No abstract

miRNAs are considered promising non-invasive biomarkers. Serum represents the major source of biomarkers, being readily accessible for many analytical tests. Recently, whole blood has drawn increasing interest in biomarker studies due to the presence of cancer-interacting cells and circulating cancer cells. Although Hepatocellular Carcinoma (HCC) is the seventh most frequent cancer worldwide, fragmented information exists regarding the miRNome characterization in blood and serum. We profiled the circulatory miRNome of paired serum and blood samples from 20 HCC patients, identifying 274 miRNA expressed in serum and 670 in blood, most of them still uncharacterized. 157 miRNA significantly differ between the two biofluids with 28 exclusively expressed in serum. Six miRNA clusters significantly characterize the two compartments, with the cluster containing miR-4484, miR-1281, miR-3178, miR-3613-3p, miR-4532, miR-4668-5p, miR-1825, miR-4487, miR-455-3p, miR-940 having the highest average expression in serum compared to blood. The ontological analysis revealed a role of these miRNAs in cancer progression, vascular invasion and cancer immune surveillance thought the regulation of DUSP1, PD-L1 and MUC1. Taken together, these results provide the most comprehensive contribution to date towards a complete miRNome profile of blood and serum for HCC patients. We show a consistent portion of circulatory miRNAs being still unknown.

We report gene profiling data on genomic processes underlying the progression towards recurrent seizures after injection of kainic acid (KA) into the mouse hippocampus. Focal injection enabled us to separate the effects of proepileptic stimuli initiated by KA injection. Both the injected and contralateral hippocampus participated in the status epilepticus. However, neuronal death induced by KA treatment was restricted to the injected hippocampus, although there was some contralateral axonal degeneration. We profiled gene expression changes in dorsal and ventral regions of both the injected and contralateral hippocampus. Changes were detected in the expression of 1526 transcripts in samples from three time-points: (i) during the KA-induced status epilepticus, (ii) at 2 weeks, before recurrent seizures emerged, and (iii) at 6 months after seizures emerged. Grouping genes with similar spatio-temporal changes revealed an early transcriptional response, strong immune, cell death and growth responses at 2 weeks and an activation of immune and extracellular matrix genes persisting at 6 months. Immunostaining for proteins coded by genes identified from array studies provided evidence for gliogenesis and suggested that the proteoglycan biglycan is synthesized by astrocytes and contributes to a glial scar. Gene changes at 6 months after KA injection were largely restricted to tissue from the injection site. This suggests that either recurrent seizures might depend on maintained processes including immune responses and changes in extracellular matrix proteins near the injection site or alternatively might result from processes, such as growth, distant from the injection site and terminated while seizures are maintained.

Mutations in PARK7/DJ-1 are associated with autosomal recessive, early onset Parkinson disease (PD). DJ-1 is an atypical peroxiredoxin-like peroxidase that may act as a redox-dependent chaperone and a regulator of transcription. Here we show that DJ-1 plays an essential role in the expression of rearranged during transfection (RET), a receptor for the glial cell line-derived neurotrophic factor, a neuroprotective molecule for dopaminergic neurons, the main target of degeneration in PD. The inducible loss of DJ-1 triggers the establishment of hypoxia and the production of reactive oxygen species that stabilize the hypoxia-inducible factor-1␣ (HIF-1a). HIF-1a expression is required for RET down-regulation. This study establishes for the first time a molecular link between the lack of functional DJ-1 and the glial cell line-derived neurotrophic factor signaling pathway that may explain the adult-onset loss of dopaminergic neurons. Furthermore, it suggests that hypoxia may play an important role in PD. Parkinson disease (PD)2 is a progressive neurodegenerative disorder characterized by tremor, akinesia/bradykinesia, and rigidity. Its neuropathological hallmark is the selective degeneration of mesencephalic DA neurons in the substantia nigra that leads to the decrease of dopamine at their synapses in the striatum (1). Although the etiology of sporadic PD remains poorly understood and therapeutic treatments are only symptomatic, the analysis of post mortem brains (2) showed many biochemical and cellular changes including evidences of oxidative stress with an alteration of the intracellular redox equilibrium.The identification of genetic loci (PARK1-14) and the molecular cloning of some of the genes linked to rare forms of familial PD have provided crucial insights into the mechanism of the pathogenesis (3). Autosomal recessive early onset PD has been associated to mutations in PARK7/DJ-1 (4). These patients present large homozygous genomic deletions as well as truncating, splice-site, and frame shifts mutations. In human post mortem brains of sporadic PD patients, DJ-1 protein is irreversibly oxidized and, thus, inactivated (5, 6). Free radicals predominantly modify DJ-1 on the cysteine residue at position 106 (Cys-106) causing a shift in the isoelectric point (pI) from 6.2 to 5.8. This modification is also observed in PD animal models and in aged flies and mice (7).DJ-1 encodes for a highly conserved, ubiquitously expressed protein involved in multiple cellular processes including sperm maturation, fertilization, and oncogenesis. It may act as an atypical peroxiredoxin-like peroxidase, a redox-dependent chaperone, and a regulator of transcription and RNA metabolism (3).To study the effects of the lack of a functional gene, DJ-1 knock-out (KO) mice and flies were generated. Although they did not show death of DA neurons, increased vulnerabilities to neurotoxic agents were observed (8 -13). Furthermore, embryonic stem cells deficient for DJ-1 expression and DA neurons derived from KO mice displayed increased sensitivit...