Signatures of Selection in the Genomes of Commercial and Non-Commercial Chicken Breeds

Identifying genomics regions that are affected by selection is important to understand the domestication and selection history of the domesticated chicken, as well as understanding molecular pathways underlying phenotypic traits and breeding goals. While whole-genome approaches, either high-density SNP chips or massively parallel sequencing, have been successfully applied to identify evidence for selective sweeps in chicken, it has been difficult to distinguish patterns of selection and stochastic and breed specific effects. Here we present a study to identify selective sweeps in a large number of chicken breeds (67 in total) using a high-density (58 K) SNP chip. We analyzed commercial chickens representing all major breeding goals. In addition, we analyzed non-commercial chicken diversity for almost all recognized traditional Dutch breeds and a selection of representative breeds from China. Based on their shared history or breeding goal we in silico grouped the breeds into 14 breed groups. We identified 396 chromosomal regions that show suggestive evidence of selection in at least one breed group with 26 of these regions showing strong evidence of selection. Of these 26 regions, 13 were previously described and 13 yield new candidate genes for performance traits in chicken. Our approach demonstrates the strength of including many different populations with similar, and breed groups with different selection histories to reduce stochastic effects based on single populations

Comparative analysis of the human hepatic and adipose tissue transcriptomes during LPS-induced inflammation leads to the identification of differential biological pathways and candidate biomarkers

<p>Abstract</p> <p>Background</p> <p>Insulin resistance (IR) is accompanied by chronic low grade systemic inflammation, obesity, and deregulation of total body energy homeostasis. We induced inflammation in adipose and liver tissues <it>in vitro </it>in order to mimic inflammation <it>in vivo </it>with the aim to identify tissue-specific processes implicated in IR and to find biomarkers indicative for tissue-specific IR.</p> <p>Methods</p> <p>Human adipose and liver tissues were cultured in the absence or presence of LPS and DNA Microarray Technology was applied for their transcriptome analysis. Gene Ontology (GO), gene functional analysis, and prediction of genes encoding for secretome were performed using publicly available bioinformatics tools (DAVID, STRING, SecretomeP). The transcriptome data were validated by proteomics analysis of the inflamed adipose tissue secretome.</p> <p>Results</p> <p>LPS treatment significantly affected 667 and 483 genes in adipose and liver tissues respectively. The GO analysis revealed that during inflammation adipose tissue, compared to liver tissue, had more significantly upregulated genes, GO terms, and functional clusters related to inflammation and angiogenesis. The secretome prediction led to identification of 399 and 236 genes in adipose and liver tissue respectively. The secretomes of both tissues shared 66 genes and the remaining genes were the differential candidate biomarkers indicative for inflamed adipose or liver tissue. The transcriptome data of the inflamed adipose tissue secretome showed excellent correlation with the proteomics data.</p> <p>Conclusions</p> <p>The higher number of altered proinflammatory genes, GO processes, and genes encoding for secretome during inflammation in adipose tissue compared to liver tissue, suggests that adipose tissue is the major organ contributing to the development of systemic inflammation observed in IR. The identified tissue-specific functional clusters and biomarkers might be used in a strategy for the development of tissue-targeted treatment of insulin resistance in patients.</p

The strengths and limitations of routine staging before treatment with abdominal CT in colorectal cancer

<p>Abstract</p> <p>Background</p> <p>Advanced colorectal cancer (CRC), either locally advanced, metastasized (mCRC) or both, is present in a relevant proportion of patients. The chances on curation of advanced CRC are continuously improving with modern multi-modality treatment options. For incurable CRC the focus lies on palliation of symptoms, which is not necessarily a resection of the primary tumor. Both situations motivate adequate staging before treatment in CRC. This prospective observational study evaluates the outcomes after the introduction of routine staging with abdominal CT before treatment.</p> <p>Methods</p> <p>In a prospective observational study of 612 consecutive patients (2007-2009), the ability of abdominal CT to find liver metastases (LM), peritoneal carcinomatosis (PC) and T4 stage in colon cancer (CC) was analysed.</p> <p>Results</p> <p>Advanced CRC was present in 58% of patients, mCRC in 31%. The ability to find LM was excellent (99%), cT4 stage CC good (86%) and PC poor (33%). In the group of surgical patients with emergency presentations, the incidences of both mCRC (51%) and locally advanced colon cancer (LACC) (69%) were higher than in the elective group (20% and 26% respectively). Staging tended to be omitted more often in the emergency group (35% versus 12% in elective surgery).</p> <p>Conclusions</p> <p>The strengths of staging with abdominal CT are to find LM and LACC, however it fails in diagnosing PC. On grounds of the incidence of advanced CRC, staging is warranted in patients with emergency presentations as well.</p

Enrichment of the tumour immune microenvironment in patients with desmoplastic colorectal liver metastasis

Background Patients with resected colorectal liver metastasis (CRLM) who display only the desmoplastic histopathological growth pattern (dHGP) exhibit superior survival compared to patients with any non-desmoplastic growth (non-dHGP). The aim of this study was to compare the tumour microenvironment between dHGP and non-dHGP. Methods The tumour microenvironment was investigated in three cohorts of chemo-naive patients surgically treated for CRLM. In cohort A semi-quantitative immunohistochemistry was performed, in cohort B intratumoural and peritumoural T cells were counted using immunohistochemistry and digital image analysis, and in cohort C the relative proportions of individual T cell subsets were determined by flow cytometry. Results One hundred and seventeen, 34, and 79 patients were included in cohorts A, B, and C, with dHGP being observed in 27%, 29%, and 15% of patients, respectively. Cohorts A and B independently demonstrated peritumoural and intratumoural enrichment of cytotoxic CD8+ T cells in dHGP, as well as a higher CD8+/CD4+ ratio (cohort A). Flow cytometric analysis of fresh tumour tissues in cohort C confirmed these results; dHGP was associated with higher CD8+ and lower CD4+ T cell subsets, resulting in a higher CD8+/CD4+ ratio. Conclusion The tumour microenvironment of patients with dHGP is characterised by an increased and distinctly cytotoxic immune infiltrate, providing a potential explanation for their superior survival

Improvements in population-based survival of patients presenting with metastatic rectal cancer in the south of the Netherlands, 1992–2008

We analysed population-based treatment and survival data of patients who presented with metastatic rectal cancer. All patients diagnosed with primary synchronous metastatic rectal cancer between 1992 and 2008 in the Eindhoven Cancer Registry area were included. Date of diagnosis was divided into three periods (1992–1999, 2000–2004, 2005–2008) according to the availability of chemotherapy type. We assessed treatment patterns and overall survival according to period of diagnosis. The proportion of patients diagnosed with stage IV disease increased from 16% in 1992–1999 to 20% in 2005–2008 (P < 0.0001). Chemotherapy use increased from 5% in 1992 to 61% in 2008 (P < 0.0001). Resection rates of the primary tumour decreased from 65% in 1992 to 27% in 2008 (P < 0.0001), while metastasectomy rates remained constant since 1999 (9%). Median survival increased from 38 weeks (95% confidence interval (CI) 32–44) in 1992–1999 to 53 weeks (95% CI 48–61) in 2005–2008. Among patients not receiving chemotherapy median survival remained approximately 30 weeks. Multivariable analysis confirmed the lower risk of death among patients diagnosed in more recent years. Increased use of chemotherapy went together with improved median survival among patients with metastatic rectal cancer in the last two decades. Stage migration as an effect of more effective imaging procedures is likely to be partly responsible for this improved survival

Quantitative in vivo assessment of radiation injury of the liver using Gd-EOB-DTPA enhanced MRI: tolerance dose of small liver volumes

<p>Abstract</p> <p>Backround</p> <p>Hepatic radiation toxicity restricts irradiation of liver malignancies. Better knowledge of hepatic tolerance dose is favourable to gain higher safety and to optimize radiation regimes in radiotherapy of the liver. In this study we sought to determine the hepatic tolerance dose to small volume single fraction high dose rate irradiation.</p> <p>Materials and methods</p> <p>23 liver metastases were treated by CT-guided interstitial brachytherapy. MRI was performed 3 days, 6, 12 and 24 weeks after therapy. MR-sequences were conducted with T1-w GRE enhanced by hepatocyte-targeted Gd-EOB-DTPA. All MRI data sets were merged with 3D-dosimetry data. The reviewer indicated the border of hypointensity on T1-w images (loss of hepatocyte function) or hyperintensity on T2-w images (edema). Based on the volume data, a dose-volume-histogram was calculated. We estimated the threshold dose for edema or function loss as the D₉₀, i.e. the dose achieved in at least 90% of the pseudolesion volume.</p> <p>Results</p> <p>At six weeks post brachytherapy, the hepatocyte function loss reached its maximum extending to the former 9.4Gy isosurface in median (i.e., ≥9.4Gy dose exposure led to hepatocyte dysfunction). After 12 and 24 weeks, the dysfunctional volume had decreased significantly to a median of 11.4Gy and 14Gy isosurface, respectively, as a result of repair mechanisms. Development of edema was maximal at six weeks post brachytherapy (9.2Gy isosurface in median), and regeneration led to a decrease of the isosurface to a median of 11.3Gy between 6 and 12 weeks. The dose exposure leading to hepatocyte dysfunction was not significantly different from the dose provoking edema.</p> <p>Conclusion</p> <p>Hepatic injury peaked 6 weeks after small volume irradiation. Ongoing repair was observed up to 6 months. Individual dose sensitivity may differ as demonstrated by a relatively high standard deviation of threshold values in our own as well as all other published data.</p

Znf202 Affects High Density Lipoprotein Cholesterol Levels and Promotes Hepatosteatosis in Hyperlipidemic Mice

Background: The zinc finger protein Znf202 is a transcriptional suppressor of lipid related genes and has been linked to hypoalphalipoproteinemia. A functional role of Znf202 in lipid metabolism in vivo still remains to be established. Methodology and Principal Findings: We generated mouse Znf202 expression vectors, the functionality of which was established in several in vitro systems. Next, effects of adenoviral znf202 overexpression in vivo were determined in normo- as well as hyperlipidemic mouse models. Znf202 overexpression in mouse hepatoma cells mhAT3F2 resulted in downregulation of members of the Apoe/c1/c2 and Apoa1/c3/a4 gene cluster. The repressive activity of Znf202 was firmly confirmed in an apoE reporter assay and Znf202 responsive elements within the ApoE promoter were identified. Adenoviral Znf202 transfer to Ldlr-/- mice resulted in downregulation of apoe, apoc1, apoa1, and apoc3 within 24 h after gene transfer. Interestingly, key genes in bile flux (abcg5/8 and bsep) and in bile acid synthesis (cyp7a1) were also downregulated. At 5 days post-infection, the expression of the aforementioned genes was normalized, but mice had developed severe hepatosteatosis accompanied by hypercholesterolemia and hypoalphalipoproteinemia. A much milder phenotype was observed in wildtype mice after 5 days of hepatic Znf202 overexpression. Interestingly and similar to Ldl-/- mice, HDL-cholesterol levels in wildtype mice were lowered after hepatic Znf202 overexpression. Conclusion/Significance: Znf202 overexpression in vivo reveals an important role of this transcriptional regulator in liver lipid homeostasis, while firmly establishing the proposed key role in the control of HDL levels

The diagnostic value of CRP, IL-8, PCT, and sTREM-1 in the detection of bacterial infections in pediatric oncology patients with febrile neutropenia

In this study, we evaluated C-reactive protein (CRP), interleukin (IL)-8, procalcitonin (PCT), and soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) as predictors for bacterial infection in febrile neutropenia, plus their usefulness in febrile neutropenia during chemotherapy-induced gastrointestinal mucositis. Plasma was obtained from pediatric oncology patients at presentation with febrile neutropenia (n = 43) and 24-48 h later (n = 17). The patients were classified as having or not having a bacterial infection. Plasma was also obtained of patients in the absence and in the presence of mucositis (n = 26). At presentation with febrile neutropenia, median IL-8 and PCT levels were significantly increased in patients with a bacterial infection, in contrast to CRP and sTREM-1. IL-8 was the most sensitive marker for the early detection of bacterial infection, in combination with clinical parameters or PCT the sensitivity reached 100%. After 24-48 h, only PCT was significantly elevated during bacterial infection. IL-8 levels were significantly increased during mucositis. Mucositis did not cause considerable changes in PCT levels. IL-8 is the most useful marker for the early detection of bacterial infections, compared with CRP, PCT, and sTREM-1. IL-8 in combination with clinical parameters or PCT might be even more useful. Gastrointestinal mucositis alone does not affect PCT levels, in contrast to IL-8 levels, and therefore, PCT might be more useful for the detection of bacterial infections during mucositis than IL-8

Modulation of Mrp1 (ABCc1) and Pgp (ABCb1) by Bilirubin at the Blood-CSF and Blood-Brain Barriers in the Gunn Rat

Accumulation of unconjugated bilirubin (UCB) in the brain causes bilirubin encephalopathy. Pgp (ABCb1) and Mrp1 (ABCc1), highly expressed in the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier (BCSFB) respectively, may modulate the accumulation of UCB in brain. We examined the effect of prolonged exposure to elevated concentrations of UCB on expression of the two transporters in homozygous, jaundiced (jj) Gunn rats compared to heterozygous, not jaundiced (Jj) littermates at different developmental stages (2, 9, 17 and 60 days after birth). BBB Pgp protein expression was low in both jj and Jj pups at 9 days (about 16–27% of adult values), despite the up-regulation in jj animals (2 and 1.3 fold higher than age matched Jj animals at P9 and P17–P60, respectively); Mrp1 protein expression was barely detectable. Conversely, at the BCSFB Mrp1 protein expression was rather high (60–70% of the adult values) in both jj and Jj at P2, but was markedly (50%) down-regulated in jj pups starting at P9, particularly in the 4th ventricle choroid plexuses: Pgp was almost undetectable. The Mrp1 protein down regulation was accompanied by a modest up-regulation of mRNA, suggesting a translational rather than a transcriptional inhibition. In vitro exposure of choroid plexus epithelial cells obtained from normal rats to UCB, also resulted in a down-regulation of Mrp1 protein. These data suggest that down-regulation of Mrp1 protein at the BSCFB, resulting from a direct effect of UCB on epithelial cells, may impact the Mrp1-mediated neuroprotective functions of the blood-cerebrospinal fluid barrier and actually potentiate UCB neurotoxicity