Science translational medicine
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Randomized Controlled Trial
Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans.
We report the discovery and translational therapeutic efficacy of a peptide with potent, balanced co-agonism at both of the receptors for the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This unimolecular dual incretin is derived from an intermixed sequence of GLP-1 and GIP, and demonstrated enhanced antihyperglycemic and insulinotropic efficacy relative to selective GLP-1 agonists. Notably, this superior efficacy translated across rodent models of obesity and diabetes, including db/db mice and ZDF rats, to primates (cynomolgus monkeys and humans). ⋯ These peptides provide comparable pharmacology to the native peptides and enhanced efficacy relative to similarly modified selective GLP-1 agonists. The pharmacokinetic enhancement lessened peak drug exposure and, in combination with less dependence on GLP-1-mediated pharmacology, avoided the adverse gastrointestinal effects that typify selective GLP-1-based agonists. This discovery and validation of a balanced and high-potency dual incretin agonist enables a more physiological approach to management of diseases associated with impaired glucose tolerance.
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Clinical Trial
Slow-wave activity saturation and thalamocortical isolation during propofol anesthesia in humans.
The altered state of consciousness produced by general anesthetics is associated with a variety of changes in the brain's electrical activity. Under hyperpolarizing influences such as anesthetic drugs, cortical neurons oscillate at ~1 Hz, which is measurable as slow waves in the electroencephalogram (EEG). We have administered propofol anesthesia to 16 subjects and found that, after they had lost behavioral responsiveness (response to standard sensory stimuli), each individual's EEG slow-wave activity (SWA) rose to saturation and then remained constant despite increasing drug concentrations. ⋯ During the transition to SWA saturation, the thalamocortical system became isolated from sensory stimuli, whereas internal thalamocortical exchange persisted. Rather, an alternative and more fundamental cortical network (which includes the precuneus) responded to all sensory stimulation. We conclude that SWA saturation is a potential individualized indicator of perception loss that could prove useful for monitoring depth of anesthesia and studying altered states of consciousness.
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Multicenter Study
A blood-based proteomic classifier for the molecular characterization of pulmonary nodules.
Each year, millions of pulmonary nodules are discovered by computed tomography and subsequently biopsied. Because most of these nodules are benign, many patients undergo unnecessary and costly invasive procedures. We present a 13-protein blood-based classifier that differentiates malignant and benign nodules with high confidence, thereby providing a diagnostic tool to avoid invasive biopsy on benign nodules. ⋯ A pathway analysis demonstrated that the classifier proteins are likely modulated by a few transcription regulators (NF2L2, AHR, MYC, and FOS) that are associated with lung cancer, lung inflammation, and oxidative stress networks. The classifier score was independent of patient nodule size, smoking history, and age, which are risk factors used for clinical management of pulmonary nodules. Thus, this molecular test provides a potential complementary tool to help physicians in lung cancer diagnosis.
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We aimed to identify peripheral blood mononuclear cell (PBMC) gene expression profiles predictive of poor outcomes in idiopathic pulmonary fibrosis (IPF) by performing microarray experiments of PBMCs in discovery and replication cohorts of IPF patients. Microarray analyses identified 52 genes associated with transplant-free survival (TFS) in the discovery cohort. Clustering the microarray samples of the replication cohort using the 52-gene outcome-predictive signature distinguished two patient groups with significant differences in TFS. ⋯ A proportional hazards model, including the qRT-PCR expression of CD28, ICOS, LCK, and ITK along with patient's age, gender, and percent predicted forced vital capacity (FVC%), demonstrated an area under the receiver operating characteristic curve of 78.5% at 2.4 months for death and lung transplant prediction in the replication cohort. To evaluate the potential cellular source of CD28, ICOS, LCK, and ITK expression, we analyzed and found significant correlation of these genes with the PBMC percentage of CD4(+)CD28(+) T cells in the replication cohort. Our results suggest that CD28, ICOS, LCK, and ITK are potential outcome biomarkers in IPF and should be further evaluated for patient prioritization for lung transplantation and stratification in drug studies.