The Role of an Oncoprotein CIP2A in Breast Cancer

Cancerous inhibitor of PP2A (CIP2A) is an oncoprotein expressed in several human cancer types. Previously, CIP2A has been shown to promote proliferation of cancer cells. Mechanistically, CIP2A is known to inhibit activity of a tumor suppressor protein phosphatase 2A (PP2A) towards an oncoprotein MYC, further stabilizing MYC in human cancer. However, the molecular mechanisms how CIP2A expression is induced during cellular transformation are not well known. Also, expression, functional role and clinical relevance of CIP2A in breast cancer had not been studied before. The results of this PhD thesis work demonstrate that CIP2A is highly expressed in human breast cancer, and that high expression of CIP2A in tumors is a poor prognostic factor in a subset of breast cancer patients. CIP2A expression correlates with inactivating mutations of tumor suppressor p53 in human cancer. Notably, we demonstrate that p53 inactivation up-regulates CIP2A expression via increased expression of an oncogenic transcription factor E2F1. Moreover, CIP2A promotes expression of E2F1, and this novel positive feedback loop between E2F1 and CIP2A is demonstrated to regulate sensitivity to both p53-dependent and -independent senescence induction in breast cancer cells. Importantly, in a CIP2A deficient breast cancer mouse model, abrogation of CIP2A attenuates mammary tumor formation and progression with features of E2F1 inhibition and induction of senescence. Furthermore, we demonstrate that CIP2A expression defines the cellular response to a senescence-inducing chemotherapy in breast cancer. Taken together, these results demonstrate that CIP2A is an essential promoter of breast cancer tumor growth by inhibiting senescence. Finally, this study implicates inhibition of CIP2A as a promising therapy target for breast cancer.

Chemoreceptors and cardiovascular control in acute and chronic systemic hypoxia

This review describes the ways in which the primary bradycardia and peripheral vasoconstriction evoked by selective stimulation of peripheral chemoreceptors can be modified by the secondary effects of a chemoreceptor-induced increase in ventilation. The evidence that strong stimulation of peripheral chemoreceptors can evoke the behavioural and cardiovascular components of the alerting or defence response which is characteristically evoked by novel or noxious stimuli is considered. The functional significance of all these influences in systemic hypoxia is then discussed with emphasis on the fact that these reflex changes can be overcome by the local effects of hypoxia: central neural hypoxia depresses ventilation, hypoxia acting on the heart causes bradycardia and local hypoxia of skeletal muscle and brain induces vasodilatation. Further, it is proposed that these local influences can become interdependent, so generating a positive feedback loop that may explain sudden infant death syndrome (SIDS). It is also argued that a major contributor to these local influences is adenosine. The role of adenosine in determining the distribution of O2 in skeletal muscle microcirculation in hypoxia is discussed, together with its possible cellular mechanisms of action. Finally, evidence is presented that in chronic systemic hypoxia, the reflex vasoconstrictor influences of the sympathetic nervous system are reduced and/or the local dilator influences of hypoxia are enhanced. In vitro and in vivo findings suggest this is partly explained by upregulation of nitric oxide (NO) synthesis by the vascular endothelium which facilitates vasodilatation induced by adenosine and other NO-dependent dilators and attenuates noradrenaline-evoked vasoconstriction.

Julkisen organisaation johdon raportoinnin kehittäminen CASE: Puolustusvoimien johtamisjärjestelmäkeskus

Tämän tutkielman tavoitteena on tutkia julkisen organisaation sisäistä taloudellista raportointia eli johdon raportointia case -organisaation avulla. Tavoitteena on kehittää ja uudistaa organisaation johdolle tuotettavaa kustannusseurantaan liittyvää raportointityökalua. Teoreettista viitekehystä luodaan pääasiassa New Public Management (NPM) -ajattelua tutkimalla. Teoriaosuudessa pohditaan myös muita julkisen organisaation johtamiseen ja raportointiin liittyviä asioita: tulosjohtamista ja suorituskyvyn mittaamista. Empiria osuudessa kehitetään tutkitun teorian, organisaation sisällä kahdessa eri vaiheessa tehtyjen haastattelujen ja jatkuvan havainnoinnin avulla uusi raportointityökalu johdolle. Tämän kehitystyön tuloksena case -organisaatiossa otettiin vuoden 2015 alussa käyttöön uudistettu johdon raportti resurssien käytöstä. Raportti sai paljon positiivista palautetta sen käyttäjiltä ja sen todettiin helpottavan kustannusseurantaa. Seurannan toteutus ja sen taustojen ymmärtäminen vaatii kuitenkin vielä paljon opettelua organisaatiossa.

Transduction motif analysis of gastric cancer based on a human signaling network

To investigate signal regulation models of gastric cancer, databases and literature were used to construct the signaling network in humans. Topological characteristics of the network were analyzed by CytoScape. After marking gastric cancer-related genes extracted from the CancerResource, GeneRIF, and COSMIC databases, the FANMOD software was used for the mining of gastric cancer-related motifs in a network with three vertices. The significant motif difference method was adopted to identify significantly different motifs in the normal and cancer states. Finally, we conducted a series of analyses of the significantly different motifs, including gene ontology, function annotation of genes, and model classification. A human signaling network was constructed, with 1643 nodes and 5089 regulating interactions. The network was configured to have the characteristics of other biological networks. There were 57,942 motifs marked with gastric cancer-related genes out of a total of 69,492 motifs, and 264 motifs were selected as significantly different motifs by calculating the significant motif difference (SMD) scores. Genes in significantly different motifs were mainly enriched in functions associated with cancer genesis, such as regulation of cell death, amino acid phosphorylation of proteins, and intracellular signaling cascades. The top five significantly different motifs were mainly cascade and positive feedback types. Almost all genes in the five motifs were cancer related, including EPOR,MAPK14, BCL2L1, KRT18,PTPN6, CASP3, TGFBR2,AR, and CASP7. The development of cancer might be curbed by inhibiting signal transductions upstream and downstream of the selected motifs.

Volume-Synchronized Probability of Informed Trading (VPIN), Market Volatility, and High-Frequency Liquidity

We assess the predictive ability of three VPIN metrics on the basis of two highly volatile market events of China, and examine the association between VPIN and toxic-induced volatility through conditional probability analysis and multiple regression. We examine the dynamic relationship on VPIN and high-frequency liquidity using Vector Auto-Regression models, Granger Causality tests, and impulse response analysis. Our results suggest that Bulk Volume VPIN has the best risk-warning effect among major VPIN metrics. VPIN has a positive association with market volatility induced by toxic information flow. Most importantly, we document a positive feedback effect between VPIN and high-frequency liquidity, where a negative liquidity shock boosts up VPIN, which, in turn, leads to further liquidity drain. Our study provides empirical evidence that reflects an intrinsic game between informed traders and market makers when facing toxic information in the high-frequency trading world.

Sea Surface Temperature-Convection Relationship in Tropical Oceans with Special Emphasis to Intraseasonal Variability of Indian Summer Monsoon

The SST convection relation over tropical ocean and its impact on the South Asian monsoon is the first part of this thesis. Understanding the complicated relation between SST and convection is important for better prediction of the variability of the Indian monsoon in subseasonal, seasonal, interannual, and longer time scales. Improved global data sets from satellite scatterometer observations of SST, precipitation and refined reanalysis of global wind fields have made it possible to do a comprehensive study of the SST convection relation. Interaction of the monsoon and Indian ocean has been discussed. A coupled feedback process between SST and the Active-Break cycle of the Asian summer monsoon is a central theme of the thesis. The relation between SST and convection is very important in the field of numerical modeling of tropical rainfall. It is well known that models generally do very well simulating rainfall in areas of tropical convergence zones but are found unable to do satisfactory simulation in the monsoon areas. Thus in this study we critically examined the different mechanisms of generation of deep convection over these two distinct regions.The study reported in chapter 3 has shown that SST - convection relation over the warm pool regions of Indian and west Pacific oceans (monsoon areas) is in such a way that convection increases with SST in the SST range 26-29 C and for SST higher than 29-30 C convection decreases with increase of SST (it is called Waliser type). It is found that convection is induced in areas with SST gradients in the warm pool areas of Indian and west Pacific oceans. Once deep convection is initiated in the south of the warmest region of warm pool, the deep tropospheric heating by the latent heat released in the convective clouds produces strong low level wind fields (Low level Jet - LLJ) on the equatorward side of the warm pool and both the convection and wind are found to grow through a positive feedback process. Thus SST through its gradient acts only as an initiator of convection. The central region of the warm pool has very small SST gradients and large values of convection are associated with the cyclonic vorticity of the LLJ in the atmospheric boundary layer. The conditionally unstable atmosphere in the tropics is favorable for the production of deep convective clouds.

SST–convection relation over tropical oceans

According to current knowledge, convection over the tropical oceans increases with sea surface temperature (SST) from 26 to 29 °C, and at SSTs above 29 °C, it sharply decreases. Our research shows that it is only over the summer warm pool areas of Indian and west Pacific Oceans (monsoon areas) where the zone of maximum SST is away from the equator that this kind of SST-convection relationship exists. In these areas (1) convection is related to the SST gradient that generates low-level moisture convergence and upward vertical motion in the atmosphere. This has modelling support. Regions of SST maxima have low SST gradients and therefore feeble convection. (2) Convection initiated by SST gradient produces strong wind fields particularly cross-equatorial low-level jetstreams (LLJs) on the equator-ward side of the warm pool and both the convection and LLJ grow through a positive feedback process. Thus, large values of convection are associated with the cyclonic vorticity of the LLJ in the atmospheric boundary layer. In the inter-tropical convergence zone (ITCZ) over the east Pacific Ocean and the south Pacific convergence zone (SPCZ) over the west Pacific Ocean, low-level winds from north and south hemisphere converge in the zone of maximum SST, which lies close to the equator producing there elongated bands of deep convection, where we find that convection increases with SST for the full range of SSTs unlike in the warm pool regions. The low-level wind divergence computed using QuikSCAT winds has large and significant linear correlation with convection in both the warm pool and ITCZ/SPCZ areas. But the linear correlation between SST and convection is large only for the ITCZ/SPCZ. These findings have important implications for the modelling of largescale atmospheric circulations and the associated convective rainfall over the tropical oceans

Las comunidades virtuales como una herramienta para la perdurabilidad empresarial

Las compañías desde su creación, están en la constante búsqueda de la perdurabilidad en el tiempo; es decir buscan el desarrollo sostenible de su negocio y para esto se encuentran con el reto no solo de mantener el personal idóneo y motivado, sino de hacer seguimiento y gestión a sus finanzas, adquirir nuevas tecnologías y generar nuevos productos o negocios, acordes a las necesidades de sus clientes. La implementación de nuevas tecnologías como la Web 2.0, han facilitado a las organizaciones esta tarea; gracias a la retroalimentación y mejora permanente de los productos, que se obtiene a través de la interacción con los clientes, en las plataformas virtuales donde se tiene la posibilidad de: Comercializar, mercadear y publicitar un producto, además de crear prototipos, conocer intereses, necesidades y gustos, que retroalimentan de manera positiva o negativa a la compañía en procesos de preventa y postventa. A través de este estudio exploratorio, se pretende sensibilizar a los directivos de las diferentes organizaciones, frente a la importancia del uso e implementación de nuevas tecnologías como Second Life, una herramienta practica, económica y eficiente para obtener mayor reconocimiento de la marca y lograr competitividad en el mercado global. Teniendo claridad que parte del éxito que se consiga con la implementación de esta herramienta, está determinado por el cambio en la estructura de la compañía y el modelo mental del CEO o líder.

Las decisiones colectivas en el caso de la titulación de activos

La literatura sobre desarrollo económico y pobreza de los últimos años ha enfatizado en el tema de los derechos de propiedad, las instituciones informales y su relación con el mercado de capitales. Este trabajo busca modelar algunos aspectos de la obra del economista Hernando De Soto en el tema de la informalidad, específicamente ¿cómo es que el establecimiento de un sistema de propiedad permite a la gente elegir de entre un conjunto mayor de socios comerciales?, y ¿por qué la decisión individual costo-beneficio de expedir un títulolegal de propiedad es considerada un asunto de redes? Para modelar este problema, se utilizó un enfoque deteoría de juegos: los pagos están relacionados con la distribución de la población total entre sectores formales e informales, y surgen fenómenos de retroalimentación positiva y externalidades. Las conclusiones incluyen análisis de política para el caso de la vivienda en Colombia.

Atmosphere feedbacks during ENSO in a coupled GCM with a modified atmospheric convection scheme

The too diverse representation of ENSO in a coupled GCM limits one’s ability to describe future change of its properties. Several studies pointed to the key role of atmosphere feedbacks in contributing to this diversity. These feedbacks are analyzed here in two simulations of a coupled GCM that differ only by the parameterization of deep atmospheric convection and the associated clouds. Using the Kerry–Emanuel (KE) scheme in the L’Institut Pierre-Simon Laplace Coupled Model, version 4 (IPSL CM4; KE simulation), ENSO has about the right amplitude, whereas it is almost suppressed when using the Tiedke (TI) scheme. Quantifying both the dynamical Bjerknes feedback and the heat flux feedback in KE, TI, and the corresponding Atmospheric Model Intercomparison Project (AMIP) atmosphere-only simulations, it is shown that the suppression of ENSO in TI is due to a doubling of the damping via heat flux feedback. Because the Bjerknes positive feedback is weak in both simulations, the KE simulation exhibits the right ENSO amplitude owing to an error compensation between a too weak heat flux feedback and a too weak Bjerknes feedback. In TI, the heat flux feedback strength is closer to estimates from observations and reanalysis, leading to ENSO suppression. The shortwave heat flux and, to a lesser extent, the latent heat flux feedbacks are the dominant contributors to the change between TI and KE. The shortwave heat flux feedback differences are traced back to a modified distribution of the large-scale regimes of deep convection (negative feedback) and subsidence (positive feedback) in the east Pacific. These are further associated with the model systematic errors. It is argued that a systematic and detailed evaluation of atmosphere feedbacks during ENSO is a necessary step to fully understand its simulation in coupled GCMs.

The role of atmosphere feedbacks during ENSO in the CMIP3 models

Several studies using ocean-atmosphere GCMs suggest that the atmospheric component plays a dominant role in the modelled ENSO. To help elucidate these findings, the two main atmosphere feedbacks relevant to ENSO, the Bjerknes positive feedback (µ) and the heat flux negative feedback (), are analysed here in 12 coupled GCMs. We find that the models generally underestimate both feedbacks, leading to an error compensation. The strength of is inversely related to the ENSO amplitude in the models and the latent heat and shortwave flux components of this feedback dominate. Furthermore, the shortwave component could help explain the model diversity in both overall and ENSO amplitude.

Two Independent Triggers for the Indian Ocean Dipole/Zonal Mode in a Coupled GCM

The question of whether and how tropical Indian Ocean dipole or zonal mode (IOZM) interannual variability is independent of El Nino-Southern Oscillation (ENSO) variability in the Pacific is addressed in a comparison of twin 200-yr runs of a coupled climate model. The first is a reference simulation, and the second has ENSO-scale variability suppressed with a constraint on the tropical Pacific wind stress. The IOZM can exist in the model without ENSO, and the composite evolution of the main anomalies in the Indian Ocean in the two simulations is virtually identical. Its growth depends on a positive feedback between anomalous equatorial easterly winds, upwelling equatorial and coastal Kelvin waves reducing the thermocline depth and sea surface temperature off the coast of Sumatra, and the atmospheric dynamical response to the subsequently reduced convection. Two IOZM triggers in the boreal spring are found. The first is an anomalous Hadley circulation over the eastern tropical Indian Ocean and Maritime Continent, with an early northward penetration of the Southern Hemisphere southeasterly trades. This situation grows out of cooler sea surface temperatures in the southeastern tropical Indian Ocean left behind by a reinforcement of the late austral summer winds. The second trigger is a consequence of a zonal shift in the center of convection associated with a developing El Nino, a Walker cell anomaly. The first trigger is the only one present in the constrained simulation and is similar to the evolution of anomalies in 1994, when the IOZM occurred in the absence of a Pacific El Nino state. The presence of these two triggers-the first independent of ENSO and the second phase locking the IOZM to El Nino-allows an understanding of both the existence of IOZM events when Pacific conditions are neutral and the significant correlation between the IOZM and El Nino.

The role of the Madden-Julian Oscillation in the El Nino and Indian drought of 2002

In 2002 India experienced a severe drought, one among the five worst droughts since records began in 1871, notable for its countrywide influence. The drought was primarily due to an unprecedented break in the monsoon during July, which persisted for almost the whole month and affected most of the sub-continent. The failure of the monsoon in 2002 was not predicted and India was not prepared for the devastating impacts on, for example, agriculture. This paper documents the evolution of the 2002 Indian summer monsoon and considers the possible factors that contributed to the drought and the failure of the forecasts. The development of the 2002/2003 El Nino and the unusually high levels of Madden-Julian Oscillation (MJO) activity during the monsoon season are identified as the central players. The 2002/2003 El Nino was characterised by very high sea-surface temperatures (SSTs) in the central Pacific that developed rapidly during the monsoon season. It is suggested that the unusual character of the developing El Nino was associated with the MJO and was a consequence of the eastward extension of the West Pacific Warm Pool, brought about primarily by a series of westerly wind events (WWEs) as part of the eastward movement of the active phase of the MJO. During the boreal summer, the MJO is usually characterised by northward movement, but in 2002 the northward component of the MJO was weak and the MJO was dominated by a strong eastward component, probably driven by the abnormally high SSTs in the central Pacific. It is suggested that a positive feedback existed between the developing El Nino and the eastward component of the MJO, which weakened the active phases of the monsoon. In particular, the unprecedented monsoon break in July could be associated with the juxtaposition of strong MJO activity with a developing El Nino, both of which interfered constructively with each other to produce major perturbations to the distribution of tropical heating. Subsequently, the main impact of the developing El Nino was a modulation of the Walker circulation that led to the overall suppression of the Indian monsoon during thess latter part of the season. It is argued that the unique combination of a rapidly developing El Nino and strong MJO activity, which was timed within the seasonal cycle to have maximum impact on the Indian summer monsoon, meant that prediction of the prolonged break in July and the seasonally deficient rainfall was a challenge for both the empirical and dynamical forecasting systems. Copyright (C) 2006 Royal Meteorological Society.

Tweaking the gain on platelet regulation: The tachykinin connection

Soluble factors such as ADP and thromboxane (TX) A(2) that are secreted or released by platelets at sites of tissue injury, mediate autocrine and paracrine regulation of platelet function, resulting in rapid localised thrombus formation. The suppression of platelet function, particularly through targeting such secondary regulatory mechanisms, that serve to 'fine-tune' the platelet response, has proven effective in the prevention of inappropriate platelet activation that results in thrombosis. The most commonly used anti-platelet approaches (ADP receptor antagonism or inhibition of TXA(2) synthesis), however, lack efficacy in many patients, suggesting the existence of additional uncharacterised mechanisms for the regulation of platelet function. Recent data, which form a focus of this review, have identified peripheral tachykinin peptide family members, such as substance P and the newly identified endokinins, as physiologically important positive feedback regulators of platelet function. The actions of tachykinins that are released from platelets during activation are mediated by the neurokinin-1 receptor. Initial analysis of the role of this receptor in platelet thrombus formation, and thrombosis in the mouse, indicate this to be a promising new target for the development of anti-thrombotic drugs. (C) 2008 Elsevier Ireland Ltd. All rights reserved.

The neurokinin 1 receptor: a potential new target for anti-platelet therapy?

The important role of platelets in the development of arterial thrombosis and cardiovascular disease is well established. Current treatments for arterial thrombosis include anti-platelet agents such as aspirin, thienopyridines and glycoprotein IIb-IIIa inhibitors. Despite these drugs being effective there remains a substantial unmet clinical demand for more effective therapeutic approaches, which may reflect the existence of alternative underlying regulatory mechanisms to those already targeted. Recent publications have demonstrated a key role for tachykinins in the positive feedback regulation of platelet aggregation and thrombus formation. The pro-thrombotic effects of tachykinins on platelets are mediated through the neurokinin 1 receptor, which may therefore offer a novel therapeutic drug target in the prevention and the treatment of arterial thrombosis.