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121.
Herbert SB Baraf Michael A Becker Sergio R Gutierrez-Urena Edward L Treadwell Janitzia Vazquez-Mellado Claudia D Rehrig Faith D Ottery John S Sundy Robert A Yood 《Arthritis research & therapy》2013,15(5):R137
Introduction
Two replicate randomized, placebo-controlled six-month trials (RCTs) and an open-label treatment extension (OLE) comprised the pegloticase development program in patients with gout refractory to conventional therapy. In the RCTs, approximately 40% of patients treated with the approved dose saw complete response (CR) of at least one tophus. Here we describe the temporal course of tophus resolution, total tophus burden in patients with multiple tophi, tophus size at baseline, and the relationship between tophus response and urate-lowering efficacy.Methods
Baseline subcutaneous tophi were analyzed quantitatively using computer-assisted digital images in patients receiving pegloticase (8 mg biweekly or monthly) or placebo in the RCTs, and pegloticase in the OLE. Tophus response, a secondary endpoint in the trials, was evaluated two ways. Overall tophus CR was the proportion of patients achieving a best response of CR (without any new/enlarging tophi) and target tophus complete response (TT-CR) was the proportion of all tophi with CR.Results
Among 212 patients randomized in the RCTs, 155 (73%) had ≥1 tophus and 547 visible tophi were recorded at baseline. Overall tophus CR was recorded in 45% of patients in the biweekly group (P = 0.002 versus placebo), 26% in the monthly group, and 8% in the placebo group after six months of RCT therapy. TT-CR rates at six months were 28%, 19%, and 2% of tophi, respectively. Patients meeting the primary endpoint of sustained urate-lowering response to therapy (responders) were more likely than nonresponders to have an overall tophus CR at six months (54% vs 20%, respectively and 8% with placebo).Both overall tophus CR and TT-CRs increased with treatment duration in the OLE, reaching 70% (39/56) of patients and 55% (132/238) of target tophi after one year of treatment in patients receiving pegloticase during both the RCTs and OLE. At that time point, more tophi had resolved in responders (102/145 or 70% of tophi) than nonresponders (30/93; 32%).Conclusions
Pegloticase reduced tophus burden in patients with refractory tophaceous gout, especially those achieving sustained urate-lowering. Complete resolution of tophi occurred in some patients by 13 weeks and in others with longer-term therapy.Trial registrations
, NCT00325195 NCT01356498相似文献122.
Shaan Chugh Maral Ouzounian Zhen Lu Shanas Mohamed Wenping Li Nicolas Bousette Peter P. Liu Anthony O. Gramolini 《Proteomics》2013,13(15):2324-2334
In‐depth proteomic analyses offer a systematic way to investigate protein alterations in disease and, as such, can be a powerful tool for the identification of novel biomarkers. Here, we analyzed proteomic data from a transgenic mouse model with cardiac‐specific overexpression of activated calcineurin (CnA), which results in severe cardiac hypertrophy. We applied statistically filtering and false discovery rate correction methods to identify 52 proteins that were significantly different in the CnA hearts compared to controls. Subsequent informatic analysis consisted of comparison of these 52 CnA proteins to another proteomic dataset of heart failure, three available independent microarray datasets, and correlation of their expression with the human plasma and urine proteome. Following this filtering strategy, four proteins passed these selection criteria, including myosin heavy chain 7, insulin‐like growth factor‐binding protein 7, annexin A2, and desmin. We assessed expression levels of these proteins in mouse plasma by immunoblotting, and observed significantly different levels of expression between healthy and failing mice for all four proteins. We verified antibody cross‐reactivity by examining human cardiac explant tissue by immunoblotting. Finally, we assessed protein levels in plasma samples obtained from four unaffected and four heart failure patients and demonstrated that all four proteins increased between twofold and 150‐fold in heart failure. We conclude that MYH7, IGFBP7, ANXA2, and DESM are all excellent candidate plasma biomarkers of heart failure in mouse and human. 相似文献
123.
Post ‘omic’ era has resulted in the development of many primary, secondary and derived databases. Many analytical and
visualization bioinformatics tools have been developed to manage and analyze the data available through large sequencing
projects. Availability of heterogeneous databases and tools make it difficult for researchers to access information from varied
sources and run different bioinformatics tools to get desired analysis done. Building integrated bioinformatics platforms is one of
the most challenging tasks that bioinformatics community is facing. Integration of various databases, tools and algorithm is a
challenging problem to deal with. This article describes the bioinformatics analysis workflow management systems that are
developed in the area of gene sequence analysis and phylogeny. This article will be useful for biotechnologists, molecular
biologists, computer scientists and statisticians engaged in computational biology and bioinformatics research. 相似文献
124.
Chugh P Fan S Planelles V Maggirwar SB Dewhurst S Kim B 《Journal of molecular biology》2007,366(1):67-81
The interaction of human immunodeficiency virus type 1 (HIV-1) with CD4+ T lymphocytes is well studied and typically results in virally induced cytolysis. In contrast, relatively little is known concerning the interplay between HIV-1 and microglia. Recent findings suggest that, counter-intuitively, HIV-1 infection may extend the lifespan of microglia. We developed a novel cell line model system to confirm and mechanistically study this phenomenon. We found that transduction of a human microglial cell line with an HIV-1 vector results in a powerful cytoprotective effect following apoptotic challenge. This effect was reproduced by ectopic expression of a single virus-encoded protein, Tat. Subsequent studies showed that the pro-survival effects of intracellular Tat could be attributed to activation of the PI-3-kinase (PI3K)/Akt pathway in the microglial cell line. Furthermore, we found that expression of Tat led to decreased expression of PTEN, a negative regulator of the PI-3-K pathway. Consistent with this, decreased p53 activity and increased E2F activity were observed. Based on these findings, a model of possible regulatory circuits that intracellular Tat and HIV-1 infection engage during the cytoprotective event in microglia has been suggested. We propose that the expression of Tat may enable HIV-1 infected microglia to survive throughout the course of infection, leading to persistent HIV-1 production and infection in the central nervous system. 相似文献
125.
Thomas D Walko III Valentina Di Caro Jon Piganelli Timothy R Billiar Robert SB Clark Rajesh K Aneja 《Molecular medicine (Cambridge, Mass.)》2014,20(1):612-624
Pathophysiological conditions that lead to the release of the prototypic damage-associated molecular pattern molecule high mobility group box 1 (HMGB1) also result in activation of poly(ADP-ribose) polymerase 1 (PARP1; now known as ADP-ribosyl transferase 1 [ARTD1]). Persistent activation of PARP1 promotes energy failure and cell death. The role of poly(ADP-ribosyl)ation in HMGB1 release has been explored previously; however, PARP1 is a versatile enzyme and performs several other functions including cross-talk with another nicotinamide adenine dinucleotide- (NAD+) dependent member of the Class III histone deacetylases (HDACs), sirtuin-1 (SIRT1). Previously, it has been shown that the hyperacetylation of HMGB1 is a seminal event prior to its secretion, a process that also is dependent on HDACs. Therefore, in this study, we seek to determine if PARP1 inhibition alters LPS-mediated HMGB1 hyperacetylation and subsequent secretion due to its effect on SIRT1. We demonstrate in an in vitro model that LPS treatment leads to hyperacetylated HMGB1 with concomitant reduction in nuclear HDAC activity. Treatment with PARP1 inhibitors mitigates the LPS-mediated reduction in nuclear HDAC activity and decreases HMGB1 acetylation. By utilizing an NAD+-based mechanism, PARP1 inhibition increases the activity of SIRT1. Consequently, there is an increased nuclear retention and decreased extracellular secretion of HMGB1. We also demonstrate that PARP1 physically interacts with SIRT1. Further confirmation of this data was obtained in a murine model of sepsis, that is, administration of PJ-34, a specific PARP1 inhibitor, led to decreased serum HMGB1 concentrations in mice subjected to cecal ligation and puncture (CLP) as compared with untreated mice. In conclusion, our study provides new insights in understanding the molecular mechanisms of HMGB1 secretion in sepsis. 相似文献
126.
Stephen A Bustin Jean-François Beaulieu Jim Huggett Rolf Jaggi Frederick SB Kibenge Pål A Olsvik Louis C Penning Stefan Toegel 《BMC molecular biology》2010,11(1):74
The conclusions of thousands of peer-reviewed publications rely on data obtained using fluorescence-based quantitative real-time
PCR technology. However, the inadequate reporting of experimental detail, combined with the frequent use of flawed protocols
is leading to the publication of papers that may not be technically appropriate. We take the view that this problem requires
the delineation of a more transparent and comprehensive reporting policy from scientific journals. This editorial aims to
provide practical guidance for the incorporation of absolute minimum standards encompassing the key assay parameters for accurate
design, documentation and reporting of qPCR experiments (MIQE précis) and guidance on the publication of pure 'reference gene'
articles. 相似文献
127.
128.
Khan Z.U. Neil L. Chandy R. Chugh T.D. Al-Sayer H. Provost F. Boiron P. 《Mycopathologia》1997,137(3):159-163
A pilot study was undertaken to determine the occurrence and distribution of pathogenic nocardiae in Kuwaiti soil. A total
of 102 soil samples collected from two localities were investigated by the paraffin bait technique. Nocardia asteroides was
the only species isolated from 42 (41%) soil samples. None of the isolates fulfilled the criteria required for identification
of N. farcinica or N. nova. Thirty one (73.8%) isolates showed equivalent growth at 45 °C and 35 °C, 17 (40.4%) isolates utilized
acetamide for carbon and nitrogen requirements and 3 (7.1%) isolates showed delayed arylsulphatase activity. Only a solitary
isolate was resistant to cefamandole. Soil samples originating from the Kuwait University Campus Shuwaikh, which were rich
in humus/organic matter, were more productive for N. asteroides (67%) than the samples which were devoid of it but were mixed
with crude oil (39%). Sand samples that lacked organic matter and crude oil samples were least productive of N. asteroides.
These preliminary findings do not suggest that massive oil contamination of soil in the Ahmadi oil field area during the Gulf
war promoted the natural occurrence of N. asteroides. However, isolation of N. asteroides in as many as 41% of the soil sample
is a significant observation warranting further epidemiologic studies including its possible role in the operation desert
storm sickness syndrome. This is the first report on the natural occurrence of N. asteroides in Kuwait.
This revised version was published online in June 2006 with corrections to the Cover Date. 相似文献
129.
130.
Phylogeny and biogeography of ratite birds inferred from DNA sequences of the mitochondrial ribosomal genes 总被引:7,自引:2,他引:5
The origin of the flightless ratite birds of the southern continents has
been debated for over a century. Whether dispersal or vicariance
(continental breakup) best explains their origin depends largely on their
phylogenetic relationships. No consensus has been reached on this issue
despite many morphological and molecular studies. To address this question
further we sequenced a 2.8-kb region of mitochondrial DNA containing the
ribosomal genes in representative ratites and a tinamou. Phylogenetic
analyses indicate that Struthio (Africa) is basal and Rhea (South America)
clusters with living Australasian ratites. This phylogeny agrees with
transferrin and DNA hybridization studies but not with sequence analyses of
some protein-coding genes. These results also require reevaluation of the
phylogenetic position of the extinct moas of New Zealand. We propose a new
hypothesis for the origin of ratites that combines elements of dispersal
and vicariance.
相似文献