Hatim Boughanem

Colorectal cancer (CRC) remains a major global health burden and a leading cause of cancer-related morbidity and mortality. Current blood-based biomarkers lack sufficient sensitivity and specificity, particularly for early detection. In this context, circulating immune-cell transcriptomic profiling has emerged as a promising minimally invasive approach. This systematic review was conducted following a PROSPERO-registered protocol (CRD42024604757) and PRISMA 2020 guidelines to evaluate the diagnostic and prognostic potential of circulating monocyte-related transcriptomic profiles in CRC. Of 295 records identified, six studies met the inclusion criteria. The available evidence consistently supports the diagnostic value of circulating transcriptomic profiles in distinguishing patients with CRC from healthy individuals and in reflecting tumour-associated immune alterations. Monocyte-related signatures, including CXCR2⁺ monocytes, were associated with disease stage and metastatic features. Epitranscriptomic modifications, such as m6A and m5C, further reinforced their diagnostic relevance, with some studies reporting higher diagnostic accuracy than classical biomarkers. In contrast, evidence for prognostic value remains limited, heterogeneous, and often indirect, largely due to small sample sizes, methodological variability, and reliance on public datasets. Overall, circulating immune-cell transcriptomic profiles are promising non-invasive biomarkers for CRC detection and characterization, although their prognostic utility remains unclear. Methodological heterogeneity limits clinical applicability, highlighting the need for standardized, CRC-specific studies with cell-type-resolved approaches.

DNA methylation plays a crucial role in regulating gene expression and is a hallmark of epigenetic dysregulation in human tumors. High-throughput DNA methylation profiling can unravel intricate patterns in cancer. Moreover, understanding immune cell dynamics is essential for comprehending cancer progression and treatment response. Using DNA methylation data in immune cells, we can apply deconvolution algorithms estimate proportions of major immune cell types, providing insights into immune status and its implications in cancer. Functional analysis can identify specific overrepresented or underrepresented immune cell subsets, potentially uncovering novel biomarkers or therapeutic targets. This pipeline presents a detailed workflow in RStudio for DNA methylation studies and immune cell deconvolution, enhancing reproducibility and efficiency. The workflow integrates preprocessing, analysis, and visualization steps, facilitating robust inference of cell-type proportions from DNA methylation data.

Aberrant DNA methylation has been shown to be a fingerprint characteristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted in both the tumor area (N = 27) and the adjacent tumor-free (NAT) area (N = 15). We found 78,935 differentially methylated CpG sites (DMCs) (FDR < 0.05), 42,888 hypomethylated and 36,047 hypermethylation showing overall hypomethylation. Gene ontology and KEGG analysis of differentially methylated genes showed significant enrichment in developmental genes, as well as in genes involved in metabolic processes and the cell cycle, such as the TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB as the most epigenetically dysregulated gene, hypomethylated and downregulated in CRC (both with p < 0.001) and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated in a dose-dependent manner, suggesting a potential role in CRC. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as indicators of malignant potential, with adverse effects associated with disease origin and progression in CRC.

Background: Aberrant DNA methylation has been shown to be a fingerprint charac-teristic in human colorectal tumors. In this study, we hypothesize that investigating global DNA methylation could offer potential candidates for clinical application in CRC. The epigenome-wide association analysis was conducted using in tumor area (N=27) and the adjacent tumor-free (NAT) area (N=15). Results. We found 78,935 differentially methylated CpG sites (DMCs) (FDR< 0.05), 42,888 hypomethylated and 36,047 hyper-methylation showing overall hypomethylation. Gene Ontology and KEGG analysis of genes differentially methylated genes showed a significant enrichment of develop-mental genes, such as and metabolic process and cell cycle, such as TFGβ and cAMP signaling pathways. Through filtered analysis, we identified TNXB gene as the most epigenetically dysregulated gene, in which it found to be hypomethylated and down-regulated in CRC (both with p< 0.001) after further validation and associated with poor overall survival. In the functional analysis, TNXB was epigenetically regulated, in dose-dependent manner, suggesting a potential role in CRC. Conclusion. The epigenetic dysregulation and functional role of TNXB in CRC could have clinical implications, serving as an indicator of malignant potential and the adverse effects associated with disease origin and progression in CRC

Background Recent evidence links diet and physical activity with type 2 diabetes mellitus (T2DM) remission, but emerging findings suggest that immune system dysregulation may play a crucial role. This study aimed to investigate the associations between neutrophils and T2DM remission. Methods We conducted a comprehensive analysis of newly-diagnosed T2DM patients (N = 183) from the CORDIOPREV study, without glucose-lowering treatment, and were randomized to follow either a Mediterranean or low-fat diet. Patients were classified into two groups: Responders, who achieved T2DM remission (n = 73), and Non-Responders, who did not achieve remission during the 5-year dietary intervention (n = 110). Neutrophil count and their related-ratio (NER, NBR, NLR and NHR, normalized with erythrocytes, basophils, lymphocytes, and HDL respectively) were measured at the baseline and 5 years of follow-up. Results The lowest baseline tertile of neutrophil count was associated with an increased likelihood of T2DM remission among patients following a Mediterranean diet (but not for low-fat diet) when compared with the highest tertile [adjusted HR of 4.23 (95% CI: 1.53–11.69)], in which similar results were observed for NER and NHR. When considering clinical and neutrophil variables, the predictive capacity of this model yielded an AUC of 0.783 (95% CI: 0.680–0.822). Furthermore, after 5-years, Responders exhibited lower neutrophil count compared to Non-responders (p = 0.006) and a significant decrease in neutrophil count (p = 0.001) compared to baseline. This decrease in neutrophil count in Responders who consumed a Mediterranean diet exhibited a significant increase in Insulin Sensitivity and Disposition Index (p = 0.011 and p = 0.018) after the follow-up period. Conclusion These findings suggest that neutrophil count can help in identifying patients that are more likely to achieve T2DM remission following a Mediterranean diet, suggesting a role on insulin sensitivity and β-cell function. Further research holds promise for providing valuable insights into the pathophysiology of T2DM. Clinical trial Registration ID: NCT00924937; URL Clinical trial: https://clinicaltrials.gov/study/NCT00924937?cond=NCT00924937&rank=1.

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Background and Aims: Several studies have supported the role of innate immune system as a key factor in the sterile inflammation underlying the pathophysiology of atherosclerosis in mice. However, its involvement in humans remains unclear. This study aimed to explore the association between neutrophil count, and the intima-media thickness of common carotid arteries (IMT-CC), as well as the potential impact of long-term dietary interventions on these associations. Methods: A comprehensive analysis was conducted within the framework of the CORDIOPREV study, a long-term secondary prevention study involving dietary interventions with either a Mediterranean or a low-fat diet. The study evaluated the relationship between absolute neutrophil count and neutrophil-related ratios with IMT-CC at baseline and after 5 and 7 years of dietary intervention. Results: At baseline, patients in the highest tertile of neutrophil count had a higher IMT-CC and number of carotid plaques, when compared to lowest tertile (P < .01 and P < .05, respectively). Logistic regression analyses supported this association. Elevated neutrophil count, neutrophil-to-erythrocyte ratio, and neutrophil-to-HDL ratio were associated with an increased likelihood of having an IMT-CC >.9 mm {odds ratio (OR) 1.17 [95% confidence interval (CI) 1.04–1.35], OR 2.21 (95% CI 1.24–4.12), and OR 1.96 (95% CI 1.09–3.55), respectively}, after adjustment for all variables, which was corroborated by linear regression. Furthermore, a linear mixed-effect model analysis from a longitudinal analysis spanning 5 and 7 years revealed an increase in 1 unit of neutrophils/μl at these time points was associated with a mean increase of .004 (.002) mm in the IMT-CC (P = .031) after adjustment for all variables. Interestingly, in patients exhibiting regression in IMT-CC after 7 years of follow-up, those following a Mediterranean diet showed a significant decrease in neutrophil count after 5 and 7 years (both with P < .05), compared to baseline. Conclusions: These findings suggest that neutrophils may represent a promising target for preventing atherosclerosis. A Mediterranean diet could serve as an effective dietary strategy to reduce neutrophil levels and potentially slow the progression of atherosclerosis, offering a new neutrophil-reducing therapy concept. Further research is essential to gain deeper insights into the role of neutrophils in the pathophysiology of atherosclerotic cardiovascular disease in humans.

Background Numerous studies have reported an association between neutrophils and T2DM, although this relationship remains unclear. This study aims to investigate the interaction of neutrophils and a dietary intervention on T2DM incidence after 60 months of follow-up. Methods A comprehensive analysis was conducted on the framework of the CORDIOPREV study, which included 462 patients without T2DM at the beginning of the study. They were randomly assigned to either a Mediterranean or a low-fat diet, of whom 107 developed T2DM. Absolute neutrophil counts and other related-ratio, were measured. Results Kaplan-Meier curves showed that the lowest tertile of basal neutrophils was associated with a reduced likelihood of T2DM incidence when compared to the middle [HR=0.499 (95%CI, 0.287–0.866)] and the highest tertiles [HR=0.442 (95%CI, 0.255–0.768)] in overall population, after adjusting for clinical variables. This association only remained significant in patients who follow a Mediterranean diet when compared the lowest to the middle [HR=0.423 (95% CI, 0.213–0.842)] and the highest tertiles [HR=0.371 (95% CI, 0.182–0.762)]. The predictive capacity yielded an AUC of 0.711 (95%CI: 0.652–0.769), being neutrophils the most important variable in the in the model. Decrease in neutrophils over the 60 months were associated with increased insulin sensitivity index (ISI) (R=-0.31; p=0.019), particularly in patients who followed the Mediterranean diet. Conclusion These findings suggest that monitoring neutrophils can help prevent the development of T2DM, as a reduction in neutrophil counts could be associated with improved insulin sensitivity. Following a Mediterranean diet might be a potential strategy to reduce the incidence of T2DM by lowering neutrophil levels. Further research is necessary to gain a deeper understanding regarding this mechanism.

A corrigendum refers to a change to their article that the author wishes to publish after publication. The publication of this article is subject to Frontiers Editorial approval.• please read through all the templates before choosing • pick the most relevant text template(s) from the following page and delete all others.• edit the text as necessary, ensuring that the original incorrect text is included for the record, please see the below. • please do not use any extra formatting when editing the templates, and only modify the red text unless absolutely necessary • submit to Frontiers following the instructions on this page.When the original text contained incorrect information, to preserve the scientific record, please include that text when editing the below templates. For example:There was a mistake in the Funding statement, an incorrect number was used. The correct number is "2015C03Bd051.". The publisher apologizes for this mistake.The original version of this article has been updated. Corrigendum on: Garcia-Flores LA, Dawid De Vera MT, Pilo J, Rego A, Gomez-Casado G, Arranz-Salas I, Hierro Martín I, Alcaide J, Torres E, Ortega-Gómez A, Boughanem H and Macias-González M (2024) Increased neutrophil counts are associated with poor overall survival in patients with colorectal cancer: a five-year retrospective analysis. Front. Immunol. 15:1415804. doi: 10.3389/fimmu.2024.1415804