Unintended Recipient - not the intended recipient of an interruption; i.e., receiving a phone call that was incorrectly dialed Indirect Recipient – the incidental recipient of an interruption; i.e., talking with another, thereby suspending the original activity Recipient Blocked – the intended recipient does not accept the interruption Recipient Delayed – the intended recipient postpones an interruption Self-interruption – a person, independent of another person, suspends one activity to perform another; i.e., while walking, stops abruptly and talks to another person Distraction – briefly disengaging from a task Organizational Design – the physical layout of the workspace that causes a disruption in workflow Artifacts Not Available – supplies and equipment that are not available in the workspace causing a disruption in workflow Initiator – a person who initiates an interruption Interruption by Organizational Design and Artifacts Not Available were identified as two new categories of interruption. These categories had not previously been cited in the literature. Analysis of the observations indicated that physicians were found to perform slightly fewer activities per hour when compared to RNs. This variance may be attributed to differing roles and responsibilities. Physicians were found to have more activities interrupted when compared to RNs. However, RNs experienced more interruptions per hour. Other people were determined to be the most commonly used medium through which to deliver an interruption. Additional mediums used to deliver an interruption vii included the telephone, pager, and one’s self. Both physicians and RNs were observed to resume an original interrupted activity more often than not. In most interruptions, both physicians and RNs performed only one or two interrupting activities before returning to the original interrupted activity. In conclusion the model was found to explain all interruptions observed during the study. However, the model will require an even more comprehensive study in order to establish its predictive value.

Ultraviolet radiation modulates the immune system through the platelet -activating factor receptor

Ultraviolet radiation plays a critical role in the induction of non-melanoma skin cancer. UV radiation is also immune suppressive. Moreover, UV-induced systemic immune suppression is a major risk factor for skin cancer induction. Previous work had shown that UV exposure in vivo activates a cytokine cascade involving PGE2, IL-4, and IL-10 that induces immune suppression. However, the earliest molecular events that occur immediately after UV-exposure, especially those upstream of PGE2, were not well defined. To determine the initial events and mediators that lead to immune suppression after a pathological dose of UV, mouse keratinocytes were analyzed after sunlamp irradiation. It is known that UV-irradiated keratinocytes secrete the phospholipid mediator of inflammation, platelet-activating factor (PAF). Since PAF stimulates the production of immunomodulatory compounds, including PGE2, the hypothesis that UV-induced PAF activates cytokine production and initiates UV-induced immune suppression was tested. Both UV and PAF activated the transcription of cyclooxygenase (COX)-2 and IL-10 reporter gene constructs. A PAF receptor antagonist blocked UV-induced IL, 10 and COX-2 transcription. PAF mimicked the effects of UV in vivo and suppressed delayed-type hypersensitivity (DTH), and immune suppression was blocked when UV-irradiated mice were injected with a PAF receptor antagonist. This work shows that UV generates PAF-like oxidized lipids, that signal through the PAF receptor, activate cytokine transcription, and induce systemic immune suppression. ^

Enfermedad de Creutzfeld Jakob, desafío diagnóstico : reporte de dos casos en la ciudad de Mendoza

La enfermedad de Creutzfeldt-Jakob (ECJ) es una afección neurodege-nerativa rápidamente progresiva y mortal producida por priones. Es la más común de las encefalopatías espongiformes. La hipótesis prevalente sugiere que se inicia y propaga por conversión de una proteína priónica normal (PrP) en una isoforma conformacional anormal (PrPreS), que se acumula en el cerebro causando destrucción neuronal. Se reporta el caso de dos pacientes asistido en el Servicio de Neurología del Hospital Lagomaggiore de la ciudad de Mendoza en el período de 2 años: mujer de 49 años con cuadro de deterioro cognitivo rápidamente progresivo asociado a trastorno de la marcha y ataxia de 2 meses de evolución; y varón de 54 años con conductas inapropiadas y desorientación temporo-espacial de 20 días de evolución. Ambos con EEG compatible y proteína 14.3.3 positiva, falleciendo semanas después del diagnóstico. Se discute ambos casos, los cuales representaron un desafío diagnóstico dada la baja frecuencia y escaso reconocimiento de esta entidad en nuestro medio, debiendo debe ser considerado en pacientes que evolucionan a una demencia rápidamente progresiva.

Reconstruction of sea surface temperature and salinity of the Arabian Sea

High-frequency suborbital variations (Dansgaard-Oeschger cycles) characterize the climatic history of the Northern Hemisphere as observed in Greenland ice cores, deep-sea sediments of the North Atlantic, the Californian borderland, the Arabian Sea, the South China Sea, and the Chinese loess area. Paleoceanographic data from core KL126 from the Bay of Bengal in combination with data from the other Asian monsoonal areas indicate that the feedback processes involving snow and dust of the Tibetan Plateau vary the summer monsoon capacity to transport moisture into central South Asia and into the atmosphere. We postulate that the summer monsoon initiates, amplifies, and terminates these cycles in the Northern Hemisphere.

Traductología : Exploración de un enfoque feminista de la traducción

Este trabajo se propone presentar la transformación de la Traductología desde la perspectiva de los Estudios de Género, dos campos del conocimiento que reconocen una impronta multi e interdisciplinaria. En cuanto a la primera, el giro cultural de los ochenta marca el momento en que se incluye a la traducción dentro del conjunto de subsistemas culturales con intereses competitivos y sujetos a las ideologías predominantes (Molina Martínez, 2006: 37). Paralelamente se instala en Canadá un terreno de estudio que vincula los desarrollos transculturales y translingüísticos surgidos de los movimientos feministas de los años setenta con la producción y recepción de textos, temas que son abarcados por la investigación sobre género y traducción. En ese contexto surge la noción de traducción en femenino o reescritura en femenino cuya finalidad es subvertir el lenguaje patriarcal y reivindicar las ideas feministas (Lotbinière-Harwood, 1991). Las estrategias discursivas y textuales utilizadas para resolver los problemas de traducción relacionados con el género "suplementación o compensación, la metatextualidad, el secuestro y el pacto especular" suelen recurrir al empleo de un lenguaje con alteraciones semánticas, neologismos o innovaciones lingüísticas, cuyo propósito es cuestionar la lengua actual y, a su vez, visibilizar la presencia femenina (Castro Vázquez, 2008: 296-298). En esta ponencia, nos detendremos en discutir y ejemplificar las estrategias citadas

El relato de un comienzo : La filosofía política de Hannah Arendt

Son pocas las obras de referencia que se detienen en analizar la importancia de la biografía de Rahel Varnhagen en el contexto de la producción de Hannah Arendt. Sin embargo, creemos poder afirmar que este estudio se constituye en un elemento fundamental para el debate acerca de su posición respecto de la tradición de la filosofía alemana así como para indagar en la conformación de su pensamiento político. En este sentido con la biografía de Rahel, Arendt inicia un itinerario de pensamiento, en el que la acción misma de relatar es un acto de responsabilidad , un acto político que testimonia y revela un comienzo.

¿Hubo ritos de paso cruentos en el orfismo?

El modo de vida a que estaban sometidos los iniciados en el orfismo se caracterizaba por la abstención de alimento animado y el rechazo al sacrificio cruento. Pese a ello, dos textos considerados testimonios clave para el estudio y reconstrucción de los ritos y creencias órficos hacen mención explícita del sacrificio cruento y el consumo de carne. Para superar la aparente contradicción de ambos testimonios con las doctrinas órficas se ha propuesto que estas prácticas se adscriben a un primer ritual de iniciación que constituiría un rito de paso entre la condición de profano y la de iniciado. Sin embargo, es preciso examinar los paralelos literarios e iconográficos que ofrecen otros rituales griegos y orientales para determinar si los citados testimonios órficos constituyen casos aislados que no responden a un uso ritual común o si, por el contrario, estas prácticas pueden ser consideradas ritos de paso para alcanzar la condición de iniciado

El acceso a la información pública y los archivos en Uruguay

El artículo analiza la situación actual de los archivos en Uruguay en relación a las leyes de Acceso a la Información Pública y de Sistema Nacional de Archivos, normativas que surge cuando el Estado uruguayo inicia una fase de reordenación de su gestión promoviendo cambios que fomentan la democratización y la eficiencia, a la vez que anulan la opacidad y extrema reserva en su administración. Se analiza cómo los profesionales archivólogos estuvieron estrechamente involucrados en el proceso de gestación de ambas leyes, dando inicio a una etapa de consecución de fuertes voluntades políticas que apoyaran los proyectos, convencidos que la premisa evidente del Derecho de Acceso es que el documento al que se pretenda acceder exista y sea recuperable. Se estudia como la coexistencia de ambas normas implicaban un cambio cultural, una evolución en el comportamiento de las organizaciones que no acompañó a la puesta en marcha de los instrumentos legales. Se concluye que el Derecho de Acceso a la Información Pública está basado en el principio fundamental de transparencia de los Órganos del Estado, por lo que no es de extrañar que una ley que obliga a brindar información tenga el riesgo de devenir en letra muerta. El Archivo debe ser "condición" administrativa, lo que exige una nueva dimensión de ellos y de sus profesionales dentro de los organismos del Estado, de forma tal que se conviertan en una inmejorable herramienta para el cumplimiento de los objetivos de la Ley de Derecho de Acceso a la Información Pública

El relato de un comienzo : La filosofía política de Hannah Arendt

Son pocas las obras de referencia que se detienen en analizar la importancia de la biografía de Rahel Varnhagen en el contexto de la producción de Hannah Arendt. Sin embargo, creemos poder afirmar que este estudio se constituye en un elemento fundamental para el debate acerca de su posición respecto de la tradición de la filosofía alemana así como para indagar en la conformación de su pensamiento político. En este sentido con la biografía de Rahel, Arendt inicia un itinerario de pensamiento, en el que la acción misma de relatar es un acto de responsabilidad , un acto político que testimonia y revela un comienzo.

¿Hubo ritos de paso cruentos en el orfismo?

El modo de vida a que estaban sometidos los iniciados en el orfismo se caracterizaba por la abstención de alimento animado y el rechazo al sacrificio cruento. Pese a ello, dos textos considerados testimonios clave para el estudio y reconstrucción de los ritos y creencias órficos hacen mención explícita del sacrificio cruento y el consumo de carne. Para superar la aparente contradicción de ambos testimonios con las doctrinas órficas se ha propuesto que estas prácticas se adscriben a un primer ritual de iniciación que constituiría un rito de paso entre la condición de profano y la de iniciado. Sin embargo, es preciso examinar los paralelos literarios e iconográficos que ofrecen otros rituales griegos y orientales para determinar si los citados testimonios órficos constituyen casos aislados que no responden a un uso ritual común o si, por el contrario, estas prácticas pueden ser consideradas ritos de paso para alcanzar la condición de iniciado

El acceso a la información pública y los archivos en Uruguay

El artículo analiza la situación actual de los archivos en Uruguay en relación a las leyes de Acceso a la Información Pública y de Sistema Nacional de Archivos, normativas que surge cuando el Estado uruguayo inicia una fase de reordenación de su gestión promoviendo cambios que fomentan la democratización y la eficiencia, a la vez que anulan la opacidad y extrema reserva en su administración. Se analiza cómo los profesionales archivólogos estuvieron estrechamente involucrados en el proceso de gestación de ambas leyes, dando inicio a una etapa de consecución de fuertes voluntades políticas que apoyaran los proyectos, convencidos que la premisa evidente del Derecho de Acceso es que el documento al que se pretenda acceder exista y sea recuperable. Se estudia como la coexistencia de ambas normas implicaban un cambio cultural, una evolución en el comportamiento de las organizaciones que no acompañó a la puesta en marcha de los instrumentos legales. Se concluye que el Derecho de Acceso a la Información Pública está basado en el principio fundamental de transparencia de los Órganos del Estado, por lo que no es de extrañar que una ley que obliga a brindar información tenga el riesgo de devenir en letra muerta. El Archivo debe ser "condición" administrativa, lo que exige una nueva dimensión de ellos y de sus profesionales dentro de los organismos del Estado, de forma tal que se conviertan en una inmejorable herramienta para el cumplimiento de los objetivos de la Ley de Derecho de Acceso a la Información Pública

Traductología : Exploración de un enfoque feminista de la traducción

Este trabajo se propone presentar la transformación de la Traductología desde la perspectiva de los Estudios de Género, dos campos del conocimiento que reconocen una impronta multi e interdisciplinaria. En cuanto a la primera, el giro cultural de los ochenta marca el momento en que se incluye a la traducción dentro del conjunto de subsistemas culturales con intereses competitivos y sujetos a las ideologías predominantes (Molina Martínez, 2006: 37). Paralelamente se instala en Canadá un terreno de estudio que vincula los desarrollos transculturales y translingüísticos surgidos de los movimientos feministas de los años setenta con la producción y recepción de textos, temas que son abarcados por la investigación sobre género y traducción. En ese contexto surge la noción de traducción en femenino o reescritura en femenino cuya finalidad es subvertir el lenguaje patriarcal y reivindicar las ideas feministas (Lotbinière-Harwood, 1991). Las estrategias discursivas y textuales utilizadas para resolver los problemas de traducción relacionados con el género "suplementación o compensación, la metatextualidad, el secuestro y el pacto especular" suelen recurrir al empleo de un lenguaje con alteraciones semánticas, neologismos o innovaciones lingüísticas, cuyo propósito es cuestionar la lengua actual y, a su vez, visibilizar la presencia femenina (Castro Vázquez, 2008: 296-298). En esta ponencia, nos detendremos en discutir y ejemplificar las estrategias citadas