TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients

<p>Abstract</p> <p>Background</p> <p>Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (<it>DR4</it>) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed <it>DR4 </it>mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC.</p> <p>Methods</p> <p>Frequencies of <it>DR4 </it>gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population.</p> <p>Results</p> <p>Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. <it>DR4 </it>variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10⁶ IU/ml vs. 1.81 ± 0.23 × 10⁶ IU/ml, p = 0.049).</p> <p>Conclusions</p> <p>The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.</p

Large expert-curated database for benchmarking document similarity detection in biomedical literature search

Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency-Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.Peer reviewe

Paradox Research in Management Science: Looking Back to Move Forward

Paradox studies offer vital and timely insights into an array of organizational tensions. Yet this field stands at a critical juncture. Over the past 25 years, management scholars have drawn foundational insights from philosophy and psychology to apply a paradox lens to organizational phenomena. Yet extant studies selectively leverage ancient wisdom, adopting some key insights while abandoning others. Using a structured content analysis to review the burgeoning management literature, we surface six key themes, which represent the building blocks of a meta-theory of paradox. These six themes received varying attention in extant studies: paradox scholars emphasize types of paradoxes, collective approaches, and outcomes, but pay less attention to relationships within paradoxes, individual approaches, and dynamics. As this analysis suggests, management scholars have increasingly simplified the intricate, often messy phenomena of paradox. Greater simplicity renders phenomena understandable and testable, however, oversimplifying complex realities can foster reductionist and incomplete theories. We therefore propose a future research agenda targeted at enriching a meta-theory of paradox by reengaging these less developed themes. Doing so can sharpen the focus of this field, while revisiting its rich conceptual roots to capture the intricacies of paradox. This future research agenda leverages the potential of paradox across diverse streams of management science

The CXCR3(+)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C.

BACKGROUND: In mouse models, natural killer (NK) cells have been shown to exert anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. Here, we analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C. METHODS: Circulating NK cells from HCV-infected patients (n = 57) and healthy controls (n = 27) were analyzed with respect to CXCR3 and co-expression of different maturation markers. Degranulation and interferon-γ secretion of CXCR3(+) and CXCR3(-) NK cell subsets were studied after co-incubation with primary human hepatic stellate cells (HSC). In addition, intra-hepatic frequency of CXCR3(+) NK cells was correlated with stage of liver fibrosis (n = 15). RESULTS: We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. In healthy controls CXCR3(+)CD56Bright NK cells displayed strongest activity against HSC. Chronic hepatitis C was associated with a significantly increased frequency of CXCR3(+)CD56Bright NK cells which showed impaired degranulation and impaired IFN-γ secretion in response to HSC. Of note, we observed intra-hepatic accumulation of this NK cell subset in advanced stages of liver fibrosis. CONCLUSION: We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. Intra-hepatic accumulation of the functionally impaired CXCR3(+)CD56Bright NK cell subset might be involved in HCV-induced liver fibrosis

CXCR3 expression dissects phenotypically distinct NK cell subsets.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g001" target="_blank">Figure 1A:</a> PBMCs in whole blood specimen were stained with anti-CD3, anti-CD56, and anti-CXCR3. CD3⁽⁻⁾ CD56⁽⁺⁾ NK cells were then gated for quantification of CXCR3 surface expression. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g001" target="_blank">Figure 1B:</a> PBMCs from at least eight healthy donors were stained with anti-CD3, anti-CD56, and anti-CXCR3–conjugated mAb, as well as a mAb directed against the indicated maturation markers. CXCR3(+) and CXCR3(−) NK cell populations were then assessed for surface expression of the respective maturation marker. Results are given as box and whisker plots, with medians and 10th, 25th, 75th, and 90th percentiles. * indicates p<0.05; **indicates p<0.01; *** indicates p<0.001.</p

Role of NKG2D in anti-fibrotic activity of CXCR3-expressing NK cells.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g003" target="_blank">Figure 3A:</a> Circulating NK cells obtained from HCV(-) individuals (n = 5) were analyzed for co-expression of NKG2D and CXCR3. The figure compares frequency of NKG2D-positive cells (left graph) as well as density of NKG2D surface expression (relative fluorescence intensity, RFI) (right graph) between the four studied NK cell subsets. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g003" target="_blank">Figure 3B</a> shows the effect of NKG2D blockade on HSC-induced degranulation of CXCR3(+) and CXCR3(−) CD56Bright NK cell subsets obtained from healthy donors (n = 8). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g003" target="_blank">Figure 3C</a> compares HSC-induced degranulation of CXCR3(+) and CXCR3(−) CD56Bright NK cell subsets (n = 8) following pre-incubation with anti-NKG2D. Results are given as box and whisker plots, with medians and 10th, 25th, 75th, and 90th percentiles. * indicates p<0.05; **indicates p<0.01; *** indicates p<0.001.</p

CXCR3(+)CD56Bright NK cells have strong anti-fibrotic potential.

<p><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2A:</a> Purified peripheral NK cells from healthy individuals (n = 14) were co-incubated with primary human hepatic stellate cells (E:T ratio 1∶1) and then analyzed with respect to degranulation (CD107a) and expression of CXCR3 by flowcytometry. <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2B</a> depicts NK cell degranulation following co-incubation with HSC at different effector : target (E:T) ratios as indicated (n = 5). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2C</a> shows CD107a expression of the four studied NK cell sub-populations obtained from healthy donors (n = 14) following co-incubation with primary hepatic stellate cells (E:T ratio 1∶1). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2D</a> illustrates IFN-γ production of purified CXCR3(+) and CXCR3(−) NK cells obtained from HCV(-) individuals (n = 14) after co-culturing with primary HSC (E:T ratio 1∶1). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2E</a> shows IFN-γ production of purified NK cells following co-incubation with hepatic stellate cells at different E:T ratios (n = 4). <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0038846#pone-0038846-g002" target="_blank">Figure 2F</a> displays IFN-γ production of the four studied NK cell sub-populations isolated from healthy donors (n = 14) following co-incubation with primary hepatic stellate cells (E:T ratio 1∶1).</p