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Assessing Concordance of Drug-Induced Transcriptional Response in Rodent Liver and Cultured Hepatocytes.

The effect of drugs, disease and other perturbations on mRNA levels are studied using gene expression microarrays or RNA-seq, with the goal of understanding molecular effects arising from the perturbation. Previous comparisons of reproducibility across laboratories have been limited in scale and focused on a single model. The use of model systems, such as cultured primary cells or cancer cell lines, assumes that mechanistic insights derived from the models would have been observed via in vivo studies. We examined the concordance of compound-induced transcriptional changes using data from several sources: rat liver and rat primary hepatocytes (RPH) from Drug Matrix (DM) and open TG-GATEs (TG), human primary hepatocytes (HPH) from TG, and mouse liver / HepG2 results from the Gene Expression Omnibus (GEO) repository. Gene expression changes for treatments were normalized to controls and analyzed with three methods: 1) gene level for 9071 high expression genes in rat liver, 2) gene set analysis (GSA) using canonical pathways and gene ontology sets, 3) weighted gene co-expression network analysis (WGCNA). Co-expression networks performed better than genes or GSA when comparing treatment effects within rat liver and rat vs. mouse liver. Genes and modules performed similarly at Connectivity Map-style analyses, where success at identifying similar treatments among a collection of reference profiles is the goal. Comparisons between rat liver and RPH, and those between RPH, HPH and HepG2 cells reveal lower concordance for all methods. We observe that the baseline state of untreated cultured cells relative to untreated rat liver shows striking similarity with toxicant-exposed cells in vivo, indicating that gross systems level perturbation in the underlying networks in culture may contribute to the low concordance.

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Cognitive Testing of an Electronic Version of the Faces Pain Scale-Revised with Pediatric and Adolescent Sickle Cell Patients.

Patient diaries and pain scales can capture the course and complications of pain managed at home in children. The Faces Pain Scale-Revised (FPS-R) is a validated scale showing reliability in children, but it has not been validated in children with sickle cell disease (SCD).
The purpose of this study was to evaluate comprehension and usability of an electronic modified version of the FPS-R among pediatric patients with SCD.
This was a cross-sectional, qualitative study involving in-person interviews with children/adolescents from the USA and their parents/legal guardians. Interviews involved cognitive debriefing and usability testing of the FPS-R.
In total, 22 children with SCD aged 4-17 years participated. Children aged 4-6 were generally unable to demonstrate clear understanding of the FPS-R and its response scale. Overall, children aged ≥7 years understood the instrument and could complete it on the electronic device, although children aged 7-8 often needed assistance from the parent. Children aged 9-17 years were able to read and complete the instrument independently. Most participants considered the electronic device easy to use.
The FPS-R was shown to be a comprehensible and usable pain measure for children aged 7-17 with SCD and to be beneficial for future clinical studies.

Genome-wide meta-analysis identifies multiple novel associations and ethnic heterogeneity of psoriasis susceptibility.

Psoriasis is a common inflammatory skin disease with complex genetics and different degrees of prevalence across ethnic populations. Here we present the largest trans-ethnic genome-wide meta-analysis (GWMA) of psoriasis in 15,369 cases and 19,517 controls of Caucasian and Chinese ancestries. We identify four novel associations at LOC144817, COG6, RUNX1 and TP63, as well as three novel secondary associations within IFIH1 and IL12B. Fine-mapping analysis of MHC region demonstrates an important role for all three HLA class I genes and a complex and heterogeneous pattern of HLA associations between Caucasian and Chinese populations. Further, trans-ethnic comparison suggests population-specific effect or allelic heterogeneity for 11 loci. These population-specific effects contribute significantly to the ethnic diversity of psoriasis prevalence. This study not only provides novel biological insights into the involvement of immune and keratinocyte development mechanism, but also demonstrates a complex and heterogeneous genetic architecture of psoriasis susceptibility across ethnic populations.

Health economic evaluation of Gd-EOB-DTPA MRI versus ECCM-MRI and multidetector computed tomography in patients with suspected hepatocellular carcinoma in Thailand and South Korea.

Objective The effectiveness of treatment decisions and economic outcomes of using gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (Gd-EOB-DTPA-MRI) were compared with extracellular contrast media-enhanced MRI (ECCM-MRI) and multidetector computed tomography (MDCT) as initial procedures in patients with suspected hepatocellular carcinoma (HCC) in South Korea and Thailand. Methods A decision-tree model simulated the clinical pathway for patients with suspected HCC from the first imaging procedure to a confirmed treatment decision. Input data (probabilities and resource consumptions) were estimated and validated by clinical experts. Costs for diagnostic alternatives and related treatment options were derived from published sources taking into account both payer’s and hospital’s perspectives. Results All experts from Korea and Thailand agreed that Gd-EOB-DTPA-MRI yields the highest diagnostic certainty and minimizes the need for additional confirmatory diagnostic procedures in HCC. In Korea, from the payer’s perspective, total cost was USD $3,087/patient to reach a confirmed treatment decision using Gd-EOB-DTPA-MRI (vs. $3,205/patient for MDCT and $3,403/patient for ECCM-MRI). From the hospital’s perspective, Gd-EOB-DTPA-MRI incurred the lowest cost ($2,289/patient vs. $2,320/patient and $2,528/patient, respectively). In Thailand, Gd-EOB-DTPA-MRI was the least costly alternative for the payer ($702/patient vs. $931/patient for MDCT and $873/patient for ECCM-MRI). From the hospital’s perspective, costs were $1,106/patient, $1,178/patient, and $1,087/patient for Gd-EOB-DTPA-MRI, MDCT, and ECCM-MRI, respectively. Conclusions Gd-EOB-DTPA-MRI as an initial imaging procedure in patients with suspected HCC provides better diagnostic certainty and relevant statutory health insurance cost savings in Thailand and Korea, compared with ECCM-MRI and MDCT.

Preoperative platelet to lymphocyte ratio is a valuable prognostic biomarker in patients with colorectal cancer.

Recent studies suggest that an elevated preoperative platelet to lymphocyte ratio (PLR) may be considered a poor prognostic biomarker in patients with colorectal cancer (CRC). The aim of this study was to evaluate the prognostic impact of PLR in patients with CRC.
We enrolled 1314 patients who underwent surgery for CRC between 2005 and 2011. Preoperative PLR level was stratified into quintiles for Kaplan-Meier analysis and multivariable Cox proportional hazard regression models.
Higher PLR quintiles were significantly associated with poorer overall survival (P = 0.002). Multivariate analysis showed that PLR was an independent risk factor for overall survival (OS) (P = 0.034). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 1.701, 95% confidence interval (CI): 1.267-2.282, P &lt; 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.522, 95% CI: 1.114-2.080, P = 0.008), this association was not significant after multivariable adjustment (P = 0.075). In the subgroup analysis, PLR remained an independent factor in terms of advanced tumor stage (III, IV), male sex, carcinoembryonic antigen (≤ 5 ng/ml), age (&gt; 65 years) and body mass index (≤ 25) (P &lt; 0.05 for all measurements). The results remained unchanged when the PLR was analyzed as a dichotomous variable by applying different cut-off values of 150, 185, 220.
Elevated preoperative PLR was independently associated with an increased risk of mortality in patients with CRC. The utility of PLR may help to improve prognostic predictors.