52 research outputs found
Endpoints in pediatric pain studies
Assessing pain intensity in (preverbal) children is more difficult than in adults. Tools to measure pain are being used as primary endpoints [e.g., pain intensity, time to first (rescue) analgesia, total analgesic consumption, adverse effects, and long-term effects] in studies on the effects of analgesic drugs. Here, we review current and promising new endpoints used in pediatric pain assessment studies
Impact of Circulating Cholesterol Levels on Growth and Intratumoral Androgen Concentration of Prostate Tumors
Prostate cancer (PCa) is the second most common cancer in men. Androgen deprivation therapy (ADT) leads to tumor involution and reduction of tumor burden. However, tumors eventually reemerge that have overcome the absence of gonadal androgens, termed castration resistant PCa (CRPC). Theories underlying the development of CRPC include androgen receptor (AR) mutation allowing for promiscuous activation by non-androgens, AR amplification and overexpression leading to hypersensitivity to low androgen levels, and/or tumoral uptake and conversion of adrenally derived androgens. More recently it has been proposed that prostate tumor cells synthesize their own androgens through de novo steroidogenesis, which involves the step-wise synthesis of androgens from cholesterol. Using the in vivo LNCaP PCa xenograft model, previous data from our group demonstrated that a hypercholesterolemia diet potentiates prostatic tumor growth via induction of angiogenesis. Using this same model we now demonstrate that circulating cholesterol levels are significantly associated with tumor size (R = 0.3957, p = 0.0049) and intratumoral levels of testosterone (R = 0.41, p = 0.0023) in LNCaP tumors grown in hormonally intact mice. We demonstrate tumoral expression of cholesterol uptake genes as well as the spectrum of steroidogenic enzymes necessary for androgen biosynthesis from cholesterol. Moreover, we show that circulating cholesterol levels are directly correlated with tumoral expression of CYP17A, the critical enzyme required for de novo synthesis of androgens from cholesterol (R = 0.4073, p = 0.025) Since hypercholesterolemia does not raise circulating androgen levels and the adrenal gland of the mouse synthesizes minimal androgens, this study provides evidence that hypercholesterolemia increases intratumoral de novo steroidogenesis. Our results are consistent with the hypothesis that cholesterol-fueled intratumoral androgen synthesis may accelerate the growth of prostate tumors, and suggest that treatment of CRPC may be optimized by inclusion of cholesterol reduction therapies in conjunction with therapies targeting androgen synthesis and the AR
Murine Cytomegalovirus Infection of Neural Stem Cells Alters Neurogenesis in the Developing Brain
Congenital cytomegalovirus (CMV) brain infection causes serious neuro-developmental sequelae including: mental retardation, cerebral palsy, and sensorineural hearing loss. But, the mechanisms of injury and pathogenesis to the fetal brain are not completely understood. The present study addresses potential pathogenic mechanisms by which this virus injures the CNS using a neonatal mouse model that mirrors congenital brain infection. This investigation focused on, analysis of cell types infected with mouse cytomegalovirus (MCMV) and the pattern of injury to the developing brain.We used our MCMV infection model and a multi-color flow cytometry approach to quantify the effect of viral infection on the developing brain, identifying specific target cells and the consequent effect on neurogenesis. In this study, we show that neural stem cells (NSCs) and neuronal precursor cells are the principal target cells for MCMV in the developing brain. In addition, viral infection was demonstrated to cause a loss of NSCs expressing CD133 and nestin. We also showed that infection of neonates leads to subsequent abnormal brain development as indicated by loss of CD24(hi) cells that incorporated BrdU. This neonatal brain infection was also associated with altered expression of Oct4, a multipotency marker; as well as down regulation of the neurotrophins BDNF and NT3, which are essential to regulate the birth and differentiation of neurons during normal brain development. Finally, we report decreased expression of doublecortin, a marker to identify young neurons, following viral brain infection.MCMV brain infection of newborn mice causes significant loss of NSCs, decreased proliferation of neuronal precursor cells, and marked loss of young neurons
Effects of temperature in juvenile seabass (Dicentrarchus labrax L.) biomarker responses and behaviour: implications for environmental monitoring
The effects of temperature on European seabass
(Dicentrarchus labrax L.) juveniles were investigated using
a 30-day bioassay carried out at 18 and 25 °C in laboratory
conditions. A multiparameter approach was applied including
fish swimming velocity and several biochemical parameters
involved in important physiological functions. Fish exposed for
four weeks to 25 °C showed a decreased swimming capacity,
concomitant with increased oxidative stress (increased catalase
and glutathione peroxidase activities) and damage (increased
lipid peroxidation levels), increased activity of an enzyme
involved in energy production through the aerobic pathway
(isocitrate dehydrogenase) and increased activities of brain and
muscle cholinesterases (neurotransmission) compared to fish
kept at 18 °C. Globally, these findings indicate that basic
functions, essential for juvenile seabass surviving and well
performing in the wild, such as predation, predator avoidance,
neurofunction and ability to face chemical stress may be compromised
with increasing water temperature. This may be of
particular concern if D. labrax recruitment phase in northwest
European estuaries and coastal areas happens gradually inmore
warm environments as a consequence of global warming.
Considering that the selected endpoints are generally applied
in monitoring studies with different species, these findings also
highlight the need of more research, including interdisciplinary
and multiparameter approaches, on the impacts of temperature
on marine species, and stress the importance of considering
scenarios of temperature increase in environmental monitoring
and in marine ecological risk assessment
Epithelial mesenchymal transition during development in fibrosis and in the progression of carcinoma
10.1684/bdc.2010.1206Bulletin du Cancer97111285-1295BUCA
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