Institution
Eli Lilly and Company
Company•Indianapolis, Indiana, United States•
About: Eli Lilly and Company is a company organization based out in Indianapolis, Indiana, United States. It is known for research contribution in the topics: Population & Agonist. The organization has 17826 authors who have published 22835 publications receiving 946714 citations. The organization is also known as: Eli Lily.
Topics: Population, Agonist, Insulin, Placebo, Olanzapine
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TL;DR: A new, sensitive, rapid, and nonradioactive method involving the use of the commercially available BOCILLIN FL, a fluorescent penicillin, as a labeling reagent for the detection and study ofPenicillin-binding proteins (PBPs) is described.
Abstract: Penicillin-binding proteins (PBPs) are the enzymes that are required for the biosynthesis of the bacterial cell wall (10, 11, 23, 31). PBPs catalyze the final steps of the polymerization (transglycosylation) and cross-linking (transpeptidation) of peptidoglycan, an essential component of the bacterial cell wall (10, 11, 23, 31). PBPs are membrane-bound enzymes and targets of β-lactam antibiotics (6, 7, 10, 11, 14, 24, 28–31). The emerging resistance of pathogenic gram-positive bacteria to β-lactam antibiotics is a serious clinical problem (6, 25, 29, 30). Resistance to β-lactam antibiotics in some species such as Streptococcus pneumoniae has occurred by development of altered high-molecular-mass PBPs which have reduced affinity for the antibiotics (6, 7, 10, 11, 14, 24, 25, 29, 30). Extensive molecular and genetic studies have been devoted to the understanding of the mechanisms of bacterial resistance to β-lactam antibiotics (6, 7, 10, 11, 25, 29, 30).
PBPs have often been detected by labeling bacterial membrane preparations with 3H-, 14C-, or 125I-labeled penicillin, separating the labeled proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), and exposing the gels to X-ray films (22, 27, 28). The major limitations of this type of methodology are time intensiveness (days to weeks), accumulation of hazardous materials, and lack of commercial availability.
In this study, we describe a new, rapid, sensitive, and nonradioactive method for the detection and study of bacterial PBPs. This method involves the use of BOCILLIN FL (Fig. (Fig.1),1), a newly synthesized and commercially available fluorescent penicillin, as a labeling reagent (Molecular Probes, Inc., Eugene, Oreg.). The BOCILLIN FL-labeled PBPs were separated by SDS-PAGE and detected with a FluorImager or with the naked eye under UV light.
FIG. 1
Structure of BOCILLIN FL.
275 citations
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TL;DR: GC has a comparably acceptable toxicity profile compared with that of GP and seems active in patients with TCC, and no differences were noted in the overall toxicity profiles and any parameter of toxicity.
275 citations
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TL;DR: It is demonstrated that, once Aβ fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Aβ 40:42 may favor the formationof CAA versus paren chymic plaques.
Abstract: Alzheimer's disease (AD) is characterized by the aggregation and deposition of the normally soluble amyloid-beta (Abeta) peptide in the extracellular spaces of the brain as parenchymal plaques and in the walls of cerebral vessels as cerebral amyloid angiopathy (CAA). CAA is a common cause of brain hemorrhage and is found in most patients with AD. As in AD, the epsilon4 allele of the apolipoprotein E (apoE) gene (APOE) is a risk factor for CAA. To determine the effect of human apoE on CAA in vivo, we bred human APOE3 and APOE4 "knock-in" mice to a transgenic mouse model (Tg2576) that develops amyloid plaques as well as CAA. The expression of both human apoE isoforms resulted in a delay in Abeta deposition of several months relative to murine apoE. Tg2576 mice expressing the more fibrillogenic murine apoE develop parenchymal amyloid plaques and CAA by 9 months of age. At 15 months of age, the expression of human apoE4 led to substantial CAA with very few parenchymal plaques, whereas the expression of human apoE3 resulted in almost no CAA or parenchymal plaques. Additionally, young apoE4-expressing mice had an elevated ratio of Abeta 40:42 in brain extracellular pools and a lower 40:42 ratio in CSF, suggesting that apoE4 results in altered clearance and transport of Abeta species within different brain compartments. These findings demonstrate that, once Abeta fibrillogenesis occurs, apoE4 favors the formation of CAA over parenchymal plaques and suggest that molecules or treatments that increase the ratio of Abeta 40:42 may favor the formation of CAA versus parenchymal plaques.
275 citations
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TL;DR: In this paper, a seven-center inter-laboratory standardization study for cerebrospinal fluid (CSF) total tau (t-tau), phospho-Tau (p-tAU(181), and Aβ(1-42) was conducted as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI).
Abstract: The close correlation between abnormally low pre-mortem cerebrospinal fluid (CSF) concentrations of amyloid-β1-42 (Aβ(1-42)) and plaque burden measured by amyloid imaging as well as between pathologically increased levels of CSF tau and the extent of neurodegeneration measured by MRI has led to growing interest in using these biomarkers to predict the presence of AD plaque and tangle pathology. A challenge for the widespread use of these CSF biomarkers is the high variability in the assays used to measure these analytes which has been ascribed to multiple pre-analytical and analytical test performance factors. To address this challenge, we conducted a seven-center inter-laboratory standardization study for CSF total tau (t-tau), phospho-tau (p-tau(181)) and Aβ(1-42) as part of the Alzheimer's Disease Neuroimaging Initiative (ADNI). Aliquots prepared from five CSF pools assembled from multiple elderly controls (n = 3) and AD patients (n = 2) were the primary test samples analyzed in each of three analytical runs by the participating laboratories using a common batch of research use only immunoassay reagents (INNO-BIA AlzBio3, xMAP technology, from Innogenetics) on the Luminex analytical platform. To account for the combined effects on overall precision of CSF samples (fixed effect), different laboratories and analytical runs (random effects), these data were analyzed by mixed-effects modeling with the following results: within center %CV 95% CI values (mean) of 4.0-6.0% (5.3%) for CSF Aβ(1-42); 6.4-6.8% (6.7%) for t-tau and 5.5-18.0% (10.8%) for p-tau(181) and inter-center %CV 95% CI range of 15.9-19.8% (17.9%) for Aβ(1-42), 9.6-15.2% (13.1%) for t-tau and 11.3-18.2% (14.6%) for p-tau(181). Long-term experience by the ADNI biomarker core laboratory replicated this degree of within-center precision. Diagnostic threshold CSF concentrations for Aβ(1-42) and for the ratio t-tau/Aβ(1-42) were determined in an ADNI independent, autopsy-confirmed AD cohort from whom ante-mortem CSF was obtained, and a clinically defined group of cognitively normal controls (NCs) provides statistically significant separation of those who progressed from MCI to AD in the ADNI study. These data suggest that interrogation of ante-mortem CSF in cognitively impaired individuals to determine levels of t-tau, p-tau(181) and Aβ(1-42), together with MRI and amyloid imaging biomarkers, could replace autopsy confirmation of AD plaque and tangle pathology as the "gold standard" for the diagnosis of definite AD in the near future.
274 citations
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TL;DR: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage.
Abstract: Background Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. Methods In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naive patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. Results More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. Conclusions In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. Trial registration number NCT01721057; Results.
274 citations
Authors
Showing all 17866 results
Name | H-index | Papers | Citations |
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Mark J. Daly | 204 | 763 | 304452 |
Irving L. Weissman | 201 | 1141 | 172504 |
Eric J. Topol | 193 | 1373 | 151025 |
Tony Hunter | 175 | 593 | 124726 |
Xiang Zhang | 154 | 1733 | 117576 |
Jerrold M. Olefsky | 143 | 595 | 77356 |
Stephen F. Badylak | 133 | 530 | 57083 |
George A. Bray | 131 | 896 | 100975 |
Lloyd Paul Aiello | 131 | 506 | 85550 |
Levi A. Garraway | 129 | 366 | 99989 |
Mark Sullivan | 126 | 802 | 63916 |
James A. Russell | 124 | 1024 | 87929 |
Tony L. Yaksh | 123 | 806 | 60898 |
Elisabetta Dejana | 122 | 430 | 48254 |
Hagop S. Akiskal | 118 | 565 | 50869 |