Science translational medicine
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Clinical Trial
Adverse metabolic consequences in humans of prolonged sleep restriction combined with circadian disruption.
Epidemiological studies link short sleep duration and circadian disruption with higher risk of metabolic syndrome and diabetes. We tested the hypotheses that prolonged sleep restriction with concurrent circadian disruption, as can occur in people performing shift work, impairs glucose regulation and metabolism. ⋯ These parameters normalized during the 9 days of recovery sleep and stable circadian re-entrainment. Thus, in humans, prolonged sleep restriction with concurrent circadian disruption alters metabolism and could increase the risk of obesity and diabetes.
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Intracranial pressure (ICP) is affected in many neurological conditions. Clinical measurement of pressure on the brain currently requires placing a probe in the cerebrospinal fluid compartment, the brain tissue, or other intracranial space. This invasiveness limits the measurement to critically ill patients. ⋯ Referenced against concurrently recorded invasive parenchymal ICP that varied over 100 millimeters of mercury (mmHg) across all records, our estimates achieved a mean error (bias) of 1.6 mmHg and SD of error (SDE) of 7.6 mmHg. For the 1673 data windows over 22 hours in which blood flow velocity recordings were available from both the left and the right MCA, averaging the resulting bilateral ICP estimates reduced the bias to 1.5 mmHg and SDE to 5.9 mmHg. This accuracy is already comparable to that of some invasive ICP measurement methods in current clinical use.
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Demonstration of safe and stable reversal of blindness after a single unilateral subretinal injection of a recombinant adeno-associated virus (AAV) carrying the RPE65 gene (AAV2-hRPE65v2) prompted us to determine whether it was possible to obtain additional benefit through a second administration of the AAV vector to the contralateral eye. Readministration of vector to the second eye was carried out in three adults with Leber congenital amaurosis due to mutations in the RPE65 gene 1.7 to 3.3 years after they had received their initial subretinal injection of AAV2-hRPE65v2. Results (through 6 months) including evaluations of immune response, retinal and visual function testing, and functional magnetic resonance imaging indicate that readministration is both safe and efficacious after previous exposure to AAV2-hRPE65v2.
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Numerous studies have implicated microRNAs (miRNAs) in cancer initiation and progression. In contrast, only recently has attention been focused on the pathway that generates these regulatory molecules. The identification of neoplasia-associated germline mutations in DICER1 has focused translational research on components of the miRNA processing pathway. Deciphering of the many links between miRNA processing perturbations and cancer will likely provide insights into mechanisms of cancer control.
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Most clinical blood biomarkers lack the necessary sensitivity and specificity to reliably detect cancer at an early stage, when it is best treatable. It is not yet clear how early a clinical blood assay can be used to detect cancer or how biomarker-based strategies can be improved to enable earlier detection of smaller tumors. To address these issues, we developed a mathematical model describing dynamic plasma biomarker kinetics in relation to the growth of a tumor, beginning with a single cancer cell. ⋯ The detection times we estimated are consistent with recently published tumor progression time lines based on clinical genomic sequencing data for several cancers. Here, we rigorously showed that shedding rates of current clinical blood biomarkers are likely 10(4)-fold too low to enable detection of a developing tumor within the first decade of tumor growth. The model presented here can be extended to virtually any solid cancer and associated biomarkers.