Cognate microRNA-Gene Regulatory Networks Mediating Glioblastoma Oncogenic Properties

Malignant gliomas, including the most common and fatal form glioblastoma (GBM, WHO grade IV astrocytoma), remain a challenge to treat. In the United States and Europe, more than 30,000 patients per year are newly diagnosed with GBM. Despite ongoing trials, the best currently available multimodal treatment approaches include surgical resection followed by concomitant and adjuvant radiation (RT) and temozolomide (TMZ) therapy, resulting in a low median overall survival (OS) rate ranging from 12.2 - 15.9 months. The important role of genetic and epigenetic changes in DNA, RNA, and protein alteration as well as epigenetic changes secondary to the tumor microenvironment and outside selection pressure (therapeutic interventions), are increasingly being recognized. In GBM treatment, the focus is shifting toward a more patient-centered (personalized) therapy. In this regard, in particular, microRNAs are being increasingly studied. MicroRNAs are non¬protein coding small RNAs that serve as negative gene regulators by binding to a specific sequence in the promoter region of a target gene, thus regulating gene expression. A single microRNA potentially targets hundreds of genes; thus, microRNAs and their cognate target genes have important roles as tumor suppressors and oncogenes as well as regulators of various cancer- specific cellular features, such as proliferation, apoptosis, invasion, and metastasis. The identification of distinct microRNA-gene regulatory networks in GBM patients can be expected to provide novel therapeutic insights by identifying candidate patients for targeted therapies. To this end, in this work we identified and validated clinically relevant and meaningful novel gene- microRNA regulatory networks that correlated with MR tumor phenotypes, histopathology, and patient survival and response rates to therapy. - Le traitement des gliomes malins, y compris sous leur forme la plus commune et meurtrière, le glioblastome (GBM, ou astrocytome de grade IV selon l'OMS), demeure à ce jour un défi. Aux États-Unis et en Europe, un nouveau diagnostic de GBM est prononcé dans plus de 30Ό00 cas par an. En dépit de tests en cours, les meilleures approches thérapeutiques combinées actuellement disponibles comprennent la résection chirurgicale de la tumeur, suivie d'une radiothérapie adjuvante ainsi que d'un traitement au temozolomide (RT/TMZ), thérapies dont résulte une médiane de survie globale basse (overall survival, OS), comprise entre 12.2 et 15.9 mois. On reconnaît de plus en plus le rôle majeur de l'ADN, de l'ARN et de l'altération des protéines ainsi que des modifications épigénétiques, secondaires par rapport au microenvironnement de la tumeur et à la pression de sélection extérieure (les interventions thérapeutiques). Dans le traitement du GBM, le centre d'intérêt se déplace vers une thérapie centrée sur le cas individuel du patient. Dans ce but, en particulier les microARN sont de plus en plus analysés. Les microARN sont de petits ARN non-codants (les protéines) qui servent de régulateurs négatifs de gènes en s'attachant à une séquence spécifique dans la région promotrice d'un gène-cible, régulant ainsi l'expression du gène. Un seul microARN cible potentiellement des centaines de gènes; on a ainsi découvert que les microARN et leurs gènes-cibles apparentés ont une fonction importante en tant que suppresseurs de tumeurs et d'oncogènes, ainsi que comme régulateurs de diverses caractéristiques cellulaires spécifiques du cancer, comme la prolifération, l'apoptose, l'invasion et la métastase. On peut s'attendre à ce que l'identification de réseaux microARN régulateurs de gènes, distincts selon les patients de GBM, fournisse une approche thérapeutique inédite par la détermination des patients susceptibles de réagir favorablement à des thérapies ciblées.

Fungal infection as a risk factor for HIV disease progression among patients with a CD4 count above 200/microl in the era of cART.

The identification of clinical risk factors for AIDS in patients with preserved immune function is of significant interest. We examined whether patients with fungal infection (FI) and CD4 cell count >or=200/microl were at higher risk of disease progression in the era of cART. 11,009 EuroSIDA patients were followed from their first CD4 cell count >or=200/microl after 1 January 1997 until progression to any non-azoles/amphotericin B susceptible (AAS) AIDS disease, last visit or death. Initiation of antimycotic therapy (AMT) was used as a marker of FI and was modelled as a time-updated covariate using Poisson regression. After adjustment for current CD4 cell count, HIV-RNA, starting cART and diagnosis of AAS-AIDS, AMT was significantly associated with an increased incidence of non-AAS-AIDS (IRR=1.55, 95% CI 1.17-2.06, p=0.0024). Despite low incidence of AIDS in the cART era, FI in patients with a CD4 cell count >or=200/microl is associated with a 55% higher risk of non-AAS-AIDS (95% confidence interval 1.17-2.06, p=0.0024). These data suggest that patients with FI are more immune compromized than would be expected from their CD4 cell count alone. FI can be used as a clinical marker for disease progression and indirect indicator for initiation/changing cART in settings where laboratory facilities are limited.

Naisia kansalaisuuden kynnyksellä

Ajankohtaista

Procès Bazaine : conseil de guerre de Trianon : compte rendu sténographique...

[Procès. Bazaine. 1873]

Procès Bazaine : conseil de guerre de Trianon : compte rendu sténographique...

[Procès. Bazaine. 1873]

Dialogeja kansalaisuuden keittiössä

Kirja-arvio

Determination of salivary glucose in healthy adults

Objectives: Our aim in this study was to determine the concentration of salivary glucose in healthy individuals and to compare it with the capillary glycemia. Study design: Samples of unstimulated whole saliva were collected from 63 non-diabetic patients. The concentration of salivary glucose and capillary blood was measured in all of the patients. The salivary glucose was determined by enzymatic method and spectrophotometry. The data was then analyzed using the Spearman correlation test, considering values of p<0.05 to be significant. Results: The whole sample consisted of 47.6% males and 52.4% women, with an average age of 37.5±15.7 years old. The average rates of unstimulated salivary flow were 0.41±0.21 ml/min among males and 0.31±0.15 ml/min among females. No significant difference was found based on these results (p=0.078). The average blood glucose among the males studied was 100.05±13.51 mg/dL, and among females, it was 99.5±13.9 mg/dL. The average salivary glucose for the whole sample was 5.97±1.87 mg/dL, with 5.91±2.19 mg/dL among males and 5.97±1.56 mg/dL among females, respectively, without presenting any significant differences (p=0.908). The concentration of salivary glucose did not present any statistically significant correlation with the capillary glycemia (p=0.732). Conclusions: The results suggest that the concentration of salivary glucose is not dependent on capillary glycemia and that the concentration of salivary glucose does not present significant differences between the measurements for males and females.

25-Hydroxyvitamin D in African-origin populations at varying latitudes challenges the construct of a physiologic norm.

BACKGROUND: The vitamin D-endocrine system is thought to play a role in physiologic processes that range from mineral metabolism to immune function. Serum 25-hydroxyvitamin D [25(OH)D] is the accepted biomarker for vitamin D status. Skin color is a key determinant of circulating 25(OH)D concentrations, and genes responsible for melanin content have been shown to be under strong evolutionary selection in populations living in temperate zones. Little is known about the effect of latitude on mean concentrations of 25(OH)D in dark-skinned populations. OBJECTIVE: The objective was to describe the distribution of 25(OH)D and its subcomponents in 5 population samples of African origin from the United States, Jamaica, Ghana, South Africa, and the Seychelles. DESIGN: Participants were drawn from the Modeling of the Epidemiologic Transition Study, a cross-sectional observational study in 2500 adults, ages 25-45 y, enrolled between January 2010 and December 2011. Five hundred participants, ∼50% of whom were female, were enrolled in each of 5 study sites: Chicago, IL (latitude: 41°N); Kingston, Jamaica (17°N); Kumasi, Ghana (6°N); Victoria, Seychelles (4°S); and Cape Town, South Africa (34°S). All participants had an ancestry primarily of African origin; participants from the Seychelles trace their history to East Africa. RESULTS: A negative correlation between 25(OH)D and distance from the equator was observed across population samples. The frequency distribution of 25(OH)D in Ghana was almost perfectly normal (Gaussian), with progressively lower means and increasing skewness observed at higher latitudes. CONCLUSIONS: It is widely assumed that lighter skin color in populations outside the tropics resulted from positive selection, driven in part by the relation between sun exposure, skin melanin content, and 25(OH)D production. Our findings show that robust compensatory mechanisms exist that create tolerance for wide variation in circulating concentrations of 25(OH)D across populations, suggesting a more complex evolutionary relation between skin color and the vitamin D pathway. This trial was registered at clinicaltrials.gov as NCT02111902.

Associative Issue Ownership as a Determinant of Voters' Campaign Attention

Campaigns raise public interest in politics and allow parties to convey their messages to voters. However, voters' exposure and attention during campaigns are biased towards parties and candidates they like. This hinders parties' ability to reach new voters. This paper theorises and empirically tests a simple way in which parties can break partisan selective attention: owning an issue. When parties own issues that are important for a voter, that voter is more likely to notice them. Using survey data collected prior to the 2009 Belgian regional elections it is shown that this effect exists independent of partisan preferences and while controlling for the absolute visibility of a party in the media. This indicates that issue ownership has an independent impact on voters' attention to campaigns. This finding shows that owning salient issues yields (potential) advantages for parties, since getting noticed is a prerequisite for conveying electoral messages and increasing electoral success.

Tien rakentajan ja kunnossapitäjän ympäristöriskit ja -vastuut moottoritien elinkaarihankkeessa

Diplomityössä on tarkasteltu moottoritien rakentajan ja kunnossapitäjän ympäristöriskejä ja -vastuita moottoritien elinkaarihankkeessa. Työssä esitellään malli ympäristöriskien analysoimiseksi. Mallin avulla tuotetun tiedon pohjalta yrityksessä on mahdollista päättää ympäristöriskien hallintastrategiasta. Työssä on tutustuttu keskeiseen ympäristölainsäädäntöön ja sen yrityksen ympäristövastuulle asettamiin vaatimuksiin. Imagotekijöitä on käsitelty osana ympäristövastuuseen liittyvää yrityskohtaista päätöksentekoa. Hankekohtainen ympäristöriskien tunnistaminen ja arviointi on tehty E18 Muurla – Lohja moottoritiehankkeen tarjouslaskentavaiheessa. Tarjousvaiheessa tehty riskianalyysi palvelee päätöksentekoa yrityksessä valittaessa ympäristöriskien hallintastrategiaa. Analyysillä tuotetun tiedon avulla voidaan ohjata suunnittelua, tarjouksen hinnoittelua ja tarjouksen liitteeksi tuotettavan ympäristömateriaalin sisältöä. Tien rakentamisen ja kunnossapidon aikana materiaalia voidaan edelleen hyödyntää ympäristöasioiden hallinnassa.

Do standard burn mortality formulae work on a population of severely burned children and adults?

Accurate prediction of mortality following burns is useful as an audit tool, and for providing treatment plan and resource allocation criteria. Common burn formulae (Ryan Score, Abbreviated Burn Severity Index (ABSI), classic and revised Baux) have not been compared with the standard Acute Physiology and Chronic Health Evaluation II (APACHEII) or re-validated in a severely (≥20% total burn surface area) burned population. Furthermore, the revised Baux (R-Baux) has been externally validated thoroughly only once and the pediatric Baux (P-Baux) has yet to be. Using 522 severely burned patients, we show that burn formulae (ABSI, Baux, revised Baux) outperform APACHEII among adults (AUROC increase p<0.001 adults; p>0.5 children). The Ryan Score performs well especially among the most at-risk populations (estimated mortality [90% CI] original versus current study: 33% [26-41%] versus 30.18% [24.25-36.86%] for Ryan Score 2; 87% [78-93%] versus 66.48% [51.31-78.87%] for Ryan Score 3). The R-Baux shows accurate discrimination (AUROC 0.908 [0.869-0.947]) and is well-calibrated. However, the ABSI and P-Baux, although showing high measures of discrimination (AUROC 0.826 [0.737-0.916] and 0.848 [0.758-0.938]) in children), exceedingly overestimates mortality, indicating poor calibration. We highlight challenges in designing and employing scores that are applicable to a wide range of populations.

Determinación de la glucosa salival en adultos sanos

Objetivos: Determinar la concentración de glucosa salival de individuos sanos y compararla con la glicemia capilar. Diseño del estudio: Se realizó una recolección de saliva total en reposo, en 63 individuos no diabéticos. Se midió la concentración de glucosa salival y sanguinea capilar en todos los individuos. La glucosa salival fue determinada por método enzimático y espectrofotometría. Los datos fueron analizados usando el test de correlación de Spearman, considerando significativos valores de p<0,05. Resultados: Del total de la muestra, 47,6% eran varones y 52,4% mujeres, con una media de edad de 37,5±15,7 años. Las medias del flujo salival en reposo fueron de 0,41±0,2l ml/min en el género masculino y de 0,31±0,15 ml/min en el género femenino. No hubo diferencia significativa (p=0,07S). La media de glucosa sanguínea entre los varones fue de l00,05± 13,51 mg/dL y de 99 ,5± 13,9 mg/dL en las mujeres. La media de glucosa salival en el total de la muestra fue de 5,97±1 ,87 mg/dL, siendo 5,91±2, 19m9/dL en los varones y 5,97±1 ,56mg/dL en las mujeres, sin presentarse diferencias significativas (p=0,908). La concentración de la glucosa salival no presentó correlación estadísticamente significativa con la glicemia capilar (p=0,732). Conclusiones: De los resultados se desprende que: la concentración de la glucosa salival no depende de la glicemia capilar; la concentración de la glucosa salival no presenta diferencias entre géneros