Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

BACKGROUND: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. METHODS AND FINDINGS: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score 64 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. CONCLUSIONS: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations

Integrative analyses identify modulators of response to neoadjuvant aromatase inhibitors in patients with early breast cancer

Introduction Aromatase inhibitors (AIs) are a vital component of estrogen receptor positive (ER+) breast cancer treatment. De novo and acquired resistance, however, is common. The aims of this study were to relate patterns of copy number aberrations to molecular and proliferative response to AIs, to study differences in the patterns of copy number aberrations between breast cancer samples pre- and post-AI neoadjuvant therapy, and to identify putative biomarkers for resistance to neoadjuvant AI therapy using an integrative analysis approach. Methods Samples from 84 patients derived from two neoadjuvant AI therapy trials were subjected to copy number profiling by microarray-based comparative genomic hybridisation (aCGH, n = 84), gene expression profiling (n = 47), matched pre- and post-AI aCGH (n = 19 pairs) and Ki67-based AI-response analysis (n = 39). Results Integrative analysis of these datasets identified a set of nine genes that, when amplified, were associated with a poor response to AIs, and were significantly overexpressed when amplified, including CHKA, LRP5 and SAPS3. Functional validation in vitro, using cell lines with and without amplification of these genes (SUM44, MDA-MB134-VI, T47D and MCF7) and a model of acquired AI-resistance (MCF7-LTED) identified CHKA as a gene that when amplified modulates estrogen receptor (ER)-driven proliferation, ER/estrogen response element (ERE) transactivation, expression of ER-regulated genes and phosphorylation of V-AKT murine thymoma viral oncogene homolog 1 (AKT1). Conclusions These data provide a rationale for investigation of the role of CHKA in further models of de novo and acquired resistance to AIs, and provide proof of concept that integrative genomic analyses can identify biologically relevant modulators of AI response

On the Practical Limitations for the Generation of Gunn Oscillations in Highly Doped GaN Diodes

Planar Gunn diodes based on doped GaN active layers with different geometries have been fabricated and characterized. Gunn oscillations have not been observed due to the catastrophic breakdown of the diodes for applied voltages around 20-25 V, much below the bias theoretically needed for the onset of Gunn oscillations. The breakdown of the diodes has been analyzed by pulsed I-V measurements at low temperature, and it has been observed to be almost independent of the geometry of the channels, thus allowing to discard self-heating effects as the origin of the device burning. The other possible mechanism for the device failure is impact-ionization avalanche due to the high electric fields present at the anode corner of the isolating trenches. However, Monte Carlo simulations using the typical value of the intervalley energy separation of GaN, ε_(1-2)=2.2 eV, show that impact ionization mechanisms are not significant for the voltages for which the experimental failure is observed. But recent experiments showed that ε_(1-2) is lower, around 0.9 eV. This lower intervalley separation leads to a much lower threshold voltage for the Gunn oscillations, not far from the experimental breakdown. Therefore, we attribute the devices failure to an avalanche process just when Gunn domains start to form, since they increase the population of electrons at the high electric field region, thus strongly enhancing impact ionization mechanisms which lead to the diode failure

Peptide based amphiphiles

Contains fulltext : 13849.pdf (publisher's version ) (Open Access

Project INTEGRATE: An Integrative Study of Brief Alcohol Interventions for College Students

This paper provides an overview of a study that synthesizes multiple, independently collected alcohol intervention studies for college students into a single, multisite longitudinal data set. This research embraced innovative analytic strategies (i.e., integrative data analysis or meta-analysis using individual participant-level data), with the overall goal of answering research questions that are difficult to address in individual studies such as moderation analysis, while providing a built-in replication for the reported efficacy of brief motivational interventions for college students. Data were pooled across 24 intervention studies, of which 21 included a comparison or control condition and all included one or more treatment conditions. This yielded a sample of 12,630 participants (42% men; 58% first-year or incoming students). The majority of the sample identified as White (74%), with 12% Asian, 7% Hispanic, 2% Black, and 5% other/mixed ethnic groups. Participants were assessed two or more times from baseline up to 12 months, with varying assessment schedules across studies. This paper describes how we combined individual participant-level data from multiple studies, and discusses the steps taken to develop commensurate measures across studies via harmonization and newly developed Markov chain Monte Carlo algorithms for two-parameter logistic item response theory models and a generalized partial credit model. This innovative approach has intriguing promises, but significant barriers exist. To lower the barriers, there is a need to increase overlap in measures and timing of follow-up assessments across studies, better define treatment and control groups, and improve transparency and documentation in future single, intervention studies

Synthesis of a Fully Conjugated Phthalocyanine-Diketopyrrolopyrrole-Phthalocyanine Triad ow Band Gap Donor in Small Molecule Bulk Heterojunction Solar Cells

We describe the synthesis and photovoltaic properties of a fully conjugated phthalocyanine-diketopyrrolopyrrole-phthalocyanine triad (ZnPc-DPP-ZnPc) that presents strong visible absorption from 400 to 900 nm. The synthesis of the phthalocyanine with full conjugation to diketopyrrolopyrrole provides access to a new family of low band gap materials (<1.6 eV). Organic solar cells employing bulk heterojunction ZnPc-DPP-ZnPc:PC70BM films using MoO3 as anodic interfacial layer (IFL) show a power conversion efficiency of 1.04 %. The power conversion efficiency decreases considerably by using PEDOT:PSS as interfacial layer as a consequence of protonation of the ZnPc

ConservedPrimers 2.0: A high-throughput pipeline for comparative genome referenced intron-flanking PCR primer design and its application in wheat SNP discovery

<p>Abstract</p> <p>Background</p> <p>In some genomic applications it is necessary to design large numbers of PCR primers in exons flanking one or several introns on the basis of orthologous gene sequences in related species. The primer pairs designed by this target gene approach are called "intron-flanking primers" or because they are located in exonic sequences which are usually conserved between related species, "conserved primers". They are useful for large-scale single nucleotide polymorphism (SNP) discovery and marker development, especially in species, such as wheat, for which a large number of ESTs are available but for which genome sequences and intron/exon boundaries are not available. To date, no suitable high-throughput tool is available for this purpose.</p> <p>Results</p> <p>We have developed, the ConservedPrimers 2.0 pipeline, for designing intron-flanking primers for large-scale SNP discovery and marker development, and demonstrated its utility in wheat. This tool uses non-redundant wheat EST sequences, such as wheat contigs and singleton ESTs, and related genomic sequences, such as those of rice, as inputs. It aligns the ESTs to the genomic sequences to identify unique colinear exon blocks and predicts intron lengths. Intron-flanking primers are then designed based on the intron/exon information using the Primer3 core program or BatchPrimer3. Finally, a tab-delimited file containing intron-flanking primer pair sequences and their primer properties is generated for primer ordering and their PCR applications. Using this tool, 1,922 bin-mapped wheat ESTs (31.8% of the 6,045 in total) were found to have unique colinear exon blocks suitable for primer design and 1,821 primer pairs were designed from these single- or low-copy genes for PCR amplification and SNP discovery. With these primers and subsequently designed genome-specific primers, a total of 1,527 loci were found to contain one or more genome-specific SNPs.</p> <p>Conclusion</p> <p>The ConservedPrimers 2.0 pipeline for designing intron-flanking primers was developed and its utility demonstrated. The tool can be used for SNP discovery, genetic variation assays and marker development for any target genome that has abundant ESTs and a related reference genome that has been fully sequenced. The ConservedPrimers 2.0 pipeline has been implemented as a command-line tool as well as a web application. Both versions are freely available at <url>http://wheat.pw.usda.gov/demos/ConservedPrimers/</url>.</p

Feasibility Study of Dual Energy Radiographic Imaging for Target Localization in Radiotherapy for Lung Tumors

Purpose Dual-energy (DE) radiographic imaging improves tissue discrimination by separating soft from hard tissues in the acquired images. This study was to establish a mathematic model of DE imaging based on intrinsic properties of tissues and quantitatively evaluate the feasibility of applying the DE imaging technique to tumor localization in radiotherapy. Methods We investigated the dependence of DE image quality on the radiological equivalent path length (EPL) of tissues with two phantoms using a stereoscopic x-ray imaging unit. 10 lung cancer patients who underwent radiotherapy each with gold markers implanted in the tumor were enrolled in the study approved by the hospital's Ethics Committee. The displacements of the centroids of the delineated gross tumor volumes (GTVs) in the digitally reconstructed radiograph (DRR) and in the bone-canceled DE image were compared with the averaged displacements of the centroids of gold markers to evaluate the feasibility of using DE imaging for tumor localization. Results The results of the phantom study indicated that the contrast-to-noise ratio (CNR) was linearly dependent on the difference of EPL and a mathematical model was established. The objects and backgrounds corresponding to ΔEPL less than 0.08 are visually indistinguishable in the bone-canceled DE image. The analysis of patient data showed that the tumor contrast in the bone-canceled images was improved significantly as compared with that in the original radiographic images and the accuracy of tumor localization using the DE imaging technique was comparable with that of using fiducial makers. Conclusion It is feasible to apply the technique for tumor localization in radiotherapy