8 research outputs found
The Effects of euro Adoption on the Slovak Economy
No full textIn this study we assess the effects of euro adoption from an economic perspective. The benefits and disadvantages of Slovak entry to the euro area were discussed already when the euro adoption strategy was adopted. This analysis utilizes the latest information, using the set euro adoption date and the chosen euro adoption scenario. We attempt to quantify the most important effects, so that the costs and benefits can be compared. The costs and risks related to the euro area entry will depend on economic conditions and policies. Therefore we analyze the economic policies, which should support euro adoption, the issues of optimal timing of euro area entry and the impacts of euro adoption on citizens, businesses and the state administration.
sFAS/sFASL and sMMP-7: New soluble markers of prognosis and response to therapy in advanced colorectal cancer
No full text[cat] 1 INTRODUCCIÓN El cáncer colorrectal (CCR) es la tercera causa de diagnóstico de cáncer en todo el mundo. El 11-27% de pacientes se diagnostican en estadio avanzado o metastático. De los inicialmente diagnosticados de CCR localizado, un 25-50% acabarán presentando metástasis. En los últimos años hemos asistido a un leve decremento de la incidencia y de la mortalidad por CCR, probablemente debido a la mejora en los programas de ¨screening¨ y a las mejoras en las estrategias terapéuticas. El CCRM tiene un pronóstico pésimo. La supervivencia global se sitúa entre los 5-6 meses, en pacientes que no reciben tratamiento. En los últimos años, la implementación de las nuevas terapias ha elevado esta media hasta los 15-18 meses. En la actualidad, ¿existe alguna manera para reconocer con que tipo de CCRM estamos tratando? ¿Cómo podemos determinar de antemano como se comportará el CCRM, en términos de pronóstico y respuesta a los tratamientos? Hasta la fecha se han realizado multitud de estudios con la intención de determinar factores pronósticos y predictivos de respuesta en CCRM. En el texto se recogen detalladamente los más importantes. Sin embargo, existen diferentes factores que explican que estos factores no se hayan implementado en la práctica clínica habitual. Entre ellos está la falta de estudios clínicos prospectivos confirmativos y, por otra parte está la heterogeneidad que impera a la hora de realizar los estudios sobre marcadores. Para solventar este último punto, el Nacional Cancer Institute ha creado unas guías a seguir (REMARK). Actualmente hace falta diseñar convenientemente estudios prospectivos confirmativos. En el Hospital Clínic de Barcelona hemos desarrollado (2001) un algoritmo terapéutico basado en el patrón de metástasis al debut de la enfermedad y los algunos de los factores más utilizados como pronósticos. 2 HIPÓTESIS Y OBJETIVOS: En nuestra hipótesis, hemos seleccionado dos determinantes moleculares (MMP-7 y sFAS/sFASL) como potenciales marcadores pro'osticos y predictivos de respuesta a terapia en CCRM. Matrilisina o metaloproteasa-7 (MMP-7) es una enzima proteolítica perteneciente a la familia de las metaloproteasas. Es sintetizada y secretada al medio por células tumorales. Detalles sobre la regulación de su expresión y función pueden hallarse en el texto original. Entre sus actividades destacamos su capacidad de cortar la proteína de membrana FASL. El receptor FAS y su ligando FASL son receptores transmebrana. Su interacción induce la activación de la vía extrínseca de apoptosis. Existen fracciones solubles de estas proteínas: sFAS y sFASL. sFAS es resultante de fenómenos de "splicing" alternativo. Su función es predominantemente proapoptótica. sFASL resulta de cortar la proteína de membrana, a cargo de proteasas como MMP-7. La función de sFASL es básicamente antiapoptótica. Las fracciones solubles pueden anularse entre sí. Su función final depende de los balances entre ellas, por lo que el ratio pude ser un estimador de la función apoptótica final. FAS y FASL son proteínas que se han relacionado con la respuesta apoptótica al tratamiento quimioterápico. El CCRM muestra un patrón de resistencia a la inducción de apoptosis vía FAS-FASL. El papel de las formas solubles sFAS y sFASL en quimioresistencia nunca ha sido evaluado. MMP-7 se ha relacionado con un fenotipo agresivo de CCRM, aunque también con quimioresistencia, debido a su capacidad de corte de FASL. Los niveles séricos de sFAS han demostrado estar aumentados en pacientes con CCRM. La medición de los niveles séricos de sFASL y MMP-7 nunca se ha llevado a cabo en pacientes con CCRM.Nuestra hipótesis es que los niveles séricos de MMP-7, sFAS y sFASL en pacientes con CCRM puden ser marcadores biológicos que estimen la agresividad y la quimioresistencia. A modo de concepto nuevo y, teniendo en cuenta que el tumor varía en el tiempo, está el hecho que los marcadores biológicos deberían poderse obtener no solo en el momento del diagnóstico sino en cualquier momento durante la evolución de la enfermedad. Si esto fuera así, el método de obtención debería ser fácil y no invasivo. Los niveles séricos de MMP-7, sFAS y sFASL y sus variaciones durante el tiempo deberían ser predictores de quimioresistencia en CCRM en cualquier momento durante la enfermedad.Los objetivos se pueden resumir en:A) Determinar si los niveles séricos basales de MMP-7 en pacientes con CCRM y establecer su valor pronóstico. B) Determinar los niveles séricos de sFAS y sFASL en pacientes con CCRM, antes y durante el tratamiento quimioterápico, y establecer una correlación con la respuesta tumoral, de manera que podamos valorar su papel como marcador predictivo de respuesta. C) En función de los resultados obtenidos, diseñar estudios clínicos prospectivos para validar el valor de los niveles séricos de MMP-7 y sFAS/sFASL como nuevos marcadores solubles de pronóstico y respuesta al tratamiento en CCRM. 3. RESULTADOS: Los resultados han sido hechos públicos en dos artículos, uno de ellos aparecido en 2005 y otro de ellos en prensa. Ambos se recogen en la tesis. 4. CONCLUSIONES: En resumen, concluimos que:-MMP-7 puede medirse en el suero y sus niveles basales son un factor pronóstico independiente en pacientes con CCRM.-Las variaciones de los niveles séricos de sFAS/FASL en pacientes con CCRM en tratamiento quimioterápico correlacionan con la respuesta tumoral.-La detección de un descenso del los valores séricos del ratio sFAS/sFASL, habitualmente debido al incremento de sFASL, se relaciona con quimioresistencia.-Los valores séricos del ratio sFAS/sFASL podrían utilizarse como un predictor dinámico de respuesta al tratamiento quimioterápico en pacientes con CCRM y su valor debería validarse en estudios clínicos prospectivos. -Nuestras observaciones, en los campos básico y clínico, indican que MMP-7 estaría implicada en quimioresistencia primaria o intrínseca y adquirida, en CCRM.-Una hipótesis generada "de novo" es que un patrón sérico consistente en niveles altos de MMP-7 y de FASL, tanto si se detecta antes de iniciar el tratamiento como durante éste, implicaría qumioresistencia y, en consecuencia, mal pronóstico. -MMP-7 y sFAS/sFASL, los nuevos marcadores solubles que proponemos, se pueden detector fácilmente a través de una técnica no invasiva.-MMP-7 y sFAS/sFASL, los nuevos marcadores solubles propuestos, se pueden detectar en cualquier momento a lo largo de la enfermedad y refleja la biología tumoral cambiante, de una manera dinámica. -De acuerdo a los resultados presentados y las hipótesis generadas a partir de éstos, hemos diseñado estudios clínicos prospectivos para determinar la relevancia clínica de los niveles séricos de MMP-7 y sFAS/sFASL, como nuevos marcadores solubles de quimioresistencia en CCRM
Genetic variation in the chicken genome: insights in selection
No full text The chicken currently provides more than a quarter of the meat and nearly all eggs produced worldwide. For future improvements in production traits and animal welfare as well as to address future consumer demands it is necessary to understand the etiology and biology underlying production traits and diseases. The primary aim of the research described in this thesis was to investigate the utility of several molecular approaches to identify causative variants underlying a variety of traits in the chicken. The general introduction in chapter 1 provides an overview of the domestication history of the chicken - with a particular focus on commercial chicken breeds - and describes the importance to identify causative variants underlying production traits and diseases. Furthermore, several different molecular techniques and methods are introduced that are being used to detect causative variants underlying monogenic and polygenic traits. Linkage maps are essential for linkage analysis, important to study recombination rates and recombination hotspots within the genome and can assist in the sequence assembly of genomes. In chapter 2 we describe the construction of a new high-resolution linkage map of the chicken genome based on two chicken populations with a total of 1619 individuals. The two populations used are a purebred broiler line and a broiler x broiler cross. This high resolution allowed accurate identification of recombination hotspots in the chicken genome, including sex specific recombination. Furthermore, to improve the current reference genome (WASHUC2), 613 unmapped markers were included in the genome-wide assay that included a total of 17,790 SNPs. The resulting linkage map comprises 13,340 SNPs, of which 360 had not been assigned to a known chromosome on chicken genome build WASHUC2. The resulting linkage map is composed of 31 linkage groups, with a total length of 3,054 cM for the sex-average map of the combined population. Regional differences in recombination hotspots between the two mapping populations were observed for several chromosomes near the telomere of the p arm. The sex-specific analysis revealed that these regional differences were mainly caused by female-specific recombination hotspots in the broiler × broiler cross. In chapter 3 we describe the molecular characterization of the locus causing the late feathering phenotype; a monogenic trait in chicken that results in a delayed emergence of flight feathers at hatch. The late feathering phenotype is beneficial to breeders as it can be used for sex typing at hatch. The locus has, therefore, been extensively used in diverse commercial chicken breeds. However, a retrovirus closely linked to the late feathering allele causes a negative pleiotropic effect on egg production and causes viral infections. Within this chapter we describe the identification of a 180 kb tandem duplication in the late feathering allele using a quantitative PCR approach. The tandem duplication results in the partial duplication of two genes; the prolactin receptor and the gene encoding sperm flagellar protein 2. Sequence analysis revealed that the duplication is identical in broiler, white egg-layer, and brown egg-layer lines. This information was also used to design a molecular test to detect this duplication, particularly in heterozygous individuals. The recent advances in massive parallel sequencing technologies have enabled rapid and cost-effective detection of all genetic variants within genomes. The detection of all genetic variants within a genome has further increased our ability to identify causative variants underlying quantitative trait loci (QTL). In chapter 4, we combined a genome-wide association study with whole-genome resequencing to identify causative variants underlying the pulmonary hypertension syndrome (PHS), a polygenic trait in chicken. PHS is a metabolic disease that has been linked to intense selection on growth rate and feed conversion ratio of modern broilers (meat-type chicken). PHS has become one of the most frequent causes of mortality within the broiler industry and leads to substantial economic losses and reduced animal welfare. In total, 18 QTL regions were identified in the genome-wide association study. In order to detect causative variants underlying these QTL regions, we sequenced the genomes of twelve individuals. To maximize the detection of causative variants we selected the individuals based on extreme phenotypes for PHS. Within 8 QTL regions we identified a total of 10 genes that contain at least one variant that is predicted to affect protein function. Moreover, 7.62 million SNPs were detected within the twelve animals compared to the reference genome. These markers can be used in the development of future genome-wide assays. Genomic regions that have undergone selection should contain loci that influence important phenotypic traits and will, therefore, include causative variant(s) that could aid in further future improvement of production traits and disease resistance. In chapter 5, we applied hitch-hiking mapping to make a broad assessment of the effects of selection histories in domesticated chicken. Towards this end, we sampled commercial chickens representing all major breeding goals from multiple breeding companies. In addition, we sampled non-commercial chicken diversity by sampling almost all recognized traditional Dutch breeds and a representative sample of breeds from China. The broad sample of 67 commercial and non-commercial breeds were assessed for signatures of selection in the genome using information of 57,636 SNPs that were genotyped on pooled DNA samples. Our approach demonstrates the strength of including many different populations with similar, and breed groups with different selection histories to reduce stochastic effects based on single populations. The detection of regions of putative selection resulted in the identification of several candidate genes that could aid in further improvement of production traits and disease resistance. Finally, the general discussion in chapter 6 describes the main findings of this thesis. In this chapter recommendations are given for the best strategies to detect causative variants underlying monogenic or polygenic traits. All strategies can benefit substantially from the recent developments in massive parallel sequencing, although the high costs of this method currently prevent large scale studies. In order to perform powerful and cost-effective studies, several strategies are discussed that combine massive parallel sequencing with other existing methods and techniques. Furthermore, the limitations of the different strategies are addressed, as well as the improvements needed in the near future to identify causative variants underlying a variety of traits in, but not limited to, the chicken. </p
The multi-factorial aetiology of urogenital carcinoma in the California sea lion (Zalophus californianus) : a case-control study
No full textCalifornia sea lions (CSLs) have an unusually high occurrence of urogenital cancer (UGC), with studies revealing metastatic carcinoma in 26 % of CSLs admitted to a rehabilitation centre between 1998 and 2012. It is likely that the aetiology of this disease is multi-factorial as genetics, viral infection and exposure to contaminants have been associated with this cancer to date. The goal of this study was to investigate the association of a number of factors using a case-control study design on animals admitted to a rehabilitation centre. The study additionally concentrates on two main areas; (i) genetic factors and (ii) the presence of herpesvirus.
Previous investigations identified cancer to be more likely in animals with specific microsatellite alleles. In the present study genotyping of CSLs at three microsatellite loci revealed that homozygosity at one marker (Pv11) was significantly associated with the presence of the disease. Pv11 was found to be located within a gene called heparanase 2 (HPSE2) and investigations into the expression of its protein revealed differences according to Pv11 genotype.
The presence of herpesvirus was investigated by two PCR methods and identified the gammaherpesvirus OtHV-1. The results of the two methods were contradictory with one method identifying a highly significant relationship between the presence of OtHV-1 and UGC whereas the other did not. Complicating factors such as potential differences in sensitivity of the tests along with the possible presence of closely related viruses or variants of OtHV-1 may explain this.
The availability of necropsy data for the CSLs in the study allowed the inclusion of body condition data in the statistical analysis to evaluate other potential risk factors. Final analysis revealed the presence of three risk factors; Pv11 genotype, OtHV-1 presence and thinner blubber.
This study is the largest study undertaken so far in order to investigate the involvement of risk factors associated with UGC in the CSL and supports a multi-factorial aetiology of this disease
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The human myeloproliferative disorders: molecular pathogenesis and clonal heterogeneity
No full textThe classical myeloproliferative disorders (MPD), comprising essential thrombocythaemia (ET), polycythaemia vera (PV) and idiopathic myelofibrosis (IMF), are clonal premalignant haematopoietic neoplasms associated with activating mutations in signalling pathway molecules and a variable tendency to develop acute myeloid leukaemia (AML). This thesis examined genotype-phenotype associations of JAK2 and MPL mutations, the presence of clonal diversity in the MPD and the genetic events associated with progressive disease.
Mutations in MPL were identified in 4% of ET and 7% of IMF but not in PV. Three different acquired MPL mutations were identified, one of which had been reported as an inherited allele. Although MPL mutations did not delineate a distinct clinical or histopathological subtype of ET, molecular testing provides an important new tool in the diagnostic armamentarium. Clones homozygous for the JAK2 V617F mutation were identified in female but not male patients with ET, suggesting that gender differences may be important in the determination of disease phenotype. In patients with two acquired genetic alterations, a signalling pathway mutation and a cytogenetic abnormality were usually present within the same clone. By contrast, coexistence of two signalling pathway mutations indicated the presence of biclonal disease that in two patients had arisen independently and not from a shared founder clone.
RAS mutations were identified as potential cooperating events in patients with JAK2 or MPL mutant IMF. In patients developing AML following a JAK2 V617F-positive MPD, those with V617F-positive leukaemia had progressed via an accelerated phase of disease and harboured acquired alterations of RUNX1 or EVI1. V617F-negative leukaemias tended to follow directly from ET or PV, and loss of the JAK2 mutation by reversion to wild-type due to mitotic recombination, gene deletion or gene conversion was excluded. The thesis concludes with a discussion of how clonal heterogeneity can be integrated into current models of MPD disease pathogenesis
The role of cervical spine range of motion in recovery from whiplash associated disorders
No full textThis thesis investigates the role of cervical spine Range of Motion in the recovery from
Whiplash Associated Disorders.
In clinical practice, Health Care Professionals attach value to measurements of cervical spine
Range of Motion for diagnostic, prognostic and treatment evaluation purposes. A systematic
literature review found conflicting evidence as to whether cervical spine Range of Motion
was a prognostic factor following a whiplash injury. Greater understanding of prognostic
factors such as this may facilitate improvements in patient management.
A second systematic literature review investigated the reliability and validity of methods for
measuring cervical spine Range of Motion. The Cervical Range Of Motion (CROM) device
was found to be the most rigorously tested and clinimetrically promising method and was
subsequently investigated for intra- and inter-observer reliability in a group of whiplashinjured
individuals and found to be substantially reliable.
The CROM device was utilised in a longitudinal cohort study of 599 whiplash-injured
patients to investigate the prognostic value of cervical spine Range of Motion for neck painrelated
disability and patient-reported recovery at short, medium and long-term follow-up. A
patient-reported version of cervical spine Range of Motion was also evaluated as a
prognostic factor.
Although useful for explaining disability at the time of measurement, active, passive and
patient-reported forms of cervical spine Range of Motion were not significant prognostic
factors for poor outcome when other physical and psychosocial factors were accounted for.
The clinical implication of this research is that if patients are experiencing reduced cervical
spine Range of Motion a few weeks after their whiplash injury they will not necessarily have
a poor outcome in the longer term as is commonly believed at present
Vibration as an exercise modality: how it may work, and what its potential might be
No full textWhilst exposure to vibration is traditionally
regarded as perilous, recent research has focussed on
potential benefits. Here, the physical principles of forced
oscillations are discussed in relation to vibration as an
exercise modality. Acute physiological responses to isolated
tendon and muscle vibration and to whole body
vibration exercise are reviewed, as well as the training
effects upon the musculature, bone mineral density and
posture. Possible applications in sports and medicine are
discussed. Evidence suggests that acute vibration exercise
seems to elicit a specific warm-up effect, and that vibration
training seems to improve muscle power, although the
potential benefits over traditional forms of resistive exercise
are still unclear. Vibration training also seems to
improve balance in sub-populations prone to fall, such as
frail elderly people. Moreover, literature suggests that
vibration is beneficial to reduce chronic lower back pain
and other types of pain. Other future indications are
perceivable
The Transcriptomic and Genomic Analysis of Lamin A/C Expression in the Colon and in Colorectal Cancer
No full textLamins A and C, also known as A-type lamins, are type V nuclear intermediate filament proteins which form an interlacing meshwork of filaments subjacent to the inner nuclear membrane termed the nuclear lamina. A-type lamins have been implicated in DNA replication, gene transcription regulation, apoptosis, regulation of growth promoters and nuclear migration. Traditionally, expression of A-type lamins has been associated with differentiated cells. As such, mutations in A-type lamins have been associated with a diverse range of genetic diseases, including premature ageing syndromes and with increased proliferation, especially in tumours.
In colorectal cancer, expression of A-type lamins, have been shown to impart an adverse prognosis. In order to understand the underlying biological processes responsible for this adverse outcome in patients with colorectal cancer, I sought to clarify the expression profile of A-type lamins and their binding partners in normal colonic/rectal mucosa, prior to investigating the expression of A-type lamins in colorectal cancers. I used fresh tissue specimens obtained from patients with colorectal cancer for my experiments. A unique finding was the expression of lamin A in the putative stem cell niche of colonic / rectal mucosal crypts.
Further studies in the form of a microarray analysis, revealed a very complex picture of up regulation involving various signalling cascades in the cancer samples expressing A-type lamins. There was no evidence to suggest a direct involvement of A-type lamins influencing the Wnt signalling cascade, however, direct involvement of other signalling cascades, such as the IGF signalling cascade, Shh signalling cascade and TGF-β signalling cascades were noted. These signalling cascades were known to influence the Wnt signalling cascades and hence could play a crucial role in the pathogenesis of colorectal cancers expressing A-type lamins.
In addition to these important signalling cascades, other key genes involved in apoptosis, growth promoters, cell adhesion, stem cell regulation, oncogenes and tumour suppression, were noted to have a unique expression profile in the cancer sample expressing A-type lamins, not observed in the cancer sample lacking A-type lamin expression. These observations were suggestive of A-type lamins having a diverse range of actions via, as yet, undefined pathways. It would appear that A-type lamins were imparting a more motile, less adherent phenotype with stem cell like features in colorectal cancers expressing A-type lamins. This could explain the observed poor prognosis of patients with colorectal cancers expressing A-type lamins.
Creatine kinase brain (CKB), was also identified as an additional, potential, prognostic indicator in the Duke’s B group of patients with colorectal cancer expressing A-type lamins. This potential marker, in conjunction with A-type lamin expression could be used to identify a sub group of Duke’s B patients at high risk. Whether adjuvant therapy in this group would help improve their long term survival is unknown since no study has been done to assess this
