Beschreibung: Background Ependymomas are rare CNS tumors. Previous studies describing the clinical course of ependymoma patients were restricted to small sample sizes, often with patients at a specific institution. Methods Clinically annotated ependymoma tissue samples from 19 institutions were centrally reviewed. Patients were all adults aged 18 years or older at the time of diagnosis. Potential prognostic clinical factors identified on univariate analysis were included in a multivariate Cox proportional hazards model with backwards selection to model progression-free survival. Results The 282 adult ependymoma patients were equally male and female with a mean age of 43 years (range, 18–80y) at diagnosis. The majority were grade II (78%) with the tumor grade for 20 cases being reclassified on central review (half to higher grade). Tumor locations were spine (46%), infratentorial (35%), and supratentorial (19%). Tumor recurrence occurred in 26% ( n = 74) of patients with a median time to progression of 14 years. A multivariate Cox proportional hazards model identified supratentorial location ( P 〈 .01), grade III (anaplastic; P 〈 .01), and subtotal resection, followed or not by radiation ( P 〈 .01), as significantly increasing risk of early progression. Conclusions We report findings from an ongoing, multicenter collaboration from a collection of clinically annotated adult ependymoma tumor samples demonstrating distinct predictors of progression-free survival. This unique resource provides the opportunity to better define the clinical course of ependymoma for clinical and translational studies.

Beschreibung: Elite controllers or suppressors (ES) are HIV-1-infected patients who maintain undetectable viral loads without antiretroviral therapy. The mechanism of control remains unclear, but the HLA-B*57 allele is overrepresented in cohorts of these patients. However, many HLA-B*57 patients develop progressive disease, and some studies have suggested that infection with defective viruses may be the cause of the lack of high levels of virus replication and disease progression in ES. We therefore performed a comprehensive comparative in vivo and in vitro characterization of viruses isolated from well-defined ES. For this purpose, we first performed full-genome sequence analysis and in vitro fitness assays on replication-competent isolates from HLA-B*57 ES and HLA-B*57 chronic progressors (CPs). Under our experimental conditions, we found that isolates from ES and CPs can replicate in vitro . However, since inherently these assays involve the use of unnaturally in vitro -activated cells, we also investigated the replication competence and pathogenic potential of these HIV isolates in vivo using humanized BLT mice. The results from these analyses demonstrate that virus isolates from ES are fully replication competent in vivo and can induce peripheral and systemic CD4 T cell depletion. These results provide the first direct in vivo evidence that viral fitness does not likely determine clinical outcome in HLA-B*57 patients and that elite suppressors can control replication-competent, fully pathogenic viruses. A better understanding of the immunological bases of viral suppression in ES will serve to inform novel approaches to preventive and therapeutic HIV vaccine design. IMPORTANCE Elite suppressors are HIV-1-infected patients who have undetectable levels of viremia despite not being on antiviral drugs. One of the most fundamental questions about this phenomenon involves the mechanism of control. To address this question, we isolated virus from elite suppressors and from HIV-1-infected patients who have the usual progressive disease course. We compared how well the isolates from the two groups of patients replicated in culture and in humanized mice. Our results suggest that elite suppressors are capable of controlling HIV-1 due to the possession of unique host factors rather than infection with defective virus.

Beschreibung: Chronic inflammation has been implicated in the pathogenesis of colorectal cancer. The objective of this study was to evaluate the association of prediagnostic circulating levels of C-reactive protein (CRP), a biomarker of systemic inflammation, with subsequent development of colorectal cancer. Prediagnostic plasma CRP levels were examined among 288 colorectal cancer cases and 576 individually-matched controls nested within the Shanghai Men’s Health Study (2002–06), a population-based cohort study of 61 482 Chinese men. The association between CRP levels and colorectal cancer risk was investigated. Baseline plasma CRP levels were 53% higher among men who subsequently developed colorectal cancer than among those who remained free of the disease (1.15 versus 0.75 μg/ml; P 〈 0.001). Multivariate analyses showed a dose-dependent relationship between CRP and colorectal cancer risk ( P trend = 0.003); men in the highest tertile (CRP 〉 1.19 μg/ml) had 1.88-fold (95% confidence interval (CI): 1.24–2.86) increased odds of developing colorectal cancer compared with men in the lowest tertile (CRP 〈 0.45 μg/ml). The association was only significant for colon cancer, when cancer site was considered, and was predominantly seen for cases diagnosed within 4 years of blood collection; adjusted odds ratios for the highest versus the lowest tertiles were 3.28 (95% CI: 1.28–8.37), 3.68 (95% CI: 1.62–8.38) and 1.05 (95% CI: 0.56–1.97), respectively, for cases diagnosed 〈2, 2–4 and 〉4 years after blood collection. The findings from our study suggest that circulating CRP level is positively associated with colorectal cancer risk in Chinese men, and this association, at least in part, is explained by inflammation-related cancerous or precancerous processes.

Beschreibung: G-protein-coupled receptor 48 (GPR48) is an orphan receptor belonging to the G-protein-coupled receptors family, which plays an important role in the development of various organs and cancer development and progression such as gastric cancer and colorectal cancer (CRC). However, the prognostic value of GPR48 expression in patients with CRC has not been reported. In this study, we observed that GPR48 was overexpressed in primary CRC and metastatic lymph nodes and closely correlated with tumor invasion and metastasis. Multivariate analysis indicated that high GPR48 expression was a poor prognostic factor for overall survival in CRC patients. In vitro and in vivo assays demonstrated that enforced expression of GPR48 contributed to enhance migration and invasion of cancer cells and tumor metastasis. In addition, we found that GPR48 increased nuclear β-catenin accumulation, T-cell factor 4 (TCF4) transcription activity, and expression of its target genes including Cyclin D1 and c-Myc in CRC cells. Correlation analysis showed that GPR48 expression in CRC tissues was positively associated with β-catenin expression. Upregulation of GPR48 resulted in increased phosphorylation of glycogen synthase kinase 3β, Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) in CRC cells, while inhibition of PI3K/Akt and mitogen-activated protein kinase /ERK1/2 pathways was sufficient to abolish the effect of GPR48 on β-catenin/TCF signaling. Taken together, GPR48 could serve as both a prognostic biomarker and a therapeutic target for resectable CRC patients.

Beschreibung: This paper is concerned with the effect of interaction ratio in a chemical reaction with zero-flux boundary condition. Treating the interaction ratio as a parameter, the existence of non-constant positive steady states is discussed by the bifurcation theory. Especially, the steady-state bifurcation from the double eigenvalue is derived. The Hopf bifurcation analysis to both ordinary differential equations and partial differential equations systems is investigated in detail. Examples of numerical simulations are shown to support and complement the analytical conclusions.

Beschreibung: DNA priming improves the response to inactivated influenza A(H5N1) vaccination. We compared the immunogenicity of an H5 DNA prime (using strain A/Indonesia/5/2005) followed by an H5N1 monovalent inactivated vaccine boost at 4, 8, 12, 16, or 24 weeks to that of 2 doses of H5N1 monovalent inactivated vaccine in adults. Antibody epitope repertoires were elucidated by genome-fragment phage-display library analysis, and antibody avidities for HA1 and HA2 domains were measured by surface plasmon resonance. H5 DNA priming expanded the H5-specific antibody epitope repertoire and enhanced antibody avidity to the HA1 (but not the HA2) domain in an interval-dependent manner. Enhanced HA1 binding and avidity after an interval of ≥12 weeks between prime and boost correlated with improved neutralization of homologous and heterologous H5N1 strains. Clinical trials registration NCT01086657.

Beschreibung: Cutinase is a multifunctional esterase with potential industrial applications. In the present study, a truncated version of the extracellular Thermobifida fusca cutinase without a signal peptide (referred to as cutinase NS ) was heterologously expressed in Escherichia coli BL21(DE3). The results showed that the majority of the cutinase activity was located in the culture medium. In a 3-liter fermentor, the cutinase activity in the culture medium reached 1,063.5 U/ml (2,380.8 mg/liter), and the productivity was 40.9 U/ml/h. Biochemical characterization of the purified cutinase NS showed that it has enzymatic properties similar to those of the wild-type enzyme. In addition, E. coli cells producing inactive cutinase NS S130A were constructed, and it was found that the majority of the inactive enzyme was located in the cytoplasm. Furthermore, T. fusca cutinase was confirmed to have hydrolytic activity toward phospholipids, an important component of the cell membrane. Compared to the cells expressing the inactive cutinase NS S130A, the cells expressing cutinase NS showed increased membrane permeability and irregular morphology. Based on these results, a hypothesis of "cell leakage induced by the limited phospholipid hydrolysis of cutinase NS " was proposed to explain the underlying mechanism for the extracellular release of cutinase NS .

Beschreibung: Aims The chemokine receptor CXCR4 modulates endothelial progenitor cell migration, homing, and differentiation, and plays a key role in cardiovascular regeneration. Here we examined the effect of ex vivo acidic preconditioning (AP) on CXCR4 expression and on the regenerative potential of mouse bone marrow (BM) ckit + cells. Methods and results Acidic preconditioning was achieved by exposing BM ckit + cells to hypercarbic acidosis (pH 7.0) for 24 h; control cells were kept at pH 7.4. Acidic preconditioning enhanced CXCR4 and stromal cell-derived factor 1 (SDF-1) mRNA levels, as well as CXCR4 phosphorylation. Acidic preconditioning ability to modulate CXCR4 expression depended on cytosolic calcium [Ca 2+ ] i mobilization and on nitric oxide (NO), as determined by [Ca 2+ ] i buffering with BAPTA, and by treatment with the NO donor (DETA/NO) and the NO synthase inhibitor (L-NAME). Further, AP increased SDF-1-driven chemotaxis, transendothelial migration, and differentiation toward the endothelial lineage in vitro . In a mouse model of hindlimb ischaemia, control and AP ckit + cells were transplanted into the ischaemic muscle; AP cells accelerated blood flow recovery, increased capillary, and arteriole number as well as the number of regenerating muscle fibres vs. control. These effects were abolished by treating AP cells with L-NAME. Conclusion Acidic preconditioning represents a novel strategy to enhance BM ckit + cell therapeutic potential via NO-dependent increase in CXCR4 expression.

Beschreibung: : Community curation—harnessing community intelligence in knowledge curation, bears great promise in dealing with the flood of biological knowledge. To exploit the full potential of the scientific community for knowledge curation, multiple biological wikis (bio-wikis) have been built to date. However, none of them have achieved a substantial impact on knowledge curation. One of the major limitations in bio-wikis is insufficient community participation, which is intrinsically because of lack of explicit authorship and thus no credit for community curation. To increase community curation in bio-wikis, here we develop AuthorReward , an extension to MediaWiki, to reward community-curated efforts in knowledge curation. AuthorReward quantifies researchers’ contributions by properly factoring both edit quantity and quality and yields automated explicit authorship according to their quantitative contributions. AuthorReward provides bio-wikis with an authorship metric, helpful to increase community participation in bio-wikis and to achieve community curation of massive biological knowledge. Availability: http://cbb.big.ac.cn/software . Contact: zhangzhang@big.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.

Beschreibung: Background Very little is known regarding correlation of micro RNA (miR)–106a with clinical outcomes of patients with glioblastoma multiforme (GBM). This study determined whether miR-106a could be used as an independent prognostic biomarker in those patients. Methods A total of 156 GBM patients were divided into 2 cohorts. In the first cohort, matched fresh frozen and formalin-fixed paraffin-embedded (FFPE) samples were collected from 24 GBM patients, while in the second cohort, only FFPE samples were collected from 132 GBM patients. MiR-106a expression levels were examined by quantitative real-time PCR in the 2 cohorts and further validated by in situ hybridization assay in the second cohort. The correlation between miR-106a expression levels and overall survival was evaluated in the second cohort of 114 GBM patients available for follow-up by a log-rank test and a multivariate Cox proportional hazards model. Results Our data showed a very good correlation of miR-106a or U6 expression between fresh frozen and FFPE GBM specimens, with Pearson's correlation coefficients of 0.849 and 0.823, respectively ( P 〈 .001). Their expression levels in archival FFPE samples were quite stable for at least 7 years when stored at room temperature. Multivariate analysis revealed that the expression level of miR-106a was an independent and significant predictor of overall survival in GBM patients ( P = .011). Conclusions MiR-106a expression was relatively abundant and stable in a large cohort of archival FFPE GBM specimens and could be used as an independent prognostic biomarker in those patients. Thus, miR-106a can be used to predict prognosis and treatment response in individual GBM patients.