We provide microarray data comparing genome-wide differential expression and pathology throughout life in four lines of "amyloid" transgenic mice (mutant human APP, PSEN1, or APP/PSEN1) and "TAU" transgenic mice (mutant human MAPT gene). Microarray data were validated by qPCR and by comparison to human studies, including genome-wide association study (GWAS) hits. Immune gene expression correlated tightly with plaques whereas synaptic genes correlated negatively with neurofibrillary tangles. Network analysis of immune gene modules revealed six hub genes in hippocampus of amyloid mice, four in common with cortex. The hippocampal network in TAU mice was similar except that Trem2 had hub status only in amyloid mice. The cortical network of TAU mice was entirely different with more hub genes and few in common with the other networks, suggesting reasons for specificity of cortical dysfunction in FTDP17. This Resource opens up many areas for investigation. All data are available and searchable at http://www.mouseac.org.
Mesial temporal lobe epilepsy with hippocampal sclerosis (mTLE+HS) represents the most common epilepsy syndrome in adult patients with medically intractable partial epilepsy. mTLE is usually regarded as a polygenic and complex disorder, still poorly understood but probably caused and perpetuated by dysregulation of numerous biological networks and cellular functions. The study of gene expression changes by SNPs in regulatory elements (eQTLs) has been shown to be a powerful complementary approach to the detection and understanding of risk loci by genome-wide association studies (GWAS). We have performed a whole (gene and exon-level) transcriptome analysis on cortical tissue samples (Brodmann areas 20 and 21) from 86 patients with mTLE+HS and 75 neurologically healthy controls. Genome-wide genotyping data from the same individuals (patients and controls) were analysed and paired with the transcriptome data. We report potential epilepsy-risk eQTLs, some of which are specific to tissue from patients with mTLE+HS. We also found large transcriptional and splicing deregulation in mTLE+HS tissue as well as gene networks involving neuronal and glial mechanisms that provide new insights into the cause and maintenance of the seizures. These data (available via the "Seizubraineac" web-tool resource, www.seizubraineac.org) will facilitate the identification of new therapeutic targets and biomarkers as well as genetic risk variants that could influence epilepsy and pharmacoresistance.
About 95 %o fp eopled iagnosed with glioblastoma die within five years. Glioblastoma is the mosta ggressivec entraln ervous systemt umour.I ti sn ecessary to make progress in the glioblastoma treatments ot hat advanced chemotherapy drugs or radiationt herapy or,i deally,t wo-in-one hybrid systems should be implemented.T yrosine kinase receptors-inhibitors and boron neutron capture therapy (BNCT), together,c ould provide at herapeutic strategy. In this work,s unitinibdecorated-carborane hybrids were prepared and biologically evaluatedi dentifying excellent antitumoral-and BNCT-agents. One of the selected hybrids was studieda gainst glioma-cells and found to be 4times more cytotoxic than sunitinib and 1.7 times more effectivet han 10 B-boronophenylalanine fructose complex when the cells were irradiated with neutrons.
We propose that these methods could be suitable for designing new screening protocols applied before melanoma BNCT treatment for each individual patient and lesion.
Radiotherapy is one of the leading treatments for clinical cancer therapy. External beam radiotherapy has been proposed as an adjuvant treatment for patients bearing differentiated thyroid cancer refractory to conventional therapy. Our purpose was to study the combined effect of HDAC inhibitors (HDACi) and ionizing irradiation in thyroid cancer cell lines (Nthy-ori 3-1, WRO, TPC-1 and 8505c). HDACi radiosensitized thyroid cancer cells as evidenced by the reduction of survival fraction, whereas they had no effect in the normal cells. HDACi enhanced radiation-induced cell death in WRO cells. Gamma-H2AX foci number increased and persisted long after ionizing exposure in the HDACi-treated cells (WRO and TPC-1). Moreover, the expression of the repair-related gene Ku80 was differentially modulated only in the cancer cells, by the compounds at the protein and/or mRNA levels. We present in vitro evidence that HDACi can enhance the radiosensitivity of human thyroid cancer cells.
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