Analysis of sleep for the diagnosis of sleep disorders such as Type-1 Narcolepsy (T1N) currently requires visual inspection of polysomnography records by trained scoring technicians. Here, we used ...neural networks in approximately 3,000 normal and abnormal sleep recordings to automate sleep stage scoring, producing a hypnodensity graph-a probability distribution conveying more information than classical hypnograms. Accuracy of sleep stage scoring was validated in 70 subjects assessed by six scorers. The best model performed better than any individual scorer (87% versus consensus). It also reliably scores sleep down to 5 s instead of 30 s scoring epochs. A T1N marker based on unusual sleep stage overlaps achieved a specificity of 96% and a sensitivity of 91%, validated in independent datasets. Addition of HLA-DQB1*06:02 typing increased specificity to 99%. Our method can reduce time spent in sleep clinics and automates T1N diagnosis. It also opens the possibility of diagnosing T1N using home sleep studies.
In this work, a tumor growth intervention by localized drug synthesis within the tumor volume, using the enzymatic repertoire of the tumor itself, is presented. Towards the overall success, ...molecular, macromolecular, and supramolecular glucuronide prodrugs were designed for a highly potent toxin, monomethyl auristatin E (MMAE). The lead candidate exhibited a fold difference in toxicity between the prodrug and the drug of 175, had an engineered mechanism to enhance the deliverable payload to tumours, and contained a highly potent toxin such that bioconversion of only a few prodrug molecules created a concentration of MMAE sufficient enough for efficient suppression of tumor growth. Each of these points is highly significant and together afford a safe, selective anticancer measure, making tumor‐targeted glucuronides attractive for translational medicine.
Targeting tumors: Safe, tumor‐accumulating prodrugs that are specific to the enzymatic repertoire of the tumor comprise an effective anticancer therapy. The lead structure could not be predicted by in vitro/ex vivo screens but was identified through in vivo monitoring.
Nanozymes, nanoparticles that mimic the natural activity of enzymes, are intriguing academically and are important in the context of the Origin of Life. However, current nanozymes offer mimicry of a ...narrow range of mammalian enzymes, near‐exclusively performing redox reactions. We present an unexpected discovery of non‐proteinaceous enzymes based on metals, metal oxides, 1D/2D‐materials, and non‐metallic nanomaterials. The specific novelty of these findings lies in the identification of nanozymes with apparent mimicry of diverse mammalian enzymes, including unique pan‐glycosidases. Further novelty lies in the identification of the substrate scope for the lead candidates, specifically in the context of bioconversion of glucuronides, that is, human metabolites and privileged prodrugs in the field of enzyme‐prodrug therapies. Lastly, nanozymes are employed for conversion of glucuronide prodrugs into marketed anti‐inflammatory and antibacterial agents, as well as “nanozyme prodrug therapy” to mediate antibacterial measures.
Non‐proteinaceous materials possess enzymatic activity: Identification of the substrate scope for these nanozymes led to the development of efficient mimics for β‐glucuronidase that convert glucuronide prodrugs for localized synthesis of anti‐inflammatory and anti‐bacterial drugs.
Substrate mediated enzyme prodrug therapy Fejerskov, Betina; Jarlstad Olesen, Morten T.; Zelikin, Alexander N.
Advanced drug delivery reviews,
09/2017, Letnik:
118
Journal Article
Recenzirano
Substrate mediated enzyme prodrug therapy (SMEPT) is a biomedical platform developed to perform a localized synthesis of drugs mediated by implantable biomaterials. This approach combines the ...benefits and at the same time offers to overcome the drawbacks for traditional pill-based drug administration and site-specific, implant mediated drug delivery. Specifically, SMEPT offers the flexibility of delivering multiple drugs – individually as monotherapy, in sequence, or as a combination therapy, all of which is also accomplished in a site-specific manner. This technology is also unique for site-specific synthesis of drugs with short half-life, such as nitric oxide. This review presents historical development of SMEPT from early reports to the most recent examples, and also outlines potential avenues for subsequent development of this platform.
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We demonstrate that an extended scaffold based on a self-immolative linker (SIL) enables the universal production of O-aryl glucuronide prodrugs: high yield glucuronidation is performed on a ...precursor substrate (SIL) and the subsequent drug conjugation proceeds via less challenging chemical reactions.
Proteomic biomarkers of sleep apnea Ambati, Aditya; Ju, Yo-El; Lin, Ling ...
Sleep (New York, N.Y.),
11/2020, Letnik:
43, Številka:
11
Journal Article
Recenzirano
Odprti dostop
Abstract
Study Objectives
Obstructive sleep apnea (OSA) is characterized by recurrent partial to complete upper airway obstructions during sleep, leading to repetitive arousals and oxygen ...desaturations. Although many OSA biomarkers have been reported individually, only a small subset have been validated through both cross-sectional and intervention studies. We sought to profile serum protein biomarkers in OSA in unbiased high throughput assay.
Methods
A highly multiplexed aptamer array (SomaScan) was used to profile 1300 proteins in serum samples from 713 individuals in the Stanford Sleep Cohort, a patient-based registry. Outcome measures derived from overnight polysomnography included Obstructive Apnea Hypopnea Index (OAHI), Central Apnea Index (CAI), 2% Oxygen Desaturation index, mean and minimum oxygen saturation indices during sleep. Additionally, a separate intervention-based cohort of 16 individuals was used to assess proteomic profiles pre- and post-intervention with positive airway pressure.
Results
OAHI was associated with 65 proteins, predominantly pathways of complement, coagulation, cytokine signaling, and hemostasis which were upregulated. CAI was associated with two proteins including Roundabout homolog 3 (ROBO3), a protein involved in bilateral synchronization of the pre-Bötzinger complex and cystatin F. Analysis of pre- and post intervention samples revealed IGFBP-3 protein to be increased while LEAP1 (Hepicidin) to be decreased with intervention. An OAHI machine learning classifier (OAHI >=15 vs OAHI<15) trained on SomaScan protein measures alone performed robustly, achieving 76% accuracy in a validation dataset.
Conclusions
Multiplex protein assays offer diagnostic potential and provide new insights into the biological basis of sleep disordered breathing.
Currently, manual scoring is the gold standard of leg movement scoring (LMs) and periodic LMs (PLMS) in overnight polysomnography (PSG) studies, which is subject to inter-scorer variability. The ...objective of this study is to design and validate an end-to-end deep learning system for the automatic scoring of LMs and PLMS in sleep.
The deep learning system was developed, validated and tested, with respect to manual annotations by expert technicians on 800 overnight PSGs using a leg electromyography channel. The study includes data from three cohorts, namely, the Wisconsin Sleep Cohort (WSC), Stanford Sleep Cohort (SSC) and MrOS Sleep Study. The performance of the system was further compared against individual expert technicians and existing PLM detectors.
The system achieved an F1 score of 0.83, 0.71, and 0.77 for the WSC, SSC, and an ancillary study (Osteoporotic Fractures in Men Study, MrOS) cohorts, respectively. In a total of 60 PSGs from the WSC and the SSC scored by nine expert technicians, the system performed better than two and comparable to seven of the individual scorers with respect to a majority-voting consensus of the remaining scorers. In 60 PSGs from the WSC scored accurately for PLMS, the system outperformed four previous PLM detectors, which were all evaluated on the same data, with an F1 score of 0.85.
The proposed system performs better or comparable to individual expert technicians while outperforming previous automatic detectors. Thereby, the study validates fully automatic methods for scoring LMs in sleep.
•We attempted to design and validate an automatic and robust scoring of leg movements in polysomnograms.•Our method performs better or comparable to individual expert technicians for leg movement scoring.•Using a deep learning framework, our method outperforms previous rule-based detectors.
Rapid eye movement (REM) sleep without atonia detection is a prerequisite for diagnosis of REM sleep behavior disorder (RBD). As the visual gold standard method is time-consuming and subjective, ...several automated methods have been proposed. This study aims to compare their performances: The REM atonia index (RAI), the supra-threshold-REM-activity metric, the Frandsen index, the short/long muscle activity indices, and the Kempfner index algorithms were applied to 27 healthy control participants (C), 25 patients with Parkinson's disease (PD) without RBD (PD-RBD), 29 patients with PD and RBD (PD + RBD), 29 idiopathic patients with RBD, and 36 patients with periodic limb movement disorder (PLMD). The indices were calculated in various configurations: (1) considering all muscle activities; (2) excluding the ones related to arousals; (3) excluding the ones during apnea events; (4) excluding the ones before and after apnea events; (5) combining configurations 2 and 3; and (6) combining configurations 2 and 4. For each of these configurations, the discrimination capability of the indices was tested for the following comparisons: (1) (C, PD-RBD, PLMD) vs (PD + RBD, RBD); (2) C vs RBD; (3) PLMD vs RBD; (4) C vs PD-RBD; (5) C vs PLMD; (6) PD-RBD vs PD + RBD; and (7) C vs PLMD vs RBD. Results showed varying methods' performances across the different configurations and comparisons, making it impossible to identify the optimal method and suggesting the need of further improvements. Nevertheless, RAI seems the most sensible one for RBD detection. Moreover, apnea and arousal-related movements seem not to influence the algorithms' performances in patients' classification.
Enzyme prodrug therapy (EPT) enables localized conversion of inert prodrugs to active drugs by enzymes. Performance of EPT necessitates that the enzyme remains active throughout the time frame of the ...envisioned therapeutic application. β‐glucuronidase is an enzyme with historically validated performance in EPT, however it retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Herein, the encapsulation of β‐glucuronidase in liposomal subcompartments within poly(vinyl alcohol) electrospun fibers is reported, leading to the assembly of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks. It is further shown that liposomes provide the highly beneficial stabilization of the enzyme when incubated in cell culture media. The assembled biocatalytic materials successfully produce antiproliferative drugs (SN‐38) using externally administered prodrugs (SN‐38‐glucuronide) and effectively suppress cell proliferation, with envisioned utility in the design of cardiovascular grafts.
β‐glucuronidase is an enzyme with historically validated performance in enzyme prodrug therapy, however β‐glucuronidase retains its activity in biomaterials for an insufficiently long period of time, typically not exceeding 7 d. Here, encapsulation of β‐glucuronidase in liposomal subcompartments within electrospun fibers affords a highly stable preparation of biocatalytically active materials with activity of the enzyme sustained over at least seven weeks.
The newest generation of cell‐based technologies relies heavily on methods to communicate to the engineered cells using artificial receptors, specifically to deactivate the cells administered to a ...patient in the event of adverse effects. Herein, artificial synthetic internalizing receptors are engineered that function in mammalian cells in 2D and in 3D and afford targeted, specific intracellular drug delivery with nanomolar potency in the most challenging cell type, namely primary, donor‐derived T cells. Receptor design comprises a lipid bilayer anchor for receptor integration into cell membrane and a small xenobiotic molecule as a recognition ligand. Artificial receptors are successfully targeted by the corresponding antibody–drug conjugate (ADC) and exhibit efficient cargo cell entry with ensuing intracellular effects. Receptor integration into cells is fast and robust and affords targeted cell entry in under 2 h. Through a combination of the receptor design and the use of ADC, combined benefits previously made available by chimeric artificial receptors (performance in T cells) and the chemical counterpart (robustness and simplicity) in a single functional platform is achieved. Artificial synthetic receptors are poised to facilitate the maturation of engineered cells as tools of biotechnology and biomedicine.
Artificial receptors are robust and simple (as small as 1 kDa), are installed into cells in under 2 h with minimal cell handling, and afford nanomolar potency of targeted drug delivery in primary T cells.
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