Aims The purpose is to find the gut microbial fingerprinting of pediatric patients with type 1 diabetes. Methods The microbiome of 31 children with type 1 diabetes at onset and of 25 healthy children was determined using multiple polymorphic region of the 16S rRNA. We performed machine learning analyses and metagenome functional analysis in order to identify significant taxa and their metabolic pathways content. Results Compared with healthy controls, patients showed a significantly higher relative abundance of the following most important taxa: B.stercoris, B.fragilis, B.intestinalis, B.bifidum, Gammaproteobacteria and its descendants, Holdemania, Synergistetes and its descendants. On the contrary the relative abundance of B.vulgatus, Deltaproteobacteria and its descendants, Parasutterella and the Lactobacillus, Turicibacter genera was significantly lower in patients with respects to healthy controls. The predicted metabolic pathway more associated with type 1 diabetes patients concerns "Carbon metabolism", sugar and iron metabolisms in particular. Among the clinical variables considered, BMI-SDS, anti insulin autoantibodies, glycemia, HbA1c, Tanner and age at onset emerged as the most significant positively or negatively correlated with specific clusters of taxa. Conclusions The relative abundance and the supervised analyses confirmed the importance of B. stercoris in type 1 diabetes patients at onset and showed a relevant role of Synergistetes and its descendants in patients with respect to healthy controls. In general the robustness and the coherence of the showed results underline the relevance of studying the microbioma using multiple polymorphic regions, different types of analysis and different approaches within each analysis.
Molecular and functional characterization of the natural cytotoxicity receptor (NCR) NKp44 in species other than Homo sapiens has been elusive, so far. Here, we provide complete phenotypic, molecular and functional characterization for NKp44 triggering receptor on Pan troglodytes NK cells, the closest human relative, and the analysis of NKp44-genomic locus and transcription in Macaca fascicularis. Similar to H. sapiens, NKp44 expression is detectable on chimpanzee NK cells only upon activation. However, basal NKp44 transcription is 5-fold higher in chimpanzees with lower differential increases upon cell activation compared with humans. Upon activation, an overall 12-fold lower NKp44 gene expression is observed in P. troglodytes compared with H. sapiens NK cells with only a slight reduction in NKp44 surface expression. Functional analysis of 'in vitro' activated purified NK cells confirms the NKp44 triggering potential compared with other major NCRs. These findings suggest the presence of a post-transcriptional regulation that evolved differently in H. sapiens. Analysis of cynomolgus NKp44-genomic sequence and transcription pattern showed very low levels of transcription with occurrence of out-of-frame transcripts and no surface expression. The present comparative analysis suggests that NKp44-genomic organization appears during macaque speciation, with considerable evolution of its transcriptional and post-transcriptional tuning. Thus, NKp44 may represent an NCR being only recently emerged during speciation, acquiring functional relevance only in non-human primates closest to H. sapiens.
HIV-1 infection in humans results in an early and progressive NK cell dysfunction and an accumulation of an ''anergic'' CD56 À CD16 1 NK subset, which is characterised by low natural cytotoxicity receptor expression and low cytokine producing capacity. In contrast to humans, chimpanzee NK cells do not display a distinguishable CD56 bright and CD56 dim subset but, as shown here, could be subdivided into functionally different CD8 1 and CD8 À subsets. The CD8 1 NK cells expressed significantly higher levels of triggering receptors including NKp46 and, upon in vitro activation, produced more IFN-c, TNF-a and CD107 than their CD8 À counterparts. In addition, chimpanzee CD8 À NK cells had relatively high levels of HLA-DR expression, suggestive of an activated state. Killing inhibitory receptors were expressed only at low levels; however, upon in vitro stimulation, they were upregulated in CD8 1 but not in CD8 À NK cells and were functionally capable of inhibiting NKp30-triggered killing. In contrast to HIV-1-infected humans, infected chimpanzees maintained their dominant CD8 1 NK cell population, with high expression of natural cytotoxicity receptors.
The surface marker PROM1 is considered one of the most important markers of tumor-initiating cells, and its expression is believed to be an adverse prognostic factor in gliomas and in other malignancies. To date, to our knowledge, no specific studies of its expression in medulloblastoma series have been performed. The aims of our study were to evaluate the expression profile of the PROM1 gene in medulloblastoma and to assess its possible role as a prognostic factor. The PROM1 gene expression was evaluated by quantitative- polymerase chain reaction on 45 medulloblastoma samples by using specific dye-labeled probe systems. A significantly higher expression of PROM1 was found both in patients with poorer prognosis (P= .007) and in those with metastasis (P= .03). Kaplan-Meier analysis showed that both overall survival (OS) and progression-free survival (PFS) were shorter in patients with higher PROM1 mRNA levels than in patients with lower expression, even when the desmoplastic cases were excluded (P= .0004 and P= .002, for OS and PFS for all cases, respectively; P= .002 and P= .008 for OS and PFS for nondesmoplastic cases, respectively). Cox regression model demonstrated that PROM1 expression is an independent prognostic factor (hazard ratio, 4.56; P= .008). The result was validated on an independent cohort of 42 cases by microarray-based analysis (P= .019). This work suggests that high mRNA levels of PROM1 are associated with poor outcome in pediatric medulloblastoma. Furthermore, high PROM1 expression levels seem to increase the likelihood of metastases. Such results need to be confirmed in larger prospective series to possibly incorporate PROM1 gene expression into risk classification systems to be used in the clinical setting.
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