57 research outputs found
Stimulating p53 down-under: a report from the 1st Australian p53 Workshop
No full textBurgeoning interest in the tumour suppressor p53 in the Australasian region provoked the birth of the first Australian p53 Workshop, held at the Peter MacCallum Cancer Centre in Melbourne, 19–21 November 2012 and attended by over 130 international and national delegates. The Workshop was organized by Ygal Haupt, Andreas Strasser, Sue Haupt, Antony Braithwaite and Paul Neilsen: 33 oral presentations and 23 posters communicated exciting new p53 findings.PM Neilsen, AW Braithwaite, C Gamell, S Haupt, A Janic, A Strasser, K Wolyniec and Y Haup
El Mundo de María y Mario : la aventura de las letras
No full textIntèrprets: Celia, Andrés ; història original: Belen C. Diaz ; voz "off": Estefania Guilarte, Juan Guilarte ; música: Oscar Gamell
Application-aware on-line failure recovery for extreme-scale HPC environments
No full textHigh Performance Computing (HPC) brings with it the promise of deeper insight into complex phenomena through the execution of various extreme-scale applications, especially those in the fields of science and engineering. The increasing computational demands of these applications continue to push the limits of current extreme scale HPC systems. As a result, the community is working toward achieving exascale systems able to compute 10^18 floating point operations per second (FLOPS). Since these systems are expected to contain a large number of components, reliability is one of the key anticipated challenges. Due to the extensive periods of time that complex applications require, future systems will likely see an increase in process and node failures during application execution. These failures, also known as hard failures, are currently handled by terminating the execution and restarting it from the last stored checkpoint. This checkpoint-restart methodology requires the application to periodically save its distributed state into a centralized, stable storage --an approach that is not expected to scale to future extreme-scale systems. While the illusion of a failure-free machine --implemented either via hardware or system software strategies-- is adequate for current HPC systems, they may prove too costly in future extreme-scale machines. Resilience is, therefore, a key challenge that must be addressed in order to realize the exascale vision. This dissertation explores new models that leverage application-awareness to enable on-line failure recovery. On-line recovery, which does not require the interruption of surviving processes in order to collectively restart the entire application, offers better cost/performance tradeoffs by reducing recovery overheads. Recovering processes on-line enables application-specific data recovery strategies and optimized in-memory checkpointing while avoiding the repetition of initialization procedures --the least optimized part of most production-level applications-- on all processes. This dissertation addresses three areas of research in on-line failure recovery. First, it explores a generic global on-line recovery model, involving all processes in the recovery process. Second, it explores optimized local recovery in which communication characteristics of certain application classes are leveraged to reduce overheads due to failure. In particular, finite difference partial differential equation solvers using stencil operators are used as the driving application class. Third, this dissertation demonstrates how the overhead of multiple, independent failures can be masked to effectively reduce the impact on total execution time. The models presented in this dissertation are implemented and evaluated in Fenix and FenixLR, a pair of generic and extensible frameworks used to demonstrate the concepts.Ph.D.Includes bibliographical referencesby Marc Gamell Balman
Exploring Cross-layer power management for PGAS applications on the SCC platform
No full textTechnological limitations and power constraints are resulting in high-performance parallel computing architectures that are based on large numbers of high-core-count processors. Commercially available processors are now at 8 and 16 cores and experimental platforms, such as the many-core Intel Single-chip Cloud Computer (SCC) platform, provide much higher core counts. These trends are presenting new sets of challenges to HPC applications including programming complexity and the need for extreme energy efficiency.
In this work, we first investigate the power behavior of scientific PGAS application kernels on the SCC platform, and explore opportunities and challenges for power management within the PGAS framework. Results obtained via empirical evaluation of Unified Parallel C (UPC) applications on the SCC platform under different constraints, show that, for specific operations, the potential for energy savings in PGAS is large; and power/performance trade-offs can be effectively managed using a cross-layer
approach. We investigate cross-layer power management using PGAS language extensions and runtime mechanisms that manipulate power/performance tradeoffs. Specifically, we present the design, implementation and evaluation of such a middleware for application-aware cross-layer power management of UPC applications on the SCC platform. Finally, based on our observations, we provide a set of recommendations and insights that can be used to support similar power management for PGAS applications on other many-core platforms.En este trabajo se investiga el comportamiento de alimentación de los núcleos de aplicaciones científicas PGAS en la plataforma de SCC y se exploran las oportunidades y desafíos para la administración de energía en el marco PGAS.En aquest treball s'investiga el comportament d'alimentació dels nuclis d'aplicacions científiques PGAS a la plataforma de SCC i s'exploren les oportunitats i desafiaments per a la gestió de l'energia en el marc PGAS
Uncovering a novel pathway for p16 silencing:Therapeutic implications for lung cancer
No full textA key step during onset of most cases of non-small cell lung cancer (NSCLC) is the loss of the tumor suppressor p16INK4a (best known as p16), commonly due to promoter hypermethylation. We recently reported a novel regulatory pathway involving E6-associated protein and cell division control protein 6, which provides a methylation-independent mechanism for p16 silencing in patients with a particularly aggressive form of NSCLC.</p
E6AP Promotes a Metastatic Phenotype in Prostate Cancer
No full textAlthough primary prostate cancer is largely curable, progression to metastatic disease is associated with very poor prognosis. E6AP is an E3 ubiquitin ligase and a transcriptional co-factor involved in normal prostate development. E6AP drives prostate cancer when overexpressed. Our study exposed a role for E6AP in the promotion of metastatic phenotype in prostate cells. We revealed that elevated levels of E6AP in primary prostate cancer correlate with regional metastasis and demonstrated that E6AP promotes acquisition of mesenchymal features, migration potential, and ability for anchorage-independent growth. We identified the metastasis suppressor NDRG1 as a target of E6AP and showed it is key in E6AP induction of mesenchymal phenotype. We showed that treatment of prostate cancer cells with pharmacological agents upregulated NDRG1 expression suppressed E6AP-induced cell migration. We propose that the E6AP-NDRG1 axis is an attractive therapeutic target for the treatment of E6AP-driven metastatic prostate cancer. Biological Sciences; Cell Biology; CancerFull Tex
Utilitat del QuantiFERON®-TB Gold Plus en el diagnòstic de la infecció tuberculosa latent i la malaltia tuberculosa en població pediàtrica
No full textPrograma de Doctorat en Medicina i Recerca Translacional / Tesi realitzada a l'Hospital Sant Joan de Déu[cat] INTRODUCCIÓ:
Els nens infectats per Mycobacterium tuberculosis tenen un major risc d’emmalaltir de tuberculosi i de fer-ho presentant-ne formes greus. La detecció de la infecció latent a través de tests d'immunodiagnòstic és essencial per poder indicar la quimioprofilaxi i disminuir la possibilitat de progressió a malaltia. A més, la positivitat dels tests reforça la sospita de tuberculosi activa, fet important atès que la confirmació microbiològica sovint no és possible en pacients pediàtrics.
El test QuantiFeron-Plus (QFT-Plus) es basa en la detecció d’interferó gamma (IFNγ) secretat per limfòcits sensibilitzats. En comparació als seus predecessors, el QFT-Plus té la particularitat de presentar un segon tub reactiu (TB2). Es planteja que el TB2 serviria per avaluar la resposta dels limfòcits CD8, fet que podria ser important en pacients joves i en aquells amb una alta càrrega bacil·lar. El test s’ha avaluat escassament en pacients pediàtrics. Així, la realització d’aquest treball es justifica per la idiosincràsia de la tuberculosi pediàtrica així com per l’escassa evidència prèvia sobre l’ús del QFT-Plus en pediatria.
MÈTODES I OBJECTIUS:
Els pacients que conformen els quatre treballs de la tesi han estat reclutats transversal i multicèntricament en el si de la pTBred. S’hi van incloure 1751 pacients menors de 18 anys a qui es va fer el test QFT-Plus. El primer estudi tenia com a objectiu estudiar la sensibilitat del QFT- Plus per diagnosticar la malaltia tuberculosa; el segon, avaluar-ne l’especificitat en pacients sotmesos al QFT-Plus per sospita clínica de malaltia però amb un diagnòstic alternatiu al de tuberculosi; el tercer, estudiar la sensibilitat per a tuberculosi i també el rendiment del test en casos d’infecció latent, així com determinar els factors independentment associats que el test presenti un resultat indeterminat; i el quart, avaluar el paper específic del TB2 i determinar com varia en el temps la concentració d’IFNγ en pacients un cop han rebut tractament antituberculós.
RESULTATS:
La sensibilitat del QFT-Plus per a tuberculosi va resultar del 83%, similar a la del QuantiFeron Gold-in-tube (QFT-GIT), predecessor del QFT-Plus. La sensibilitat va ser major en pacients amb malaltia confirmada. La sensibilitat del PPD va ser similar a la del QFT-Plus. Per contra, la concordança entre ambdós tests va ser moderada. L’especificitat va resultar del 91,5%, similar a la d’estudis que avaluaven l’especificitat del QFT-GIT seguint la mateixa metodologia. D’entre els infants amb infecció latent, la taxa de positivitat del QFT-Plus va ser del 68,2%, essent la concordança entre QFT-Plus i PPD en aquests pacients del 54,7%.
Mitjançant una regressió logística, es van identificar com a factors de risc independents de presentar un resultat indeterminat per al test: 1) edat menor de 5 anys; 2) recompte baix de limfòcits; i 3) nivells elevats de proteïna C reactiva.
Al quart estudi s’hi van reclutar 295 pacients amb un QFT-Plus positiu. Es va avaluar la diferència de concentració d’IFNγ entre ambdós tubs reactius (DCI) com a marcador subrogat de la resposta dels limfòcits CD8. Ni en el global dels pacients ni en aquells en qui caldria esperar una resposta CD8 més marcada no es va veure una DCI significativa. Estudis citomètrics previs mostraven detecció de resposta CD8 al TB2 però també, i sovint de manera més marcada, al TB1; de manera que el QFT-Plus podria no estar correctament dissenyat per a la detecció de resposta específica CD8.
Es va repetir el test a 65 pacients amb un resultat positiu, un cop van finalitzar el tractament antituberculós. Només la meitat dels infants van presentar una disminució marcada dels nivells d’IFNγ, sense que resultés possible la identificació d’un perfil concret de pacient en qui la concentració disminuís més marcadament. Així, no sembla que el test sigui útil per a la monitorització de la resposta al tractament.[eng] INTRODUCTION:
Young children infected with Mycobacterium tuberculosis are at increased risk of developing active tuberculosis. Thus, identifying latent tuberculosis infection through immunodiagnostic tests is essential to reduce the risk of disease progression.
QuantiFeron-Plus test (QFT-Plus) is based on the detection of released interferon gamma (IFNγ). Distinctively, it has a second reactive tube (TB2), which is meant to be able to evaluate the response of CD8 lymphocytes. However, there is a lack of previous studies evaluating this test in pediatric patients.
OBJECTIVES AND METHODS:
This thesis includes four articles. Patients were recruited within the pTBred network. Up to 1751 children younger than 18 years tested with QFT-Plus were finally included.
The objectives of these articles were: a) to evaluate both the sensitivity and specificity of QFT- Plus; b) to analyze its performance in patients with latent infection; c) to determine independent risk factors to present an indeterminate result; d) to describe the specific role of the TB2; and e) to identify released IFNγ concentration changes after completing tuberculosis treatment.
RESULTS:
The sensitivity of QFT-Plus was 83% and its specificity was 91.5%, similarly to previously reported results for its predecessor QuantiFeron Gold-in-tube. TST sensitivity was similar to that of QFT- Plus, whereas the concordance between both tests was moderate. Among children with latent infection, the QFT-Plus positivity rate was 68.2%, while the concordance between QFT-Plus and TST in these patients was 54.7%.
Using logistic regression, the following independent risk factors for presenting an indeterminate result were identified: 1) age under 5 years; 2) low lymphocyte account; and 3) elevated C- reactive protein levels.
In the fourth study, we included 295 patients with a positive QFT-Plus result. The difference in IFNγ concentration (DIC) between both reagent tubes was used as a surrogate marker of CD8 response. We did not observe a significant DIC, nor in the overall of patients neither in those in whom an increased CD8 response would be expected. Sixty-five patients with an initial positive result had the test repeated after completing the treatment. Only half of them presented a significant decrease in IFNγ levels. Thus, QFT-Plus does not appear to be useful for monitoring treatment response
Utilitat del QuantiFERON®-TB Gold Plus en el diagnòstic de la infecció tuberculosa latent i la malaltia tuberculosa en població pediàtrica
No full text[cat] INTRODUCCIÓ:
Els nens infectats per Mycobacterium tuberculosis tenen un major risc d’emmalaltir de tuberculosi i de fer-ho presentant-ne formes greus. La detecció de la infecció latent a través de tests d'immunodiagnòstic és essencial per poder indicar la quimioprofilaxi i disminuir la possibilitat de progressió a malaltia. A més, la positivitat dels tests reforça la sospita de tuberculosi activa, fet important atès que la confirmació microbiològica sovint no és possible en pacients pediàtrics.
El test QuantiFeron-Plus (QFT-Plus) es basa en la detecció d’interferó gamma (IFNγ) secretat per limfòcits sensibilitzats. En comparació als seus predecessors, el QFT-Plus té la particularitat de presentar un segon tub reactiu (TB2). Es planteja que el TB2 serviria per avaluar la resposta dels limfòcits CD8, fet que podria ser important en pacients joves i en aquells amb una alta càrrega bacil·lar. El test s’ha avaluat escassament en pacients pediàtrics. Així, la realització d’aquest treball es justifica per la idiosincràsia de la tuberculosi pediàtrica així com per l’escassa evidència prèvia sobre l’ús del QFT-Plus en pediatria.
MÈTODES I OBJECTIUS:
Els pacients que conformen els quatre treballs de la tesi han estat reclutats transversal i multicèntricament en el si de la pTBred. S’hi van incloure 1751 pacients menors de 18 anys a qui es va fer el test QFT-Plus. El primer estudi tenia com a objectiu estudiar la sensibilitat del QFT- Plus per diagnosticar la malaltia tuberculosa; el segon, avaluar-ne l’especificitat en pacients sotmesos al QFT-Plus per sospita clínica de malaltia però amb un diagnòstic alternatiu al de tuberculosi; el tercer, estudiar la sensibilitat per a tuberculosi i també el rendiment del test en casos d’infecció latent, així com determinar els factors independentment associats que el test presenti un resultat indeterminat; i el quart, avaluar el paper específic del TB2 i determinar com varia en el temps la concentració d’IFNγ en pacients un cop han rebut tractament antituberculós.
RESULTATS:
La sensibilitat del QFT-Plus per a tuberculosi va resultar del 83%, similar a la del QuantiFeron Gold-in-tube (QFT-GIT), predecessor del QFT-Plus. La sensibilitat va ser major en pacients amb malaltia confirmada. La sensibilitat del PPD va ser similar a la del QFT-Plus. Per contra, la concordança entre ambdós tests va ser moderada. L’especificitat va resultar del 91,5%, similar a la d’estudis que avaluaven l’especificitat del QFT-GIT seguint la mateixa metodologia. D’entre els infants amb infecció latent, la taxa de positivitat del QFT-Plus va ser del 68,2%, essent la concordança entre QFT-Plus i PPD en aquests pacients del 54,7%.
Mitjançant una regressió logística, es van identificar com a factors de risc independents de presentar un resultat indeterminat per al test: 1) edat menor de 5 anys; 2) recompte baix de limfòcits; i 3) nivells elevats de proteïna C reactiva.
Al quart estudi s’hi van reclutar 295 pacients amb un QFT-Plus positiu. Es va avaluar la diferència de concentració d’IFNγ entre ambdós tubs reactius (DCI) com a marcador subrogat de la resposta dels limfòcits CD8. Ni en el global dels pacients ni en aquells en qui caldria esperar una resposta CD8 més marcada no es va veure una DCI significativa. Estudis citomètrics previs mostraven detecció de resposta CD8 al TB2 però també, i sovint de manera més marcada, al TB1; de manera que el QFT-Plus podria no estar correctament dissenyat per a la detecció de resposta específica CD8.
Es va repetir el test a 65 pacients amb un resultat positiu, un cop van finalitzar el tractament antituberculós. Només la meitat dels infants van presentar una disminució marcada dels nivells d’IFNγ, sense que resultés possible la identificació d’un perfil concret de pacient en qui la concentració disminuís més marcadament. Així, no sembla que el test sigui útil per a la monitorització de la resposta al tractament.[eng] INTRODUCTION:
Young children infected with Mycobacterium tuberculosis are at increased risk of developing active tuberculosis. Thus, identifying latent tuberculosis infection through immunodiagnostic tests is essential to reduce the risk of disease progression.
QuantiFeron-Plus test (QFT-Plus) is based on the detection of released interferon gamma (IFNγ). Distinctively, it has a second reactive tube (TB2), which is meant to be able to evaluate the response of CD8 lymphocytes. However, there is a lack of previous studies evaluating this test in pediatric patients.
OBJECTIVES AND METHODS:
This thesis includes four articles. Patients were recruited within the pTBred network. Up to 1751 children younger than 18 years tested with QFT-Plus were finally included.
The objectives of these articles were: a) to evaluate both the sensitivity and specificity of QFT- Plus; b) to analyze its performance in patients with latent infection; c) to determine independent risk factors to present an indeterminate result; d) to describe the specific role of the TB2; and e) to identify released IFNγ concentration changes after completing tuberculosis treatment.
RESULTS:
The sensitivity of QFT-Plus was 83% and its specificity was 91.5%, similarly to previously reported results for its predecessor QuantiFeron Gold-in-tube. TST sensitivity was similar to that of QFT- Plus, whereas the concordance between both tests was moderate. Among children with latent infection, the QFT-Plus positivity rate was 68.2%, while the concordance between QFT-Plus and TST in these patients was 54.7%.
Using logistic regression, the following independent risk factors for presenting an indeterminate result were identified: 1) age under 5 years; 2) low lymphocyte account; and 3) elevated C- reactive protein levels.
In the fourth study, we included 295 patients with a positive QFT-Plus result. The difference in IFNγ concentration (DIC) between both reagent tubes was used as a surrogate marker of CD8 response. We did not observe a significant DIC, nor in the overall of patients neither in those in whom an increased CD8 response would be expected. Sixty-five patients with an initial positive result had the test repeated after completing the treatment. Only half of them presented a significant decrease in IFNγ levels. Thus, QFT-Plus does not appear to be useful for monitoring treatment response
Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP
No full textRestoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP–PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation
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