Organoids as a tool in drug discovery and patient-specific therapy for head and neck cancer.

Organoids more accurately reflect tumor microenvironment than traditional models. Millen et al. demonstrated organoids replicated from patient tissues may predict patient-specific response to radiation therapy and have potential to be utilized for validation of biomarkers in drug discovery and treatment planning.

A low-cost high-fidelity model for abscess simulation.

BACKGROUND: Treatment of a subcutaneous abscess is a commonly encountered scenario across multiple specialties. Prior simulation models for abscess incision and drainage have been limited by their cost and reproducibility. METHODS: We developed a realistic abscess model with commonly available materials that can be utilized in fresh cadaver labs at a cost of less than $1 USD per use. The model was evaluated for content validity with pre- and post-measures by 25 pre-clinical medical students. RESULTS: The model described herein successfully simulates commonly encountered subcutaneous abscesses. Pre and post-training surveys demonstrated a significant increase in all outcomes measures. CONCLUSIONS: The model presented in this manuscript can be easily incorporated into training programs that utilize a fresh cadaver lab for multi-procedural resident training. It provides a realistic abscess that can be placed in almost any anatomical location at a fraction of the cost, and significantly reduced preparation time compared to previously described models.

Virtual coach: the next tool in functional endoscopic sinus surgery education.

BACKGOUND: Functional endoscopic sinus surgery (FESS) can be challenging as novices become accustomed to handling endoscopes and instruments while navigating complex sinonasal anatomy. Experts demonstrate fluid and efficient motions when addressing pathology. The training process from novice to expert relies on hands-on experience in cadaveric laboratories and preceptorship models that require significant time and expense. This study aims to validate the use of a virtual coach to guide users step-by-step through a basic FESS. METHODS: Seventeen surgeons were grouped into novice (n = 10) and expert (n = 7) based on self-reported levels of surgical experience. Users were trained using the maxillary antrostomy module in the Neurorhinological Surgery (NRS) simulator combining the physical craniofacial model with virtual reality (VR)-tracked surgical instruments in the VR operating room. The virtual coach guided the user using surgical videos, auditory, and visual cues. The coach recorded data for each subject including the number of times borders of the nasal cavity were encountered and time to completion. Users graded the usefulness of the virtual coach on a Likert questionnaire. RESULTS: Face validity of our NRS simulator was replicated by user questionnaires, and construct validity replicated by differentiation between novice and expert level surgeons (p < 0.01). Novices contacted a significantly higher number of anatomic borders (n = 17) and had a longer operative time (t = 370 seconds). All users reported high scores on the benefit and usefulness of the virtual coach. CONCLUSION: The virtual coach provides a useful tool to enhance FESS education by providing objective real-time data in a novel mixed-reality surgical environment.

Effect of exercise intensity on Nrf2 signalling in young men.

INTRODUCTION: The transcription factor Nrf2 is the master regulator of antioxidant defence. Recent data indicate a single bout of moderate-intensity stationary cycling at a constant workload upregulates Nrf2 signalling in young, but not older men; however, the role of exercise intensity on Nrf2 activation has not been tested. We hypothesised that a high-intensity interval session would elicit a greater Nrf2 response than moderate aerobic exercise. METHODS: Nrf2 signalling in response to two 30-min cycling protocols (high-intensity interval and constant workload) was compared in young men (25 ± 1y, n = 16). Participants completed exercise trials in random order with blood collected pre-, immediately post-, and 30-mins post exercise. Five participants completed a control trial without any physical activity. Nrf2 signalling was determined by measuring protein expression of Nrf2 in whole cell and nuclear fractions. Plasma 8-isoprostanes as well as peripheral mononuclear cell glutathione reductase (GR) and superoxide dismutase activity were measured as markers of oxidative stress. RESULTS: The exercise trials elicited significant increases in nuclear Nrf2 (p < .01), but increases in whole cell Nrf2 did not reach statistical significance. GR activity and plasma 8-isoprostanes increased significantly in response to exercise (p < .05), and GR response was higher in the high-intensity trial (p < .05). CONCLUSION: Our findings indicate that acute aerobic exercise elicits activation of nuclear Nrf2, regardless of exercise intensity, but that higher-intensity exercise results in greater activity of GR. Future experiments should explore the effect of exercise mode and duration on Nrf2 signalling, and the role of intensity in compromised populations.

Nrf2 mediates redox adaptations to exercise.

The primary aim of this review is to summarize the current literature on the effects of acute exercise and regular exercise on nuclear factor erythroid 2-related factor 2 (Nrf2) activity and downstream targets of Nrf2 signaling. Nrf2 (encoded in humans by the NFE2L2 gene) is the master regulator of antioxidant defenses, a transcription factor that regulates expression of more than 200 cytoprotective genes. Increasing evidence indicates that Nrf2 signaling plays a key role in how oxidative stress mediates the beneficial effects of exercise. Episodic increases in oxidative stress induced through bouts of acute exercise stimulate Nrf2 activation and when applied repeatedly, as with regular exercise, leads to upregulation of endogenous antioxidant defenses and overall greater ability to counteract the damaging effects of oxidative stress. The evidence of Nrf2 activation in response to exercise across variety of tissues may be an important mechanism of how exercise exerts its well-known systemic effects that are not limited to skeletal muscle and myocardium. Additionally there are emerging data that results from animal studies translate to humans.

Aerobic exercise increases resistance to oxidative stress in sedentary older middle-aged adults. A pilot study.

Older individuals who exercise regularly exhibit greater resistance to oxidative stress than their sedentary peers, suggesting that exercise can modify age-associated loss of resistance to oxidative stress. However, we recently demonstrated that a single bout of exercise confers protection against a subsequent oxidative challenge in young, but not older adults. We therefore hypothesized that repeated bouts of exercise would be needed to increase resistance to an oxidative challenge in sedentary older middle-aged adults. Sedentary older middle-aged men and women (50-63 years, n = 11) participated in an 8-week exercise intervention. Maximal oxygen consumption was measured before and after the intervention. The exercise intervention consisted of three sessions per week, for 45 min at an intensity corresponding to 70-85 % maximal heart rate (HRmax). Resistance to oxidative stress was measured by F2-isoprostane response to a forearm ischemia/reperfusion (I/R) trial. Each participant underwent the I/R trial before and after the exercise intervention. The intervention elicited a significant increase in maximal oxygen consumption (VO2max) (P < 0.0001). Baseline levels of F2-isoprostanes pre- and post-intervention did not differ, but the F2-isoprostane response to the I/R trial was significantly lower following the exercise intervention (time-by-trial interaction, P = 0.043). Individual improvements in aerobic fitness were associated with greater improvements in the F2-isoprostane response (r = -0.761, P = 0.011), further supporting the role of aerobic fitness in resistance to oxidative stress. These data demonstrate that regular exercise with improved fitness leads to increased resistance to oxidative stress in older middle-aged adults and that this measure is modifiable in previously sedentary individuals.

Exercise-induced Nrf2-signaling is impaired in aging.

PURPOSE: The transcription factor nuclear erythroid-2 like factor-2 (Nrf2) is the master regulator of antioxidant defense. Data from animal studies suggest exercise elicits significant increases in Nrf2 signaling, and that signaling is impaired with aging resulting in decreased induction of phase II detoxifying enzymes and greater susceptibility to oxidative damage. We have previously shown that older adults have lower resistance to an oxidative challenge as compared to young, and that this response is modified with physical fitness and phytonutrient intervention. We hypothesized that a single bout of submaximal exercise would elicit increased nuclear accumulation of Nrf2, and that this response to exercise would be attenuated with aging. METHODS: Nrf2 signaling in response to 30-min cycling at 70% VO2max was compared in young (23±1y, n=10) and older (63±1, n=10) men. Blood was collected at six time points; pre-exercise, and 10min, 30min, 1h, 4h, and 24h post-exercise. Nrf2 signaling was determined in peripheral blood mononuclear cells by measuring protein expression by western blot of Nrf2 in whole cell and nuclear fractions, and whole cell SOD1, and HMOX, as well as gene expression (RT-PCR) of downstream Nrf2-ARE antioxidants SOD1, HMOX, and NQO1. RESULTS: Baseline differences in protein expression did not differ between groups. The exercise trial elicited significant increase in whole cell Nrf2 (P=0.003) for both young and older groups. Nuclear Nrf2 levels were increased significantly in the young but not older group (P=0.031). Exercise elicited significant increases in gene expression of HMOX1 and NQO1 in the young (P=0.006, and P=0.055, respectively) whereas gene expression in the older adults was repressed. There were no significant differences in SOD1 or HMOX1 protein expression. CONCLUSION: These findings indicate a single session of submaximal aerobic exercise is sufficient to activate Nrf2 at the whole cell level in both young and older adults, but that nuclear import is impaired with aging. Additionally we have shown repressed gene expression of downstream antioxidant targets of Nrf2 in older adults. Together these translational data demonstrate for the first time the attenuation of Nrf2 activity in response to exercise in older adults.

Acute exercise increases resistance to oxidative stress in young but not older adults.

A single bout of acute exercise increases oxidative stress and stimulates a transient increase in antioxidant enzymes. We asked whether this response would induce protection from a subsequent oxidative challenge, different from that of exercise, and whether the effects were affected by aging. We compared young (20 ± 1 years, n = 8) and older (58 ± 6 years, n = 9) healthy men and women. Resistance to oxidative stress was measured by the F2-isoprostane response to forearm ischemia/reperfusion (I/R) trial. Each participant underwent the I/R trial twice, in random order; once after performing 45 min of cycling on the preceding day (IRX) and a control trial without any physical activity (IRC). Baseline F2-isoprostane levels were significantly lower at IRX compared to IRC (P < 0.05) and not different between groups. F2-isoprostane response to IRX was significantly lower compared to IRC in young (P < 0.05) but not different in the older group. Superoxide dismutase activity in response to acute exercise was significantly higher in young compared to older adults (P < 0.05). These data suggest that signal transduction of acute exercise may be impaired with aging. Repeated bouts of transient reactive oxygen species production as seen with regular exercise may be needed to increase resistance to oxidative stress in older individuals.