Severe congenital microcephaly with AP4M1 mutation, a case report

Background: Autosomal recessive defects of either the B1, E1, M1 or S1 subunit of the Adaptor Protein complex-4 (AP4) are characterized by developmental delay, severe intellectual disability, spasticity, and occasionally mild to moderate microcephaly of essentially postnatal onset. Case presentation: We report on a patient with severe microcephaly of prenatal onset, and progressive spasticity, developmental delay, and severe intellectual deficiency. Exome sequencing showed a homozygous mutation in AP4M1, causing the replacement of an arginine by a stop codon at position 338 of the protein (p.Arg338X). The premature stop codon truncates the Mu homology domain of AP4M1, with predicted loss of function. Exome analysis also showed heterozygous variants in three genes, ATR, MCPH1 and BLM, which are known causes of autosomal recessive primary microcephaly. Conclusions: Our findings expand the AP4M1 phenotype to severe microcephaly of prenatal onset, and more generally suggest that the AP4 defect might share mechanisms of prenatal neuronal depletion with other genetic defects of brain development causing congenital, primary microcephaly

Congenital hydrocephalus : new Mendelian mutations and evidence for oligogenic inheritance

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31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Implication of the thioredoxin/peroxiredoxin system in spinal cord development

Due, in part, to its elevated metabolism, the central nervous system (CNS) is exposed to considerable oxidative stress deriving from endogenously produced reactive oxygen and nitrogen species (ROS/RNS). Though these toxic molecules can react with different cellular components and lead to cell damage and death, numerous studies also highlight these compounds as essential actors in redox signaling cascades. This dual role of ROS/RNS requires finely tuned regulation of cellular concentrations of these species which is accomplished by antioxidant systems. Peroxiredoxins (Prdxs), a family of thiol-dependent peroxidases, and their main reductants, thioredoxins (Trxs), represent one of the major enzymatic antioxidant systems in animal cells. In addition to their cytoprotective role, Trxs and Prdxs have been shown to modulate cellular processes, either via direct interactions or indirectly through their ability to reduce ROS/RNS. In particular, over the past few years, growing evidence has underlined the role of ROS/RNS and antioxidant enzymes in CNS development. In order to study the potential involvement of Trxs and Prdxs in processes taking place during spinal cord development, the expression of these enzymes at different stages of murine embryonic development was studied. Several striking patterns were uncovered including intense immunoreactivity of Trxs and Prdxs, in particular mitochondrial enzymes Prdx3, Prdx5 and Trx2, in spinal cord motor neurons. Thereafter, with focus on Trx2, the biological meaning of these patterns was investigated using the in ovo electroporation technique to overexpress and silence Trx2 during chick spinal cord embryonic development. Interestingly, increased motor neuronal expression of Trx2 in both the mouse and chick embryo coincided with stages at which these cells undergo developmental programmed cell death (PCD). Trx2 gain and loss of function in the spinal cord of chick embryo at this stage and in a cultured explant model of neuron PCD highlighted alterations in the number of dying neurons suggesting an implication of Trx2 in this process. The final part of this work stemmed from the apparent absence of Prdx5 in chicken tissue. Indeed, converging experimental and in silico data support the disappearance of Prdx5 in birds though it is conserved in non-avian amniotes. This observation and discussion as to the reasons behind this loss could provide insight as to the role of Prdx5 in other species and further highlights this enzyme as a particular Prdx.(SC - Sciences) -- UCL, 201

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The curious case of peroxiredoxin-5 : what its absence in aves can tell us and how it can be used.

BACKGROUND: Peroxiredoxins are ubiquitous thiol-dependent peroxidases that represent a major antioxidant defense in both prokaryotic cells and eukaryotic organisms. Among the six vertebrate peroxiredoxin isoforms, peroxiredoxin-5 (PRDX5) appears to be a particular peroxiredoxin, displaying a different catalytic mechanism, as well as a wider substrate specificity and subcellular distribution. In addition, several evolutionary peculiarities, such as loss of subcellular targeting in certain species, have been reported for this enzyme. RESULTS: Western blotting analyses of 2-cys PRDXs (PRDX1-5) failed to identify the PRDX5 isoform in chicken tissue homogenates. Thereafter, via in silico analysis of PRDX5 orthologs, we went on to show that the PRDX5 gene is conserved in all branches of the amniotes clade, with the exception of aves. Further investigation of bird genomic sequences and expressed tag sequences confirmed the disappearance of the gene, though TRMT112, a gene located closely to the 5' extremity of the PRDX5 gene, is conserved. Finally, using in ovo electroporation to overexpress the long and short forms of human PRDX5, we showed that, though the gene is lost in birds, subcellular targeting of human PRDX5 is conserved in the chick. CONCLUSIONS: Further adding to the distinctiveness of this enzyme, this study reports converging evidence supporting loss of PRDX5 in aves. In-depth analysis revealed that this absence is proper to birds as PRDX5 appears to be conserved in non-avian amniotes. Finally, taking advantage of the in ovo electroporation technique, we validate the subcellular targeting of human PRDX5 in the chick embryo and bring forward this gain-of-function model as a potent way to study PRDX5 functions in vivo

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