Clinical Outcomes Before and After Complete Everolimus-Eluting Bioresorbable Scaffold Resorption: Five-Year Follow-Up From the ABSORB III Trial.

BACKGROUND: The Absorb everolimus-eluting bioresorbable vascular scaffold (BVS) provides early drug delivery and mechanical support similar to those of metallic drug-eluting stents, followed by complete resorption in ≈3 years with recovery of vascular structure and function. The ABSORB III trial demonstrated noninferior rates of target lesion failure (cardiac death, target vessel myocardial infarction, or ischemia-driven target lesion revascularization) at 1 year with BVS compared with cobalt chromium everolimus-eluting stents. Between 1 and 3 years and cumulative to 3 years, adverse event rates (particularly target vessel myocardial infarction and scaffold thrombosis) were increased after BVS. We sought to assess clinical outcomes after BVS through 5 years, including beyond the 3-year time point of complete scaffold resorption. METHODS: Clinical outcomes from ABSORB III were analyzed by randomized device (intention to treat) cumulative to 5 years and between 3 and 5 years. RESULTS: Rates of target lesion failure, target vessel myocardial infarction, and scaffold thrombosis were increased through the 5-year follow-up with BVS compared with everolimus-eluting stents. However, between 3 and 5 years, reductions in the relative hazards of the BVS compared with everolimus-eluting stents were observed, particularly for target lesion failure (hazard ratio, 0.83 [95% CI, 0.55-1.24] versus 1.35 [95% CI, 1.02-1.78]; Pint=0.052) and scaffold thrombosis (hazard ratio, 0.26 [95% CI, 0.02-2.87] versus 3.23 [95% CI, 1.25-8.30]; Pint=0.056) compared with the 0- to 3-year time period. CONCLUSIONS: In the ABSORB III trial, cumulative 5-year adverse event rates were increased after BVS compared with everolimus-eluting stents. However, the period of excess risk for BVS ended at 3 years, coincident with complete scaffold resorption. CLINICAL TRIAL REGISTRATION: URL: https://clinicaltrials.gov. Unique identifier: NCT01751906.

Simultaneous identification of differential gene expression and connectivity in inflammation, adipogenesis and cancer.

MOTIVATION: Biological differences between classes are reflected in transcriptional changes which in turn affect the levels by which essential genes are individually expressed and collectively connected. The purpose of this communication is to introduce an analytical procedure to simultaneously identify genes that are differentially expressed (DE) as well as differentially connected (DC) in two or more classes of interest. RESULTS: Our procedure is based on a two-step approach: First, mixed-model equations are applied to obtain the normalized expression levels of each gene in each class treatment. These normalized expressions form the basis to compute a measure of (possible) DE as well as the correlation structure existing among genes. Second, a two-component mixture of bi-variate distributions is fitted to identify the component that encapsulates those genes that are DE and/or DC. We demonstrate our approach using three distinct datasets including a human systemic inflammation oligonucleotide data; a spotted cDNA data dealing with bovine in vitro adipogenesis and SAGE database on cancerous and normal tissue samples.

A gene coexpression network for bovine skeletal muscle inferred from microarray data.

We present the application of large-scale multivariate mixed-model equations to the joint analysis of nine gene expression experiments in beef cattle muscle and fat tissues with a total of 147 hybridizations, and we explore 47 experimental conditions or treatments. Using a correlation-based method, we constructed a gene network for 822 genes. Modules of muscle structural proteins and enzymes, extracellular matrix, fat metabolism, and protein synthesis were clearly evident. Detailed analysis of the network identified groupings of proteins on the basis of physical association. For example, expression of three components of the z-disk, MYOZ1, TCAP, and PDLIM3, was significantly correlated. In contrast, expression of these z-disk proteins was not highly correlated with the expression of a cluster of thick (myosins) and thin (actin and tropomyosins) filament proteins or of titin, the third major filament system. However, expression of titin was itself not significantly correlated with the cluster of thick and thin filament proteins and enzymes. Correlation in expression of many fast-twitch muscle structural proteins and enzymes was observed, but slow-twitch-specific proteins were not correlated with the fast-twitch proteins or with each other. In addition, a number of significant associations between genes and transcription factors were also identified. Our results not only recapitulate the known biology of muscle but have also started to reveal some of the underlying associations between and within the structural components of skeletal muscle.

A key gene of the RNA interference pathway in the black tiger shrimp, Penaeus monodon: identification and functional characterisation of Dicer-1.

RNA interference (RNAi) is an evolutionarily conserved mechanism by which double-stranded RNA (dsRNA) initiates post-transcriptional silencing of homologous genes. Here we report the amplification and characterisation of a full length cDNA from black tiger shrimp (Penaeus monodon) that encodes the bidentate RNAase III Dicer, a key component of the RNAi pathway. The full length of the shrimp Dicer (Pm Dcr1) cDNA is 7629bp in length, including a 5' untranslated region (UTR) of 130bp, a 3' UTR of 77bp, and an open reading frame of 7422bp encoding a polypeptide of 2473 amino acids with an estimated molecular mass of 277.895kDa and a predicted isoelectric point of 4.86. Analysis of the deduced amino acid sequence indicated that the mature peptide contains all the seven recognised functional domains and is most similar to the mosquito (Aedes aegypti) Dicer-1 sequence with a similarity of 34.6%. Quantitative RT-PCR analysis showed that Pm Dcr1 mRNA is most highly expressed in haemolymph and lymphoid organ tissues (P<0.05). However, there was no correlation between Pm Dcr1 mRNA levels in lymphoid organ and the viral genetic loads in shrimp naturally infected with gill-associated virus (GAV) and Mourilyan virus (P>0.05). Treatment with synthetic dsRNA corresponding to Pm Dcr1 sequence resulted in knock-down of Pm Dcr1 mRNA expression in both uninfected shrimp and shrimp infected experimentally with GAV. Knock-down of Pm Dcr1 expression resulted in more rapid mortalities and higher viral loads. These data demonstrated that Dicer is involved in antiviral defence in shrimp.

Gene expression profiling of bovine in vitro adipogenesis using a cDNA microarray.

The gene expression profile of bovine bone marrow stromal cells undergoing adipogenesis was established using a custom cDNA microarray. Cells that were treated with adipogenic stimulants and those that were not were collected at each of the six time points, and gene expression differences between the treated and untreated samples within each time point were compared using a microarray. Statistical analyses revealed that 158 genes showed a minimum fold change of 2 in at least one of the five post-differentiation time points. These genes are involved in various cellular pathways and functions, including lipogenesis, glycolysis, cytoskeleton remodelling, extracellular matrix, transcription as well as various signalling pathways such as insulin, calcium and wingless signalling. The experiment also identified 17 differentially expressed (DE) microarray elements with no assigned function. Quantitative real-time PCR was employed to validate eight DE genes, and the PCR data were found to reproduce the microarray data for these eight genes. Subsequent gene ontology annotation was able to provide a global overview of the molecular function of DE genes during adipogenesis. This analysis was able to indicate the importance of different gene categories at various stages of adipogenic conversion, thereby providing further insights into the molecular changes during bovine adipogenesis.