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Frontiers in Immunology 2024Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains...
BACKGROUND
Previous studies have highlighted the crucial role of immune cells in lung cancer development; however, the direct link between immunophenotypes and lung cancer remains underexplored.
METHODS
We applied two-sample Mendelian randomization (MR) analysis, using genetic variants as instruments to determine the causal influence of exposures on outcomes. This method, unlike traditional randomized controlled trials (RCTs), leverages genetic variants inherited randomly at conception, thus reducing confounding and preventing reverse causation. Our analysis involved three genome-wide association studies to assess the causal impact of 731 immune cell signatures on lung cancer using genetic instrumental variables (IVs). We initially used the standard inverse variance weighted (IVW) method and further validated our findings with three supplementary MR techniques (MR-Egger, weighted median, and MR-PRESSO) to ensure robustness. We also conducted MR-Egger intercept and Cochran's Q tests to assess heterogeneity and pleiotropy. Additionally, reverse MR analysis was performed to explore potential causality between lung cancer subtypes and identified immunophenotypes, using R software for all statistical calculations.
RESULTS
Our MR analysis identified 106 immune signatures significantly associated with lung cancer. Notably, we found five suggestive associations across all sensitivity tests (<0.05): CD25 on IgD- CD24- cells in small cell lung carcinoma (OR =0.885; 95% CI: 0.798-0.983; =0.022); CD27 on IgD+ CD24+ cells in lung squamous cell carcinoma (OR =1.054; 95% CI: 1.010-1.100; =0.015); CCR2 on monocyte cells in lung squamous cell carcinoma (OR =0.941; 95% CI: 0.898-0.987; =0.012); CD123 on CD62L+ plasmacytoid dendritic cells (OR =0.958; 95% CI: 0.924-0.992; =0.017) as well as on plasmacytoid dendritic cells (OR =0.958; 95% CI: 0.924-0.992; =0.017) in lung squamous cell carcinoma.
CONCLUSION
This study establishes a significant genomic link between immune cells and lung cancer, providing a robust basis for future clinical research aimed at lung cancer management.
Topics: Humans; Lung Neoplasms; Mendelian Randomization Analysis; Genome-Wide Association Study; Genetic Predisposition to Disease; Polymorphism, Single Nucleotide; Risk Factors; Immunophenotyping
PubMed: 38962009
DOI: 10.3389/fimmu.2024.1433299 -
Frontiers in Immunology 2024Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as...
Human T-Lymphotropic Virus type-1 (HTLV-1) is a unique retrovirus associated with both leukemogenesis and a specific neuroinflammatory condition known as HTLV-1-Associated Myelopathy (HAM). Currently, most proposed HAM biomarkers require invasive CSF sampling, which is not suitable for large cohorts or repeated prospective screening. To identify non-invasive biomarkers for incident HAM in a large Brazilian cohort of PLwHTLV-1 (n=615 with 6,673 person-years of clinical follow-up), we selected all plasma samples available at the time of entry in the cohort (between 1997-2019), in which up to 43 cytokines/chemokines and immune mediators were measured. Thus, we selected 110 People Living with HTLV-1 (PLwHTLV-1), of which 68 were neurologically asymptomatic (AS) at baseline and 42 HAM patients. Nine incident HAM cases were identified among 68 AS during follow-up. Using multivariate logistic regression, we found that lower IL-10, IL-4 and female sex were independent predictors of clinical progression to definite HAM (AUROC 0.91), and outperformed previously suggested biomarkers age, sex and proviral load (AUROC 0.77). Moreover, baseline IL-10 significantly predicted proviral load dynamics at follow-up in all PLwHTLV-1. In an exploratory analysis, we identified additional plasma biomarkers which were able to discriminate iHAM from either AS (IL6Rα, IL-27) or HAM (IL-29/IFN-λ1, Osteopontin, and TNFR2). In conclusion, female sex and low anti-inflammatory IL-10 and IL-4 are independent risk factors for incident HAM in PLwHTLV-1,while proviral load is not, in agreement with IL-10 being upstream of proviral load dynamics. Additional candidate biomarkers IL-29/IL-6R/TNFR2 represent plausible therapeutic targets for future clinical trials in HAM patients.
Topics: Humans; Female; Male; Brazil; Human T-lymphotropic virus 1; Viral Load; Interleukin-10; Biomarkers; Middle Aged; Adult; HTLV-I Infections; Proviruses; Cohort Studies; Paraparesis, Tropical Spastic; Incidence
PubMed: 38962007
DOI: 10.3389/fimmu.2024.1416476 -
Alzheimer's & Dementia : the Journal of... Jul 2024Assessing the potential sources of bias and variability of the Centiloid (CL) scale is fundamental for its appropriate clinical application.
INTRODUCTION
Assessing the potential sources of bias and variability of the Centiloid (CL) scale is fundamental for its appropriate clinical application.
METHODS
We included 533 participants from AMYloid imaging to Prevent Alzheimer's Disease (AMYPAD DPMS) and Alzheimer's Disease Neuroimaging Initiative (ADNI) cohorts. Thirty-two CL pipelines were created using different combinations of reference region (RR), RR and target types, and quantification spaces. Generalized estimating equations stratified by amyloid positivity were used to assess the impact of the quantification pipeline, radiotracer, age, brain atrophy, and harmonization status on CL.
RESULTS
RR selection and RR type impact CL the most, particularly in amyloid-negative individuals. The standard CL pipeline with the whole cerebellum as RR is robust against brain atrophy and differences in image resolution, with 95% confidence intervals below ± 3.95 CL for amyloid beta positivity cutoffs (CL < 24).
DISCUSSION
The standard CL pipeline is recommended for most scenarios. Confidence intervals should be considered when operationalizing CL cutoffs in clinical and research settings.
HIGHLIGHTS
We developed a framework for evaluating Centiloid (CL) variability to different factors. Reference region selection and delineation had the highest impact on CL values. Whole cerebellum (WCB) and whole cerebellum plus brainstem (WCB+BSTM) as reference regions yielded consistent results across tracers. The standard CL pipeline is robust against atrophy and image resolution variation. Estimated within- and between-pipeline variability (95% confidence interval) in absolute CL units.
PubMed: 38961808
DOI: 10.1002/alz.13883 -
BJU International Jul 2024To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients...
OBJECTIVES
To assess the risk of venous thromboembolic events (VTEs) and bleeding with or without thromboprophylaxis during neoadjuvant chemotherapy in bladder cancer patients scheduled for radical cystectomy.
MATERIALS AND METHODS
We conducted a retrospective cohort study in 4886 patients with non-metastatic bladder cancer undergoing cystectomy across 28 centres in 13 countries between 1990 and 2021. Inverse probability weighting analyses were performed to estimate the effect of thromboprophylaxis on VTE and bleeding.
RESULTS
In 147 patients (3%) VTEs were recorded within the first year. These occurred a median (interquartile range [IQR]) of 127 (82-198) days after bladder cancer diagnosis. Bleeding events occurred in 131 patients (3%) within the first year. These occurred a median (IQR) of 101 (83-171) days after cancer diagnosis. In inverse probability weighting analyses, compared to patients without thromboprophylaxis during chemotherapy, patients with thromboprophylaxis had not only a lower risk of VTE (hazard ratio [HR] 0.32, 95% confidence interval [CI] 0.12-0.81; P = 0.016) but also a lower bleeding risk (HR 0.03, 95% CI 0.09-0.12; P <0.0001). The retrospective nature of the study was its main limitation.
CONCLUSIONS
In this retrospective analysis, the benefit of thromboprophylaxis during neoadjuvant chemotherapy before cystectomy is in line with data from randomised trials in other malignancies. Our data suggest thromboprophylaxis is protective against VTEs and should be the standard of care during neoadjuvant chemotherapy.
PubMed: 38961717
DOI: 10.1111/bju.16444 -
Diabetes/metabolism Research and Reviews Jul 2024Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting...
AIMS
Heterogeneity in the rate of β-cell loss in newly diagnosed type 1 diabetes patients is poorly understood and creates a barrier to designing and interpreting disease-modifying clinical trials. Integrative analyses of baseline multi-omics data obtained after the diagnosis of type 1 diabetes may provide mechanistic insight into the diverse rates of disease progression after type 1 diabetes diagnosis.
METHODS
We collected samples in a pan-European consortium that enabled the concerted analysis of five different omics modalities in data from 97 newly diagnosed patients. In this study, we used Multi-Omics Factor Analysis to identify molecular signatures correlating with post-diagnosis decline in β-cell mass measured as fasting C-peptide.
RESULTS
Two molecular signatures were significantly correlated with fasting C-peptide levels. One signature showed a correlation to neutrophil degranulation, cytokine signalling, lymphoid and non-lymphoid cell interactions and G-protein coupled receptor signalling events that were inversely associated with a rapid decline in β-cell function. The second signature was related to translation and viral infection was inversely associated with change in β-cell function. In addition, the immunomics data revealed a Natural Killer cell signature associated with rapid β-cell decline.
CONCLUSIONS
Features that differ between individuals with slow and rapid decline in β-cell mass could be valuable in staging and prediction of the rate of disease progression and thus enable smarter (shorter and smaller) trial designs for disease modifying therapies as well as offering biomarkers of therapeutic effect.
Topics: Humans; Diabetes Mellitus, Type 1; Insulin-Secreting Cells; Female; Male; Adult; Disease Progression; Biomarkers; Follow-Up Studies; Adolescent; Young Adult; Prognosis; Proteomics; C-Peptide; Child; Middle Aged; Genomics; Multiomics
PubMed: 38961656
DOI: 10.1002/dmrr.3833 -
Genomics, Proteomics & Bioinformatics Jul 2024Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed...
Small cell lung cancer (SCLC) is a highly malignant and heterogeneous cancer with limited therapeutic options and prognosis prediction models. Here, we analyzed formalin-fixed, paraffin-embedded (FFPE) samples of surgical resections by proteomic profiling, and stratified SCLC into three proteomic subtypes (S-I, S-II, and S-III) with distinct clinical outcomes and chemotherapy responses. The proteomic subtyping was an independent prognostic factor and performed better than current tumor-node-metastasis or Veterans Administration Lung Study Group staging methods. The subtyping results could be further validated using FFPE biopsy samples from an independent cohort, extending the analysis to both surgical and biopsy samples. The signatures of the S-II subtype in particular suggested potential benefits from immunotherapy. Differentially overexpressed proteins in S-III, the worst prognostic subtype, allowed us to nominate potential therapeutic targets, indicating that patient selection may bring new hope for previously failed clinical trials. Finally, analysis of an independent cohort of SCLC patients who had received immunotherapy validated the prediction that the S-II patients had better progression-free survival and overall survival after first-line immunotherapy. Collectively, our study provides the rationale for future clinical investigations to validate the current findings for more accurate prognosis prediction and precise treatments.
Topics: Humans; Small Cell Lung Carcinoma; Lung Neoplasms; Proteomics; Prognosis; Male; Female; Middle Aged; Aged; Immunotherapy; Biomarkers, Tumor; Proteome
PubMed: 38961535
DOI: 10.1093/gpbjnl/qzae033 -
Scandinavian Journal of Medicine &... Jul 2024The importance of exercise electrocardiogram (ECG) is still controversial in the prevention of cardiovascular events among sportsmen and sportswomen. The aim of this...
INTRODUCTION
The importance of exercise electrocardiogram (ECG) is still controversial in the prevention of cardiovascular events among sportsmen and sportswomen. The aim of this study was to assess the relevance of exercise ECG as a screening tool to prevent cardiovascular events when any cardiovascular disease (CVD) risk factors are present.
METHODS
The study included leisure time asymptomatic sportsmen and sportswomen over age 35 evaluated from 2011 to 2016 at the University Hospital of Saint-Etienne (France). Major adverse cardiovascular events (MACE) and atrial fibrillation were collected at 3 years.
RESULTS
Of the cohort of 2457 sportsmen and sportswomen (mean age 50.2 ± 9.4 years), 50 (2%) had a high-risk SCORE2. A total of 256 exercise ECGs (10%) were defined as positive, most of them due to silent myocardial ischemia (SMI) (n = 196; 8%). These 196 SMI cases led to 33 coronary angiograms (1%), which revealed 23 significant coronary stenoses requiring revascularization. In multivariate logistic regression analysis, having at least two CVD risk factors was independently associated with (1) positive exercise ECG (OR = 1.80 [95% CI: 1.29-2.52], p = 0.0006), with (2) suspected SMI (OR = 2.57 [95% CI: 1.10-6.02], p = 0.0304), with (3) confirmed SMI (OR = 8.20 [95% CI: 3.46-19.46], p < 0.0001) and with (4) cardiovascular events (MACE or atrial fibrillation) (OR = 6.95 [95% CI: 3.49-13.81], p < 0.0001) at 3 years (median).
CONCLUSIONS
The study supports the European recommendations for the use of exercise ECG in evaluation of asymptomatic leisure time sportsmen over age 35. Having at least two CVD risk factors was the best predictor for presence of coronary artery stenosis that may increase the risk for adverse events.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT06024863.
Topics: Humans; Electrocardiography; Female; Middle Aged; Male; Adult; Exercise Test; Cardiovascular Diseases; Atrial Fibrillation; Athletes; France; Risk Factors; Mass Screening; Myocardial Ischemia; Heart Disease Risk Factors; Coronary Angiography
PubMed: 38961532
DOI: 10.1111/sms.14686 -
CPT: Pharmacometrics & Systems... Jul 2024Clinical trials seeking to delay or prevent the onset of type 1 diabetes (T1D) face a series of pragmatic challenges. Despite more than 100 years since the discovery...
Clinical trials seeking to delay or prevent the onset of type 1 diabetes (T1D) face a series of pragmatic challenges. Despite more than 100 years since the discovery of insulin, teplizumab remains the only FDA-approved therapy to delay progression from Stage 2 to Stage 3 T1D. To increase the efficiency of clinical trials seeking this goal, our project sought to inform T1D clinical trial designs by developing a disease progression model-based clinical trial simulation tool. Using individual-level data collected from the TrialNet Pathway to Prevention and The Environmental Determinants of Diabetes in the Young natural history studies, we previously developed a quantitative joint model to predict the time to T1D onset. We then applied trial-specific inclusion/exclusion criteria, sample sizes in treatment and placebo arms, trial duration, assessment interval, and dropout rate. We implemented a function for presumed drug effects. To increase the size of the population pool, we generated virtual populations using multivariate normal distribution and ctree machine learning algorithms. As an output, power was calculated, which summarizes the probability of success, showing a statistically significant difference in the time distribution until the T1D diagnosis between the two arms. Using this tool, power curves can also be generated through iterations. The web-based tool is publicly available: https://app.cop.ufl.edu/t1d/. Herein, we briefly describe the tool and provide instructions for simulating a planned clinical trial with two case studies. This tool will allow for improved clinical trial designs and accelerate efforts seeking to prevent or delay the onset of T1D.
PubMed: 38961520
DOI: 10.1002/psp4.13193 -
Trials Jul 2024Body weight loss (BWL) after gastrectomy impact on the short- and long-term outcomes. Oral nutritional supplement (ONS) has potential to prevent BWL in patients after...
The efficacy of simple oral nutritional supplements versus usual care in postoperative patients with gastric cancer: study protocol for a multicenter, open-label, parallel, randomized controlled trial.
BACKGROUND
Body weight loss (BWL) after gastrectomy impact on the short- and long-term outcomes. Oral nutritional supplement (ONS) has potential to prevent BWL in patients after gastrectomy. However, there is no consistent evidence supporting the beneficial effects of ONS on BWL, muscle strength and health-related quality of life (HRQoL). This study aimed to evaluate the effects of ONS formulated primarily with carbohydrate and protein on BWL, muscle strength, and HRQoL.
METHODS
This will be a multicenter, open-label, parallel, randomized controlled trial in patients with gastric cancer who will undergo gastrectomy. A total of 120 patients who will undergo gastrectomy will be randomly assigned to the ONS group or usual care (control) group in a 1:1 ratio. The stratification factors will be the clinical stage (I or ≥ II) and surgical procedures (total gastrectomy or other procedure). In the ONS group, the patients will receive 400 kcal (400 ml)/day of ONS from postoperative day 5 to 7, and the intervention will continue postoperatively for 8 weeks. The control group patients will be given a regular diet. The primary outcome will be the percentage of BWL (%BWL) from baseline to 8 weeks postoperatively. The secondary outcomes will be muscle strength (handgrip strength), HRQoL (EORTC QLQ-C30, QLQ-OG25, EQ-5D-5L), nutritional status (hemoglobin, lymphocyte count, albumin), and dietary intake. All analyses will be performed on an intention-to-treat basis.
DISCUSSION
This study will provide evidence showing whether or not ONS with simple nutritional ingredients can improve patient adherence and HRQoL by reducing BWL after gastrectomy. If supported by the study results, nutritional support with simple nutrients will be recommended to patients after gastrectomy for gastric cancer.
TRIAL REGISTRATION
jRCTs051230012; Japan Registry of Clinical Trails. Registered on Apr. 13, 2023.
Topics: Humans; Stomach Neoplasms; Gastrectomy; Dietary Supplements; Quality of Life; Multicenter Studies as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Weight Loss; Administration, Oral; Middle Aged; Male; Female; Adult; Aged; Nutritional Status; Time Factors; Hand Strength; Muscle Strength
PubMed: 38961505
DOI: 10.1186/s13063-024-08169-8 -
Critical Care (London, England) Jul 2024The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The outcomes of several randomized trials on extracorporeal cardiopulmonary resuscitation (ECPR) in patients with refractory out-of-hospital cardiac arrest were examined using frequentist methods, resulting in a dichotomous interpretation of results based on p-values rather than in the probability of clinically relevant treatment effects. To determine such a probability of a clinically relevant ECPR-based treatment effect on neurological outcomes, the authors of these trials performed a Bayesian meta-analysis of the totality of randomized ECPR evidence.
METHODS
A systematic search was applied to three electronic databases. Randomized trials that compared ECPR-based treatment with conventional CPR for refractory out-of-hospital cardiac arrest were included. The study was preregistered in INPLASY (INPLASY2023120060). The primary Bayesian hierarchical meta-analysis estimated the difference in 6-month neurologically favorable survival in patients with all rhythms, and a secondary analysis assessed this difference in patients with shockable rhythms (Bayesian hierarchical random-effects model). Primary Bayesian analyses were performed under vague priors. Outcomes were formulated as estimated median relative risks, mean absolute risk differences, and numbers needed to treat with corresponding 95% credible intervals (CrIs). The posterior probabilities of various clinically relevant absolute risk difference thresholds were estimated.
RESULTS
Three randomized trials were included in the analysis (ECPR, n = 209 patients; conventional CPR, n = 211 patients). The estimated median relative risk of ECPR for 6-month neurologically favorable survival was 1.47 (95%CrI 0.73-3.32) with a mean absolute risk difference of 8.7% (- 5.0; 42.7%) in patients with all rhythms, and the median relative risk was 1.54 (95%CrI 0.79-3.71) with a mean absolute risk difference of 10.8% (95%CrI - 4.2; 73.9%) in patients with shockable rhythms. The posterior probabilities of an absolute risk difference > 0% and > 5% were 91.0% and 71.1% in patients with all rhythms and 92.4% and 75.8% in patients with shockable rhythms, respectively.
CONCLUSION
The current Bayesian meta-analysis found a 71.1% and 75.8% posterior probability of a clinically relevant ECPR-based treatment effect on 6-month neurologically favorable survival in patients with all rhythms and shockable rhythms. These results must be interpreted within the context of the reported credible intervals and varying designs of the randomized trials.
REGISTRATION
INPLASY (INPLASY2023120060, December 14th, 2023, https://doi.org/10.37766/inplasy2023.12.0060 ).
Topics: Humans; Out-of-Hospital Cardiac Arrest; Bayes Theorem; Cardiopulmonary Resuscitation; Extracorporeal Membrane Oxygenation; Randomized Controlled Trials as Topic; Treatment Outcome
PubMed: 38961495
DOI: 10.1186/s13054-024-05008-9