Molecular medicine has fully entered in to the oncology arena. The development of targeted therapies is one of the major ongoing efforts in cancer treatment. Targeted therapy refers to treatment ...strategies directed against molecular targets considered to be involved in neoplastic transformation. Such molecularly targeted agents (MTA) are currently under study in all treatment settings including that of chemoprevention, defined as the use of natural or synthetic agents to interrupt the carcinogenic process, to nip tumours in the bud. This review article aims to provide a general overview of the potential use of some of these MTA in the chemoprevention setting.
Among the diverse mechanisms involved in the pathophysiology of post-ischemic and post-traumatic injuries, excitotoxicity and nuclear factor-κB (NF-κB) activation through induction of IκB kinase ...(IKK) complex have a primary role. We investigated the effects of the selective inhibitor of the IKK2 subunit, the anilinopyrimidine derivative AS602868, on excitotoxic injury produced in rat organotypic hippocampal slices and cerebellar primary neurons. Brief exposure to
N
-methyl-
d
-aspartate (NMDA) induces astrocyte reactivity, neuron cell death and oligodendrocyte degeneration in hippocampal slices. Application of AS602868 elicited a long-lasting protection of both neurons and oligodendrocytes. Maximal effect was observed with prolonged application of the compound after NMDA exposure. Neuroprotection was also evident in primary cultures of cerebellar granule cells starting from 20 nM concentration. AS602868-elicited neuroprotection correlated with inhibition of NF-κB activity. Our results suggest that AS602868 may prove to be a valuable approach in treating neurodegeneration and demyelination associated with cerebral trauma and ischemia.
Nerve growth factor (NGF) is well characterized for its neurotrophic actions on peripheral sensory and sympathetic neurons and on central cholinergic neurons of the basal forebrain. Recent evidence, ...however, has shown high levels of NGF to be present in a variety of biological fluids after inflammatory and autoimmune responses, suggesting that NGF is a mediator of immune interactions. Increased NGF serum levels have been reported in both humans and experimental animal models of psychological and physical stress, thus implicating NGF in neuroendocrine interactions as well. The possible source(s) and the regulatory mechanisms involved in the control of serum NGF levels, however, still remain to be elucidated. We now report the presence of both NGF gene transcripts and protein in the anterior pituitary. Immunofluorescence analysis indicated that hypophysial NGF is selectively localized in mammotroph cells and stored in secretory granules. NGF is cosecreted with prolactin from mammotroph cells by a neurotransmitter-dependent mechanism that can be pharmacologically regulated. Activation of the dopamine D2 receptor subtype, which physiologically controls prolactin release, resulted in a complete inhibition of vasoactive intestinal peptide-stimulated NGF secretion in vitro, whereas the specific D2 antagonist (--)-sulpiride stimulated NGF secretion in vivo, suggesting that the anterior pituitary is a possible source of circulating NGF. Given the increased NGF serum levels in stressful conditions and the newly recognized immunoregulatory function of this protein, NGF, together with prolactin, may thus be envisaged as an immunological alerting signal under neuronal control.
Résumé
L’immunodépression, qu’elle soit innée ou acquise, notamment chez les patients transplantés ou en cas d’infection par le VIH, est associée à une augmentation de l’incidence de nombreux ...cancers, responsable d’une importante morbidité et mortalité dans ces populations. L’épidémiologie et la présentation clinique de ces cancers sont différentes de celles de la population générale, avec un rôle important d’agents infectieux dans l’oncogenèse, favorisé par ces situations d’immunodépression, et un diagnostic parfois plus tardif, une pathologie plus agressive et un pronostic souvent plus péjoratif. En l’absence de recommandations précises sur le plan thérapeutique, l’attention doit être portée sur les comorbidités et les interactions médicamenteuses potentielles, en particulier via le cytochrome P450, nécessitant le recours à une prise en charge multidisciplinaire avec une réunion de concertation comme celle du groupe CANCERVIH en France. L’objectif de cette revue est de présenter une actualité scientifique concernant l’épidémiologie des cancers associés à l’immunodépression, les causes potentielles et la spécificité de leur prise en charge.
Abstract Reelin (RELN) is a key molecule for the regulation of neuronal migration in the developing CNS. The reeler mice, which have spontaneous autosomal recessive mutation in the RELN gene, reveal ...multiple defects in brain development. Morphological, neurochemical and behavioral alterations have been detected in heterozygous reeler (HR) mice, suggesting that not only the presence, but also the level of RELN influences brain development. Several studies implicate an involvement of RELN in the pathophysiology of neuropsychiatric disorders in which an alteration of the cholinergic cortical pathways is implicated as well. Thus, we decided to investigate whether the basal forebrain (BF) cholinergic system is altered in HR mice by examining cholinergic markers at the level of both cell body and nerve terminals. In septal and rostral, but not caudal, basal forebrain region, HR mice exhibited a significant reduction in the number of choline acetyltransferase (ChAT) immunoreactive (ir) cell bodies compared with control mice. Instead, an increase in ChAT ir neurons was detected in lateral striatum. This suggests that an alteration in ChAT ir cell migration which leads to a redistribution of cholinergic neurons in subcortical forebrain regions occurs in HR mice. The reduction of ChAT ir neurons in the BF was paralleled by an alteration of cortical cholinergic nerve terminals. In particular, the HR mice presented a marked reduction of acetylcholinesterase (AChE) staining accompanied by a small reduction of cortical thickness in the rostral dorsomedial cortex, while the density of AChE staining was not altered in the lateral and ventral cortices. Present results show that the cholinergic basalo-cortical system is markedly, though selectively, impaired in HR mice. Rostral sub-regions of the BF and rostro-medial cortical areas show significant decreases of cholinergic neurons and innervation, respectively.
Dementia with Lewy bodies is a common form of dementia in the elderly, characterised clinically by fluctuating cognitive impairment, attention deficits, visual hallucinations, parkinsonism, and other ...neuropsychiatric features. Neuroleptic medication can provoke severe sensitivity reactions in patients with dementia of this type. Many deficits in cholinergic neurotransmission are seen in the brain of patients with Lewy-body dementia; therefore, drugs enhancing central cholinergic function represent a rationally-based therapeutic approach to this disorder. Rivastigmine, a cholinesterase inhibitor, was tested in a group of clinically characterised patients with Lewy-body dementia.
A placebo-controlled, double-blind, multicentre study was done in 120 patients with Lewy-body dementia from the UK, Spain, and Italy. Individuals were given up to 12 mg rivastigmine daily or placebo for 20 weeks, followed by 3 weeks rest. Assessment by means of the neuropsychiatric inventory was made at baseline, and again at weeks 12, 20, and 23. A computerised cognitive assessment system and neuropsychological tests were also used, and patients underwent close medical and laboratory safety analysis.
Patients taking rivastigmine were significantly less apathetic and anxious, and had fewer delusions and hallucinations while on treatment than controls. Almost twice as many patients on rivastigmine (37, 63%), than on placebo (18, 30%), showed at least a 30% improvement from baseline. In the computerised cognitive assessment system and the neuropsychological tests, patients were significantly faster and better than those on placebo, particularly on tasks with a substantial attentional component. Both predefined primary efficacy measures differed significantly between rivastigmine and placebo. After drug discontinuation differences between rivastigmine and placebo tended to disappear. Known adverse events of cholinesterase inhibitors (nausea, vomiting, anorexia) were seen more frequently with rivastigmine than with placebo, but safety and tolerability of the drug in these mostly multimorbid patients were judged acceptable.
Rivastigmine 6–12 mg daily produces statistically and clinically significant behavioural effects in patients with Lewy-body dementia, and seems safe and well tolerated if titrated individually.
Recent studies suggested substantial differences between primary tumors and metastases for EGFR expression in colorectal cancer (CRC). The aim of the study was to correlate the expression of a panel ...of molecular markers between primary CRC samples and metastases.
Expressions of EGFR, pEGFR, VEGF, pVEGF, PTEN, pAKT and p21 were analyzed in 28 primary tumors and 32 liver metastases by immunohistochemistry performed on formalin-fixed, paraffin-embedded sections from 46 CRC patients. The molecular profiles were evaluated by tissue micro-array. The correlation between tumor and metastasis biomarker expressions was tested.
Among 60 CRC samples, 25% were EGFR positive, 38% were pEGFR positive, 38% were VEGF positive, 48% were pVEGF positive, 70% were pAKT positive and 51% were p21 positive. PTEN was deleted in 39% of cases and absence of p21 expression was found in 49% of cases. A significant correlation was observed between primary tumors and metastases for pAKT (p = 0.037) and pEGFR (p = 0.0002) status. In patients treated with cetuximab-based therapy (n = 18), p21 appeared as a significant predictive factor of response (p = 0.036).
Biomarkers status may change between primary and metastatic sites in CRC, with potential implications for the identification of patients who are likely to respond to anti-EGFR treatment.
Here we report three experimental paradigms in which tau proteins are differentially localized and expressed in human neuroblastoma cells SH-SY5Y. We found that in undifferentiated cells, tau ...proteins were predominantly localized in the nucleus. Western blot analysis of nuclear extracts revealed, among the others, a high molecular weight tau isoform and evaluation of tau mRNA levels showed a single tau isoform. After differentiation, tau immunoreactivity was detected only in cytosol and along neuritic processes. The high molecular weight tau isoform disappeared and an additional tau mRNA species was detected. Treatment of differentiated cells with doxorubicin or okadaic acid resulted in an increase of tau immunoreactivity and in a subsequent cell loss. Our results indicate that both subcellular localization and pattern of expression of tau proteins vary depending on the developmental and functional state of the cells, thus suggesting different roles in cell function.
A role of nerve growth factor (NGF) in the neuro-endocrine-immune interactions has been recently suggested by the presence of NGF and its receptors in cells of the immune and endocrine systems. The ...improvement in the comprehension of the role played by NGF in humans is linked to the availability of a sensitive and reliable method to quantify NGF concentrations in body fluids and tissues. As a consequence of different methods used, normal levels of human serum NGF reported in the literature show wide differences. The present results indicate that ELISA appears very sensitive (detection limit 1.4
pg/ml) and allows the discrimination of subtle variations of serum NGF concentrations. ELISA performed in serum obtained from men indicated that NGF concentration was 40.8±10.8
pg/ml, whereas women showed significantly lower levels that were influenced by the menstrual cycle. In particular, the mean value of this neurotrophin during the follicular phase was 8.2±1.4
pg/ml; the luteal phase, in turn, showed levels up to 14.4±2.9
pg/ml. The difference of serum NGF concentrations between the follicular and luteal phase in each woman was statistically significant. Differences in NGF concentrations between men and women (in both phases of the menstrual cycles) were also statistically significant. In conclusion, a possible role of sex steroids as modulators of NGF secretion in humans is strongly supported by the present paper. However, mechanisms underlying this phenomenon are still unknown. The evidence indicating physiological sex hormone-related variations in NGF levels would be of interest in view of the possible use of circulating NGF modifications as a laboratory biomarker in different diseases.
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