Demyelination is the cause of disability in various neurological disorders. It is therefore crucial to understand the molecular regulation of oligodendrocytes, the myelin forming cells in the CNS. Growth factors are known to be essential for the development and maintenance of oligodendrocytes and are involved in the regulation of glial responses in various pathological conditions. We employed the well established murine cuprizone model of toxic demyelination to analyze the expression of 13 growth factors in the CNS during de- and remyelination. The temporal mRNA expression profile during demyelination and the subsequent remyelination were analyzed separately in the corpus callosum and cerebral cortex using laser microdissection and real-time PCR techniques. During demyelination a similar pattern of growth factor mRNA expression was observed in both areas with a strong up-regulation of NRG1 and GDNF and a slight increase of CNTF in the first week of cuprizone treatment. HGF, FGF-2, LIF, IGF-I, and TGF-ß1 were up-regulated mainly during peak demyelination. In contrast, during remyelination there were regional differences in growth factor mRNA expression levels. GDNF, CNTF, HGF, FGF-2, and BDNF were elevated in the corpus callosum but not in the cortex, suggesting tissue differences in the molecular regulation of remyelination in the white and grey matter. To clarify the cellular source we isolated microglia from the cuprizone lesions. GDNF, IGF-1, and FGF mRNA were detected in the microglial fraction with a temporal pattern corresponding to that from whole tissue PCR. In addition, immunohistochemical analysis revealed IGF-1 protein expression also in the reactive astrocytes. CNTF was located in astrocytes. This study identified seven different temporal expression patterns for growth factors in white and grey matter and demonstrated the importance of early tissue priming and exact orchestration of different steps during callosal and cortical de- and remyelination.
The p53 tumor suppressor directs the cellular response to many mechanistically distinct DNA-damaging agents and is selected against during the pathogenesis of therapy-related acute myeloid leukemia (t-AML). We hypothesized that constitutional genetic variation in the p53 pathway would affect t-AML risk. Therefore, we tested associations between patients with t-AML (n ؍ 171) and 2 common functional p53-pathway variants, the MDM2 SNP309 and the TP53 codon 72 polymorphism. Although neither polymorphism alone influenced the risk of t-AML, an interactive effect was detected such that MDM2 TT TP53 Arg/Arg double homozygotes, and individuals carrying both a MDM2 G allele and a TP53 Pro allele, were at increased risk of t-AML (P value for interaction is .009). This interactive effect was observed in patients previously treated with chemotherapy but not in patients treated with radiotherapy, and in patients with loss of chromosomes 5 and/or 7, acquired abnormalities associated with prior exposure to alkylator chemotherapy. In addition, there was a trend toward shorter latency to t-AML in MDM2 GG versus TT homozygotes in females but not in males, and in younger but not older patients.
The aim of this study was to compare the safety, efficacy, tolerability, and the effects of atomoxetine and OROS-MPH on executive functions in children with ADHD. This study was an open-label study that only included two medication groups. Children were randomized to open-label atomoxetine or OROS-MPH for 12 weeks. Primary efficacy measures were T-DSM-IV-S, CGI-I and neuropsychological tests battery. Safety assessments included electrocardiogram, adverse events checklist and laboratory tests. According to the endpoint improvement scores of CGI and parents T-DSM-IV-S, treatment responses were not significantly different between the two study groups. OROS-MPH led to a significantly greater reduction in teacher T-DSM-IV-S scale scores. OROS-MPH was more effective than atomoxetine on Stroop-5 time and number of corrections. Significant decrease in the percentage of perseverative errors on WCST in the OROS-MPH group was seen (p = 0.005). The most frequently reported adverse events in the atomoxetine group were anorexia, nausea, nervousness, weight loss, abdominal pain, and somnolence. In the OROS-MPH group, patients most frequently reported anorexia, nervousness, insomnia, headache, nausea, and weight loss. When all these results are considered, although both drugs can be considered effective in ADHD treatment, more remarkable improvement is provided by OROS-MPH based on the rates across informant (i.e., teachers, clinicians) and neuropsychological evaluation.
Triple-negative breast cancer (TNBC) is a high medical need disease with limited treatment options. CD8+ T cell-mediated immunotherapy may represent an attractive approach to address TNBC. The objectives of this study were to assess the expression of CXorf61 in TNBCs and healthy tissues and to evaluate its capability to induce T cell responses.We show by transcriptional profiling of a broad comprehensive set of normal human tissue that CXorf61 expression is strictly restricted to testis. 53% of TNBC patients express this antigen in at least 30% of their tumor cells. In CXorf61-negative breast cancer cell lines CXorf61 expression is activated by treatment with the hypomethylating agent 5-aza-2′-deoxycytidine.By vaccination of HLA-A*02-transgenic mice with CXorf61 encoding RNA we obtained high frequencies of CXorf61-specific T cells. Cloning and characterization of T cell receptors (TCRs) from responding T cells resulted in the identification of the two HLA-A*0201-restricted T cell epitopes CXorf6166–74 and CXorf6179–87. Furthermore, by in vitro priming of human CD8+ T cells derived from a healthy donor recognizing CXorf6166–74 we were able to induce a strong antigen-specific immune response and clone a human TCR recognizing this epitope.In summary, our data confirms this antigen as promising target for T cell based therapies.
Apart from their involvement in the pathogenesis of demyelinating diseases such as multiple sclerosis, there is emerging evidence that matrix metalloproteinases (MMPs) also promote remyelination. We investigated region-specific expression patterns of 11 MMPs and 4 tissueinhibitors of metalloproteinases (TIMPs) in the cuprizone murine demyelination model. Messenger RNA (mRNA) was extracted at different time points of exposure to cuprizone from microdissected samples of corpus callosum, cortex, and ex vivo isolated microglia and analyzedusing quantitative reverse transcription-polymerase chain reaction.Matrix metalloproteinase 12 and TIMP-1 mRNA were significantly upregulated versus age-matched controls in both areas during demyelination and remyelination. Matrix metalloproteinases 3, 11, and 14 mRNA were upregulated only in white matter during remyelination. Matrix metalloproteinase 24 mRNA was downregulated during both demyelination and remyelination. To identify potential cellular sources of the MMPs and TIMPs, we isolated microglia and detected high MMP-12and TIMP-2 mRNA upregulation at the peak of demyelination.By immunohistochemistry, MMP-3 protein was localized in astrocytes and MMP-12 was identified in microglia, astrocytes, and cells of oligodendrocyte lineage. These findings suggest that MMPs and TIMPs have roles in the regulation of demyelination and remyelination in thismodel. Moreover, differences in the expression levels of these genesbetween white and gray matter reveal region-specific molecularmechanisms.
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