Characterization of 10MAG/LDAO reverse micelles: Understanding versatility for protein encapsulation.

Reverse micelles (RMs) are spontaneously organizing nanobubbles composed of an organic solvent, surfactants, and an aqueous phase that can encapsulate biological macromolecules for various biophysical studies. Unlike other RM systems, the 1-decanoyl-rac-glycerol (10MAG) and lauryldimethylamine-N-oxide (LDAO) surfactant system has proven to house proteins with higher stability than other RM mixtures with little sensitivity to the water loading (W0, defined by the ratio of water to surfactant). We investigated this unique property by encapsulating three model proteins - cytochrome c, myoglobin, and flavodoxin - in 10MAG/LDAO RMs and applying a variety of experimental methods to characterize this system's behavior. We found that this surfactant system differs greatly from the traditional, spherical, monodisperse RM population model. 10MAG/LDAO RMs were discovered to be oblate ellipsoids at all conditions, and as W0 was increased, surfactants redistributed to form a greater number of increasingly spherical ellipsoidal particles with pools of more bulk-like water. Proteins distinctively influence the thermodynamics of the mixture, encapsulating at their optimal RM size and driving protein-free RM sizes to scale accordingly. These findings inform the future development of similarly malleable encapsulation systems and build a foundation for application of 10MAG/LDAO RMs to analyze biological and chemical processes under nanoscale confinement.

Successful conversion from butorphanol nasal spray to buprenorphine/naloxone using a low-dose regimen to assist with opioid tapering in the setting of chronic pain and migraine management in an older adult patient: A case report.

Background: Butorphanol is marketed as a treatment for migraines; however, evidence suggests that the harms of its use exceed the benefits. The short half-life of butorphanol places patients at high risk for opioid dependence and makes tapering a challenge. Buprenorphine/naloxone has unique pharmacological properties that are beneficial in chronic pain treatment. At this time there is limited published data on the use of micro-dosing initiation regimens in patients with chronic pain, especially in older adult patients. Aims: This article presents the case of an older adult patient for whom a buprenorphine/naloxone micro-dosing regimen was successfully utilized to aid discontinuation of butorphanol nasal spray, assist with opioid tapering, and manage chronic pain. Methods: This case took place in an outpatient setting while the patient was receiving care from an interprofessional chronic pain service. The electronic medical record was reviewed to obtain a summary of the case data. Informed patient consent was obtained. Results: We present a case of an older adult patient who had been using butorphanol nasal spray for migraine and general pain management for over 20 years. The risks of ongoing use of butorphanol (i.e., inter-dose-related pain, opioid dependence, possible opioid-induced hyperalgesia, and fall risk) no longer exceeded any perceived benefit. The patient was successfully transitioned onto sublingual buprenorphine/naloxone using a micro-dosing regimen. Conclusions: This case provides an example of the potential benefit buprenorphine/naloxone can have for patients with chronic pain and previous opioid exposure, especially older adults at risk of central adverse effects of opioids.

Contexte: Le butorphanol est commercialisé comme traitement des migraines; cependant, les données probantes indiquent que les méfaits de son utilisation dépassent les avantages. La courte demi-vie du butorphanol expose les patients à un risque élevé de dépendance aux opioïdes et rend la réduction progressive un défi. La buprénorphine/naloxone possède des propriétés pharmacologiques uniques qui sont bénéfiques dans le traitement de la douleur chronique. À l'heure actuelle, il existe peu de données publiées sur l'utilisation de programmes d'initiation de microdosage chez les patients souffrant de douleur chronique, en particulier chez les patients adultes âgés.Buts: Cet article présente le cas d'un patient adulte âgé pour lequel un programme de microdosage buprénorphine/naloxone a été utilisé avec succès pour aider à l'arrêt de la pulvérisation nasale de butorphanol, à la réduction progressive des opioïdes et à la prise en charge de la douleur chronique.Méthodes: Ce cas s'est produit dans un cadre ambulatoire alors que le patient recevait des soins d'un service interprofessionnel de traitement de la douleur chronique. Le dossier médical électronique a été examiné pour obtenir un résumé des données du cas. Le consentement éclairé du patient a été obtenu.Résultats: Nous présentons le cas d'un patient adulte âgé qui utilisait un vaporisateur nasal au butorphanol pour la migraine et la prise en charge générale de la douleur depuis plus de 20 ans. Les risques liés à l'utilisation continue du butorphanol (c.-à-d. la douleur interdose, la dépendance aux opioïdes, l'hyperalgésie possible induite par les opioïdes et le risque de chute) ne dépassaient plus les avantages perçus. Le patient a été transféré avec succès vers le buprénorphine/naloxone sublingual en utilisant un programme de microdosage.Conclusions: Ce cas fournit un exemple de l'avantage potentiel de la buprénorphine/naloxone pour les patients présentant une douleur chronique et une exposition antérieure aux opioïdes, en particulier les personnes âgées à risque d'effets indésirables centraux des opioïdes.

FRK inhibits breast cancer cell migration and invasion by suppressing epithelial-mesenchymal transition.

The human fyn-related kinase (FRK) is a non-receptor tyrosine kinase known to have tumor suppressor activity in breast cancer cells. However, its mechanism of action has not been fully characterized. We generated FRK-stable MDA-MB-231 breast cancer cell lines and analyzed the effect on cell proliferation, migration, and invasiveness. We also used kinome analysis to identify potential FRK-regulated signaling pathways. We employed both immunoblotting and RT-PCR to identify/validate FRK-regulated targets (proteins and genes) in these cells. Finally, we interrogated the TCGA and GENT gene expression databases to determine the correlation between the expression of FRK and epithelial/mesenchymal markers. We observed that FRK overexpression suppressed cell proliferation, migration, and invasiveness, inhibited various JAK/STAT, MAPK and Akt signaling pathways, and suppressed the expression of some STAT3 target genes. Also, FRK overexpression increased the expression of epithelial markers including E-cadherin mRNA and down-regulated the transcript levels of vimentin, fibronectin, and slug. Finally, we observed an inverse correlation between FRK expression and mesenchymal markers in a large cohort of breast cancer cells. Our data, therefore, suggests that FRK represses cell proliferation, migration and invasiveness by suppressing epithelial to mesenchymal transition.

Restoring the sense of touch with a prosthetic hand through a brain interface.

Our ability to manipulate objects dexterously relies fundamentally on sensory signals originating from the hand. To restore motor function with upper-limb neuroprostheses requires that somatosensory feedback be provided to the tetraplegic patient or amputee. Given the complexity of state-of-the-art prosthetic limbs and, thus, the huge state space they can traverse, it is desirable to minimize the need for the patient to learn associations between events impinging on the limb and arbitrary sensations. Accordingly, we have developed approaches to intuitively convey sensory information that is critical for object manipulation--information about contact location, pressure, and timing--through intracortical microstimulation of primary somatosensory cortex. In experiments with nonhuman primates, we show that we can elicit percepts that are projected to a localized patch of skin and that track the pressure exerted on the skin. In a real-time application, we demonstrate that animals can perform a tactile discrimination task equally well whether mechanical stimuli are delivered to their native fingers or to a prosthetic one. Finally, we propose that the timing of contact events can be signaled through phasic intracortical microstimulation at the onset and offset of object contact that mimics the ubiquitous on and off responses observed in primary somatosensory cortex to complement slowly varying pressure-related feedback. We anticipate that the proposed biomimetic feedback will considerably increase the dexterity and embodiment of upper-limb neuroprostheses and will constitute an important step in restoring touch to individuals who have lost it.

A model for intracortical visual prosthesis research.

In the field of visual prosthesis research, it has generally been held that animal models are limited to testing the safety of implantable hardware due to the inability of the animal to provide a linguistic report of perceptions. In contrast, vision scientists make extensive use of trained animal models to investigate the links between visual stimuli, neural activities, and perception. We describe an animal model for cortical visual prosthesis research in which novel animal psychophysical testing has been employed to compensate for the lack of a linguistic report. One hundred and fifty-two intracortical microelectrodes were chronically implanted in area V1 of a male macaque. Receptive field mapping was combined with eye-tracking to develop a reward-based training procedure. The animal was trained to use electrically induced point-flash percepts, called phosphenes, in performing a memory saccade task. It is our long-term goal to use this animal model to investigate stimulation strategies in developing a multichannel sensory cortical interface.