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Descriptive statistics | The means and standard deviations for compassion, relevance, and interest in each video are presented in Table
Relevance(Range: 13.33–100) | PMC10061748 | ||
Engagement in videos among women | All descriptive statistics for ANOVAs and ANCOVA analyses for women examining the differences in engagement by video condition are displayed in Table
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Engagement in videos among men | As measures of pre-test muscularity, weight, and shape dissatisfaction were unrelated to interest in women, a univariate ANOVA was conducted to examine the differences between video conditions on interest. There was no significant effect of video condition on interest, As measures of pre-test weight satisfaction, shape satisfaction, and muscularity satisfaction were related to relevance in women, an ANCOVA controlling for these variables was conducted to examine the differences between video conditions on relevance. Pre-test weight satisfaction (As measures of pre-test muscularity, weight, and shape dissatisfaction were unrelated to compassion in women, univariate ANOVA was conducted to examine the differences between video conditions on compassion. There was a significant effect of video condition on compassion, All descriptive statistics for ANOVAs and ANCOVA analyses for men examining the differences in engagement by video condition are displayed in Table
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Discussion | SE, cognitive and affective, eating disorders, cognitive, affective, and behavioural | As measures of pre-test muscularity, weight, and shape dissatisfaction were unrelated to interest in men, a univariate ANOVA was conducted to examine the differences between video conditions on interest. There was no significant effect of video condition on interest, As measures of pre-test weight satisfaction, shape satisfaction, and muscularity satisfaction were related to relevance in men, an ANCOVA controlling for these variables was conducted to examine the differences between video conditions on relevance. Pre-test shape satisfaction was significantly related to relevance; Holm corrections revealed that the information only video (M = 70.61, SE = 2.18) resulted in significantly greater relevance than the narrative only video (M = 59.93, SE = 2.18; adjusted As measures of pre-test muscularity, weight, and shape dissatisfaction were unrelated to compassion in men, a univariate ANOVA was conducted to examine the differences between video conditions on compassion. There was a significant effect of video condition on compassion, The aim of this study was to compare participants’ reported engagement with different forms of persuasive communication about body dissatisfaction, focusing on informational, narrative, and direct persuasive appeal. We proposed two research questions. The first was whether a particular persuasive approach resulted in superior engagement over other approaches in the context of body dissatisfaction mental health literacy. It was found that there was some advantage for both persuasive appeals and information-only approaches over a narrative approach for both gender groups, and some advantage for the information approach with the addition of a persuasive appeal for men. The second was to understand whether different persuasive communication approaches impacted cognitive, affective, and behavioural domains of engagement differently. It was found that there were some domains impacted differently depending on the communication approach, in particular for cognitive and affective domains.Overall, while all communication types were engaging, there appeared to be some advantage for persuasive appeals and informational videos across both men and women. This is only partially consistent with the previous literature around persuasive communication, which has found benefits overall for both informational and narrative approaches [The benefits observed from viewing a persuasive appeal (relative to the narrative videos) are a novel finding, as to our knowledge the effects of viewing a standalone persuasive appeal were previously unexamined in the literature. This finding may indicate that the nature of a persuasive appeal is appropriate for use on social media or in other forms of media. The message is short, clear, and action-based, giving viewers a specific call to action to learn more about body dissatisfaction as an important mental health issue. This appeal bears resemblance to very successful strategies commonly used in social media (e.g. call to action) which are intended to generate engagement [Different impacts on domains of engagement were found, which were partially consistent with literature on processing communication [Inconsistent with theories of processing and attitude bases [Notably, although short videos showed differences for compassion and relevance (for men) and compassion (for women), no videos appeared to produce superior results in all domains of engagement across genders. This finding is not especially concerning in itself, particularly when examining the findings for relevance and interest in women (i.e., both relevance and interest were fairly high among women regardless of video condition). It should be of note, however, that interest (i.e., behavioural engagement) was moderate among men, which may indicate less intent to engage with body image content more generally as body dissatisfaction and eating disorders are perceived to be feminine issues [The findings of this study have implications for social marketing campaigns within the body image field, and research into their efficacy. First, it is clear that further research exploring the impact of persuasive appeals should be conducted, as they were more engaging than narrative approaches within some contexts. Second, contextualising the current study’s findings with our previous work, social marketing campaigns that aim to educate and promote awareness through engagement may take a different approach from those aimed at improving body satisfaction. There may be some advantages to informational and persuasive appeals relative to narrative approaches within the context of engagement. Campaigns may wish to use expert information, or direct appeals to the audience, particularly to generate interest online. Third, research should further examine the impact of particular persuasive communication approaches on domains of engagement. For instance, a call to action may best be used to impact affective engagement. Further examination of persuasive communication approaches on specific domains of engagement would be beneficial for social marketers and researchers. | PMC10061748 | |
Strengths and Limitations | eating disorders | A strength of this study was its generalisability; a mixed-age, community sample of men and women was used, which is not common in evaluating social marketing or anti-stigma campaigns for body image and eating disorders [Further limitations were that engagement was examined at one point in time, which precluded examination of change in engagement resulting from video viewing, and that the use for the cover story likely did not fully conceal the purpose of the study. In addition, the standalone persuasive appeal video was rated as less visually appealing and with lower production quality than the other videos, which may have impacted interest and attention to the videos. Another limitation is the varying length of the videos, in particular the difference in viewing time between the persuasive appeal only video, and the conditions to which the persuasive appeal video was added. As such, the effects of video length from video content may be difficult to separate. Although all videos were short in duration, future research should consider using equivalent length videos in all conditions. An additional limitation is around cultural relevance; although we collected country of residence, we did not collect information on other demographic characteristics; which may be of relevance considering academics and actors appearing in the videos were white. Future research examining engagement in such videos may wish to collect information such as cultural background, to better assess generalisability of the research, and aim to ensure the cast is not all or majority white to better reflect a community sample’s characteristics. Finally, a limitation is that most people in the video were thin; this may have unintentionally reinforced the idea that body dissatisfaction is only a problem when the person’s body is smaller; further research should examine the impact and potential benefits of educating the public that body dissatisfaction has a negative impact at all sizes, the issue of weight stigma, and attempt to include more size diversity. | PMC10061748 | |
Acknowledgements | Thank you to The Mannequin Project at Big Picture Storytelling for video production and permission to use the videos in this research. | PMC10061748 | ||
Authors’ contributions | Jo Doley: conceptualisation, formal analysis, data curation, writing – original draft preparation, writing – review and editing. Siân McLean: conceptualisation, data curation, supervision, methodology, resources, investigation, writing – original draft preparation, writing – review and editing, project administration, funding acquisition. | PMC10061748 | ||
Funding | This research was partially supported by funding from Australian Rotary Health to the second author. | PMC10061748 | ||
Data Availability | The datasets generated and/or analysed during the current study are not publicly available as this was not a condition outlined to our participants, but are available from the corresponding author on reasonable request. | PMC10061748 | ||
Declarations | PMC10061748 | |||
Ethics approval and consent to participate | This study was approved by the La Trobe University Human Research Ethics Committee, approval number HEC15-116. All methods were carried out in accordance with the National Statement on Ethical Conduct in Human Research, the Australian Code for the Responsible Conduct of Research and Commonwealth and state laws. All participants provided informed consent to participate. | PMC10061748 | ||
Consent for publication | Not applicable. | PMC10061748 | ||
Competing interests | The authors have no competing interests to declare. | PMC10061748 | ||
References | PMC10061748 | |||
Subject terms | hypoxia, fatigue, impairments in exercise performanceMoreover | HYPOXIA | Ten male cyclists were randomized into four experimental conditions in this randomized, cross-over, double-blind, and sham-controlled study to test the combined effect of acute dark chocolate (DC) ingestion and anodal concurrent dual-site transcranial direct current stimulation (a-tDCS) targeting M1 and left DLPFC on cognitive and whole-body endurance performance in hypoxia after performing a cognitive task. Two hours before the sessions, chocolate was consumed. After arriving at the lab, participants completed an incongruent Stroop task for 30 min in hypoxia (OBy increasing altitude, the partial pressure of OStudies have also demonstrated that hypoxia has a detrimental effect on cognitive function (i.e., impaired attentional ability, executive function, and memory function) and the psychophysiological homeostasis of the bodyNutritional interventions are the most common strategies to counteract hypoxia-induced impairments in exercise performanceMoreover, anodal transcranial direct current stimulation (a-tDCS) has recently been suggested to boost exercise performanceThus, considering the detrimental effect of both hypoxia and mental fatigue on cognitive and physical performance, and the overlapping between its underlying mechanisms with the action mechanisms of DC and tDCS, it is possible to speculate that the combination of DC and a-tDCS | PMC10542360 |
Results | PMC10542360 | |||
Effect of the demanding cognitive task | fatigue | Performing the incongruent only Stroop task for 30 min did not induce a state of mental fatigue as we found no significant main effect of time Reaction time changes in the four experimental conditions. Comparison of choice reaction time performance ( | PMC10542360 | |
Effect of DC and a-tDCS | Our results showed a significant condition x time interaction | PMC10542360 | ||
Effect of DC and a-tDCS | The concomitant use of DC and a-tDCSEndurance performance and physiological responses in the four experimental conditions. Time to exhaustion test ( | PMC10542360 | ||
Effect of DC and a-tDCS | DC and/or a-tDCS | PMC10542360 | ||
Effect of DC and a-tDCS | RPE | DC and/or a-tDCSPsychophysiological responses to exercise in the four experimental conditions. Ratings of perceived exertion (RPE; | PMC10542360 | |
Discussion | hypoxia, cognitive improvements | HYPOXIA, VASODILATION | The main results of the present study were that (1) ‘DC + a-tDCS’ resulted in longer TTE in hypoxia than ‘WC + a-tDCS’ and ‘WC + sh-tDCS’ conditions, (2) with greater EMG activity of the VM muscle, and (3) improved cognitive performance during and after TTE. These results suggest the possibility of a synergistic effect between DC and a-tDCSFirst, it is important to note that despite performing the modified incongruent Stroop task for 30 min in hypoxia, cognitive performance was unchanged over time On the other hand, DC + a-tDCS improved cognitive performance during and after TTE in hypoxia. This is partially in line with previous studies showing cognitive improvements at rest with either DCThe improved cognitive performance with DC + a-tDCS might be due to increased blood flow and oxygenation to the brainWe found improved endurance performance (i.e., longer TTE) in hypoxia with DC + a-tDCS. This is also a novel finding of the present study. It should be noted that only DC + a-tDCS improved cognitive and endurance performance. Thus, we propose that this could be a synergistic effect since neither DC alone (DC + sh-tDCS) nor tDCS alone (WC + a-tDCS) improved cognitive or endurance performance. Despite previous studies have shown that a-tDCS targeting M1 or DLPFC separately improved endurance performance in cyclingOne possible mechanism for this synergistic effect is that the possible vascular effect of DC supplementation (i.e., vasodilation) allowed for the neuromodulatory effect of a-tDCS to take place. Theoretically, a tDCS-induced increase in corticospinal excitability and the change in the use of motor units can lead to an improvement in TTEWe found an increased EMG of the VM muscle under both DC + a-tDCS and DC + sh-tDCS compared to WC + sh-tDCS, but no difference in EMG of the RF and VL. Few studies analyzed the effect of tDCS on EMG during an endurance task, which limits comparisons. Vitor-Costa et al.On other hand, there was no change in HR, SpOThe interpretation and generalization of the findings of the present study should be made with caution since the participants were endurance-trained male cyclists. In addition, the lack of a measure of brain activity (e.g., EEG, fNIRS), corticospinal excitability, muscle, and brain blood flow, and oxygenation does not allow us to fully understand the mechanisms involved in the present findings. Future studies should consider these limitations and also expand the present findings, for instance, to higher levels of hypoxia. On the other hand, the strengths of the present study include a large array of outcome variables assessed and a complex experimental design testing the isolated and combined effects of DC and tDCS on cognitive and endurance performance in hypoxia and its related physiological and psychophysiological responses in professional athletes. From a practical perspective, if consistently replicated, the present findings indicate that athletes and coaches can use DC supplementation and tDCS to boost endurance performance in hypoxia.The present study showed a possible acute synergistic effect of a-tDCS targeting concurrently M1 and left DLPFC along with the consumption of dark chocolate on improving whole-body endurance performance after prior cognitive effort, with greater EMG of VM muscle, cognitive performance during and after endurance TTE under hypoxia, despite unchanged HR, SpO | PMC10542360 |
Methods | PMC10542360 | |||
Participants | Ten endurance-trained male cyclists voluntarily participated in this randomized, sham-controlled, and double-blind trial. The general characteristics of the participants are presented in Table General characteristics of the participants (n = 10). | PMC10542360 | ||
General experimental procedure | hypoxia | HYPOXIA | The participants visited the laboratory on six different occasions at one-week intervals. In the first session, participants underwent an anthropometric assessment and were familiarized with the whole experimental procedure. An individual not involved in the research team randomized the order of four experimental conditions using the Latin Square method. The participants and research team were blinded to the order of the experimental conditions throughout the study. In the second session, peak power output (PPO) was measured using an incremental cycling test in hypoxia (OStudy flowchart. | PMC10542360 |
Maximal incremental test | hypoxia | HYPOXIC, HYPOXIA | In the second session, after 30 min being under hypoxia at rest, participants underwent the maximal incremental test (Astrand Test for Men) on a cycle ergometer (Cyclus 2, RBM Elektronik-Automation GmbH, Leipzig, Germany) to measure PPO under the hypoxic condition. The test was started with 100 watts and a cadence of 60 rpm for three minutes and 50 watts increments every three minutes | PMC10542360 |
Dark chocolate supplementation | In the DC conditions (DC), 2 h before the experimental sessions participants consumed ~ 467 kcal of a typical commercial 70% cocoa product (Nestlé Noir 70%) containing the ingredients cocoa liquor, sugar, cocoa butter, milk fat, lecithin and vanilla | PMC10542360 | ||
Cognitive function—choice reaction time | hypoxia | HYPOXIA | The Visual Choice Reaction Time Apparatus (Model 63035A, Lafayette Instrument Company, Indiana, USA) with a four-choice compatible stimulus–response paradigm was used to measure cognitive performance. Three visual stimuli (lights turning on) were manually given to the participants, and they were instructed to respond as quickly as possible by pushing the corresponding button on the response panel. The reaction time in each stimulation was recorded and the mean value of 3 efforts was calculated. The CRT was performed at the beginning of each experimental session in normoxia, after the prolonged cognitive effort, and during and after TTE in hypoxia. | PMC10542360 |
MIVC | At the beginning of each session, participants performed 3–5 s knee extension MIVC three times with a 150-s rest in between on a custom-made chair with knee and hip fixed at 90° as recommended for VL, VM, and RF muscles MIVC test | PMC10542360 | ||
EMG | The surface EMG signals were collected strictly according to the recommended standards | PMC10542360 | ||
Hypoxic exposure | HYPOXIC | The hypoxic condition (O | PMC10542360 | |
Prolonged cognitive effort | hypoxia | HYPOXIA | Participants performed a modified computerized version of CWST (100% incongruent) for 30 min under hypoxia. The incongruent CWST consisted of four-color words (yellow, blue, green, and red) in different font inks (yellow, blue, green, and red) that were randomly displayed on a computer screen until the participant entered an answer and were followed by a 1500 ms interval. There were four colored buttons on the keyboard. The participants were instructed to press the button corresponding to the ink color displayed on the screen. There was an exception to this rule, however, if the word appeared in red ink, then the correct answer was pressing the button corresponding to the color word itself | PMC10542360 |
Transcranial direct current electrical stimulation (tDCS) | CORTEX | Two-channel battery-driven stimulators (NeuroStim 2, Medina Tebgostar, Tehran, Iran) were used to apply tDCS over the target brain areas during the 3rd to 6th experimental sessions (two devices were used). Four carbon electrodes covered by saline-soaked surface sponges (NaCl 140 mmol dissolved in Milli-Q water) were used as anodes (5 × 4; 20 cmStrength and radial component of the electric field induced by tDCS. Finite Element Models derived from Magnetic Resonance Imaging in a head model (MNI152) of the strength and radial (normal to the cortical surface) component of the electric field (EF) induced by tDCS. Electrode montage targeting the simultaneous stimulation with anodal tDCS of the representation of the lower limbs in the primary motor cortex and the left dorsolateral prefrontal cortex (Two channels of the tDCS device were used for the simultaneous stimulation of these two regions. For anodal stimulation, the current was gradually ramped up for 30 s, maintained at 2 mA for 20 min, and then progressively ramped down for 30 s. In the sham condition (sh-tDCS), the same electrode position was applied, and the current was ramped up for 30 s, but the 2-mA current was only maintained for 30 s, and then ramped down for 30 s remaining off the rest of the time. This protocol has been shown to be adequate for blinding participants in tDCS studies | PMC10542360 | |
tDCS modeling | The brain current flow during tDCS was calculated using a finite element model (FEM) following the standard pipeline in SimNIBS 4.0.0 | PMC10542360 | ||
tDCS-induced sensations and blinding assessment | Participants completed a questionnaire provided by Fertonani et al. | PMC10542360 | ||
Whole-body exhausting endurance task | hypoxia | HYPOXIA | Within the 3rd to 6th sessions, after 30 min performing CWST, followed by 20 min of tDCS, participants performed the TTE on a cycle ergometer (Cyclus 2, RBM Elektronik-Automation GmbH, Leipzig, Germany), all under hypoxia. Before TTE, participants warmed up cycling for 5 min at 45% PPO. After warming up, TTE started with a load of 60% of PPO and a 60 rpm cadence until exhaustion. The time between the beginning and interruption of the test was considered the TTE. HR and SpO | PMC10542360 |
HR and SpO | During the whole experimental session, HR was continuously monitored by the use of a chest strap (M430, Polar, Finland) connected to the cycle ergometer. SpO | PMC10542360 | ||
Ratings of perceived exertion | RPE, hypoxia | HYPOXIA | The 0–100 Borg scale was used to measure RPE. Participants received the instruction to report their RPE at the end of each stage and the point of exhaustion in the incremental test, and every 3 min and upon reaching the point of exhaustion in the TTE in hypoxia | PMC10542360 |
Affective responses and felt arousal | bipolar | The affective responses were reported using the Feeling Scale (FS), which is a bipolar scale comprising eleven items ranging from − 5 (very bad) to + 5 (very good), validated by Hardy and Rejeski | PMC10542360 | |
Statistical analyses | The normal distribution of each data set was evaluated by the Shapiro–Wilk normality test. Values are presented as means and standard deviation (SD) or median and interquartile range (IQR) as stated. The Friedman test was used to compare tDCS-induced sensations, end-of-study guess rate accuracy, and active stimulation guess rate, followed by Wilcoxon signed-rank tests with a Bonferroni correction for pair-wise comparisons (0.05/6 = Bonferroni corrected One-way repeated measures ANOVA was performed to analyze the mean value of TTE, HR, SpO | PMC10542360 | ||
Acknowledgements | The authors would like to thank Iman Talebi-Rasa and Matin Etemadi for their help in data acquisition. The authors also express their sincere gratitude to the participants for their commitment to the experimental procedure. This research was conducted in the Exercise Metabolism and Performance Lab (EMPL), Faculty of Sport Sciences, Razi University, Kermanshah, Iran. | PMC10542360 | ||
Author contributions | P.B., V.T., E.A., and D.M. conceptualized and designed the study. P.B., V.T., and E.A. conducted the experiments. P.B., V.T., E.A., and D.M. participated in the formal analysis. P.B. wrote the original draft of the manuscript. V.T., E.A., and D.M. reviewed and edited the manuscript. All authors read and approved the final manuscript. | PMC10542360 | ||
Funding | This research was conducted in the Exercise Metabolism and Performance Lab (EMPL), Faculty of Sport Sciences, Razi University, Kermanshah, Iran. | PMC10542360 | ||
Data availability | The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. | PMC10542360 | ||
Competing interests | The authors declare no competing interests. | PMC10542360 | ||
References | PMC10542360 | |||
Keywords | CONTRACTION, CONTRACTIONS | Communicated by Francesco Lacquaniti.This study used transcranial magnetic stimulation (TMS) to determine if muscarinic receptor blockade affects muscle responses during voluntary contractions. Motor evoked potentials (MEPs) were recorded from biceps brachii in 10 subjects (age: 23 ± 2) during 10%, 25%, 50%, 75%, and 100% maximal voluntary contractions (MVCs). Each contraction intensity was examined under non-fatigued and fatigued conditions. All measurements were obtained post-ingestion of 25 mg promethazine or placebo. MEP area and the duration of the TMS-evoked silent period (SP) were calculated for all contractions. No drug-related differences were detected for MEP area during non-fatigued or fatigued contractions. A main effect of drug was detected for the SP ( Open Access funding enabled and organized by CAUL and its Member Institutions | PMC10224869 | |
Introduction | gain of motor circuits, voluntary muscle contraction, muscle fatigue, voluntary muscle contractions | CONTRACTION, CORTEX | Four primary neuromodulator systems exist in the central nervous system (CNS): dopaminergic, adrenergic, serotonergic, and cholinergic. While there is a good understanding of how the first three systems regulate the gain of motor circuits in the CNS, our understanding of how the cholinergic system regulates the excitability of motor pathways during voluntary muscle contraction is limited. Muscarinic acetylcholine receptors (mAChRs) are the predominant cholinergic receptor in the CNS, where activation of mAChRs initiates G-protein–coupled signal transduction pathways (Caulfield The use of atropine for the insight of anti-muscarinic effects within human studies has been vastly used, however, promethazine allows the same insight without as considerable side-effects. Promethazine is one of the most potent antihistaminergic drugs with obvious antimuscarinic and sedative effects (Cantisani et al. Transcranial magnetic stimulation (TMS) is a non-invasive tool that can be used to assess the excitability of cortical circuits and motor pathways in humans. A single TMS pulse applied to the motor representation of a muscle induces a motor evoked potential (MEP) in the target muscle. The amplitude of the MEP reflects the excitability of the corticospinal pathway, where facilitation of MEP responses progressively increases until 50–70% MVC for upper limb muscles (Taylor et al. The purpose of this study was to assess if muscarinic receptor blockade modulates TMS-evoked MEPs and SPs during voluntary muscle contractions. The target muscle in this study was the biceps brachii, where EMG responses to single TMS pulses were recorded during elbow flexions of 10%, 25%, 50%, 75%, and 100% of MVC. To determine if muscarinic receptors have a neuromodulatory role when the motor system is fatigued, the range of contraction intensities were again examined. However, this time they were preceded by a sustained maximal effort elbow flexion that reduced the individuals force generating capacity to 60% of their initial MVC. It was hypothesised that a mAChR blockade would increase biceps brachii MEP area, and lengthen biceps brachii SP, during the voluntary elbow flexions regardless of whether muscle fatigue was present. Moreover, it was hypothesized that these antimuscarinic effects would be most prominent during higher contraction intensities when voluntary drive from the motor cortex to the target muscle is high. | PMC10224869 |
Methods | PMC10224869 | |||
Participants | Ten healthy individuals (mean age 23 ± 2) were involved in the study. Each participant attended two sessions spaced 10 days apart. Participants were screened using a modified medical history questionnaire that identified contraindications to promethazine, TMS, percutaneous electrical stimulation, and the exercise tasks employed in this study. No participant was taking any form of CNS medication that could impact measurements. | PMC10224869 | ||
Compliance with ethical standards | Written and informed consent was obtained before the commencement of testing. This experiment was approved by the Griffith University Human Research Ethics Committee and conformed to the standards set by the Declaration of Helsinki. | PMC10224869 | ||
Experiment design and drug administration | This study was a human, double-blinded, placebo-controlled, crossover design. Participants were administered either a placebo or 25 mg promethazine capsule. Promethazine was chosen for its high potency and antagonistic affects upon mAChRs (Kubo et al. | PMC10224869 | ||
Force and EMG recording | Participants were seated with their elbow flexed and held at 90° in a custom designed force transducer (Fig. Participants were seated with their arm attached to a custom designed force transducer. Biceps brachii EMG was recorded from the right limb following the administration of promethazine or a placebo ( | PMC10224869 | ||
Motor cortical stimulation | CORTEX | A circular coil with a 90 mm outside diameter was positioned over the vertex of the head and delivered single-pulse stimulations to the motor cortex via a MagStim 200 | PMC10224869 | |
Active motor threshold (AMT) | CONTRACTION | Each participant’s motor threshold was determined during light contraction of the biceps brachii. To ensure consistency between participants and between sessions, a horizontal cursor of 0.01% peak-to-peak Mmax was displayed on a monitor, and participants were required to track the cursor with their rectified biceps brachii EMG amplitude (0.2 s bins). TMS intensity was adjusted by 1% MSO increments in that at least five out of ten TMS pulses elicited an MEP greater than 100 V | PMC10224869 | |
TMS stimulus–response curves | Muscle responses were obtained from the lightly contracted biceps brachii from 90% AMT to 190% AMT in 10% AMT increments in a semi-randomised protocol. Six stimulations were delivered for each of the 11 stimulator intensities, where a 20 s rest was provided between each stimulation. One participant did not reach 190% AMT as the intensity would have been higher than 100% MSO. MEP area was subsequently normalised to Mmax. The TMS intensity that produced the largest normalised MEP with the smallest stimulator output was chosen as the TMS intensity for the remainder of the testing session (54–84% MSO). | PMC10224869 | ||
Contraction protocol 1: unfatigued muscle | torques | CONTRACTION, CONTRACTIONS | Participants performed 5 maximal effort contractions, where the trial that produced the largest torque was deemed the participants maximal voluntary contraction (MVC). Cortical and brachial plexus stimulation was delivered during initial baseline contractions, with a minimum of 2 min rest occurring between each effort. Target torques of 10%, 25%, 50%, and 75% MVC were then calculated from the measured MVC and displayed on a monitor. Participants performed 5 contractions for each target torque, whereby a maximal contraction was followed immediately by a submaximal contraction with no relaxation of the muscles when reducing force to submaximal contraction. Each maximal contraction within protocol 1 was a brief (~ 4 s) maximal contraction followed directly by a brief (4 s) submaximal contraction (Fig. | PMC10224869 |
Contraction protocol 2: fatigued muscle | fatigue | CONTRACTION, CONTRACTIONS | After the unfatigued protocol was completed, a second protocol was performed that involved a fatigue-inducing sustained maximal contraction. Each participant held a maximal contraction until their force had reduced to 60% of their initial unfatigued MVC. This ensured that each trial, and each participant, had the same level of fatigue (decline in force) for neurophysiological assessments. Immediately after 60% MVC was reached, the participant performed a brief (4 s) submaximal contraction (10%, 25%, 50%, or 75% MVC). The submaximal contractions were based directly off the (fatigued) 60% MVC. Participants performed 5 contractions for each target torque. Each maximal contraction within protocol 2 was a sustained maximal contraction, in which the cortical and brachial plexus stimulation were delivered once the participants force had dropped to 60% of initial MVC. The sustained maximal contractions were followed directly by a brief (4 s) submaximal contraction (Fig. | PMC10224869 |
Data analysis | EVENT, CONTRACTION | Data were analysed using built-in functions in Spike2 v7.02a software (Cambridge Electronic Design). MEP area and Mmax area were calculated from biceps brachii EMG following cortical and brachial plexus stimulations, respectively. MEP area and Mmax area was calculated from the first deflection from baseline created by the stimulation to the end of the waveform (which was defined as the return to baseline after all phases of the wave had ended). MEPs were normalised to Mmax, and then averaged for each contraction intensity. TMS-evoked silent period duration was calculated as the time from the stimulus artifact to the return of EMG activity following the TMS pulse (SP was calculated in Spike2 by placing cursors at each event). SPs were averaged for each contraction intensity. | PMC10224869 | |
Statistical analysis | All statistical analyses were performed in R, using RStudio (version 2022.02.0 + 443 "Prairie Trillium" release, Boston, MA) where significance level of Input–output curve for MEP area ( | PMC10224869 | ||
Results | PMC10224869 | |||
Active motor threshold and TMS stimulus–response | Promethazine did not affect AMT as there were no drug-related differences in stimulator output when MEPs were first detected in the lightly contracting muscle ( | PMC10224869 | ||
Maximal voluntary contraction torque | Promethazine did not affect maximal elbow flexion torque as there were no drug-related differences in MVC ( | PMC10224869 | ||
MEP and silent period duration during brief voluntary contractions. | CONTRACTIONS | There was no main effect of drug on MEP area during brief unfatigued voluntary contractions (Protocol 1 MEP area (There was a main effect of drug identified for the TMS-evoked SP ( | PMC10224869 | |
MEP and silent period duration following fatiguing sustained contractions | CONTRACTIONS | There was no main effect of drug on MEP area following the maximal effort sustained contractions (Protocol 2 MEP area (Unlike the unfatigued contractions, there was no main effect of the drug detected for TMS-evoked SP duration following the sustained voluntary contractions ( | PMC10224869 | |
Discussion | voluntary muscle contractions, fatigue | CONTRACTION, CONTRACTIONS | The present study assessed the effects of a potent antimuscarinic drug on MEP area and TMS-evoked SP during voluntary contractions. To achieve this, a contraction protocol was used to assess cholinergic effects during brief contractions of 10%, 25%, 50%, 75%, and 100% MVC. This was followed by a second protocol that assessed MEPs during the same contraction intensities, however, a consistent within-subject and between-subject level of fatigue was induced before each contraction. The main finding was that the antimuscarinic drug reduced the TMS-evoked SP during unfatigued contractions but did not affect MEPs under any contraction condition. This suggests that the cholinergic system does not influence corticospinal excitability during voluntary muscle contractions, but instead affects inhibitory circuits associated with the TMS-evoked silent period. | PMC10224869 |
Silent period is affected by antimuscarinic activity during unfatigued voluntary contractions | voluntary muscle contractions | CONTRACTION, CONTRACTIONS | The current study revealed that SP duration shortened during voluntary muscle contractions, where the duration of TMS-evoked SP progressively reduced with an increase in contraction intensity. The relationship between SP and contraction intensity has been reported on a number of occasions, where many studies report that SP duration is unaffected by voluntary contractions (Haug et al. The initial 50–80 ms of the TMS-evoked SP has been linked to spinal mechanisms such as recurrent inhibition, after-hyperpolarization of activated motoneurons, and activation of 1a inhibitory interneurons (Duchateau and Baudry The lengthening of SP due to promethazine contrasts with two previous TMS studies exploring anticholinergic effects in the CNS. However, there are a number of factors that differ between previous studies and the current investigation. The study of Di Lazzaro (Di Lazzaro et al. | PMC10224869 |
Antimuscarinic activity did not affect MEP area during unfatigued voluntary contractions | CONTRACTION | A hypothesis of the current study was that mAChRs would modulate MEPs. However, there were no antimuscarinic effects detected for MEP area measured during a full range of voluntary contraction intensities. While the TMS-evoked SP involved inhibitory processes that are mediated by GABA | PMC10224869 | |
The cholinergic system did not modulate MEPs or SPs under conditions of fatigue | failure of the muscle, fatigue | CONTRACTIONS | Fatigue-inducing contractions cause a reduction in the maximal force generating capacity of the muscle, where the decline in force may be due to an inability of the nervous system to activate the muscle, or a failure of the muscle itself to contract. The current study normalised the amount of fatigue that was induced for each participant and assessed corticospinal excitability by normalising the MEP to Mmax. These procedures allow us to identify the role that mAChR blockade has on fatigue-related central motor responses. Surprisingly, the administration of promethazine did not affect any measurement of corticospinal excitability (or TMS-evoked SP), which suggests that mAChRs have no role in muscle activation while experiencing significant amounts of fatigue. Our previous work examined antimuscarinic effects on MEP area immediately following a fatigue-inducing 60 s MVC. In doing, we revealed that MEP area was increased from resting levels by 153% for a promethazine condition and 131% for a placebo condition, with MEPs for both conditions returning to resting levels in less than 10 s (Dempsey and Kavanagh | PMC10224869 |
Considerations | Although we have attributed our findings for the motor system to anticholinergic effects, we must acknowledge that the medication used in this study also has strong antihistaminergic effects. We have previously used single choice, and multiple choice, reaction time paradigms to demonstrate that CNS acting antihistamines can influence the ability to react quickly (Kavanagh et al. | PMC10224869 | ||
Funding | Open Access funding enabled and organized by CAUL and its Member Institutions. The authors did not receive support from any organization for the submitted work. No funding was received to assist with the preparation of this manuscript. No funding was received for conducting this study. No funds, grants, or other support was received. All authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript. | PMC10224869 | ||
Data availability | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10224869 | ||
Declarations | PMC10224869 | |||
Ethical approval | This experiment was approved by the Griffith University Human Research Ethics Committee and conformed to the standards set by the Declaration of Helsinki. | PMC10224869 | ||
References | PMC10224869 | |||
Background | advanced-stage solid, tumors | GSK3368715, a first-in-class, reversible inhibitor of type I protein methyltransferases (PRMTs) demonstrated anticancer activity in preclinical studies. This Phase 1 study (NCT03666988) evaluated safety, pharmacokinetics, pharmacodynamics, and preliminary efficacy of GSK3368715 in adults with advanced-stage solid tumors. | PMC10338470 | |
Methods | TEEs | THROMBOEMBOLIC EVENT | In part 1, escalating doses of oral once-daily GSK3368715 (50, 100, and 200 mg) were evaluated. Enrollment was paused at 200 mg following a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants, resuming under a protocol amendment starting at 100 mg. Part 2 (to evaluate preliminary efficacy) was not initiated. | PMC10338470 |
Results | toxicities, tumor | PULMONARY EMBOLISM, TUMOR, DISEASE, BEST, EVENTS | Dose-limiting toxicities were reported in 3/12 (25%) patients at 200 mg. Nine of 31 (29%) patients across dose groups experienced 12 TEEs (8 grade 3 events and 1 grade 5 pulmonary embolism). Best response achieved was stable disease, occurring in 9/31 (29%) patients. Following single and repeat dosing, GSK3368715 maximum plasma concentration was reached within 1 h post dosing. Target engagement was observed in the blood, but was modest and variable in tumor biopsies at 100 mg. | PMC10338470 |
Conclusion | Based on higher-than-expected incidence of TEEs, limited target engagement at lower doses, and lack of observed clinical efficacy, a risk/benefit analysis led to early study termination. | PMC10338470 | ||
Trial registration number | NCT03666988.
| PMC10338470 | ||
Subject terms | PMC10338470 | |||
Background | tumor | TUMOR | Arginine methylation is an important posttranslational modification of proteins involved in diverse cellular processes such as gene regulation, ribonucleic acid (RNA) processing, mRNA splicing, deoxyribonucleic acid (DNA) repair, and signal transduction [GSK3368715 is a potent, reversible, S-adenosylmethionine (SAM)-uncompetitive inhibitor that binds to the protein substrate binding pocket of type I PRMTs. Inhibition of type I PRMTs reduces intracellular ADMA and leads to accumulation of MMA and SDMA [Genetic loss of the With or without MTAP loss, overexpression of PRMTs may represent a targetable vulnerability in many tumor types [ | PMC10338470 |
Methods | PMC10338470 | |||
Study design | This was a Phase 1, open-label study consisting of a dose escalation, followed by a planned dose-expansion cohort of oral administration of GSK3368715 conducted between October 26, 2018 and March 4, 2021 (Fig. | PMC10338470 | ||
Planned study design. | thrombosis, tumor, DLTs, toxicity, toxicities, TEEs, chemotherapy-associated venous thromboembolism, PK/PD, DLBCL, PD | THROMBOSIS, DISEASE PROGRESSION, TUMOR, THROMBOEMBOLIC EVENT, ADVERSE EVENTS, EVALUABLE, REGRESSION, DIFFUSE LARGE B-CELL LYMPHOMA | DLBCL diffuse large B-cell lymphoma, PD pharmacodynamic, PK pharmacokinetic, po orally, qd once daily, RP2D recommended Phase 2 dose. Part 1 of this study included a dose-escalation cohort to assess the incidence of dose-limiting toxicities (DLTs) and adverse events, and a PK/PD cohort to characterize the PK/PD profile of GSK3368715 (Fig. The starting dose for the dose escalation cohort was 50 mg. Based on toxicity studies in dogs and preclinical studies of tumor regression in mice, tumor regression was observed at daily doses ranging from >75 mg/kg to 300 mg/kg (depending on tumor type), and 50 mg provided 16- and 33-fold safety margins for the steady state AUC and For each dosing group in the dose-escalation cohort, GSK3368715 was administered on day 1, no treatment was administered on days 2 and 3 (to characterize single-dose PK), and daily dosing continued thereafter until disease progression, unacceptable toxicity, or withdrawal of consent. Study treatment was dosed at approximately the same time of day (±4 h), with no food for 1 h before and 2 h after each dose. Evaluable patients for dose escalation received at least 21 days of study intervention and completed the postintervention follow-up visit.Due to a higher-than-expected incidence of thromboembolic events (TEEs) among the first 19 participants in the dose-escalation cohort, enrollment was paused at the 200-mg dose, and several measures were implemented to reduce the risk of TEE in subsequent patients enrolled in the study. The study resumed under a protocol amendment with the PK/PD cohort starting at a daily dose of 100 mg, and dose escalation was limited to 50-mg increments. The incidence and frequency of TEEs were added to the DLT criteria (grade 2 TEE requiring systemic anticoagulation or ≥grade 3 TEE) with extended monitoring to 8 weeks or until study discontinuation, whichever occurred first. Further, eligibility criteria were modified to exclude patients at high risk of thrombosis (ie, Khorana score ≥3 or prior medical history of TEE). Patients with a Khorana score of 2 were considered for prophylactic anticoagulation if deemed appropriate by the investigator. Khorana score is a risk assessment model based on clinical and laboratory parameters to classify the risk for chemotherapy-associated venous thromboembolism (Supplemental Table The study was halted prior to initiation of part 2 due to a comprehensive risk/benefit analysis. No recommended Phase 2 dose was determined and no food effect analysis was performed as planned in part 1. | PMC10338470 |
Study population | venous thromboembolism | Full inclusion/exclusion criteria for both parts 1 and 2 are included in Supplemental Table As mentioned above, following the study amendment, patients at high risk of venous thromboembolism as defined by either Khorana Score of ≥3, or prior medical history of venous thromboembolism, were ineligible. | PMC10338470 | |
Study assessments | tumor, Tumor, cancer, PK/PD, partial loss, PD | TUMOR, TUMOR, ADVERSE EVENT, CANCER, BLOOD | Adverse events were coded using the standard MedDRA groupings and graded according to NCI-CTCAE version 5.0. Clinical chemistry, urinalysis, and coagulation tests were performed predose on days 1, 8, 15, 22, and weekly thereafter. Tumor imaging occurred every 8 weeks until week 33, and then every 16 weeks thereafter.In both the dose-escalation and PK/PD cohorts, plasma samples for PK analysis were obtained following dosing on day 1 and pre- and postdose on days 2, 3, 4, 8, 15, 16, 22, and predose every 4 weeks thereafter. Plasma concentrations for GSK3368715 and its metabolites (GSK3963583, GSK3983164, and GSK3510519) were quantified using a validated ultra high-performance liquid chromatography-mass spectrometry-mass spectrometry (LC-MS-MS) method. PK parameters were analyzed using noncompartmental methods.MTAP loss was determined by IHC using formalin-fixed paraffin. A positive result was defined by a complete loss (absence of IHC cytoplasmic staining) in tumor cells or partial loss (reduced cytoplasmic staining or heterogeneous staining). A negative result was defined by retained staining (no loss of cytoplasmic staining) of tumor cells as compared with the retained staining of the internal control lymphocytes. MTAP status was distinctly binary where the cytoplasmic expression for a whole tumor sample was determined to be either lost (positive) or retained (negative).Tumor cell and plasma target engagement PD biomarkers were assessed in the dose-escalation cohort on days 1, 8, 15, and 22. In the PK/PD cohort, urine for PK and metabolite profiling was collected postdose on day 1 and through 48 h postdose on day 2, and for 24 h postdose on day 15. Participants underwent an on-treatment tumor biopsy on day 15. Asymmetric arginine 225 (R225) methylation of heterogeneous nuclear ribonucleoprotein A1 (hnRNP-A1) was identified as a target engagement PD of type I PRMT inhibition; treatment with GSK3368715 results in the reduction of asymmetric dimethylarginine 225 (ADMA-R225) on hnRNP-A1 protein in cancer cell lines and peripheral blood mononuclear cells (PBMCs). Noto et al. describe in detail the identification of hnRNP-A1 as a pharmacodynamic biomarker of type I PRMT inhibition, and the development of novel methodologies to accurately and precisely quantitate changes in the levels of ADMA on hnRNP-A1 in both blood and tumor compartments [To measure the ADMA-R225-hnRNP-A1 in the PBMCs, blood was collected using the standard technique for BD Vacutainer® Evacuated Blood Collection Tubes. The PBMC aspirate prepared was used for the ADMA analyses as previously described by the LC-MS method [ | PMC10338470 |
Statistical analyses | toxicity, tumor, DLTs, PK/PD | ADVERSE EVENT, TUMOR, BEST | The Neuenschwander Continual Reassessment Method dose-escalation design has been previously described. Briefly, the dose level with the highest posterior probability of having a DLT rate within the target toxicity range (≥16% and <33%) was recommended for the next cohort. Additionally, following the protocol amendment, dose escalations were limited to 50-mg increments.Adverse events and DLTs were summarized descriptively by dose cohort. Pharmacokinetic parameters of GSK3368715 and its metabolites (GSK3963583 and GSK3983164) were estimated in the PK/PD population (all participants for whom a PK sample was obtained) using a noncompartmental analysis model (WinNonlin version 8.1) and summarized descriptively. Best overall response as per RECIST 1.1 was summarized descriptively by dose cohort. Levels of tumor cell and plasma pharmacodynamic biomarkers were also summarized descriptively. | PMC10338470 |
Results | PMC10338470 | |||
Pharmacokinetics | Following single and repeated oral administration, GSK3368715 was rapidly absorbed, with maximum plasma concentration (Two metabolites (GSK3963583, GSK3983164) rapidly formed with time to | PMC10338470 | ||
Pharmacodynamics | SE | Reduction of levels of ADMA-R225-hnRNP-A1 in PBMCs was time dependent with a mean (SE) reduction of 54.7% (6.92%) in the GSK3368715 200-mg dose group on day 15. A mean (SE) day 15 reduction of 43.1% (5.81%) was observed at 100 mg (Fig. | PMC10338470 | |
Discussion | tumor, cancers, TEEs, cancer, pleomorphic adenoma, tumors, MTAP loss | TUMOR, CANCERS, CANCER, DISEASE, ADVANCED CANCER, PERIVASCULAR EPITHELIOID CELL TUMOR, DELETION, PLEOMORPHIC ADENOMA, TUMOR GROWTH, TUMORS, DISEASE CHARACTERISTIC | GSK3368715 is a first-in-class type I PRMT inhibitor that exhibited strong anticancer activity in preclinical studies. Despite this encouraging finding, and early evidence in the current study of target engagement in peripheral blood at doses of 200 mg, the study was paused due to concern over a higher-than-expected rate of TEEs and limited clinical activity as manifested by disease stability in 29% of patients. These results should be interpreted with caution, considering that only 5/31 (16%) participants had treatment for 3–6 months, and only 1 participant had treatment beyond 6 months. Taken together, the lack of observed clinical efficacy, the cumulative incidence of TEEs over a relatively short period of time, and limited and variable target engagement in the tumor at lower doses (100 mg) led to a comprehensive risk/benefit analysis and early study termination.The expected rate of TEEs in a population of patients with advanced cancer treated in Phase I studies has been previously described [Efficacy in this unselected patient population was limited and no clear trend regarding treatment response and disease characteristics was apparent. Efficacy may have been influenced by the incidence of TEEs and low target engagement in tumor. In a subset of in vivo preclinical xenograft models, a 40–60% decrease in ADMA-hnRNP-A1 measured by IHC in tumors was associated with 80–100% tumor growth inhibition. Thus, a response would have been expected at the 200-mg dose level. While the incidence of TEEs precluded evaluation of target engagement and efficacy at 200 mg which may have confirmed a relationship between dose level and efficacy, limited tumor target engagement at 100 mg suggested an association with the lack of efficacy at this dose level. Additionally, some tumor types with frequent MTAP gene deletion were included in part 1, but MTAP loss was not required for enrollment. Only 6 patients in the study had MTAP gene deletion and of those, 4 had progressive disease with treatment exposure ranging from 15 days to 37 days and 2 achieved stable disease. The two patients who achieved stable disease included the patient with a primary diagnosis of pleomorphic adenoma who had 224 days of exposure to GSK3368715 100-mg and a patient who had a uterine perivascular epithelioid cell tumor and 57 days of treatment exposure at the 200-mg dose level. Due to the small number of patients with MTAP loss included in the study and limited exposure to treatment, no conclusions can be made regarding efficacy in this specific patient population.Despite the findings in this study, additional investigation of PRMT inhibition remains warranted regarding, both the interplay between type I and type II PRMT (PRMT5) inhibition and the respective utility of targeting each individually for the treatment of cancer. Preclinical studies suggest a synthetic lethal relationship between PRMT5 and loss of type I PRMT function [With respect to PRMT5, overexpression has been linked with multiple hematopoietic and solid cancers, and several selective PRMT5 inhibitors have recently been studied in Phase 1/2 trials, particularly to target tumor dependencies on PRMT5 functioning as a splicing regulator [Overall, in the current study, which targeted type 1 PRMT in isolation, heterogeneity of the study population may be contributing to the study results. | PMC10338470 |
Conclusions | TEEs, tumor, cancer | CANCER, TUMOR | Despite promising preclinical results and observed peripheral target engagement at higher doses, the incidence of TEEs, variable target engagement at the tumor level, and observed limited clinical efficacy led to early termination of this trial. It is not known whether the lack of clinical efficacy and elevated risk of TEEs is specific to GSK3368715 or if type I PRMT inhibition may still be a viable cancer treatment alone or in combination with other therapies. No future clinical trials are planned at this time for GSK3368715 and it would be important that further development of drugs in the same class will require an understanding of the mechanism by which inhibition of type I PRMTs may impact the risk for TEEs. | PMC10338470 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41416-023-02276-0. | PMC10338470 | ||
Acknowledgements | HORNER, BRUCE | All listed authors meet the criteria for authorship set forth by the International Committee for Medical Journal Editors. Editorial support (Allyson Lehrman, DPM, assembling tables and figures, collating author comments, copyediting, fact checking, and referencing) and graphic services were provided by AOIC, LLC and were funded by GSK. The authors wish to thank Thierry Horner, Kenneth Cooper, Bruce Hug, and Ivan Diaz-Padilla for their assistance. | PMC10338470 | |
Author contributions | ABE-K, TN, IG-L, EC, JR, BT, PJO’D, AC, and ARAR contributed to the conception or design of the study. ABE-K, EC, JR, BT, PJO’D, AC, and ARAR contributed to the acquisition of the data. JC, TN, TC, NR, CR, PN, AT, IG-L, and AC data analysis or interpretation. ABE-K, JC, TN, TC, NR, CR, PN, AT, IG-L, EC, JR, BT, PJO’D, AC, and ARAR provided critical review and gave final approval of the publication. All authors agree to be accountable for the work. | PMC10338470 | ||
Funding | Authors who are or were employees of GSK contributed to the design of the study, analysis of the data, and in the decision to publish. Funding for this study (NCT03666988 available from | PMC10338470 | ||
Data availability | Within 6 months of this publication, anonymized individual participant data, the annotated case report form, protocol, reporting and analysis plan, dataset specifications, raw dataset, analysis-ready dataset, and clinical study report will be available for research proposals approved by an independent review committee. Proposals should be submitted to | PMC10338470 | ||
Competing interests | Cancer, Oncology/Cancer | ONCOLOGY, CANCER, FOUNDER, EMD | ABE-K reports honoraria from ABL bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, CytomX Therapeutics, EISAI, EMD Serono, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Roche/Genentech, SERVIER, and Tallac Therapeutics; consulting or advisory board roles with BL Bio, Agenus, AstraZeneca/MedImmune, Bayer, Bristol-Myers Squibb, CytomX Therapeutics, Eisai, EMD Serono, Exelixis, Gilead Sciences, Merck, Pieris Pharmaceuticals, QED Therapeutics, Roche, SERVIER, and Tallac Therapeutics; and institutional research funding from Astex Pharmaceuticals, AstraZeneca, Fulgent Genetics, and GSK. JC, TC, NR, CR, and AT are employees of and hold equity in GSK. PN is a former employee of and holds equity in GSK. TN is a former employee of GSK. IG-L reports consulting or advisory board roles for SOTIO, Kanaph, JAZZ, and ONCXer, and institutional research funding from Novartis, Bayer, Bristol-Myers Squibb, Pfizer, MedImmune, Lilly, Incyte, GSK, Tolero Pharmaceuticals, BridgeBio Pharma, Jacobio, Repare Therapeutics, and Sumitomo Dainippon Pharma Oncology. EC reports a leadership role in START, Pharma Mar, EORTC, Sanofi, BeiGene and Novartis; stock and other ownership interests with Oncoart Associated and START; honoraria from HM Hospitals Group; consulting or advisory roles to Adcendo, Amunix, Anaveon, AstraZeneca/MedImmune, Bristol-Myers Squibb, Chugai Pharma, Elevation Oncology, Ellipses Pharma, Genmab, Janssen-Cilag, MonTa Biosciences, MSD Oncology, Nanobiotix, Nouscom, Novartis, OncoDNA, PharmaMar, Roche/Genentech, Servier, Syneos Health, T-Knife, and TargImmune Therapeutics; research funding START, and GSK; and President and Founder of Foundation role for INTHEOS (Investigational Therapeutics in Oncological Sciences). JR reports non-financial support and reasonable reimbursement for travel from the European Society for Medical Oncology; consulting and travel fees and advisory board membership for Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, and IONCTURA; consulting fees from Vall d’Hebron Institute of Oncology/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, LLC, and Tang Advisors, LLC; research funding for him or his institution from Blueprint Medicines, Black Diamond Therapeutics, Merck Sharp & Dohme, Hummingbird, Yingli, and Vall d’Hebron Institute of Oncology/Cancer Core Europe; serving as an investigator in clinical trials or clinical research funding to him or his institution from Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GSK, Taiho, Roche Pharmaceuticals, Hummingbird, Yingli, Bicycle Therapeutics, Merus, Curis, Bayer, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati Linnaeus Therapeutics, and Cancer Core Europe. He holds no patents, nor does he have close relationships, academic rivalries, political party memberships, or religious convictions that would affect the content of this manuscript. BT reports consulting fees from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Ipsen, IQVIA, Janssen-Cilag, Merck Sharp & Dohme, Novartis, Pfizer/EMD Serono, Roche, Sanofi, and Tomar; research funding from Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, GSK, Ipsen, Janssen-Cilag, Merck Sharp & Dohme, and Pfizer; honoraria from Amgen, Astellas, Bristol-Myers Squibb, Janssen-Cilag, Sanofi, and Tolmar; and travel reimbursement from Amgen and Astellas. He reports personal fees from IQVIA, Sanofi, Tolmar, Novartis, and Roche. PJO’D reports research support from Pfizer, Genentech, GSK, BMS, AZ, Five Prime, FortySeven, Merck, Syndax, RRI, Novartis, Celgene, Incyte, Lilly/Imclone, array, H3 Biomedicine, Taiho, Minneamrata, Pharmacyclics/Abbvie, and Mirati; consulting relationships with Genentech and Array, and has provided expert testimony for Bayer and Lilly. He reports no stock or patents or other relationships that would affect the content of this manuscript. AC has served as a consultant for Synergy; received authorship royalties from UpToDate; and his institution has received research support on his behalf from Alexion, Bayer, Novartis, Novo Nordisk, Pfizer, Sanofi, Spark, and Takeda. AR reports grants from Merck, Bristol-Myers Squibb, Novartis, Karyopharm, Boston Biochemical, Deciphera, Genentech, Roche, Pfizer, Medimmune, Eli Lilly, Boehringer Ingelheim, Entremed/CASI Pharmaceuticals, Amgen, Champions Oncology, Iterion, Blueprint, Adaptimmune, Neoleukin, and GSK during the conduct of the study, as well as personal fees from Eli Lilly, Boehringer Ingelheim, Merck, Adaptimmune, Bayer, Medison, and GSK outside the submitted work. | PMC10338470 |
Ethics approval and consent to participate | Cancer | DEL, CANCER | The study was approved by the ethics committee at every participating institution [Melbourne Health Human Research Ethics Committee Parkville, Australia; University Health Network Research Ethics Board, Toronto, Canada; Comite Etico De Investigacion Clinica con medicamentos (CEIm) CEIC del Hospital Universitari Vall d’Hebron, Secretaria del CEIC. Institut Recerca HUVH, Barcelona Spain; Office of Science and Research Institutional Review, New York, NY, USA; New York University School of Medicine IRB, New York, NY, USA; Advarra, Columbia, MD, USA; University of Southern California (USC) Institutional Review Board, Los Angeles, CA, USA; University of Utah Institutional Review Board Research Administration, Salt Lake City, UT, USA; Dana-Farber Cancer Institute Institutional Review Board 450, Boston, MA, USA; Western Institutional Review Board (WIRB), Puyallup, WA, USA; University of Southern California (USC) Institutional Review Board 1640, Los Angeles, CA, USA. The study was conducted according to the recommendations of Good Clinical Practice and the Declaration of Helsinki. All patients provided written informed consent to participate in the study. | PMC10338470 |
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