Network meta-regression for ordinal outcomes: Applications in comparing Crohn's disease treatments.

Crohn's disease (CD) is a life-long condition associated with recurrent relapses characterized by abdominal pain, weight loss, anemia, and persistent diarrhea. In the US, there are approximately 780 000 CD patients and 33 000 new cases added each year. In this article, we propose a new network meta-regression approach for modeling ordinal outcomes in order to assess the efficacy of treatments for CD. Specifically, we develop regression models based on aggregate covariates for the underlying cut points of the ordinal outcomes as well as for the variances of the random effects to capture heterogeneity across trials. Our proposed models are particularly useful for indirect comparisons of multiple treatments that have not been compared head-to-head within the network meta-analysis framework. Moreover, we introduce Pearson residuals and construct an invariant test statistic to evaluate goodness-of-fit in the setting of ordinal outcome data. A detailed case study demonstrating the usefulness of the proposed methodology is carried out using aggregate ordinal outcome data from 16 clinical trials for treating CD.

Human Intestinal Allografts Contain Functional Hematopoietic Stem and Progenitor Cells that Are Maintained by a Circulating Pool.

Human intestinal transplantation often results in long-term mixed chimerism of donor and recipient blood in transplant patients. We followed the phenotypes of chimeric peripheral blood cells in 21 patients receiving intestinal allografts over 5 years. Donor lymphocyte phenotypes suggested a contribution of hematopoietic stem and progenitor cells (HSPCs) from the graft. Surprisingly, we detected donor-derived HSPCs in intestinal mucosa, Peyer's patches, mesenteric lymph nodes, and liver. Human gut HSPCs are phenotypically similar to bone marrow HSPCs and have multilineage differentiation potential in vitro and in vivo. Analysis of circulating post-transplant donor T cells suggests that they undergo selection in recipient lymphoid organs to acquire immune tolerance. Our longitudinal study of human HSPCs carried in intestinal allografts demonstrates their turnover kinetics and gradual replacement of donor-derived HSPCs from a circulating pool. Thus, we have demonstrated the existence of functioning HSPCs in human intestines with implications for promoting tolerance in transplant recipients.

Identification of novel peptoid agonists of fibroblast growth factor receptor using microarray-based screening.

Drug development targeting fibroblast growth factor receptors (FGFRs) represents an emerging theme in the field of medicinal chemistry. Considering the fact that most of the currently identified FGFR agonists are long chain peptides with limited stability, the discovery of novel non-peptide FGFR ligands is still highly demanded. A linear one-bead-one-compound peptoid (oligomers of N-substituted glycine units) library with a theoretical diversity of 106 was designed and synthesized. Microarray-based screening led to the identification of four hit sequences 1-4 as FGFR1α ligands, which were further confirmed using both solution-phase and solid-phase binding assays. Western blot results indicated that peptoids 2-4 activated FGFR signaling pathways, resulting in increased levels of p-Akt and p-ERK in different cell lines. Our work discovered novel peptoid ligands as FGFR agonists, shedding new light on FGFR-based drug discovery.

Design-Based Peptidomimetic Ligand Discovery to Target HIV TAR RNA Using Comparative Analysis of Different Docking Methods.

Discovering molecules capable of binding to HIV trans-activation responsive region (TAR) RNA thereby disrupting its interaction with Tat protein is an attractive strategy for developing novel antiviral drugs. Computational docking is considered as a useful tool for predicting binding affinity and conducting virtual screening. Although great progress in predicting protein-ligand interactions has been achieved in the past few decades, modeling RNA-ligand interactions is still largely unexplored due to the highly flexible nature of RNA. In this work, we performed molecular docking study with HIV TAR RNA using previously identified cyclic peptide L22 and its analogues with varying affinities toward HIV-1 TAR RNA. Furthermore, sarcosine scan was conducted to generate derivatives of CGP64222, a peptide-peptoid hybrid with inhibitory activity on Tat/TAR RNA interaction. Each compound was docked using CDOCKER, Surflex-Dock and FlexiDock to compare the effectiveness of each method. It was found that FlexiDock energy values correlated well with the experimental Kd values and could be used to predict the affinity of the ligands toward HIV-1 TAR RNA with a superior accuracy. Our results based on comparative analysis of different docking methods in RNA-ligand modeling will facilitate the structure-based discovery of HIV TAR RNA ligands for antiviral therapy.

Gene expression profiling leads to discovery of correlation of matrix metalloproteinase 11 and heparanase 2 in breast cancer progression.

BACKGROUND: In order to identify biomarkers involved in breast cancer, gene expression profiling was conducted using human breast cancer tissues. METHODS: Total RNAs were extracted from 150 clinical patient tissues covering three breast cancer subtypes (Luminal A, Luminal B, and Triple negative) as well as normal tissues. The expression profiles of a total of 50,739 genes were established from a training set of 32 samples using the Agilent Sure Print G3 Human Gene Expression Microarray technology. Data were analyzed using Agilent Gene Spring GX 12.6 software. The expression of several genes was validated using real-time RT-qPCR. RESULTS: Data analysis with Agilent GeneSpring GX 12.6 software showed distinct expression patterns between cancer and normal tissue samples. A group of 28 promising genes were identified with ≥ 10-fold changes of expression level and p-values < 0.05. In particular, MMP11 and HPSE2 were closely examined due to the important roles they play in cancer cell growth and migration. Real-time RT-qPCR analyses of both training and testing sets validated the gene expression profiles of MMP11 and HPSE2. CONCLUSIONS: Our findings identified these 2 genes as a novel breast cancer biomarker gene set, which may facilitate the diagnosis and treatment in breast cancer clinical therapies.

Discovery of Gene Regulation Pattern in Lung Cancer by Gene Expression Profiling Using Human Tissues.

Lung cancer continues to be one the most prevalent and life threatening cancers worldwide. In order to study the gene regulation pattern in lung cancer for new therapeutics discovery, gene expression profiling using human lung cancer tissues was conducted. The gene expression profiles were established using Affymetrix Human Exon 1.0 ST Array with RNA extracts from six clinical patients (five lung cancer samples and one normal control). The raw data were analyzed with Affymetrix Expression Console and Affymetrix Transcriptome Analysis Console 2.0. The regulation of several genes were further validated using real-time reverse transcription quantitative polymerase chain reaction (RT-qPCR). Here we provide detailed experimental methods and analysis for the microarray data, which have been deposited into Gene Expression Omnibus (GEO) under GSE63571.

Identification of Biomarkers in Breast Cancer by Gene Expression Profiling Using Human Tissues.

Breast cancer is the second leading cause of death by cancer in women. To identify biomarkers with potential diagnostic and therapeutic utilities in breast cancer, gene expression profiling from real patient tissues were used to discover significantly deregulated genes out of 50,739 genes of human transcriptome. Total RNAs were extracted, and the gene expression profiles of 32 cancerous and normal tissues were established using Agilent gene expression microarray technology. The results were analyzed with Agilent GeneSpring 12.6 software. Here we provide detailed experimental methods and analysis for the microarray data, which have been deposited into Gene Expression Omnibus (GEO) under GSE57297.

Distinct conformational transition patterns of noncoding 7SK snRNA and HIV TAR RNAs upon Tat binding.

Noncoding 7SK snRNA is believed to play an important role in the recruitment of P-TEFb by viral protein Tat to stimulate HIV processive transcription. Because HIV-2 TAR RNA and 7SK both evolved to feature a dinucleotide bulge region, compared to the trinucleotide bulge for HIV-1 TAR, ultrafast time-resolved fluorescence spectroscopy has been used to probe the conformational landscape of HIV-2 TAR and 7SK-SL4 RNA to monitor the conformational changes upon Tat binding. Our studies demonstrate that both HIV-1/2 TAR and 7SK-SL4 sample heterogeneous ensembles in the free state and undergo distinct conformational transitions upon Tat binding. These findings provide exquisite knowledge on the conformational complexity and intricate mechanism of molecular recognition and pave the way for drug design and discovery that incorporate dynamics information.

Dissect conformational distribution and drug-induced population shift of prokaryotic rRNA A-site.

The dynamic behavior of the rRNA A-site plays an important functional role. We have employed femtosecond time-resolved spectroscopy to investigate the nature of the conformational dynamics. In the drug-free state, the A-site samples multiple distinct conformations. Drug binding shifts the population distribution in a drug-specific manner. Motions of bases on nanosecond and picosecond time scales are differentially affected by the drug binding. Our results underscore the importance of understanding the detailed dynamic picture of molecular recognition by resolving dynamics in the distinct picosecond time regime and facilitate development of antimicrobial drugs targeting dynamic RNAs.

Etanercept for the treatment of psoriasis in the elderly.

This study's objective was to analyze the effect of etanercept on Psoriasis Area and Severity Index (PASI) 50, PASI 75, and Dermatology Life Quality Index in geriatric and nongeriatric populations. We conducted a post hoc analysis of two large phase III randomized placebo trials of etanercept. There were no statistically significant differences between the elderly and young with regard to the number of patients reaching a PASI 50 or PASI 75 at any of the 3 dosing regimens. Baseline Dermatology Life Quality Index scores were not statistically significant between both groups and both the elderly and young had similar changes in Dermatology Life Quality Index with therapy. A limitation of the study was the small number of patients in the elderly group. In conclusion, psoriasis and its treatment has a similar impact on quality of life in the elderly as it does in the young.

Temporal patterns of ventricular tachyarrhythmia recurrences follow a Weibull distribution.

UNLABELLED: Temporal patterns of ventricular tachyarrhythmias. INTRODUCTION: The objective of this study was to test whether the temporal patterns of ventricular tachyarrhythmia recurrences in patients with implantable cardioverter-defibrillator (ICD) follow a random or a clustered distribution. METHODS: Data analysis was conducted using the Medtronic (Minneapolis, MN) Gem DR database of 521 ICD patients. Patients with >or=3 sustained ventricular tachyarrhythmia detections that resulted in shock or antitachycardia pacing therapies were studied. The times between consecutively treated ICD detections for each patient were compared to an exponential model of random recurrences and a Weibull model for clustered recurrences. RESULTS: Seventy-one patients had >or=3VT episodes during follow-up of 131+/-86 days. A total of 2347 VT episodes were recorded (33+/-65 episodes/patient, median 10 episodes/patient). Patient age was 66+/-13 years, 78% male, 83% coronary artery disease, ejection fraction 31+/-11%, and 63% were taking antiarrhythmic drugs. By the Kolmogorov-Smirnov goodness-of-fit test, 38 of 71 patients (53.5%) showed that the pattern of detections differed from an exponential model (P<0.01 for each patient and the proportion of patients was similar to chance at P=0.65). In contrast, only 11 out of 71 patients (15.5%) showed that the pattern differed from the Weibull model (P<0.01 for each patient). The proportion of patients fitting the Weibull model was significantly greater than chance and was greater that the proportion fitting the exponential model (both P<0.001). The time interval between consecutive detections was less than 1 hour for 78% of all 2347 detections. The proportion of all 521 patients with >or=2, >or=3, >or= 4, >or=6, >or=8, and >or=10 ICD detections in a 24-hour period was 10.5%, 9.5%, 8.1%, 7.0%, 6.3%, and 5.2%, respectively. CONCLUSION: In most patients with >or=3 ICD detections, the recurrence pattern of treated ventricular tachyarrhythmia detections are clustered and can be described by a Weibull distribution. The proportion of patients with multiple detections in a 24-hour period declines in a linear fashion as the number of events in 24 hours increases from 2 to 10 events.