Characterization of Luteinizing hormone-releasing hormone (LH-RH-I) receptor type I as a potential molecular target in OCM-1 and OCM-3 human uveal melanoma cell lines

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Concurrence of chromosome 3 and 4 aberrations in human uveal melanoma

Uveal melanoma (UM) is the most common primary intraocular malignancy with a very poor prognosis. The most frequent chromosome aberration in UM is the monosomy of chromosome 3. Previously, we demonstrated that ~50% of UMs express type-I receptor for luteinizing hormone-releasing hormone (LH-RH-R). The gene encoding LH-RH-R is located in chromosome 4 (location: 4q21.2); however, the occurrence of numerical aberrations of chromosome 4 have never been studied in UM. In the present study, we investigated the abnormalities of chromosome 3 and 4, and the possible correlation between them, as well as with LH-RH-R expression. Forty-six specimens of UM were obtained after enucleation. Numerical aberrations of chromosome 3 and 4 were studied by fluorescence in situ hybridization (FISH). Chromosome 4 was detected in normal biparental disomy only in 14 (30%) samples; however, 32 cases (70%) showed more than 2 signals/nucleus. Monosomy of chromosome 3 could be found in 16 (35%) samples. In 6 specimens (13%), more than 2 copies of chromosome 3 were found, while normal biparental disomy was detected in 24 (52%) samples. Statistical analysis indicated a statistically significant (p<0.05) correlation between the copy number of chromosome 3 and 4. Moreover, moderate difference was revealed in the survival rate of the UM patients with various pathological profiles. No correlation was found between chromosome aberrations and LH-RH-R expression. Our results clearly demonstrate abnormalities in chromosome 3 and 4 and the incidence of the monosomy of chromosome 3 in human UM. In summary, our results provide new incite concerning the genetic background of this tumor. Our findings could contribute to a more precise determination of the prognosis of human UM and to the development of new therapeutic approaches to this malignancy

The targeted LHRH analog AEZS-108 alters expression of genes related to angiogenesis and development of metastasis in uveal melanoma

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Neuroinflammation in depression

Nieuw bewijs dat neuro-inflammatie theorie voor depressie klopt De neuro-inflammatie theorie, die ervan uitgaat dat depressie een gevolg is van een ontstekingsreactie in de hersenen, klopt waarschijnlijk. Dat concludeert Niki Dobos in haar promotieonderzoek, dat ze uitvoerde met behulp van een muismodel. De resultaten kunnen mogelijk helpen om een nieuwe behandeling te ontwikkelen tegen depressie. Wanneer ons immuunsysteem wordt geactiveerd, ofwel in het lichaam zelf of in het centrale zenuwstelsel, reageert het lichaam daarop met een ontstekingsreactie. Wetenschappers vermoedden al langer dat de productie van cytokines (ontstekingsfactoren) en activatie van de kynurenine-route (betrokken bij fysiologische functies zoals gedrag en slaap) betrokken zijn bij het ontstaan van depressie. Niki Dobos testte deze hypothese in muizen. Dobos ontdekte dat het door een ontstekingsreactie veroorzaakte depressieve gedrag van de muizen afhankelijk was van de activatie van het ‘ontstekingsenzym’ Indoleamine 2,3-dioxygenase (IDO). Het depressieve gedrag van de muizen kon worden onderdrukt met een remmer van IDO. Deze resultaten bevestigen dat de neuro-inflammatie theorie van depressie waarschijnlijk klopt, en geven sterke aanwijzingen voor de betrokkenheid van de kynurenine-route en de activatie van IDO. De inzichten zouden de basis kunnen vormen voor een nieuwe, op IDO-remmers gebaseerde benadering van therapie tegen depressie. Major depression (MD) is a devastating disease with a high lifetime prevalence worldwide. There have been several hypotheses proposed for MD, however, to date, none of them can meet all criteria to explain the pathogenesis of the disorder. Among others, neuroinflammation has been pointed out to be a key component of depression; therefore the rationale of the present thesis was to investigate the role of neuroinflammation in depression. Immune activation, either in the periphery or in the central nervous system generates an inflammatory cascade, which might be responsible for altered brain functioning and behavioral changes. Inflammation-induced cytokine production and subsequent activation of the kynurenine pathway has been implicated in the pathophysiology of depression. Along the kynurenine pathway, tryptophan is metabolized and several neuroactive compounds are produced. The reduction of tryptophan levels may lead to serotonin depletion, which is believed to be one of the main causes of MD. Moreover, neurotoxic metabolites can further contribute to excitotoxicity and immune activation. The first and rate-limiting step of the kynurenine pathway is mediated by indoleamine 2,3 dioxygenase (IDO). We could demonstrate that neuroinflammation-induced depressive-like behavior is dependent on the activation of IDO what we could further confirm using a competitive IDO-inhibitor. In the present thesis, novel findings support the neuroinflammatory theory of depression and evidence are provided for the involvement of the kynurenine pathway and the upregulation of IDO in major depression. The results presented here can contribute to open a new avenue in novel antidepressant therapies.

STRESS INDUCES EQUIVALENT REMODELING OF HIPPOCAMPAL SPINE SYNAPSES IN A SIMULATED POSTPARTUM ENVIRONMENT AND IN A FEMALE RAT MODEL OF MAJOR DEPRESSION

Stress and withdrawal of female reproductive hormones are known risk factors of postpartum depression. Although both of these factors are capable of powerfully modulating neuronal plasticity, there is no direct electron microscopic evidence of hippocampal spine synapse remodeling in postpartum depression. To address this issue, hormonal conditions of pregnancy and postpartum period were simulated in ovariectomized adult female Sprague Dawley rats (n = 76). The number of hippocampal spine synapses and the depressive behavior of rats in an active escape task were investigated in untreated control, hormone-withdrawn 'postpartum', simulated proestrus, and hormone-treated 'postpartum' animals. After 'postpartum' withdrawal of gonadal steroids, inescapable stress caused a loss of hippocampal spine synapses, which was related to poor escape performance in hormone-withdrawn 'postpartum' females. These responses were equivalent with the changes observed in untreated controls that is an established animal model of major depression. Maintaining proestrus levels of ovarian hormones during 'postpartum' stress exposure did not affect synaptic and behavioral responses to inescapable stress in simulated proestrus animals. By contrast, maintaining pregnancy levels of estradiol and progesterone during 'postpartum' stress exposure completely prevented the stress-induced loss of hippocampal spine synapses, which was associated with improved escape performance in hormone-treated 'postpartum' females. This protective effect appears to be mediated by a muted stress response as measured by serum corticosterone concentrations. In line with our emerging 'synaptogenic hypothesis' of depression, the loss of hippocampal spine synapses may be a novel perspective both in the pathomechanism and in the clinical management of postpartum affective illness. (C) 2016 IBRO. Published by Elsevier Ltd. All rights reserved