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Therapy using anti-PD-1 immune checkpoint inhibitors (ICI) has revolutionized the treatment of many cancers including head and neck squamous cell carcinomas (HNSCC), but only a fraction of patients respond. To better understand the molecular mechanisms driving resistance, we performed extensive analysis of plasma and tumor tissues before and after a 4-week neoadjuvant trial in which HNSCC patients were treated with the anti-PD-1 inhibitor, nivolumab. Luminex cytokine analysis of patient plasma demonstrated that HPV pos nonresponders displayed high levels of the proinflammatory chemokine, interleukin-8 (IL-8), which decreased after ICI treatment, but remained higher than responders. miRNAseq analysis of tetraspanin-enriched small extracellular vesicles (sEV) purified from plasma of HPV pos nonresponders demonstrated significantly lower levels of seven miRNAs that target IL-8 including miR-146a. Levels of the pro-survival oncoprotein Dsg2, which has been to down-regulate miR-146a, are elevated with HPV pos tumors displaying higher levels than HPV neg tumors. Dsg2 levels decrease significantly following ICI in responders but not in nonresponders. In cultured HPV pos cells, restoration of miR-146a by forced expression or treatment with miR-146a-loaded sEV, reduced IL-8 level, blocked cell cycle progression, and promoted cell death. These findings identify Dsg2, miR-146a, and IL-8 as potential biomarkers for ICI response and suggest that the Dsg2/miR-146a/IL-8 signaling axis negatively impacts ICI treatment outcomes and could be targeted to improve ICI responsiveness in HPV pos HNSCC patients., (© 2023 The Authors. Molecular Carcinogenesis published by Wiley Periodicals LLC.)

Gilmore, SL, Brilla, LR, Suprak, DN, Chalmers, GR, and Dahlquist, DT. Effect of a high-intensity isometric potentiating warm-up on bat velocity. J Strength Cond Res 33(1): 152-158, 2019-This study examined the acute effect of a high-intensity isometric potentiating warm-up on subsequent maximal horizontal bat velocity in experienced female softball players (n = 28). The isometric potentiating warm-up consisted of 3 sets of 5-second maximal voluntary contractions held in the early swing phase position, pulling against an immovable device. As one of the simplest methods to use the postactivation potentiation (PAP) stimulus, the warm-up was designed to acutely enhance muscle performance by inducing PAP. Because optimal recovery duration after a potentiating warm-up can be highly variable, swing trials were conducted at predetermined rest intervals (1, 2, 4, 6, 8, 10, and 12 minutes) to identify the recovery time that may have allowed for maximal possible benefits. Bat velocity was measured immediately before bat-ball impact using MaxTRAQ motion analysis software. The results showed that maximal horizontal bat velocity was significantly enhanced 6 minutes after the isometric warm-up protocol (+1.27 m·s, +2.84 mph, +4.93%; p < 0.05). In experienced female softball athletes, a specific isometric warm-up may acutely enhance maximal horizontal bat velocity.

Objective: To describe the relationships between cardiovascular and natural killer (NK) cell number changes on acute psychological stress in women., Method: Data from eight different studies were analyzed. A total of 128 healthy female subjects, 85 younger (18-45 years) and 43 older (49-87 years), had been subjected to a speech stressor (N = 80) or a mental effort stressor (N = 48), mental arithmetic, or the Stroop test. Correlations between changes in NK cell numbers, systolic (SBP) and diastolic (DBP) blood pressure, and heart rate (HR) were computed. Meta-analysis programs were used to study correlations across studies and to examine whether correlations differed with stressors or age., Results: In all studies, significant increases over baseline were observed for each variable. Across studies, the mean weighted r between changes in HR, DBP, and SBP was medium (rw = .25) to large (rw = .64). A medium to large average correlation between HR and NK changes (rw = .37) was observed, whereas average correlations of changes in NK cell numbers with blood pressure changes were small to medium (rw < or = .23). Correlations between changes in NK cell numbers and cardiovascular variables were homogeneous across studies, whereas mutual correlations between cardiovascular variables were heterogeneous. One moderator variable showed itself: correlations between HR and DBP reactions were larger in studies with older than younger subjects., Conclusion: NK cell changes and HR responses induced by acute stress in women are regulated, to some extent, by the same mechanisms. Neither the type of stressor nor age seem to be very important when considering correlations between NK cell and cardiovascular changes. This study integrates information about NK cell and cardiovascular responses in women that can be used as reference material in future studies.

The present study examined the effects of progressive relaxation training and EMG biofeedback on acute glucose disposal in diabetic subjects, as measured by glucose tolerance and three other measures of diabetic metabolic control. Twenty subjects with non-insulin-using Type II diabetes took part in progressive relaxation training and EMG biofeedback in a pre-post treatment versus wait-list experimental design. Treatment effects were assessed on glucose tolerance along with three measures of diabetic control: fasting blood glucose, two-hour postprandial blood glucose, and fructosamine. Stress reduction and relaxation was assessed with two physiological measures and two subjective questionnaires. The training program produced significant reductions in stress, as measured by State Anxiety, and significant changes in physiological measures of muscle activity and skin conductance compared to the control condition. However, no changes were found in glucose tolerance (while practicing relaxation) nor in any of the three measures of general diabetic metabolic control. The major implication of this study is that relaxation training does not appear to directly improve diabetic control in mildly stressed non-insulin-using Type II diabetic patients.

Recent laboratory studies have shown several immune system changes consistently associated with brief stress including increases in circulating natural killer (NK) cell numbers, increases in NK cell cytotoxicity (NKCC), increases in suppressor cytotoxic (CD8) T cell numbers, and decreases in the in vitro proliferative response to mitogen stimulation. In the present study, we use a confrontational role-play, which brings out responses varying from assertion to capitulation and examine the psychological, behavioral, physiological, and immune system responses to this task compared to a resting control task. Compared to the control condition, the brief confrontational role-play led to significant subjective and physiological arousal and increases in circulating NK (CD16, CD56) as well as large granular lymphocyte (CD57) cells and suppressor/cytotoxic T cells (CD8). There were also significant relationships between stress-related increases in the cardiovascular measures and the numbers of circulating NK cells. These findings support sympathetic nervous system activation as a primary mechanism for increases in NK cell numbers under challenge. These role-play results are generally consistent with those from other laboratory tasks such as mental arithmetic. However, in contrast to previously examined brief stressors, the role-play led to decreased NKCC adjusted for percentage of NK cells. This apparent differential change in NK cytotoxicity across different types of activating experimental tasks points to the importance of examining dimensions of the behavioral and emotional response to challenge or threat in addition to that of autonomic arousal.

This study investigated subjective, cardiovascular, and cellular immune system responses in 20 healthy young men during brief mental arithmetic stress compared with a video-watching control task. The role of endogenous opioids in mediating the immunological change to stress was examined by pre-task administration of the opiate antagonist naloxone. Immune changes were followed over a 1 hr post-task period. The results indicate significant physiological arousal and subjective distress as well as increases in NK cell cytotoxicity, numbers of circulating CD8 suppressor/cytotoxic T cells and NK lymphocytes following mental arithmetic but not the control task. Immune measures generally returned to baseline by 1 hr after the stress. Naloxone did not block the increase in NK cell activity or cell numbers following the stressor and had no effect on the other physiological or subjective measures. Thus, the results do not support endogenous opioids as a primary mechanism for immune changes to this type of acute stress. Naloxone did, however, increase NK cell cytotoxicity during the video task without effecting NK cell numbers, suggesting naloxone itself can increase per-cell NK cytotoxicity. Affective ratings for the week preceding testing were inversely related to the increase in NK cell numbers during mental arithmetic. If the increase in NK cell numbers under brief stress is part of an adaptive response to potential injury, then our data suggest that increases in general distress may impede normal immune system adaptation. Acute stress paradigms may be used as potential probes for investigations of individual differences in immune system responsivity.

Purpose: To examine the effects of advanced age and diabetes on the response to standard tests of cardiovascular reflexes., Design: Group comparison., Setting: Psychophysiology laboratory, Department of Veterans Affairs Medical Center., Patients: Sixteen elderly male (67-81 years old) non-insulin dependent diabetic subjects without hypertension and nine elderly male (63-77 years old) controls., Main Outcome Measures: Continuous (beat-by-beat) measures of heart rate, systolic blood pressure, diastolic blood pressure, and skin conductance were studied during tests of Valsalva maneuver, deep breathing, and postural change from sitting to standing., Results: In comparison with elderly controls, the diabetic patients showed altered cardiovascular responses in measures of heart rate variability during Valsalva and standing. None of the subjects evidenced frank postural hypotension, but there was a greater fall in diastolic blood pressure immediately after standing for the diabetic patients compared with the controls. There was also a significant relationship between this response and decreased heart rate variability during Valsalva., Conclusions: Older type II diabetic patients compared with healthy controls had mild cardiovascular abnormalities. These results parallel those of studies comparing younger diabetics and controls.

Few data are available on the response of the human immune system to acute psychological stressors under controlled laboratory conditions. Young female subjects (21-41 years) showed increases in natural killer (NK) cell activity, and in the numbers of circulating CD8 suppressor/cytotoxic T cells, and natural killer lymphocytes following a brief (12 minute) stressful mental arithmetic examination. Older female subjects (65-85 years) failed to show the stress-related increase in NK activity. The psychological stress did lead to increases in the numbers of circulating CD8 suppressor/cytotoxic T cells and NK lymphocytes in old subjects to a similar degree as that seen in the young group. No changes in the numbers of helper/inducer T cells (CD4), total T cells (CD3), or B cells (CD20) were found following the stressor for either group. Cardiovascular, catecholamine, and subjective stress responses were similar for the two age groups. These results demonstrate that brief psychological stress is associated with some rapid immune cell changes, including release of CD8 suppressor/cytotoxic T cells and NK cells into circulation, and in young subjects, increases in NK activity. The absence of an NK activity increase in the older subjects indicates that NK cell mobilization and cell lysis induced by NK cells may be differentially affected by stress. The results also suggest the possibility of an age-related deficit in the up-regulation of NK activity under some environmental demands.

Helping the adult with spinal cord injury to adjust to sexual limitations is an important and neglected part of his rehabilitation. Health professionals of all fields have been perceived to be deficient in their knowledge of the sexuality of the adult with spinal cord injury. A test with 40 statements reflecting myths, misconceptions, and truths about the effect of spinal cord injury on sexual function was administered to 30 physical therapists responsible for rehabilitating these adults. At least 28 of the 40 items were missed by 10 percent or more of the therapists. Experience and participation in educational programs appeared to contribute to the respondents' knowledge, as reflected by the test, but only experience was a statistically significant variable.