Identification of a ß-arrestin-biased negative allosteric modulator for the ß2-adrenergic receptor.

Catecholamine-stimulated ß2-adrenergic receptor (ß2AR) signaling via the canonical Gs-adenylyl cyclase-cAMP-PKA pathway regulates numerous physiological functions, including the therapeutic effects of exogenous ß-agonists in the treatment of airway disease. ß2AR signaling is tightly regulated by GRKs and ß-arrestins, which together promote ß2AR desensitization and internalization as well as downstream signaling, often antithetical to the canonical pathway. Thus, the ability to bias ß2AR signaling toward the Gs pathway while avoiding ß-arrestin-mediated effects may provide a strategy to improve the functional consequences of ß2AR activation. Since attempts to develop Gs-biased agonists and allosteric modulators for the ß2AR have been largely unsuccessful, here we screened small molecule libraries for allosteric modulators that selectively inhibit ß-arrestin recruitment to the receptor. This screen identified several compounds that met this profile, and, of these, a difluorophenyl quinazoline (DFPQ) derivative was found to be a selective negative allosteric modulator of ß-arrestin recruitment to the ß2AR while having no effect on ß2AR coupling to Gs. DFPQ effectively inhibits agonist-promoted phosphorylation and internalization of the ß2AR and protects against the functional desensitization of ß-agonist mediated regulation in cell and tissue models. The effects of DFPQ were also specific to the ß2AR with minimal effects on the ß1AR. Modeling, mutagenesis, and medicinal chemistry studies support DFPQ derivatives binding to an intracellular membrane-facing region of the ß2AR, including residues within transmembrane domains 3 and 4 and intracellular loop 2. DFPQ thus represents a class of biased allosteric modulators that targets an allosteric site of the ß2AR.

Suppression of Lung Oxidative Stress, Inflammation, and Fibrosis following Nitrogen Mustard Exposure by the Selective Farnesoid X Receptor Agonist Obeticholic Acid.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause pulmonary injury that can progress to fibrosis. NM toxicity is associated with an influx of inflammatory macrophages in the lung. Farnesoid X receptor (FXR) is a nuclear receptor involved in bile acid and lipid homeostasis that has anti-inflammatory activity. In these studies, we analyzed the effects of FXR activation on lung injury, oxidative stress, and fibrosis induced by NM. Male Wistar rats were exposed to phosphate-buffered saline (vehicle control) or NM (0.125 mg/kg) by intratracheal Penncentury-MicroSprayer aerosolization; this was followed by treatment with the FXR synthetic agonist, obeticholic acid (OCA, 15 mg/kg), or vehicle control (0.13-0.18 g peanut butter) 2 hours later and then once per day, 5 days per week thereafter for 28 days. NM caused histopathological changes in the lung, including epithelial thickening, alveolar circularization, and pulmonary edema. Picrosirius red staining and lung hydroxyproline content were increased, indicative of fibrosis; foamy lipid-laden macrophages were also identified in the lung. This was associated with aberrations in pulmonary function, including increases in resistance and hysteresis. Following NM exposure, lung expression of HO-1 and iNOS, and the ratio of nitrates/nitrites in bronchoalveolar lavage fluid (BAL), markers of oxidative stress increased, along with BAL levels of inflammatory proteins, fibrinogen, and sRAGE. Administration of OCA attenuated NM-induced histopathology, oxidative stress, inflammation, and altered lung function. These findings demonstrate that FXR plays a role in limiting NM-induced lung injury and chronic disease, suggesting that activating FXR may represent an effective approach to limiting NM-induced toxicity. SIGNIFICANCE STATEMENT: In this study, the role of farnesoid-X-receptor (FXR) in mustard vesicant-induced pulmonary toxicity was analyzed using nitrogen mustard (NM) as a model. This study's findings that administration of obeticholic acid, an FXR agonist, to rats reduces NM-induced pulmonary injury, oxidative stress, and fibrosis provide novel mechanistic insights into vesicant toxicity, which may be useful in the development of efficacious therapeutics.

Sympathoinhibition during cardiopulmonary baroreceptor loading is attenuated in older females.

The purpose of the present study was to clarify the impact of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. Nine older females (mean ± SD, 70 ± 6 yr) and 11 younger females (20 ± 1 yr) completed the study. A passive leg raising (PLR) test was performed wherein the participants were positioned supine (baseline, 0°), and their lower limbs were passively lifted at 10°, 20°, 30°, and 40° (3 min at each angle). Muscle sympathetic nerve activity (MSNA) was recorded via microneurography of the left radial nerve. The central venous pressure was estimated based on peripheral venous pressure (eCVP), which was monitored using a cannula in the right large antecubital vein. Baseline MSNA was higher in older females than in younger females. MSNA burst frequency (BF) decreased during the PLR test in both older and younger females, but the magnitude of the decrease in MSNA BF was smaller in older females than in younger females (older, -3.5 ± 1.5 vs. younger, -6.3 ± 1.5 bursts/min at 40° from baseline, P = 0.014). The eCVP increased during the PLR in both groups, and there was no difference in the changes in eCVP between the two groups (older, +1.07 ± 0.37 vs. younger, +1.12 ± 0.33 mmHg at 40° from baseline, P = 0.941). These results suggest that inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age in females.NEW & NOTEWORTHY There were no available data concerning the effect of age on the sympathoinhibitory response to cardiopulmonary baroreceptor loading in females. The magnitude of the decrease in muscle sympathetic nerve activity during passive leg raising (10°-40°) was smaller in older females than in young females. In females, inhibition of sympathetic vasomotor outflow during cardiopulmonary baroreceptor loading could be blunted with advancing age.

Aging in females has minimal effect on changes in celiac artery blood flow during dynamic light-intensity exercise.

Blood flow to the active muscles and arterial blood pressure (ABP) increase during dynamic exercise, whereas blood flow to inactive organs (e.g., splanchnic organs and inactive limbs) declines. Aging leads to exaggerated ABP responses to exercise in females, but whether this is related to greater splanchnic vasoconstriction is unknown. This study sought to clarify the effect of aging in females on celiac artery blood flow during dynamic light-intensity exercise. Twelve healthy young females (YF: 20 ± 2 yr, mean ± SD) and 12 healthy older females (OF: 71 ± 4 yr) performed dynamic knee-extension and knee-flexion exercises at 30% of heart rate reserve for 4 min. The absolute changes from baseline (Δ) for mean arterial blood pressure (MAP), celiac artery mean blood flow (celMBF), and celiac vascular conductance (celVC) during exercise were calculated. ABP was measured using an automated sphygmomanometer, and celMBF was recorded by Doppler ultrasonography. The increase in MAP during exercise was greater in OF than in YF (YF: +14 ± 7 mmHg, OF: +24 ± 13 mmHg, P = 0.028). The celMBF decreased during exercise in both groups, but there was no significant difference in the response between YF and OF (YF: -93.0 ± 66.1 mL/min, OF: -89.6 ± 64.0 mL/min, P = 0.951). The celVC also decreased during exercise and remained lower than baseline during exercise. However, the response was not different between YF and OF (YF: -1.8 ± 1.0 mL/min/mmHg, OF: -1.5 ± 0.6 mL/min/mmHg, P = 0.517). These results demonstrate that aging in females has minimal influence on splanchnic artery hemodynamic responses during dynamic light-intensity exercise, suggesting that exaggerated ABP responses during exercise in OF are not due to greater splanchnic vasoconstriction.NEW & NOTEWORTHY During exercise, the splanchnic arteries vasoconstrict, contributing to blood flow redistribution and the blood pressure response. Blood pressure responses to exercise are exaggerated with aging in females; however, the physiological mechanism responsible has not been clarified. We show that celiac artery blood flow changes during light-intensity dynamic exercise do not differ with age in females. This indicates the exaggerated blood pressure to exercise with aging is likely not due to a difference in splanchnic vasoconstriction.

The Impact of Nutrition on Pain: A Narrative Review of Recent Literature.

PURPOSE OF REVIEW: Pain is a complex phenomenon that affects millions of individuals worldwide and poses a significant burden on public health. While pain management typically focuses on pharmacological and physical interventions, emerging research suggests that nutrition plays a crucial role in pain modulation. This narrative review aims to explore the relationship between nutrition and pain, providing a comprehensive overview of recent literature. The review covers various dietary factors, including macronutrients, micronutrients, dietary patterns, and specific dietary interventions. Additionally, the potential mechanisms underlying the impact of nutrition on pain are discussed. The findings highlight the potential for dietary interventions to complement traditional pain management approaches and provide valuable insights for future research and clinical practice. RECENT FINDINGS: Literature suggested the impact of healthy nutrition on improvement in pain and that certain types of food may increase and worsen different pain conditions. Nutrition plays an important role in modulating pain. It is important to counsel patients in pain on best diet for their pain condition to alleviate pain. Our article summarizes very well the issue of nutrition and pain and provides a guide to all practitioners caring for patients with chronic pain.

Rtt105 promotes high-fidelity DNA replication and repair by regulating the single-stranded DNA-binding factor RPA.

Single-stranded DNA (ssDNA) covered with the heterotrimeric Replication Protein A (RPA) complex is a central intermediate of DNA replication and repair. How RPA is regulated to ensure the fidelity of DNA replication and repair remains poorly understood. Yeast Rtt105 is an RPA-interacting protein required for RPA nuclear import and efficient ssDNA binding. Here, we describe an important role of Rtt105 in high-fidelity DNA replication and recombination and demonstrate that these functions of Rtt105 primarily depend on its regulation of RPA. The deletion of RTT105 causes elevated spontaneous DNA mutations with large duplications or deletions mediated by microhomologies. Rtt105 is recruited to DNA double-stranded break (DSB) ends where it promotes RPA assembly and homologous recombination repair by gene conversion or break-induced replication. In contrast, Rtt105 attenuates DSB repair by the mutagenic single-strand annealing or alternative end joining pathway. Thus, Rtt105-mediated regulation of RPA promotes high-fidelity replication and recombination while suppressing repair by deleterious pathways. Finally, we show that the human RPA-interacting protein hRIP-α, a putative functional homolog of Rtt105, also stimulates RPA assembly on ssDNA, suggesting the conservation of an Rtt105-mediated mechanism.

A Par3/LIM Kinase/Cofilin Pathway Mediates Human Airway Smooth Muscle Relaxation by TAS2R14.

TAS2Rs (bitter taste receptors) are GPCRs (G protein-coupled receptors) expressed on human airway smooth muscle (HASM) cells; when activated by receptor agonists they evoke marked airway relaxation. In both taste and HASM cells, TAS2Rs activate a canonical Gßγ-mediated stimulation of Ca2+ release from intracellular stores by activation of PLCß (phospholipase Cß). Alone, this [Ca2+]i signaling does not readily account for relaxation, particularly since bronchoconstrictive agonists acting at Gq-coupled receptors also increase [Ca2+]i. We established that TAS2R14 activation in HASM promotes relaxation through F-actin (filamentous actin) severing. This destabilization of actin was from agonist-promoted activation (dephosphorylation) of cofilin, which was pertussis toxin sensitive. Cofilin dephosphorylation was due to TAS2R-mediated deactivation of LIM domain kinase. The link between early receptor action and the distal cofilin dephosphorylation was found to be the polarity protein partitioning defective 3 (Par3), a known binding partner with PLCß that inhibits LIM kinase. The physiologic relevance of this pathway was assessed using knock-downs of cofilin and Par3 in HASM cells and in human precision-cut lung slices. Relaxation by TAS2R14 agonists was ablated with knock-down of either protein as assessed by magnetic twisting cytometry in isolated cells or intact airways in the slices. Blocking [Ca2+]i release by TAS2R14 inhibited agonist-promoted cofilin dephosphorylation, confirming a role for [Ca2+]i in actin-modifying pathways. These results further elucidate the mechanistic basis of TAS2R-mediated HASM relaxation and point toward nodal points that may act as asthma or chronic obstructive pulmonary disease response modifiers or additional targets for novel bronchodilators.

Mitochondrial DNA in cell death and inflammation.

Cytosolic DNA is recognized by the innate immune system as a potential threat. During apoptotic cell death, mitochondrial DNA (mtDNA) release activates the DNA sensor cyclic GMP-AMP synthase (cGAS) to promote a pro-inflammatory type I interferon response. Inflammation following mtDNA release during apoptotic cell death can be exploited to engage anti-tumor immunity and represents a potential avenue for cancer therapy. Additionally, various studies have described leakage of mtDNA, independent of cell death, with different underlying cues such as pathogenic infections, changes in mtDNA packaging, mtDNA stress or reduced mitochondrial clearance. The interferon response in these scenarios can be beneficial but also potentially disadvantageous, as suggested by a variety of disease phenotypes. In this review, we discuss mechanisms underlying mtDNA release governed by cell death pathways and summarize release mechanisms independent of cell death. We further highlight the similarities and differences in mtDNA release pathways, outlining gaps in our knowledge and questions for further research. Together, a deeper understanding of how and when mtDNA is released may enable the development of drugs to specifically target or inhibit mtDNA release in different disease settings.

Redefining American conservation for equitable and inclusive social-environmental management.

Efforts to recruit, retain, and include Blacks, Indigenous, and People of Color (BIPOC) in environmental fields often fall short, in part due to limited conceptualizations of conservation and environment. At the core of this is the North American Model for Wildlife Conservation, an important approach to conservation and wildlife management that has influenced conservation globally. This model, however, is based upon a specific subset of worldviews, driven by Western and Eurocentric constructions of wilderness and nature. This model creates a narrow view of human-environment relationships and erases cultures and communities that explicitly view themselves as part of nature. We review the seven tenets of the North American Model for Wildlife Conservation, highlighting their limitations and exclusion of other models of environmental and natural resource management and alternative relationships with nature. In order to support long-term environmental engagement and culturally responsive research, 21st century environmental practitioners should shift our thinking around conservation to center counter narratives of BIPOC communities, scientists, and professionals as part of and meaningfully connected to nature. We argue that relying solely on the historically dominant language and ideologies at the core of the North American Model perpetuates disparities in environmental engagement and limits retention of BIPOC in environmental fields. We further highlight how shifts in understanding conservation and relationships to nature enables us to re-frame our work to support equitable, inclusive, and just conservation science and practice.

Epinephrine evokes shortening of human airway smooth muscle cells following ß2 adrenergic receptor desensitization.

Epinephrine (EPI), an endogenous catecholamine involved in the body's fight-or-flight responses to stress, activates α1-adrenergic receptors (α1ARs) expressed on various organs to evoke a wide range of physiological functions, including vasoconstriction. In the smooth muscle of human bronchi, however, the functional role of EPI on α1ARs remains controversial. Classically, evidence suggests that EPI promotes bronchodilation by stimulating ß2-adrenergic receptors (ß2ARs). Conventionally, the selective ß2AR agonism of EPI was thought to be, in part, due to a predominance of ß2ARs and/or a sparse, or lack of α1AR activity in human airway smooth muscle (HASM) cells. Surprisingly, we find that HASM cells express a high abundance of ADRA1B (the α1AR subtype B) and identify a spontaneous "switch-like" activation of α1ARs that evokes intracellular calcium, myosin light chain phosphorylation, and HASM cell shortening. The switch-like responses, and related EPI-induced biochemical and mechanical signals, emerged upon pharmacological inhibition of ß2ARs and/or under experimental conditions that induce ß2AR tachyphylaxis. EPI-induced procontractile effects were abrogated by an α1AR antagonist, doxazosin mesylate (DM). These data collectively uncover a previously unrecognized feed-forward mechanism driving bronchospasm via two distinct classes of G protein-coupled receptors (GPCRs) and provide a basis for reexamining α1AR inhibition for the management of stress/exercise-induced asthma and/or ß2-agonist insensitivity in patients with difficult-to-control, disease subtypes.

Assessing functional sympatholysis during rhythmic handgrip exercise using Doppler ultrasound and near-infrared spectroscopy: sex differences and test-retest reliability.

The effects of sympathetic activity on vasoconstriction are dampened in active skeletal muscle during exercise, a phenomenon termed functional sympatholysis. Limited work has examined the influence of sex on the magnitude of sympatholysis or the test-retest reliability of measurements. In 16 women and 15 men, forearm blood flow (FBF; Doppler ultrasound), muscle oxygenation (near-infrared spectroscopy, NIRS), and beat-to-beat mean arterial pressure (MAP; photoplethysmography) were measured during lower-body negative pressure (LBNP; -20 mmHg) at rest and simultaneously during rhythmic handgrip exercise (30% maximum contraction). Measures were taken twice within the same visit (separated by 15 min) and repeated on a second visit. Forearm vascular conductance (FVC) was calculated as FBF/MAP. The magnitude of sympatholysis was calculated as the difference of LBNP-induced changes between handgrip and rest. LBNP decreased FBF (Δ-45 ± 15%), FVC (Δ-45 ± 16%), and muscle oxygenation (Δ-14 ± 11%); however, these responses were attenuated when LBNP was applied during rhythmic handgrip exercise (Δ-7 ± 9%, Δ-9 ± 10%, and Δ-6 ± 9%, respectively). The magnitude of sympatholysis was not different between men and women (FBF: 40 ± 16% vs. 35 ± 9%, P = 0.37; FVC: 38 ± 16% vs. 35 ± 11%, P = 0.53; muscle oxygenation: 5 ± 9% vs. 11 ± 10%, P = 0.11). Furthermore, sympatholysis measurements demonstrated good to excellent intraday (intraclass-correlation coefficients; ICC ≥ 0.85) and interday (ICC ≥ 0.72) test-retest reliability (all P ≤ 0.01) in both sexes. The coefficients of variation were larger with NIRS (68-91%) than with Doppler ultrasound (16%-22%) assessments of functional sympatholysis. Collectively, these findings demonstrate that assessments of functional sympatholysis are not impacted by biological sex and that Doppler ultrasound-derived measures of sympatholysis have better within-subject reliability than NIRS-derived measures in young healthy adults.

Sympathetic transduction of blood pressure during graded lower body negative pressure in young healthy adults.

Sympathetic transduction of blood pressure (BP) is correlated negatively with resting muscle sympathetic nerve activity (MSNA) in cross-sectional data, but the acute effects of increasing MSNA are unclear. Sixteen (4 female) healthy adults (26 ± 3 years) underwent continuous measurement of heart rate, BP, and MSNA at rest and during graded lower body negative pressure (LBNP) at -10, -20, and -30 mmHg. Sympathetic transduction of BP was quantified in the time (signal averaging) and frequency (MSNA-BP gain) domains. The proportions of MSNA bursts firing within each tertile of BP were calculated. As expected, LBNP increased MSNA burst frequency (P < 0.01) and burst amplitude (P < 0.02), although the proportions of MSNA bursts firing across each BP tertile remained stable (all P > 0.44). The MSNA-diastolic BP low-frequency transfer function gain (P = 0.25) was unchanged during LBNP; the spectral coherence was increased (P = 0.03). Signal-averaged sympathetic transduction of diastolic BP was unchanged (from 2.1 ± 1.0 at rest to 2.4 ± 1.5, 2.2 ± 1.3, and 2.3 ± 1.4 mmHg; P = 0.43) during LBNP, but diastolic BP responses following nonburst cardiac cycles progressively decreased (from -0.8 ± 0.4 at rest to -1.0 ± 0.6, -1.2 ± 0.6, and -1.6 ± 0.9 mmHg; P < 0.01). As a result, the difference between MSNA burst and nonburst diastolic BP responses was increased (from 2.9 ± 1.4 at rest to 3.4 ± 1.9, 3.4 ± 1.9, and 3.9 ± 2.1 mmHg; P < 0.01). In conclusion, acute increases in MSNA using LBNP did not alter traditional signal-averaged or frequency-domain measures of sympathetic transduction of BP or the proportion of MSNA bursts firing at different BP levels. The factors that determine changes in the firing of MSNA bursts relative to oscillations in BP require further investigation.

Farnesoid X receptor regulates lung macrophage activation and injury following nitrogen mustard exposure.

Nitrogen mustard (NM) is a cytotoxic vesicant known to cause acute lung injury which progresses to fibrosis; this is associated with a sequential accumulation of pro- and anti-inflammatory macrophages in the lung which have been implicated in NM toxicity. Farnesoid X receptor (FXR) is a nuclear receptor involved in regulating lipid homeostasis and inflammation. In these studies, we analyzed the role of FXR in inflammatory macrophage activation, lung injury and oxidative stress following NM exposure. Wild-type (WT) and FXR-/- mice were treated intratracheally with PBS (control) or NM (0.08 mg/kg). Bronchoalveolar lavage fluid (BAL) and lung tissue were collected 3, 14 and 28 d later. NM caused progressive histopathologic alterations in the lung including inflammatory cell infiltration and alveolar wall thickening and increases in protein and cells in BAL; oxidative stress was also noted, as reflected by upregulation of heme oxygenase-1. These changes were more prominent in male FXR-/- mice. Flow cytometric analysis revealed that loss of FXR resulted in increases in proinflammatory macrophages at 3 d post NM; this correlated with upregulation of COX-2 and ARL11, markers of macrophage activation. Markers of anti-inflammatory macrophage activation, CD163 and STAT6, were also upregulated after NM; this response was exacerbated in FXR-/- mice at 14 d post-NM. These findings demonstrate that FXR plays a role in limiting macrophage inflammatory responses important in lung injury and oxidative stress. Maintaining or enhancing FXR function may represent a useful strategy in the development of countermeasures to treat mustard lung toxicity.

Baseline fatigue in early breast cancer survivors: understanding its prevalence in community-based exercise.

PURPOSE: Examine baseline fatigue levels in early-breast cancer survivors (EBCS) compared to inactive controls (CON) and identify associated physical and psychosocial factors with fatigue prior to community-based exercise. METHODS: A total of 33 EBCS (53.9 ± 11.4 years) and 21 CON (54.0 ± 8.0 years) were recruited. Participants completed questionnaires for demographics and patient-reported outcome measures pertaining to fatigue, quality of life, mental health, and physical activity, and completed a 6-min walk test, balance assessment, cardiopulmonary exercise test (VO2peak), and muscular strength test. A Mann-Whitney U test compared fatigue between groups and unadjusted univariable linear regressions were used to explore relationships with fatigue. RESULTS: Fatigue in EBCS was not statistically different from CON (EBCS: 16.9 ± 5.75; CON: 14.2 ± 3.4, p = 0.121). Univariable analyses showed lower fatigue in EBCS was associated with better Physical and Mental Health (both R2 = 0.435; p < 0.01), better outcome expectations for exercise (R2 = 0.237; p < 0.01), better self-efficacy (R2 = 0.407; p < 0.01), lower depression (R2 = 0.383; p < 0.001), lower anxiety (R2 = 0.104; p < 0.05), and better balance (R2 = 0.265; p < 0.01). Lower fatigue in the CON group was associated with better sleep quality (R2 = 0.263; p < 0.05) and self-efficacy (R2 = 0.417; p < 0.05). CONCLUSIONS: Mild fatigue was prevalent in EBCS, whereas moderate/severe fatigue was not. This discrepancy should be explored provided the benefits of exercise for fatigue management. Further, fatigue in EBCS was associated with multiple psychosocial and functional outcomes, which emphasized both its multi-factorial nature and uniqueness to the EBCS population. CLINICALTRIALS: gov Number: NCT03760536.

Patient-reported symptom severity, interference with daily activities, and adverse events in older and younger women receiving chemotherapy for early breast cancer.

BACKGROUND: To the authors' knowledge, it is unknown whether patient-reported symptom severity and symptom interference with daily activities differ between younger (aged <65 years) and older (aged ≥65 years) women receiving similar chemotherapy regimens for early breast cancer (EBC). METHODS: Study participants rated 17 side effects of chemotherapy regimens currently in use in clinical practice (2014-2019). RESULTS: Of 284 women with EBC (stage I-III), approximately 57% were aged <65 years and 43% were aged ≥65 years. For anthracycline-based regimens, a higher percentage of younger women reported moderate, severe, or very severe (MSVS) hot flashes (49% vs 18%) (P < .001). For nonanthracycline regimens, a higher percentage of younger women reported MSVS hot flashes (38% vs 19%) (P = .009) and a lower percentage reported MSVS arthralgia (28% vs 49%) (P = .005). With regard to symptom interference with daily activities, a higher percentage of younger women being treated with anthracycline-based regimens reported MSVS hot flashes (32% vs 7%) (P = .001) and myalgia (38% vs 18%) (P = .02). For nonanthracycline chemotherapy, a higher percentage of younger women reported MSVS interference for hot flashes (26% vs 9%) (P = .006) and lower percentages reported abdominal pain (13% vs 28%) (P = .02). Overall, there were no significant differences noted among younger versus older patients with regard to hospitalizations (19% vs 12%; P = .19), dose reductions (34% vs 31%; P = .50), dose delays (22% vs 25%; P = .59), or early treatment discontinuation (16% vs 16%; P = .9546). CONCLUSIONS: Older and younger women with EBC who were treated with identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events. LAY SUMMARY: In this study, women receiving chemotherapy for early breast cancer rated the severity of 17 symptoms and symptom interference with their activities of daily living. Older (aged ≥65 years) and younger (aged <65 years) women who received identical chemotherapy regimens generally experienced similar levels of symptom severity, symptom-related interference with daily activities, and adverse events.

Signal-averaged resting sympathetic transduction of blood pressure: is it time to account for prevailing muscle sympathetic burst frequency?

Calculating the blood pressure (BP) response to a burst of muscle sympathetic nerve activity (MSNA), termed sympathetic transduction, may be influenced by an individual's resting burst frequency. We examined the relationships between sympathetic transduction and MSNA in 107 healthy males and females and developed a normalized sympathetic transduction metric to incorporate resting MSNA. Burst-triggered signal averaging was used to calculate the peak diastolic BP response following each MSNA burst (sympathetic transduction of BP) and following incorporation of MSNA burst cluster patterns and amplitudes (sympathetic transduction slope). MSNA burst frequency was negatively correlated with sympathetic transduction of BP (r = -0.42; P < 0.01) and the sympathetic transduction slope (r = -0.66; P < 0.01), independent of sex. MSNA burst amplitude was unrelated to sympathetic transduction of BP in males (r = 0.04; P = 0.78), but positively correlated in females (r = 0.44; P < 0.01) and with the sympathetic transduction slope in all participants (r = 0.42; P < 0.01). To control for MSNA, the linear regression slope of the log-log relationship between sympathetic transduction and MSNA burst frequency was used as a correction exponent. In subanalysis of males (38 ± 10 vs. 14 ± 4 bursts/min) and females (28 ± 5 vs. 12 ± 4 bursts/min) with high versus low MSNA, sympathetic transduction of BP and sympathetic transduction slope were lower in participants with high MSNA (all P < 0.05). In contrast, normalized sympathetic transduction of BP and normalized sympathetic transduction slope were similar in males and females with high versus low MSNA (all P > 0.22). We propose that incorporating MSNA burst frequency into the calculation of sympathetic transduction will allow comparisons between participants with varying levels of resting MSNA.

Is neoadjuvant therapy an alternative strategy to immediate surgery in locally perforated colon cancer?

BACKGROUND: Perforations are a rare but serious complication of colorectal cancer. The current standard of treatment is emergent surgery followed by adjuvant chemotherapy. The concern with this approach is not only the uncertainty of achieving a R0 resection but also potential injury to adjacent vessels, nerves and ureters due to inflamed tissue planes. A subset of this patient population with a contained perforation who are clinically stable may have superior oncological outcomes with local sepsis control, neoadjuvant therapy followed by radical resection. The aim of this study is to report on the pre-operative safety profile for neoadjuvant therapy in the setting of an abscess from colon cancer perforation and the short-term oncological surgical quality outcomes. METHODS: In this retrospective observational study, all consecutive perforated colon cancer receiving neoadjuvant therapy from Jan 2010 to Dec 2019 were included. RESULTS: There were 21 patients that met the inclusion criteria. The most common symptom at presentation was abdominal pain (71.4%) and most common site of perforation was sigmoid colon (61.9%). Local sepsis control was achieved with a combination of radiological or surgical drainage, diverting ostomy and/or intravenous antibiotics. Thirteen patients had long-course chemoradiation and eight patients had neoadjuvant chemotherapy. Of these, 13 (61.9%) had tumour regression, with one patient having a pathological complete response. All patients achieved a R0 resection. CONCLUSIONS: In a small subset of patients with colon cancer perforation, this study has demonstrated the potential safe usage of neoadjuvant therapy first before radical surgery to achieve a clear resection margin.

Community-based exercise programs and cancer-related fatigue: a systematic review and meta-analysis.

PURPOSE: To explore the prevalence of cancer-related fatigue (CRF) within community-based exercise programs and to determine the overall impact that participation in community-based exercise programs have on CRF. METHODS: Literature searches were performed in March and updated in April of 2020. Studies that were community-based in adult cancer populations and reported CRF outcomes were included. Mean and standard deviations for CRF from 12 studies were extracted in order to compute a pooled effect size via a random effects model. An overall percentage was computed to discern how many community-based exercise programs reported CRF. RESULTS: Sample sizes varied among studies with most patients being middle-aged with breast cancer in the post-treatment setting. Most programs implemented aerobic + resistance exercise training interventions (~77%). Only ~42% of programs identified in the review reported CRF outcomes. The random effects model produced a pooled effect size of 0.30 (p < 0.001). CONCLUSIONS: Fewer than half of the identified community-based exercise programs reported CRF outcomes (~42%). Of those that did, the random effects model revealed a small yet significant impact on improving CRF after exercise participation, though more research is certainly needed in this area. This review produced promising preliminary evidence for the impact of community-based exercise programs on CRF. As exercise interventions transition to community-based facilities, patients should feel confident that these programs will continue to assist in managing CRF that is commonly experienced across the cancer continuum.

Muscle sympathetic single-unit response patterns during progressive muscle metaboreflex activation in young healthy adults.

Muscle sympathetic single units can respond differentially to stress, but whether these responses are linked to the degree of sympathoexcitation is unclear. Fifty-three muscle sympathetic single units (microneurography) were recorded in 17 participants (8 women; 24 ± 3 yr). Five 40-s bouts of 10% static handgrip were performed during a 10-min forearm ischemia to progressively increase metabolite accumulation. Each static handgrip was separated by a 75-s ischemic rest [postexercise circulatory occlusion (PECO)] to assess the isolated action of the muscle metaboreflex. During each set of PECO, individual single units were classified as activated, nonresponsive, or inhibited if the spike frequency was above, within, or below the baseline variability, respectively. From sets 1-5 of PECO, the proportion of single units with activated (34, 45, 68, 87, and 89%), nonresponsive (43, 44, 23, 7, and 9%), or inhibited (23, 11, 9, 6, and 2%) responses changed (P < 0.001) as total muscle sympathoexcitation increased. A total of 51/53 (96%) single units were activated in at least one set of PECO, 16 (31%) initially inhibited before activation. This response pattern delayed the activation onset compared with noninhibited units (set 3 ± 1 vs. 2 ± 1, P < 0.001). Once activated, the spike-frequency rate of rise was similar (8.5 ± 6.5 vs. 7.1 ± 6.0 spikes/min per set, P = 0.48). Muscle sympathetic single-unit firing demonstrated differential control during muscle metaboreflex activation. Single units that were initially inhibited during progressive metaboreflex activation were capable of being activated in later sets. These findings reveal that single-unit activity is influenced by convergent neural inputs (i.e., both inhibitory and excitatory), which yield heterogenous single-unit activation thresholds.NEW & NOTEWORTHY Muscle sympathetic single units respond differentially to sympathoexcitatory stress such that single units can increase firing to contribute to the sympathoexcitatory response or can be nonresponsive or even inhibited. We observed a subgroup of single units that can respond bidirectionally, being first inhibited before activated by progressive increases in forearm muscle metaboreflex activation. These results suggest convergent neural inputs (i.e., inhibitory and excitatory), which yield heterogenous muscle sympathetic single-unit activation thresholds.

Congruence of patient- and clinician-reported toxicity in women receiving chemotherapy for early breast cancer.

BACKGROUND: The National Cancer Institute's Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse Events, collected alongside the clinician-reported Common Terminology Criteria for Adverse Events, enables comparisons of patient and clinician reports on treatment toxicity. METHODS: In a multisite study of women receiving chemotherapy for early-stage breast cancer, symptom reports were collected on the same day from patients and their clinicians for 17 symptoms; their data were not shared with each other. The proportions of moderate, severe, or very severe patient-reported symptom severity were compared with the proportions of clinician-rated grade 2, 3, or 4 toxicity. Patient-clinician agreement was assessed via κ statistics. Chi-square tests investigated whether patient characteristics were associated with patient-clinician agreement. RESULTS: Among 267 women, the median age was 58 years (range, 24-83 years), and 26% were nonwhite. There was moderate scoring agreement (κ = 0.413-0.570) for 53% of symptoms, fair agreement for 41% (κ = 0.220-0.378), and slight agreement for 6% (κ = 0.188). For example, patient-reported and clinician-rated percentages were 22% and 8% for severe or very severe fatigue, 41% and 46% for moderate fatigue, 32% and 39% for mild fatigue, and 6% and 7% for none. Clinician severity scores were lower for nonwhite patients in comparison with white patients for peripheral neuropathy, nausea, arthralgia, and dyspnea. CONCLUSIONS: Although clinician reporting of symptoms is common practice in oncology, there is suboptimal agreement with the gold standard of patient self-reporting. These data provide further evidence supporting the integration of patient-reported outcomes into oncological clinical research and clinical practice to improve monitoring of symptoms as well as timely interventions for symptoms.