Targeting the eicosanoid pathway in hepatocellular carcinoma.

Liver cancer has variable incidence worldwide and high mortality. Histologically, the most common subtype of liver cancer is hepatocellular carcinoma (HCC). Approximately 30-40% of HCC patients are diagnosed at an advanced stage, and at present, there are limited treatment options for such patients. The current first-line therapy with tyrosine kinase inhibitors, sorafenib or lenvatinib, prolongs survival by a median of about 2.5-3 months after which the disease normally progresses. Additionally, many patients discontinue the use of tyrosine kinase inhibitors due to toxicity or may not be suitable candidates due to co-morbidity or frailty. It is, therefore, imperative to identify novel therapeutic targets for advanced HCC patients. Persistent injury to the liver as a result of insults such as hepatitis B or C viral (HBV or HCV) infections, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), results in chronic inflammation, which progresses to hepatic fibrosis and later, cirrhosis, provides the conditions for initiation of HCC. One of the key pathways studied for its role in inflammation and carcinogenesis is the eicosanoid pathway. In this review, we briefly outline the eicosanoid pathway, describe the mechanisms by which some pathway members either facilitate or counter the development of liver diseases, with the focus on NAFLD/hepatic fibrosis/cirrhosis, and HCC. We describe the link between the eicosanoid pathway, inflammation and these liver diseases, and identify components of the eicosanoid pathway that may be used as potential therapeutic targets in HCC.

Shortcomings of human-in-the-loop optimization of an ankle-foot prosthesis emulator: a case series.

Human-in-the-loop optimization allows for individualized device control based on measured human performance. This technique has been used to produce large reductions in energy expenditure during walking with exoskeletons but has not yet been applied to prosthetic devices. In this series of case studies, we applied human-in-the-loop optimization to the control of an active ankle-foot prosthesis used by participants with unilateral transtibial amputation. We optimized the parameters of five control architectures that captured aspects of successful exoskeletons and commercial prostheses, but none resulted in significantly lower metabolic rate than generic control. In one control architecture, we increased the exposure time per condition by a factor of five, but the optimized controller still resulted in higher metabolic rate. Finally, we optimized for self-reported comfort instead of metabolic rate, but the resulting controller was not preferred. There are several reasons why human-in-the-loop optimization may have failed for people with amputation. Control architecture is an unlikely cause given the variety of controllers tested. The lack of effect likely relates to changes in motor adaptation, learning, or objectives in people with amputation. Future work should investigate these potential causes to determine whether human-in-the-loop optimization for prostheses could be successful.

The effects of ground-irregularity-cancelling prosthesis control on balance over uneven surfaces.

Over half of individuals with a lower-limb amputation are unable to walk on uneven terrain. Using a prosthesis emulator system, we developed an irregularity-cancelling controller intended to reduce the effect of disturbances resulting from uneven surfaces. This controller functions by changing the neutral angles of two forefoot digits in response to local terrain heights. To isolate the effects of the controller, we also programmed a spring-like controller that maintained fixed neutral angles. Five participants with transtibial amputation walked on a treadmill with an uneven walking surface. Compared with the spring-like controller, the irregularity-cancelling controller reduced ankle torque variability by 41% in the sagittal plane and 64% in the frontal plane. However, user outcomes associated with balance were mostly unaffected; only trunk movement variability was reduced, whereas metabolic rate, mediolateral centre of mass motion, and variabilities in step width, step length and step time were unchanged. We conclude that reducing ankle torque variability of the affected limb is not sufficient for reducing the overall effect of disturbances due to uneven terrain. It is possible that other factors, such as changes in step height or disturbances to the intact limb, play a larger role in difficulty balancing while walking over uneven surfaces.

Teleoperation of an Ankle-Foot Prosthesis With a Wrist Exoskeleton.

OBJECTIVE: We aimed to develop a system for people with amputation that non-invasively restores missing control and sensory information for an ankle-foot prosthesis. METHODS: In our approach, a wrist exoskeleton allows people with amputation to control and receive feedback from their prosthetic ankle via teleoperation. We implemented two control schemes: position control with haptic feedback of ankle torque at the wrist; and torque control that allows the user to modify a baseline torque profile by moving their wrist against a virtual spring. We measured tracking error and frequency response for the ankle-foot prosthesis and the wrist exoskeleton. To demonstrate feasibility and evaluate system performance, we conducted an experiment in which one participant with a transtibial amputation tracked desired wrist trajectories during walking, while we measured wrist and ankle response. RESULTS: Benchtop testing demonstrated that for relevant walking frequencies, system error was below human perceptual error. During the walking experiment, the participant was able to voluntarily follow different wrist trajectories with an average RMS error of 1.55 ° after training. The ankle was also able to track desired trajectories below human perceptual error for both position control (RMSE = 0.8 °) and torque control (RMSE = 8.4%). CONCLUSION: We present a system that allows a user with amputation to control an ankle-foot prosthesis and receive feedback about its state using a wrist exoskeleton, with accuracy comparable to biological neuromotor control. SIGNIFICANCE: This bilateral teleoperation system enables novel prosthesis control and feedback strategies that could improve prosthesis control and aid motor learning.

An Ankle-Foot Prosthesis Emulator Capable of Modulating Center of Pressure.

OBJECTIVE: Several powered ankle-foot prostheses have demonstrated moderate reductions in energy expenditure by restoring pushoff work in late stance or by assisting with balance. However, it is possible that center of pressure trajectory modulation could provide even further improvements in user performance. Here, we describe the design of a prosthesis emulator with two torque-controlled forefoot digits and a torque-controlled heel digit. Independent actuation of these three digits can modulate the origin and magnitude of the total ground reaction force vector. METHODS: The emulator was designed to be compact and lightweight while exceeding the range of motion and torque requirements of the biological ankle during walking. We ran a series of tests to determine torque-measurement accuracy, closed-loop torque control bandwidth, torque-tracking error, and center of pressure control accuracy. RESULTS: Each of the three digits demonstrated less than 2 Nm of RMS torque measurement error, a 90% rise time of 19 ms, and a bandwidth of 33 Hz. The untethered end-effector has a mass of 1.2 kg. During walking trials, the emulator demonstrated less than 2 Nm of RMS torque-tracking error and was able to maintain full digit ground contact for 56% of stance. In fixed, standing, and walking conditions, the emulator was able to control center of pressure along a prescribed pattern with RMS errors of about 10% the length of the pattern. CONCLUSION: The proposed emulator system meets all design criteria and can effectively modulate center of pressure and ground reaction force magnitude. SIGNIFICANCE: This emulator system will enable rapid development of controllers designed to enhance user balance and reduce user energy expenditure. Experiments conducted using this emulator could identify beneficial control behaviors that can be implemented on autonomous devices, thus improving mobility and quality of life of individuals with amputation.

Allergic environment enhances airway epithelial pro-inflammatory responses to rhinovirus infection.

Airway epithelial cells (AEC) exhibit a pro-inflammatory phenotype in patients with allergic asthma. We examined the effect of an allergic cytokine environment on the response of AEC to rhinovirus (RV), the most common trigger of acute exacerbations of asthma. Calu-3 cells, a well-differentiated human AEC line, were cultured with or without the T-helper type 2 cytokines interleukin (IL)-4 and IL-13, then stimulated with a toll-like receptor (TLR) 3 agonist (poly I:C, dsRNA) or a TLR7 agonist (imiquimod), or infected with RV 16. Expression of pro-inflammatory and antiviral mediators, and of viral pattern-recognition molecules, was assessed using nCounter assays, quantitative real-time PCR (qRT-PCR) and protein immunoassays. Both dsRNA and imiquimod stimulated expression of mRNA for IL6 and IL8 whereas expression of several chemokines and antiviral response genes was induced only by dsRNA. Conversely, expression of other cytokines and growth factors was induced only by imiquimod. RV infection not only stimulated expression of the inflammation-related genes induced by dsRNA, but also of complement factor B and the novel pro-inflammatory cytokine IL-32. In the T helper type 2 (Th2) cytokine environment, several mediators exhibited significantly enhanced expression, whereas expression of interferons was either unchanged or enhanced. The allergic environment also increased expression of pattern-recognition receptors and of intercellular adhesion molecule 1, the cell surface receptor for RV. We conclude that Th2 cytokines promote increased production of pro-inflammatory mediators by AEC following infection with RV. Increased viral entry or enhanced signalling via pattern-recognition receptors could also contribute to the exaggerated inflammatory response to RV observed in allergic asthmatics.

Evaluating the maximum playback sound levels from portable digital audio players.

To assess the maximum sound levels that may be experienced by young people in Canada from modern digital audio players, this study measured nine recent models of players and 20 earphones. Measurement methodology followed European standard BS EN 50332. Playback levels ranged from 101 to 107 dBA at maximum volume level. Estimated listener sound levels could vary from 79 to 125 dBA due to the following factors: (i) earphone seal against the ear, (ii) player output voltage, (iii) earphone sensitivity, and (iv) recorded music levels. There was a greater potential for high sound levels if intra-concha "earbud" earphones were used due to the effect of earphone seal. Simpler measurement techniques were explored as field test methods; the best results were obtained by sealing the microphone of a sound level meter to the earphone using a cupped hand and correcting for the free field response of the ear. Measurement of noise levels 0.25 m from the earphone showed that a bystander is unlikely to accurately judge listener sound levels.