The evaluation of a series of 4,6-bis-anilino-1H-pyrrolo2,3-dpyrimidines as inhibitors of the IGF-1R (IGF-IR) receptor tyrosine kinase is reported. Examples demonstrate nanomolar potencies in in ...vitro enzyme and mechanistic cellular assays as well as promising in vivo pharmacokinetics in rat.
A series of thiophene PLK1 inhibitors was optimized for increased solubility and reduced protein binding through the appendage of basic amine functionality. Interesting selectivity between PLK1 and ...PLK3 was also obtained through these modifications.
The optimization of imidazo1,2-
apyridine inhibitors as potent and selective inhibitors of IGF-1R is presented. Further optimization of oral exposure in mice is also discussed. Detailed selectivity, ...in vitro activity, and in vivo PK profiles of an optimized compound is also highlighted.
Sleep traits are associated with cardiometabolic disease risk, with evidence from Mendelian randomization (MR) suggesting that insomnia symptoms and shorter sleep duration increase coronary artery ...disease risk. We combined adjusted multivariable regression (AMV) and MR analyses of phenotypes of unfavourable sleep on 113 metabolomic traits to investigate possible biochemical mechanisms linking sleep to cardiovascular disease.
We used AMV (N = 17,368) combined with two-sample MR (N = 38,618) to examine effects of self-reported insomnia symptoms, total habitual sleep duration, and chronotype on 113 metabolomic traits. The AMV analyses were conducted on data from 10 cohorts of mostly Europeans, adjusted for age, sex, and body mass index. For the MR analyses, we used summary results from published European-ancestry genome-wide association studies of self-reported sleep traits and of nuclear magnetic resonance (NMR) serum metabolites. We used the inverse-variance weighted (IVW) method and complemented this with sensitivity analyses to assess MR assumptions.
We found consistent evidence from AMV and MR analyses for associations of usual vs. sometimes/rare/never insomnia symptoms with lower citrate (- 0.08 standard deviation (SD)95% confidence interval (CI) - 0.12, - 0.03 in AMV and - 0.03SD - 0.07, - 0.003 in MR), higher glycoprotein acetyls (0.08SD 95% CI 0.03, 0.12 in AMV and 0.06SD 0.03, 0.10) in MR), lower total very large HDL particles (- 0.04SD - 0.08, 0.00 in AMV and - 0.05SD - 0.09, - 0.02 in MR), and lower phospholipids in very large HDL particles (- 0.04SD - 0.08, 0.002 in AMV and - 0.05SD - 0.08, - 0.02 in MR). Longer total sleep duration associated with higher creatinine concentrations using both methods (0.02SD per 1 h 0.01, 0.03 in AMV and 0.15SD 0.02, 0.29 in MR) and with isoleucine in MR analyses (0.22SD 0.08, 0.35). No consistent evidence was observed for effects of chronotype on metabolomic measures.
Whilst our results suggested that unfavourable sleep traits may not cause widespread metabolic disruption, some notable effects were observed. The evidence for possible effects of insomnia symptoms on glycoprotein acetyls and citrate and longer total sleep duration on creatinine and isoleucine might explain some of the effects, found in MR analyses of these sleep traits on coronary heart disease, which warrant further investigation.
High-field magnetic resonance-linear accelerators (MR-Linacs), linear accelerators combined with a diagnostic magnetic resonance imaging (MRI) scanner and online adaptive workflow, potentially give ...rise to novel online anatomic and response adaptive radiation therapy paradigms. The first high-field (1.5T) MR-Linac received regulatory approval in late 2018, and little is known about clinical use, patient tolerability of daily high-field MRI, and toxicity of treatments. Herein we report the initial experience within the MOMENTUM Study (NCT04075305), a prospective international registry of the MR-Linac Consortium.
Patients were included between February 2019 and October 2020 at 7 institutions in 4 countries. We used descriptive statistics to describe the patterns of care, tolerability (the percentage of patients discontinuing their course early), and safety (grade 3-5 Common Terminology Criteria for Adverse Events v.5 acute toxicity within 3 months after the end of treatment).
A total 943 patients participated in the MOMENTUM Study, 702 of whom had complete baseline data at the time of this analysis. Patients were primarily male (79%) with a median age of 68 years (range, 22-93) and were treated for 39 different indications. The most frequent indications were prostate (40%), oligometastatic lymph node (17%), brain (12%), and rectal (10%) cancers. The median number of fractions was 5 (range, 1-35). Six patients discontinued MR-Linac treatments, but none due to an inability to tolerate repeated high-field MRI. Of the 415 patients with complete data on acute toxicity at 3-month follow-up, 18 (4%) patients experienced grade 3 acute toxicity related to radiation. No grade 4 or 5 acute toxicity related to radiation was observed.
In the first 21 months of our study, patterns of care were diverse with respect to clinical utilization, body sites, and radiation prescriptions. No patient discontinued treatment due to inability to tolerate daily high-field MRI scans, and the acute radiation toxicity experience was encouraging.
Skin autofluorescence, a biomarker for advanced glycation end products (AGEs) accumulation, has been shown to predict diabetes-related cardiovascular complications and is associated with several ...environmental and lifestyle factors. In the present study, we examined the association between various smoking behaviors and skin autofluorescence, as well as the association between several cotinine biomarkers and skin autofluorescence, using both epidemiological and metabolomics data.
In a cross-sectional study, we evaluated participants from the LifeLines Cohort Study and the Qatar Metabolomics Study on Diabetes (QMDiab). In the LifeLines Cohort Study smoking behavior and secondhand smoking were assessed in 8,905 individuals including 309 individuals (3.5%) with type 2 diabetes. In QMDiab, cotinine biomarkers were measured in saliva, plasma and urine in 364 individuals of whom 188 (51%) had type 2 diabetes. Skin autofluorescence was measured non-invasively in all participants using the AGE Reader.
Skin autofluorescence levels increased with a higher number of hours being exposed to secondhand smoking. Skin autofluorescence levels of former smokers approached levels of never smokers after around 15 years of smoking cessation. Urinary cotinine N-oxide, a biomarker of nicotine exposure, was found to be positively associated with skin autofluorescence in the QMDiab study (p = 0.03).
In the present study, we have demonstrated that secondhand smoking is associated with higher skin autofluorescence levels whereas smoking cessation has a beneficial effect on skin autofluorescence. Finally, urinary cotinine N-oxide might be used as an alternative way for questionnaires to examine the effect of (environmental) tobacco smoking on skin autofluorescence.
No replacement for succinylcholine is yet available. GW280430A (AV430A) is a representative of a new class of nondepolarizing neuromuscular blocking drugs called asymmetric mixed-onium ...chlorofumarates. It undergoes rapid degradation in plasma by chemical hydrolysis and inactivation by cysteine adduction, resulting in a very short duration of effect. The neuromuscular, cardiovascular, and autonomic pharmacology of GW280430A is compared herein with that of mivacurium.
Adult male rhesus monkeys and adult male cats were anesthetized with nitrous oxide-oxygen-halothane and chloralose-pentobarbital, respectively. The neuromuscular blocking properties of GW280430A and mivacurium were compared at a stimulation rate of 0.15 Hz in the extensor digitorum of the foot (monkey) and the tibialis anterior (cat). Sympathetic responses were assayed in the cat in the nictitating membrane preparation, and vagal effects were evaluated in the cat via observation of bradycardic responses after stimulation of the cervical right vagus nerve.
GW280430A and mivacurium were equipotent in the monkey (ED95 was 0.06 mg/kg in each case). GW280430A was half as potent as mivacurium in the cat. The total duration of action of GW280430A was less than half that of mivacurium in the monkey; recovery slopes were more than twice as rapid. The 25-75% recovery index of GW280430A did not vary significantly after various bolus doses or infusions, averaging 1.4-1.8 min in the monkey, significantly shorter than the same time interval (4.8-5.7 min) for mivacurium. Dose ratios for autonomic versus neuromuscular blocking properties in the cat were greater than 25 for both GW280430A and mivacurium. The ratio ED Hist:ED95 Neuromuscular Block in the monkey was significantly greater (approximately 53 vs. 13) for GW280430A, indicating approximately four times less relative prominence of the side effects of skin flushing and decrease of blood pressure, which are associated with release of histamine.
These experiments show a much shorter neuromuscular blocking effect and much-reduced side effects in the case of GW280430A vis-à-vis mivacurium. These results, together with the novel chemical degradation of GW280430A, suggest further evaluation in human subjects.
A potent series of inhibitors against the B-Raf(V600E) kinase have been developed that show excellent activity in cellular assays and good oral bioavailability in rats. The key structural features of ...the series are an arylsulfonamide headgroup, a thiazole core, and a fluorine ortho to the sulfonamide nitrogen.
The process of neurogenesis in mammals, which is prolific and widespread at birth, gradually slows with aging and in humans becomes restricted to areas including the cerebellum and hippocampus. It ...has been reported that exposure to glucocorticoids can impair neurogenesis in both adults and children. Glucocorticoids are known to bind with high affinity to intracellular receptors. Glucocorticoid blood levels are normally regulated by environmental stresses, but because of their clinical utility, exogenous glucocorticoids are frequently administered in drug formulations. Consequently, concerns have arisen about the consequences of glucocorticoid use on neurogenesis and health, especially in the pediatric population. In this article, we will review recent findings that a select number of related glucocorticoids, halcinonide, fluticasone propionate, clobetasol propionate, and fluocinonide, also bind the hedgehog pathway receptor Smoothened. We will discuss their pharmacology and also a most surprising result; that this select group of compounds, which includes FDA approved drugs, unlike typical glucocorticoids such as dexamethasone, stimulate stem cell growth, and thus enhance neurogenesis.
Development of antisense technology has focused in part on creating improved methods for delivering oligodeoxynucleotides (ODNs) to cells. In this report, we describe a cationic lipid that, when ...formulated with the fusogenic lipid dioleoylphosphatidylethanolamine, greatly improves the cellular uptake properties of antisense ODNs, as well as plasmid DNA. This lipid formulation, termed GS 2888 cytofectin, (i) efficiently transfects ODNs and plasmids into many cell types in the presence or absence of 10% serum in the medium, (ii) uses a 4- to 10-fold lower concentration of the agent as compared to the commercially available Lipofectin liposome, and (iii) is ≥ 20-fold more effective at eliciting antisense effects in the presence of serum when compared to Lipofectin. Here we show antisense effects using GS 2888 cytofectin together with C-5 propynyl pyrimidine phosphorothioate ODNs in which we achieve inhibition of gene expression using low nanomolar concentrations of ODN. This agent expands the utility of antisense ODNs for their use in understanding gene function and offers the potential for its use in DNA delivery applications in vivo.
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