Inhibition of vascular endothelial growth factor (VEGF) signaling has shown great promise for the treatment of ocular neovascular disease. Current anti-VEGF therapies in late-stage development, while ...efficacious, require dosing by frequent intravitreal injections that are inconvenient to patients. VEGF signaling inhibitors that demonstrate more convenient dosing regimens could lead to the improved treatment of neovascular diseases such as wet age related macular degeneration (AMD) and proliferative diabetic retinopathy (PDR). Here we describe the assessment of a KDR (VEGFR2) kinase inhibitor in two well-established models of ocular neovascularization following oral administration.
A novel KDR kinase inhibitor was dosed by oral gavage for 12 days at 0, 10, 30, or 100 mg/kg in an adult male Brown Norway rat laser induced choroidal neovascularization (CNV) model. The areas of CNV lesions were quantitated by fluorescence image analysis of FITC-dextran perfused animals. The kinase inhibitor was also assessed in a rat oxygen induced retinopathy (OIR) model in which neonatal rats were placed in an oxygen chamber that delivered alternating 24 h cycles of 50% and 10% oxygen for 14 days. After 14 days of oxygen treatment, the animals were returned to room air and dosed orally for 7 days with 0, 10, or 30 mg/kg kinase inhibitor. The extent of retinal neovascularization was assessed by counting pre-retinal neovascular nuclei on histological sections.
At doses of 100 mg/kg, the KDR kinase inhibitor resulted in a 98% reduction in lesion size in the rat CNV model. 30 mg/kg doses of the inhibitor showed a 70% and 80% reduction in lesion size in the laser CNV and OIR models, respectively.
Oral dosing of the described KDR kinase inhibitor effectively inhibits neovascularization in two well-established animal models of ocular neovascularization. These data suggest that compounds of this class may prove to be useful for the treatment of a variety of ocular neovascular diseases using a convenient oral dosing regimen.
Fibulin is a 100-kDa calcium-binding, extracellular matrix (ECM), and plasma glycoprotein (Argraves et al., Cell 58, pp. 623-629, 1989; Argraves et al., J. Cell Biol. 111, 3155-3164). ...Immunoprecipitation analysis showed that antibodies against human fibulin react with an avian isoform (M(r) 100,000). The spatial and temporal distribution of fibulin was examined in the early avian embryo using immunofluorescence microscopy. In stage 15-22 quail embryos fibulin is a constituent of most basement membranes. Areas undergoing epithelial-mesenchymal transitions such as the endocardial cushions, developing myotomes, and neural crest display especially prominent immunostaining. In the early heart fibulin expression was most pronounced in the cardiac jelly at sites where endocardial cushion cells begin the migrations that lead to the formation of valvular and septal primordia. Laser scanning confocal microscopy showed extensive extracellular accumulations of fibulin on the surface of endocardial mesenchyme cells that were motile at the time of fixation (stage 19). These data suggest that enhanced deposition of fibulin at sites of epithelial-mesenchymal transitions may influence cell behavior.
In recent years, credit union lending powers have been extended to mortgage and commercial lending, but their primary lending activity remains consumer oriented. Consumer lending for state-chartered ...credit unions is governed primarily by state law and those federal laws relevant to most federally regulated lenders, or it is based on federal insurance requirements. In contrast, federally chartered credit unions are subject to few state consumer lending laws and, instead, are governed almost exclusively by federal law. Federal credit unions are granted broad preemptive rights with regard to their lending authority. Their lending powers are derived from the Federal Credit Union Act and regulations promulgated by the National Credit Union Administration. Federal preemption of a state consumer credit law provision will depend on whether the state law is consistent with the federal law and regulation and whether a preemption determination is obtained by the particular state.
The experience with the submission of a nonclinical (pharmacology and toxicology) computer-assisted New Drug Application (CANDA) is reviewed. This system consisted of a stand-alone personal computer ...running several commercial programs in Microsoft Windows to access both text and data. WordPerfect was used as the word processor that contained all the documents and data tables (in read-only format) that were submitted in hard copy, and Andyne GQL was used as a tool to query the data in an Oracle relational database. Microsoft Excel was provided as a spreadsheet for graphics and analysis of data. Documents appeared virtually identical to those in the hard copy NDA submission. Searching the text was facilitated by the use of buttons on the screen, which allowed the NDA to be searched for a particular term. Data could be located either in WordPerfect documents, or in an Oracle database (using Andyne GQL) by querying the data. The data queries could be performed ad hoc, in which the reviewer selected all the parameters for a search, or with predefined query buttons, which retrieved data for principal treatment-related changes. This type of system also could serve as a useful model for both inhouse nonclinical review and the submission of INDs and IND amendments.
Gestation day 11 (GD11) and 14 (GD14) embryos were cultured for up to 4 hours in the presence of Dofetilide (0.01-0.50 microgram/ml), a potent Class III Antiarrhythmic which selectively inhibits the ...rapid component of the time dependent outward potassium current (IKr). Significant (P < or = 0.05) reductions in heart rate (HR) as measured over a 4 hour period were dose dependent and reversible. The sensitivity of the GD11 embryos was greater than GD14 embryos (14-64% decrease in HR vs. an 11-43% decrease in HR, respectively) at the same concentrations tested. These in vitro results support the hypothesis that the embryo-lethality of Class III Antiarrhythmics observed in vivo may be a class effect of the IKr subtype potassium channel blockers. The data suggest a possible mechanism of embryotoxicity is to lower embryonic HR resulting in subsequent hypoxia and death. Dofetilide's effects on GD11 HR were partially reversible by the sequential addition of Isoproterenol or Theophylline.
A challenge when interpreting replications is determining whether the results of a replication "successfully" replicate the original study. Looking for consistency between two studies is challenging ...because individual studies are susceptible to many sources of error that can cause study results to deviate from each other and the population effect in unpredictable directions and magnitudes. In the current paper, we derive methods to compute a prediction interval, a range of results that can be expected in a replication due to chance (i.e., sampling error), for means and commonly used indexes of effect size: correlations and d-values. The prediction interval is calculable based on objective study characteristics (i.e., effect size of the original study and sample sizes of the original study and planned replication) even when sample sizes across studies are unequal. The prediction interval provides an a priori method for assessing if the difference between an original and replication result is consistent with what can be expected due to sample error alone. We provide open-source software tools that allow researchers, reviewers, replicators, and editors to easily calculate prediction intervals.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Failures to replicate published psychological research findings have contributed to a "crisis of confidence." Several reasons for these failures have been proposed, the most notable being ...questionable research practices and data fraud. We examine replication from a different perspective and illustrate that current intuitive expectations for replication are unreasonable. We used computer simulations to create thousands of ideal replications, with the same participants, wherein the only difference across replications was random measurement error. In the first set of simulations, study results differed substantially across replications as a result of measurement error alone. This raises questions about how researchers should interpret failed replication attempts, given the large impact that even modest amounts of measurement error can have on observed associations. In the second set of simulations, we illustrated the difficulties that researchers face when trying to interpret and replicate a published finding. We also assessed the relative importance of both sampling error and measurement error in producing variability in replications. Conventionally, replication attempts are viewed through the lens of verifying or falsifying published findings. We suggest that this is a flawed perspective and that researchers should adjust their expectations concerning replications and shift to a meta-analytic mind-set.
One challenge when communicating science to practitioners and the general public is accurately representing statistical results. In particular, describing the meaning of statistical significance to a ...non-scientific audience is especially difficult given the technical nature of a correct definition. Correct interpretations of statistical significance can be unintuitive, nuanced, and use unfamiliar technical language. As a result, when researchers are tasked with providing short and understandable interpretations of statistical significance it can be tempting to default to convenient but incorrect interpretations. In the current paper, we offer a concise, simple, and correct interpretation of statistical significance that is suitable for communications targeting a general audience.
Over the last decade, replication research in the psychological sciences has become more visible. One way that replication research can be conducted is to compare the results of the replication study ...with the original study to look for consistency, that is to say, to evaluate whether the original study is “replicable.” Unfortunately, many popular and readily accessible methods for ascertaining replicability, such as comparing significance levels across studies or eyeballing confidence intervals, are generally ill suited to the task of comparing results across studies. To address this issue, we present the prediction interval as a statistic that is effective for determining whether a replication study is inconsistent with the original study. We review the statistical rationale for prediction intervals, demonstrate hand calculations, and provide a walkthrough using an R package for obtaining prediction intervals for means, d values, and correlations. To aid the effective adoption of prediction intervals, we provide guidance on the correct interpretation of results when using prediction intervals in replication research.
Glucokinase (GK) activation as a potential strategy to treat type 2 diabetes (T2D) is well recognized. Compound 1, a glucokinase activator (GKA) lead that we have previously disclosed, caused ...reversible hepatic lipidosis in repeat-dose toxicology studies. We hypothesized that the hepatic lipidosis was due to the structure-based toxicity and later established that it was due to the formation of a thiourea metabolite, 2. Subsequent SAR studies of 1 led to the identification of a pyrazine-based lead analogue 3, lacking the thiazole moiety. In vivo metabolite identification studies, followed by the independent synthesis and profiling of the cyclopentyl keto- and hydroxyl- metabolites of 3, led to the selection of piragliatin, 4, as the clinical lead. Piragliatin was found to lower pre- and postprandial glucose levels, improve the insulin secretory profile, increase β-cell sensitivity to glucose, and decrease hepatic glucose output in patients with T2D.
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