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Funding
KDS
HEART
The information and opinions contained in this Article do not necessarily reflect the views or policies of the supporting organisations. JB was supported by a National Heart and Medical Research Council (NHMRC) Translating Research into Practice Fellowship (1168333). EMc was supported by a co-funded NHMRC and Australia...
PMC9938595
Availability of data and materials
The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.
PMC9938595
Declarations
PMC9938595
Ethics approval and consent to participate
Ethical approval was provided for this research by the Northern Territory Top End (HREC-2018–3048) and Far North Queensland (HREC-18-QCH-23–1211) Human Research Ethics Committees and was conducted in line with the National Health and Medical Research Council Australian Code for the Responsible Conduct of Research and G...
PMC9938595
Consent for publication
Not Applicable.
PMC9938595
Competing interests
The authors declare that they have no competing interests.
PMC9938595
References
PMC9938595
Background
METASTATIC COLORECTAL CANCER
PRECONNECT was an international, phase IIIb trial evaluating the safety and efficacy of trifluridine/tipiracil (FTD/TPI) for metastatic colorectal cancer (mCRC).
PMC9881327
Methods
Patients with mCRC received FTD/TPI 35 mg/m
PMC9881327
Results
anaemia, asthenia, neutropenia
ANAEMIA, METASTASIS, NEUTROPENIA, ADVERSE EVENTS, LIVER METASTASIS
Of 914 patients, 69% completed 0–3, 24% completed 4–7, and 7% completed ≥8 cycles of FTD/TPI. Drug-related grade ≥ 3 adverse events included neutropenia (38.1%), anaemia (7.2%) and asthenia (3.4%). Median [95% CI] time to ECOG PS deterioration was 8.7 [8.1-not calculable] months and increased with duration of treatment...
PMC9881327
Conclusions
No new safety concerns for FTD/TPI were identified and PFS increased with DoT. These data provide confidence for the use of FTD/TPI, including the use of multiple cycles, in routine practice.
PMC9881327
Supplementary Information
The online version contains supplementary material available at 10.1186/s12885-022-10489-4.
PMC9881327
Introduction
colorectal cancer, death, neutropenia, CRC, cancer, deaths
CANCER, COLORECTAL CANCER, NEUTROPENIA
Globally, colorectal cancer (CRC) is ranked as the third most common cancer and the second leading cause of cancer-related death, accounting for approximately 10% of all new cases of cancer and 10% of all deaths from cancer in 2020 [Trifluridine/tipiracil (FTD/TPI), an oral cytotoxic chemotherapy consisting of the thym...
PMC9881327
Methods
PMC9881327
Study design
This was an international, multicentre, open-label, single-arm, phase IIIb trial (EudraCT Number: 2016-002311-18; registered 19/09/2016;
PMC9881327
Patients
hepatic, cardiac and bone marrow function, ascites, pulmonary fibrosis, toxicity, active malignancies, infection, diabetes
BRAIN METASTASIS, ASCITES, PULMONARY FIBROSIS, TUMOURS, POLAND, INFECTION, ONCOLOGY, DIABETES
Patients were enrolled in 16 countries (Australia, Belgium, Brazil, Bulgaria, Croatia, France, Ireland, Italy, Panama, Poland, Portugal, Romania, Slovakia, Slovenia, Turkey, and Ukraine) and treated between October 2016 and November 2020. Eligible patients with mCRC were refractory to, or not candidates for, standard c...
PMC9881327
Treatment
Patients received oral FTD/TPI 35 mg/m
PMC9881327
Assessments and endpoints
death, neutropenia, SD, tumour, treatment-emergent adverse events, Cancer
ADVERSE EVENT, DISEASE PROGRESSION, NEUTROPENIA, DISEASE, ADVERSE EVENT, TUMOUR, CANCER
Patients were assessed at baseline (within 7 days of the first FTD/TPI dose), and on the first day of each 28-day cycle of FTD/TPI treatment. Additional unscheduled assessments could be made according to the investigators’ assessment (e.g., for tumour and adverse event evaluation).The primary endpoint was safety, asses...
PMC9881327
Statistical methods
death, tumour, neutropenia
DISEASE PROGRESSION, METASTASIS, LIVER METASTASES, NEUTROPENIA, MUTANT, LUNG METASTASES, TUMOUR, REGRESSION
Descriptive statistics were used to summarise baseline patient and clinical characteristics, TEAEs, ECOG PS, and QoL. Median and 95% confidence intervals (CIs) were reported for survival analyses and were estimated using the Kaplan-Meier method. For the PFS analysis, patients without disease progression or death before...
PMC9881327
Efficacy
FTD/TPI treatment was associated with a median (95% CI) PFS of 2.8 (2.7–3.0) months in the overall population. Median PFS increased with increasing durations of FTD/TPI treatment, from 2.2 (2.0–2.3) months in the group completing 0–3 cycles to 9.4 (8.7–10.5) months in the group completing ≥8 cycles (Fig. Median progres...
PMC9881327
Exploratory analyses of prognostic factors
neutropenia
LIVER METASTASIS, METASTASIS, NEUTROPENIA
Baseline characteristics associated with neutropenia and PFS were explored in the analysis of potential prognostic factors. In total, 836 patients with complete data on prognostic factors were retained in the final model of prognostic factors for neutropenia or severe neutropenia, and 808 patients were retained in the ...
PMC9881327
Quality of life
QoL was maintained during treatment with FTD/TPI in the overall population and in the DoT subgroups: there were no clinically relevant changes (> 10-point mean change from baseline) in QLQ-C30-GHS scores during the study (Supplementary Fig. 
PMC9881327
Discussion
tumour, neutropenia
TUMOUR, NEUTROPENIA
The final results from the PRECONNECT study in patients with mCRC in daily clinical practice confirm the interim data published in 2020 [There is a lack of information on potential prognostic factors in later lines of treatment in patients with mCRC. In patients naïve to chemotherapy treatment, CEA, number of metastati...
PMC9881327
Acknowledgements
We thank the patients and their families who made this study possible, all the participating physicians and their multidisciplinary health care teams that were involved in the study, and the data and safety monitoring board members. The authors thank Martin Gilmour, PhD, CMPP, Editorial Director at Empowering Strategic...
PMC9881327
Authors’ contributions
All authors were involved in the concept and design of the study, discussed statistical analyses, participated in writing the manuscript, and read and approved the final draft before submission. LV performed the statistical analyses. JT, TP, LW and J-BB enrolled patients in the study. JT assumes final responsibility fo...
PMC9881327
Funding
The PRECONNECT study was funded by Institut de Recherches Internationales, Servier, France. Institut de Recherches Internationales, Servier, did not influence the study design or interpretation of the data, but assisted in the collection and analysis of data, and in the writing of the report. The decision to submit the...
PMC9881327
Availability of data and materials
Data are available on reasonable request. All data relevant to the study are included in the article or uploaded as supplementary information. Anonymised patient-level, study-level clinical trial data will be shared in agreement with the Servier Data-Sharing Policy available at
PMC9881327
Declaration
PMC9881327
Ethics approval and consent to participate
All relevant Institutional Review Board/Independent Ethics Committee approvals were gained before commencement of the study, and are listed in the supplementary information (Supplementary Table 
PMC9881327
Consent for publication
Not applicable.
PMC9881327
Competing interests
The PRECONNECT study was funded by Institut de Recherches Internationales, Servier, France; JT has received honoraria for speaker or advisory role from Servier, Roche, Lilly, Celgene, Shire, Amgen, Sanofi, Merck, Lilly and Sirtex; TP has received compensation for advisory board for Amgen (paid self), Merck, Roche and T...
PMC9881327
References
PMC9881327
Subject terms
obesity, associative learning
OBESITY, INSULIN SENSITIVITY
Survival under selective pressure is driven by the ability of our brain to use sensory information to our advantage to control physiological needs. To that end, neural circuits receive and integrate external environmental cues and internal metabolic signals to form learned sensory associations, consequently motivating ...
PMC10447249
Main
obesity, metabolic dysfunction, metabolic impairments, associative learning
OBESITY, INSULIN RESISTANCE, INSULIN SENSITIVITY
Learning associations emerging from the sensory information that we perceive in a changing environment are essential to survive and thrive under selective pressureThe regulation of energy balance, for instance, requires our behaviour to adapt to our physiological needsOn a neural level, dopamine (DA) neurons of the ven...
PMC10447249
Results
We report findings from human participants with normal (IS
PMC10447249
Behavioural analysis
We first fitted the HGF model to the sequence of choices from each participant for each session to estimate the individual trajectories of cue–outcome association learning. Thus, we recovered three critical covert computational quantities reflecting the learning process: the sensory prediction error, the adaptive learn...
PMC10447249
Liraglutide normalizes dysregulated behavioural updating in insulin-resistant humans
INSULIN SENSITIVITY
We then assessed whether the formation of the prediction errors differed between participants with impaired insulin sensitivity (IS
PMC10447249
fMRI data analysis
INSULIN SENSITIVITY
To assess the neural responses underlying the differential effects of liraglutide intervention on learning depending on peripheral insulin sensitivity, we analysed the fMRI data to identify brain regions encoding adaptive prediction errors and studied whether liraglutide intervention (relative to placebo) enhanced this...
PMC10447249
Adaptive prediction errors are encoded in the NAc and ventromedial prefrontal cortex
First, we tested for brain regions that encode adaptive prediction error. Reproducing the results of prior work
PMC10447249
Liraglutide upregulates adaptive prediction error encoding in the subcallosal area and the NAc
INSULIN SENSITIVITY, CORTEX
As our behavioural analysis revealed that liraglutide intervention significantly enhanced the amplitude of adaptive prediction error encoding in the group with impaired insulin sensitivity, we specifically tested for brain regions in which liraglutide (relative to placebo) enhanced the neural encoding of adaptive predi...
PMC10447249
Discussion
impairment of metabolic signalling, obesity, impaired learning of sensory associations, impaired outcome learning, deficiencies in associative learning
OBESITY, EVENTS, INSULIN SENSITIVITY
Arguing that the motivational force prompting behavioural adaptation must ultimately rely on learned sensory associations, we scrutinize a general role for metabolic sensing in associative learning. Here, our main hypothesis rests on the assumption that metabolic signals from the periphery affect DA neuron function in ...
PMC10447249
Limitations
obesity, associative learning
OBESITY
Although our behavioural and fMRI results are remarkably compatible with the above-presented animal dataCollectively, our behavioural and fMRI findings reveal that GLP-1 receptor activation normalizes associative learning in insulin-resistant humans by modulating the encoding of adaptive prediction errors within the me...
PMC10447249
Methods
PMC10447249
Participants
psychiatric, associative sensory learning task, gastrointestinal or eating disorders
INSULIN SENSITIVITY
Fifty-four healthy volunteers with a large variance in body weight (Table All participants were recruited from the preexisting database of volunteers maintained at the Max Planck Institute for Metabolism Research. Participants were medication-free non-smokers without any history of neurological, psychiatric, gastrointe...
PMC10447249
Study procedure
The study was performed in a single-blinded, placebo-controlled, randomized crossover design. Each volunteer participated on two testing days lasting a maximum of 2 h each. Both testing days were separated by a minimum of 1 week to allow for a sufficient washout periodThe evening before each testing day, participants f...
PMC10447249
GLP-1 analogue
A subcutaneous injection of 0.6 mg of liraglutide (Novo Nordisk) was used as an agonistic GLP-1 analogue. As the maximum plasma concentration of liraglutide is reached approximately 11–13 h after injection
PMC10447249
Hunger ratings
To control for differences in hunger states between testing days, we instructed the participants to rate hunger before the task on each testing day using a visual analogue scale, as described previously
PMC10447249
Insulin and glucose levels
As GLP-1 was reported to increase insulin secretion
PMC10447249
Experimental design: associative learning task
Participants performed the same associative learning task as described previously (fMRI study 2 by Iglesias and colleaguesAt the beginning of each trial, participants heard either a high tone (576 Hz) or a low tone (352 Hz). After this cue, they had to predict whether the upcoming picture would be a face or a house by ...
PMC10447249
Computational modelling of behavioural data
For analysis of the behavioural data from the learning task, we modelled the trial-by-trial changes in participants’ choices with the HGFThe first level of the HGF simply represents the occurrence of the auditory and visual stimuli (that is, perception of the ‘stimulus category’). The second level captures the learning...
PMC10447249
Statistical inference
INSULIN SENSITIVITY
All behavioural, blood and anthropomorphic data were analysed using RStudio (version 1.4.1717) and R (version 4.0.0). First, we performed normality testing using ‘Q-Q plots’ in R. If residuals were normally distributed, analysis of variance (ANOVA) tests based on mixed effect models (test statistic Considering the abov...
PMC10447249
fMRI acquisition parameters
All imaging was performed on a 3T MRI system with a 64-channel head coil (Siemens Magnetom Prisma Fit). The MRI data were acquired using a Magnetom Prisma
PMC10447249
fMRI statistical analysis
INSULIN SENSITIVITY
The individual data sets were preprocessed before running statistical analyses using tools from the FMRIB Software Library (FSL version 5.08, Statistical analyses were conducted using Statistical Parametric Mapping version 12 (r6225, Wellcome Trust Centre for Neuroimaging) implemented in MATLAB R2019b (MathWorks) in th...
PMC10447249
Reporting summary
Further information on research design is available in the
PMC10447249
Supplementary information
Study protocol as approved by the Institutional Review Board (ethics committee of the Medical Faculty of the University of Cologne, number 16-251).Reporting SummaryTest for the effects of intervention (placebo and liraglutide) and group (ISNeural tracking of the adaptive prediction error.Standardized dinner the evenin...
PMC10447249
Source data
Data points used to generate Fig. 2.Data points used to generate Fig. 3.Data points used to generate Extended Data Fig. 1.
PMC10447249
Extended data
PMC10447249
Extended data
is available for this paper at 10.1038/s42255-023-00859-y.
PMC10447249
Supplementary information
The online version contains supplementary material available at 10.1038/s42255-023-00859-y.
PMC10447249
Acknowledgements
P., Diabetes
DIABETES
We are extremely grateful to K. Friston (University College London) for generously providing time to discuss conjoint testing for multiple effects in fMRI data and are also grateful to K. E. Stephan (ETH Zurich) for providing the learning task and engaging in many fruitful discussions regarding its analysis. Furthermor...
PMC10447249
Author contributions
All authors contributed to the work presented in this paper. M.T., J.C.B. and R.H. conceptualized the study. The experimental setup was designed by M.T., R.H. and S.E.T., while S.I. designed and established the experimental task applied. Data acquisition was performed by R.H., A.C.K., K.A. and T.S. Statistical analyses...
PMC10447249
Peer review
PMC10447249
Funding
Open access funding provided by Max Planck Society.
PMC10447249
Data availability
The human data reported in this study cannot be deposited in a public repository per General Data Protection Regulation and Institutional Review Board data protection policies. To request access, please contact the lead contact. Data provision may include processed and unprocessed data and will require a data-sharing a...
PMC10447249
Competing interests
DGI
O.A.C. reports grants or contracts from Amplyx, Basilea, BMBF, Cidara, DZIF, EU-DG RTD (101037867), F2G, Gilead, Matinas, MedPace, MSD, Mundipharma, Octapharma, Pfizer and Scynexis; consulting fees from Abbvie, Amplyx, Biocon, Biosys, Cidara, Da Volterra, Gilead, IQVIA, Janssen, Matinas, MedPace, Menarini, Molecular Pa...
PMC10447249
References
PMC10447249
1. Introduction
inflammatory disorder of the lungs, COPD
CHRONIC OBSTRUCTIVE PULMONARY DISEASE, INFLAMMATORY DISORDER, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, PATHOGENESIS
These authors contributed equally to this work.Background: Macrophages and monocytes orchestrate inflammatory processes in the lungs. However, their role in the pathogenesis of chronic obstructive pulmonary disease (COPD), an inflammatory condition, is not well known. Here, we determined the characteristics of these ce...
PMC10741950
2. Methods
All statistical analyses were performed in R. Here are the details: (1) Version 4.1.1, Seurat, New York, NY, United States. (2) Version 1.0.0, Monocle 3, Seattle, WA, United States. (3) QIAGEN, Hilden, Germany. (4) Illumina, San Diego, CA, USA.
PMC10741950
2.1. Quality Control and Cell Clustering
COPD
COPD
To investigate the subtypes of macrophages and monocytes and their roles in COPD, we analyzed a published single-cell sequencing (scRNA-seq) dataset obtained from Gene Expression Omnibus (GEO) (GSE136831 [A principal component analysis (PCA) [
PMC10741950
2.2. Analysis of Differential Expressed Genes (DEGs)
We used MAST [
PMC10741950
2.3. Pseudo-Time Analysis
We used Monocle 3 (version 1.0.0) [
PMC10741950
2.4. Ingenuity Pathway Analyses (IPA) and Gene Set Enrichment Analysis (GSEA)
Cluster-specific DEGs, in addition to their respective log
PMC10741950
2.5. Randomized Controlled Trial (RCT) Data to Validate the Effects of Fluticasone on the Expression of Specific Genes
COPD
COPD
One of the top therapeutic hits in IPA was fluticasone. To validate this predicted drug target in vivo, we used data from the DISARM trial, which was a RCT (clinicaltrials.gov NCT02833480) in which patients with COPD were treated for 3 months with (1) inhaled fluticasone (in combination with salmeterol), (2) inhaled bu...
PMC10741950
3. Results
PMC10741950
3.1. Cell Clusters and Annotations
The distribution of the four cell types within the COPD/control samples is summarized in Cluster analyses identified 16 cell groups (We used the MAST [These clusters matched or were related to numerous previously reported myeloid clusters derived from human lung studies [
PMC10741950
3.2. A Pseudo-Time Analysis Revealed Three Significantly Different Cellular Evolutionary Trajectories
DISEASE
To determine how the cell types changed along the disease’s trajectory, we performed a pseudo-time analysis (trajectory inference,
PMC10741950
3.3. Differential Expression and Gene Set Enrichment Analysis of COPD-Predominant Clusters
To determine the gene expression signatures specific to COPD-predominant clusters, we performed a DE analysis (Next, we investigated the COPD-predominant IL1B-high classical monocyte Cluster 15. Classical monocytes are considered to be highly phagocytic cells, with capacity for a potent inflammatory immune response and...
PMC10741950
3.4. Predicted Chemical and Biological Drug Targets in COPD-Predominant Monocyte and Alveolar Macrophage Clusters
COPD
COPD
We predicted the drug targets on the basis of the DEGs in the COPD-related clusters. To do this, we included an analysis of the differentially expressed genes from COPD-predominant vs. control-predominant clusters (e.g., alveolar macrophages (Cluster 0 vs. Cluster 12) and classical monocytes (Cluster 15 vs. Cluster 11)...
PMC10741950
3.5. Clinical Trial Evaluation
We validated the differential expression of fluticasone-regulated genes across monocyte and macrophage clusters identified by IPA in the DISARM trial [
PMC10741950
Supplementary Materials
The following supporting information can be downloaded at Click here for additional data file.
PMC10741950
Author Contributions
Y.H.: data curation, formal analysis, investigation, software, visualization, writing—original draft. X.S.: investigation, methodology, writing—review and editing. L.X.: conceptualization, funding acquisition, methodology, resources, supervision, writing—original draft, writing—review and editing. X.L.: data curation, ...
PMC10741950
Institutional Review Board Statement
Not applicable.
PMC10741950
Informed Consent Statement
Not applicable.
PMC10741950
Data Availability Statement
There is no new data were created.
PMC10741950
Conflicts of Interest
COPD
COPD
Don D. Sin have received a small honorarium from AstraZeneca, Boehringer Ingelheim and GSK for giving a lecture on COPD. Don D. Sin chairs a DSMB for NHLBI sponsored clinical trial in COPD.
PMC10741950
References
COPD
CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, DISEASES
(Pseudo-time trajectories projected on a UMAP graph. (Top downstream diseases and biological functions and canonical pathways from COPD-predominant vs. control-predominant clusters predicted using Ingenuity Pathway Analysis. (Validation of the IPA-predicted fluticasone genes in DISARM. (Distribution of monocytes/macrop...
PMC10741950
Background
diabetes-related foot ulcers, Diabetes-related, ulcer, diabetes
FOOT ULCERS, ULCER, DIABETES
Diabetes-related foot ulcers result in significant mortality, morbidity and economic costs. Pressure offloading is important for ulcer healing, but patients with diabetes-related foot ulcers are presented with a dilemma, because whilst they are often advised to minimise standing and walking, there are also clear guidel...
PMC10043540
Methods
diabetes-related foot ulcers, ulcer
ADVERSE EVENTS, RECRUITMENT, ULCER
Patients with diabetes-related foot ulcers were recruited from an inpatient hospital setting. Baseline demographics and ulcer characteristics were collected, and participants undertook a supervised exercise training session comprising aerobic and resistance exercises followed by prescription of a home exercise programm...
PMC10043540
Results
ADVERSE EVENTS
Twenty participants were recruited to the study. The retention rate (95%), adherence to inpatient and outpatient follow up (75%) and adherence to home exercise (50.0%) were all acceptable. No adverse events occurred.
PMC10043540
Conclusions
diabetes-related foot ulcers
RECRUITMENT
Targeted exercise appears safe to be undertaken by patients with diabetes-related foot ulcers during and after an acute hospital admission. Recruitment in this cohort may prove challenging, but adherence, retention and satisfaction with participation in exercise were high.
PMC10043540
Trial registration
The trial is registered in the Australian New Zealand Clinical Trials Registry (ACTRN12622001370796).
PMC10043540
Supplementary Information
The online version contains supplementary material available at 10.1186/s13047-023-00616-0.
PMC10043540
Keywords
PMC10043540
Introduction
diabetes-related foot ulcers, Diabetic Foot (IWGDF), diabetes
FOOT ULCER, FOOT ULCERATION, ULCERATION, FOOT ULCERS, PERIPHERAL NEUROPATHY, DIABETES
Pressure offloading is a critical component of a multidisciplinary management plan to achieve diabetes related foot ulcer (DFU) healing [As such, people living with diabetes-related foot ulcers (DFU) are often faced with a dilemma on what role physical activity and exercise has in the overall management plan for diabet...
PMC10043540
Methods
PMC10043540
Study Design
This non-randomised pilot study aimed to determine safety and feasibility of targeted exercise commencing during an acute inpatient setting. Ethics approval was granted by the South Metropolitan Health Service Human Research Ethics Committee (RGS 4173). Study data were collected and managed using Research Electronic Da...
PMC10043540
Participants
cardiac arrhythmias, cognitive impairment, diabetes mellitus, musculoskeletal or neurological conditions, heart failure
ACUTE MYOCARDIAL INFARCTION, CARDIAC ARRHYTHMIAS, HEART, DIABETES MELLITUS, UNSTABLE ANGINA, RECRUITMENT, HEART FAILURE
Patients admitted to hospital under the care of the Multidisciplinary DFU team between October 2020 to April 2021 were screened for eligibility. Participants were eligible if they were over the age of 18, had a diagnosis of diabetes mellitus and requiring admission to hospital for DFU of any type or severity. People we...
PMC10043540
Study procedures
ADVERSE EVENT
Demographic information was collected, surveys and physical assessments (described in After completion of the inpatient phase of the study, participants were reviewed at their routine outpatient follow-up clinic, scheduled for two weeks after discharge. Adherence to their home exercise programme was assessed by review ...
PMC10043540
Intervention
BLOOD
Exercise was commenced during hospital admission. Where a participant required surgery for their DFU, clearance from the treating team was obtained for the patient to commence exercise. The treating team made weight bearing orders in relation to the DFU location for each participant to follow. Participants who were abl...
PMC10043540
Outcomes
PMC10043540