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Longitudinal Clinical, Physiological, and Molecular Profiling of Female Patients With Metastatic Cancer: Protocol and Feasibility of a Multicenter High-Definition Oncology Study.

PURPOSE: A substantial proportion of patients receiving genomically matched therapies do not achieve clinical benefit, underscoring the influence of nongenetic factors on cancer outcomes. High-Definition Oncology (HDO) proposes integrating longitudinal, multimodal patient data-spanning clinical, molecular, physiological, and behavioral domains-to enable truly individualized cancer care. This manuscript describes the HDO study design, framework, and feasibility results in women with metastatic cancer. METHODS: We initiated a prospective, multicenter observational study (HDO study; ClinicalTrials.gov identifier: NCT06590506) enrolling 300 female patients with newly diagnosed metastatic breast, lung, or colorectal cancer. Here, we report the study design, standardized workflows, prespecified feasibility criteria, and early internal pilot results. Eleven data modalities are collected longitudinally, including tumor and germline genomics, germline epigenomics, gut microbiome, blood and stool metabolomics and proteomics, exposome characterization, wearable-derived physiological monitoring, digital footprint assessment, medical imaging, and patient-reported outcomes. Standardized workflows govern clinical procedures, data acquisition, biospecimen processing, and quality control across all participating sites. RESULTS: Feasibility was evaluated in the first 30 participants (10% of planned accrual). Patients completed 100% of scheduled clinical visits, 97.4% of planned plasma collections, 80.7% of stool samples, and all tumor biopsies. Wearable devices captured activity, heart rate, sleep, and blood oxygen saturation data during 95.0%, 84.2%, 90.6%, and 70.7% of total patient-days, respectively. Biospecimens met predefined quality control metrics across all molecular modalities. Engagement with mobile applications for pain and emotion reporting exceeded 80%. CONCLUSION: The HDO study demonstrates the feasibility of comprehensive, longitudinal, multimodal data collection in women with metastatic cancer. This internal pilot establishes an integrated framework for future analyses aimed at characterizing disease trajectories, defining molecular and physiological determinants of outcomes, and developing patient-specific computational models.

Humans↗

Pangenome analysis of Lactobacillus mulieris strains reveals distinct subspecies clusters with defined ecological adaptations.

Lactobacillus mulieris is a recently described species, reportedly isolated from human urine, vagina, and gut. Previous genomic studies of L. mulieris highlighted significant genetic diversity among its strains. To gain a deeper understanding of this genomic diversity, we conducted a comprehensive genomic comparison of 70 L. mulieris strains from diverse sources. Phylogenomic and genome relatedness analysis identified three distinct clades, each representing a potential subspecies cluster. Pangenome analysis revealed distinct gene clusters shaping the functional characteristics and unique ecological adaptations of each clade. Clade 1 demonstrated a generalist lifestyle, with strains isolated from diverse sources and enriched in serine/threonine protein kinases, suggesting adaptive versatility. Clade 2, predominantly composed of urinary isolates, displayed enrichment in genes facilitating nutrient acquisition and osmotic regulation, enabling survival in the nutrient-limited and high osmolarity conditions of the urinary tract. Clade 3, exclusively composed of vaginal isolates, exhibited significant enrichment in genes supporting glycogen metabolism, carbohydrate transport, and capsular polysaccharide biosynthesis-features indicative of adaptation to the vaginal environment. Collectively, our findings provide essential genomic insights into the ecological specialization of L. mulieris, shedding light on their genetic variability and adaptive traits within their respective ecological niches.IMPORTANCERecognizing the genomic diversity within Lactobacillus mulieris is essential for understanding its ecological specialization and adaptation strategies across distinct human-associated environments. By identifying three distinct clades with unique functional traits, our study highlights the critical role of niche-specific genetic adaptations in microbial survival. The presence of specialized gene functions within each clade underscores how evolutionary pressures shape bacterial resilience in different environments. Despite their coexistence in overlapping environments, these clades exhibit distinct genomic profiles that may influence their colonization potential and interactions with the host and within the host-associated microbiota. Our findings emphasize the need for a classification framework that accounts for these genetic and functional differences and the necessity for further investigation to understand their distinct roles and impact on human health.

Humans↗

Gene and protein expression in the myometrium in pregnancy and labor.

Microarray technologies widen our comprehension of the major structural and metabolic transformations which affect the myometrium from the very beginning of pregnancy until parturition. The results are coherent with the mass of information which was accumulated previously, primarily on the basis of studies of selected critical factors. They highlight the activation of precise signaling pathways, some of which may have been previously under evaluated. The remodelling and maturation processes that the myometrium undergoes in pregnancy appear clearly as phenomena which last during the full course of gestation. Comparatively, the onset of labor is perhaps the phenomenon which remains the least well described by these methods of analysis. Nevertheless, genomic studies constitute a necessary first step of orientation and help establishing new links between the generic signaling pathways that are activated during the normal or pathological gestation. These studies also represent an indicative step that will have to be paralleled, in the future, with the results of the systematic proteomic analysis of the myometrium.

Animals↗

Initial transcriptome and proteome analyses of low culture temperature-induced expression in CHO cells producing erythropoietin.

Low culture temperature is known to enhance the specific productivity of Chinese hamster ovary (CHO) cells expressing erythropoietin (EPO) (LGE10-9-27). Genomic and proteomic approaches were taken to better understand the intracellular responses of these CHO cells resulting from use of low culture temperature (33 degrees C). For transcriptome analysis, commercially available rat and mouse cDNA microarrays were used. The data obtained from the rat and mouse cDNA chips were only somewhat informative in understanding the gene expression profile of CHO cells because of their different sequence homologies with CHO transcriptomes. Overall, transcriptome analysis revealed that low culture temperature could lead to changes in gene expression in various cellular processes such as metabolism, transport, and signaling pathways. Proteome analysis was carried out using 2-D PAGE. Based on spot intensity, 60 high intensity protein spots, from a total of more than 800, were chosen for MS analysis. Forty of the 60 protein spots, which represent 26 different kinds of proteins, were identified by MALDI-TOF-MS and validated by MS/MS. Compared to the reference temperature (37 degrees C), the expression levels of seven proteins (PDI, vimentin, NDK B, ERp57, RIKEN cDNA, phosphoglycerate kinase, and heat shock cognate 71 kDa protein) were increased over twofold at 33 degrees C and those of two proteins (HSP90-beta and EF2) were decreased over twofold at 33 degrees C. Taken together, the results demonstrate the potential of combined analysis of transcriptome and proteome analyses as a tool for the systematic comprehension of cellular mechanisms in CHO cells.

Animals↗

Characterization of the Caenorhabditis elegans G protein-coupled serotonin receptors.

Serotonin (5-HT) regulates a wide range of behaviors in Caenorhabditis elegans, including egg laying, male mating, locomotion and pharyngeal pumping. So far, four serotonin receptors have been described in the nematode C. elegans, three of which are G protein-coupled receptors (GPCR), (SER-1, SER-4 and SER-7), and one is an ion channel (MOD-1). By searching the C. elegans genome for additional 5-HT GPCR genes, we identified five further genes which encode putative 5-HT receptors, based on sequence similarities to 5-HT receptors from other species. Using loss-of-function mutants and RNAi, we performed a systematic study of the role of the eight GPCR genes in serotonin-modulated behaviors of C. elegans (F59C12.2, Y22D7AR.13, K02F2.6, C09B7.1, M03F4.3, F16D3.7, T02E9.3, C24A8.1). We also examined their expression patterns. Finally, we tested whether the most likely candidate receptors were able to modulate adenylate cyclase activity in transfected cells in a 5-HT-dependent manner. This paper is the first comprehensive study of G protein-coupled serotonin receptors of C. elegans. It provides a direct comparison of the expression patterns and functional roles for 5-HT receptors in C. elegans.

Amino Acid Sequence↗

Multiomic single-nucleus profiling reveals cell-type-specific epigenetic and transcriptional dysregulation in major depressive disorder brain.

OBJECTIVE: Major depressive disorder (MDD) is a leading global cause of disability, marked by persistent mood disturbances, cognitive deficits, and changes in prefrontal cortex neural circuitry. In this study, we aimed to define cell-type-specific molecular and regulatory mechanisms underlying MDD by mapping gene-expression and chromatin-accessibility changes in the dorsolateral prefrontal cortex (PFC) (dlPFC). METHODS: Postmortem dlPFC (BA9) tissue from 7 MDD and 8 well-matched controls was analyzed using 10× Genomics snRNA-seq and paired ATAC+RNA multiome sequencing. Sequencing data were processed with Cell Ranger pipelines, nuclei were filtered for quality and doublets/debris, and datasets were integrated and clustered using Seurat/Signac packages. Differential gene expression, chromatin accessibility, and transcription factor motif activity were tested between MDD and controls within each cell type, followed by peak-to-gene linkage and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and PsyGeNET enrichment to interpret dysregulated regulatory mechanisms. RESULTS: A total of 20 distinct clusters encompassing major neuronal and non-neuronal populations were identified. Differential analyses uncovered extensive cell type-specific changes in chromatin accessibility and gene expression, particularly within excitatory layer 5/6 and inhibitory Pvalb neurons, as well as glial and vascular populations. Functional enrichment indicated dysregulation of synaptic organization, neurotransmission, myelination, stress-response, and immune-regulatory pathways across neuronal and non-neuronal cells. Notably, glucocorticoid-responsive transcription factors NR3C1/NR3C2 exhibited conserved regulatory networks implicating stress signaling in MDD pathophysiology. CONCLUSIONS: Together, these findings provide a comprehensive single-nucleus atlas of gene regulation in the MDD PFC, highlighting coordinated dysfunction across neurons, glia, and vascular cells.

Major Depressive Disorder↗

The expression profile of microRNAs in mouse embryos.

MicroRNAs (miRNAs), which are non-coding RNAs 18-25 nt in length, regulate a variety of biological processes, including vertebrate development. To identify new species of miRNA and to simultaneously obtain a comprehensive quantitative profile of small RNA expression in mouse embryos, we used the massively parallel signature sequencing technology that potentially identifies virtually all of the small RNAs in a sample. This approach allowed us to detect a total of 390 miRNAs, including 195 known miRNAs covering approximately 80% of previously registered mouse miRNAs as well as 195 new miRNAs, which are so far unknown in mouse. Some of these miRNAs showed temporal expression profiles during prenatal development (E9.5, E10.5 and E11.5). Several miRNAs were positioned in polycistron clusters, including one particular large transcription unit consisting of 16 known and 23 new miRNAs. Our results indicate existence of a significant number of new miRNAs expressed at specific stages of mammalian embryonic development and which were not detected by earlier methods.

Animals↗

An expression analysis of a gene family encoding plasma membrane aquaporins in response to abiotic stresses in Arabidopsis thaliana.

Aquaporin belongs to a highly conserved group of membrane proteins called major intrinsic proteins that facilitate water transport across biological membranes. The genome of Arabidopsis encodes 35 aquaporin genes with 13 homologs in the plasma membrane intrinsic protein (PIP) subgroup. However, the function of each individual aquaporin isoform and the integrated function of plant aquaporins under various physiological conditions remain unclear. As a step toward understanding the aquaporin function in plants under various environmental stimuli, the expressions of a gene family encoding 13 PIPs in Arabidopsis thaliana under various abiotic stress conditions including drought, cold, and high salinity, or abscisic acid (ABA) treatment were investigated by a quantitative real-time reverse transcription-PCR analysis. Several PIP genes were predominantly expressed either in the roots or in the flowers. The expressions of both the highly expressed aquaporins including PIP1;1, PIP1;2, and PIP2;7 and the weakly expressed aquaporins such as PIP1;4, PIP2;1, PIP2;4, and PIP2;5 were modulated by external stimuli. The analyses of our data revealed that only the PIP2;5 was up-regulated by cold treatment, and most of the PIP genes were down-regulated by cold stress. Marked up- or down-regulation in PIP expression was observed by drought stress, whereas PIP genes were less-severely modulated by high salinity. The responsiveness of each aquaporin to ABA were different, implying that the regulation of aquaporin expression involves both ABA-dependent and ABA-independent signaling pathways. Together, our comprehensive expression profile of the 13 members of the PIP gene family provides novel basis to allocate the stress-related biological function to each PIP gene.

Abscisic Acid↗

Pan-cancer analysis identifies APOC1 as a TAM-derived modulator of adaptive immune resistance and predictor of therapeutic response.

BACKGROUND: Apolipoprotein C1 (APOC1) has been implicated in several malignancies, yet its expression patterns, clinical significance, and immunomodulatory roles across cancer types remain poorly characterized. METHODS: We performed a comprehensive multi-omic analysis of APOC1 across 33 cancer types integrating transcriptomic, proteomic, genomic, epigenomic, and pharmacogenomic data from TCGA, GTEx, CPTAC, and multiple independent external cohorts. Immune infiltration was assessed using seven complementary algorithms. Spatial transcriptomics and single-cell RNA sequencing were employed to determine the cellular source of APOC1 expression. RESULTS: APOC1 upregulation in most cancers was associated with cancer type-specific prognosis. After adjustment for clinical covariates and macrophage infiltration, high APOC1 remained an independent adverse factor in KIRC, LGG, and STAD. APOC1 expression positively correlated with genomic instability hallmarks, including homologous recombination deficiency and aneuploidy, with these associations largely independent of immune infiltration; in contrast, associations with tumor mutational burden were substantially confounded by macrophage abundance. Immune infiltration analysis revealed a pattern consistent with adaptive immune resistance: APOC1 correlated positively with immune-activating signatures (STAT1, MHC-II, TCR signaling) and immunosuppressive M2 macrophages and Tregs, yet negatively with anti-tumor effectors (activated NK cells, dendritic cells). Spatial transcriptomics and single-cell RNA sequencing identified tumor-associated macrophages (TAMs) as the primary cellular source of APOC1, with transcripts co-localizing with CD68 in tissue sections. APOC1 expression correlated with multiple immune checkpoint molecules and was elevated in responders to immune checkpoint blockade, consistent with an inflamed yet regulated tumor microenvironment. Pharmacogenomic analyses revealed that APOC1-high tumors display distinct drug response profiles, characterized by resistance to MAPK pathway inhibitors and potential sensitivity to the HDAC inhibitor Entinostat. CONCLUSION: This pan-cancer analysis establishes APOC1 as a context-dependent biomarker and a TAM-derived modulator of adaptive immune resistance, with prognostic and therapeutic implications across malignancies. APOC1-expressing TAMs represent a potential target for combination immunotherapy strategies.

APOC1↗

Nitric oxide and gene regulation in plants.

There is increasing evidence that nitric oxide (NO), which was first identified as a unique diffusible molecular messenger in animals, plays an important role in diverse physiological processes in plants. Recent progress that has deepened our understanding of NO signalling functions in plants, with special emphasis on defence signalling, is discussed here. Several studies, based on plants with altered NO-levels, have recently provided genetic evidence for the importance of NO in gene induction. For a general overview of which gene expression levels are altered by NO, two studies, involving large-scale transcriptional analyses of Arabidopsis thaliana using custom-made or commercial DNA-microarrays, were performed. Furthermore, a comprehensive transcript profiling by cDNA-amplification fragment length polymorphism (AFLP) revealed a number of Arabidopsis thaliana genes that are involved in signal transduction, disease resistance and stress response, photosynthesis, cellular transport, and basic metabolism. In addition, NO affects the expression of numerous genes in other plant species such as tobacco or soybean. The NO-dependent intracellular signalling pathway(s) that lead to the activation or suppression of these genes have not yet been defined. Several lines of evidence point to an interrelationship between NO and salicylic acid (SA) in plant defence. Recent evidence suggests that NO also plays a role in the wounding/jasmonic acid (JA) signalling pathway. NO donors affect both wounding-induced H2O2 synthesis and wounding- or JA-induced expression of defence genes. One of the major challenges ahead is to determine how the correct specific response is evoked, despite shared use of the NO signal and, in some cases, its downstream second messengers.

Cell Death↗

Gene profiling techniques and their application in angiogenesis and vascular development.

The analysis of gene expression in specific tissues and physiological processes has evolved over the last 20 years from the painstaking identification of selected genes to the relatively efficient and open-ended surveying of potentially all genes expressed in a tissue. Current art for gene discovery includes the use of large-scale arrays of cDNA sequences or oligonucleotides, and molecular 'tagging' techniques such as GeneCalling and SAGE. Common to each of these techniques is a reliance on the increasingly comprehensive databases of human and mouse EST and full-length gene sequences. Early efforts to characterize candidate genes were limited by their narrow scope, while current efforts are confounded by the enormous volume of data returned. Sophisticated software tools are an integral part of the analysis, helping to organize information into coherent groups with temporal or functional similarity. These techniques, in conjunction with the continued analysis of human genetic syndromes, transgenic, and knockout mice, have driven genetic analysis of angiogenesis and vascular development from describing which individual genes are involved to defining the outlines of regulatory networks.

Animals↗

The complexity of the mammalian transcriptome.

A comprehensive understanding of protein and regulatory networks is strictly dependent on the complete description of the transcriptome of cells. After the determination of the genome sequence of several mammalian species, gene identification is based on in silico predictions followed by evidence of transcription. Conservative estimates suggest that there are about 20,000 protein-encoding genes in the mammalian genome. In the last few years the combination of full-length cDNA cloning, cap-analysis gene expression (CAGE) tag sequencing and tiling arrays experiments have unveiled unexpected additional complexities in the transcriptome. Here we describe the current view of the mammalian transcriptome focusing on transcripts diversity, the growing non-coding RNA world, the organization of transcriptional units in the genome and promoter structures. In-depth analysis of the brain transcriptome has been challenging due to the cellular complexity of this organ. Here we present a computational analysis of CAGE data from different regions of the central nervous system, suggesting distinctive mechanisms of brain-specific transcription.

Alternative Splicing↗

The analysis of large-scale gene expression correlated to the phase changes of the migratory locust.

The migratory locust is one of the most notorious agricultural pests that undergo a well known reversible, density-dependent phase transition from the solitary to the gregarious. To demonstrate the underlying molecular mechanisms of the phase change, we generated 76,012 ESTs from the whole body and dissected organs in the two phases. Comparing 12,161 unigene clusters, we identified 532 genes as phase-related (P < 0.01). Comprehensive assessment of the phase-related expression revealed that, whereas most of the genes in various categories from hind legs and the midgut are down-regulated in the gregarious phase, several gene classes in the head are impressively up-regulated, including those with peptidase, receptor, and oxygen-binding activities and those related to development, cell growth, and responses to external stimuli. Among them, a superfamily of proteins, the JHPH super-family, which includes juvenile hormone-binding protein, hexamerins, prophenoloxidase, and hemocyanins, were highly expressed in the heads of the gregarious hoppers and hind legs of the solitary hoppers. Quantitative PCR experiments confirmed in part the EST results. These differentially regulated genes have strong functional implications that numerous molecular activities are involved in phase plasticity. This study provides ample molecular markers and genomic information on hemimetabolous insects and insights into the genetic and molecular mechanisms of phase changes in locusts.

Animals↗

Database of repetitive elements in complete genomes and data mining using transcription factor binding sites.

Approximately 43% of the human genome is occupied by repetitive elements. Even more, around 51% of the rice genome is occupied by repetitive elements. The analysis presented here indicates that repetitive elements in complete genomes may have been very important in the evolutionary genomics. In this study, a database, called the Repeat Sequence Database, is first designed and implemented to store complete and comprehensive repetitive sequences. See http://rsdb.csie.ncu.edu.tw for more information. The database contains direct, inverted and palindromic repetitive sequences, and each repetitive sequence has a variable length ranging from seven to many hundred nucleotides. The repetitive sequences in the database are explored using a mathematical algorithm to mine rules on how combinations of individual binding sites are distributed among repetitive sequences in the database. Combinations of transcription factor binding sites in the repetitive sequences are obtained and then data mining techniques are applied to mine association rules from these combinations. The discovered associations are further pruned to remove insignificant associations and obtain a set of associations. The mined association rules facilitate efforts to identify gene classes regulated by similar mechanisms and accurately predict regulatory elements. Experiments are performed on several genomes including C. elegans, human chromosome 22, and yeast.

Algorithms↗

Molecular complexity of sexual development and gene regulation in Plasmodium falciparum.

The malaria parasite, Plasmodium falciparum, has a complex life cycle which alternates between the vertebrate host and the invertebrate vector. Various morphological changes as well as stage-specific transcripts and gene expression profiles that accompany parasite's asexual and sexual life cycle suggest that gene regulation is crucial for the parasite's continual adaptations to survive the changing environments as well as for pathogenesis. Development of sexual stages is crucial for malaria transmission and relatively little is known about the role of specific gene products during asexual to sexual differentiation and further development. Therefore, in order to have a full understanding of the biology of the malaria parasite, gene regulation on a genome-wide global level must be understood, an area remaining to be elucidated in P. falciparum. Parasite features, such as A-T bias, difficulties in cloning, labor-intensive culture and purification of specific stages of the parasite, all contribute to the difficulties to investigate many aspects of parasite biology. However, despite these challenges, limited studies have revealed a number of parallelisms with eukaryotic transcription. For example, the parasite's genes are organised in a similar fashion, contain promoter elements and upstream activation sequences, as shown by structural searches and functional assays, and some of the basal machinery and general transcription factors have been found in Plasmodium. The completion of the full genome sequence of P. falciparum and other species of Plasmodium has resulted in the search for specific transcription factors through genome mining. Although genome mining may identify some of the factors, search for these factors solely by primary sequence homology would result in a non-comprehensive list for transcription factors present in the genome. Here, we present further discussion on putative transcription factors like activities detected in the asexual and sexual stages of P. falciparum.

Animals↗

PotatoRTD and TomatoRTD: Comprehensive Reference Transcript Datasets for Accurate Transcriptome Analysis and Isoform Discovery.

Transcriptome annotations provide essential information on transcript locations, sequences and structures, including transcription start, end sites and splice junctions. They underpin key biological analyses such as gene and transcript quantification, and the study of transcriptional and post-transcriptional regulation, including alternative transcription initiation, polyadenylation and splicing. Accurate characterisation of transcript isoforms is critical for understanding how gene expression relates to functional protein products. However, for many species-including Solanaceae crops such as potato and tomato-current annotations suffer from limited isoform coverage, with tens or hundreds of thousands of splice junctions and transcript isoforms missing. This undermines the completeness and accuracy of transcript-level analyses. Here, by generating Iso-seq and RNA-seq on a range of tissues and samples, we have produced transcriptome annotations for both potato and tomato with improved coverage, diversity, accurate splice junctions, and transcript start and end sites. We have also made these high-quality resources accessible through genome browsers. These enhanced annotations will enable more accurate transcriptome analyses, supporting higher-resolution and novel biological discoveries.

Solanum tuberosum↗

Identification and characterization of optimal gene expression markers for detection of breast cancer metastasis.

Sentinel lymph node (SLN) status is highly predictive of overall axillary lymph node involvement in breast cancer. Historically, SLN-positive patients have undergone axillary lymph node dissection in a second surgery. Intraoperative SLN analysis could reduce the cost and complications of a second surgery; however, existing histopathological methods lack standardization and exhibit poor sensitivity. Rapid molecular methods may lead to improved intraoperative diagnosis of SLN metastasis. In this study, we used a genome-wide gene expression analysis of breast and other tissues to identify seven putative markers for detecting breast cancer metastasis. We assessed the utility of these markers for identifying clinically actionable metastases in lymph nodes through reverse transcriptase-polymerase chain reaction analysis of SLNs from 254 breast cancer patients. Polymerase chain reaction signals were compared to pathology on a per-patient basis. The optimal two-gene combination, mammaglobin and cytokeratin 19, detected clinically actionable metastasis in breast SLNs with 90% sensitivity and 94% specificity. Application of stringent criteria for identifying presumptive hematoxylin- and eosin-positive samples increased sensitivity and specificity to 91 and 97%, respectively. This study represents the first comprehensive demonstration of the utility of gene expression markers for detecting clinically actionable breast metastases. An intraoperative molecular assay using these markers has the potential to significantly reduce second surgeries for patients undergoing SLN dissection.

Biomarkers, Tumor↗

Ultra-processed Foods, Cancer, and Early-onset Cancer: A Comprehensive Review.

The classification of foods according to their degree of processing, and particularly the concept of ultra-processed foods, is relatively new. Consumption of ultra-processed foods has increased markedly worldwide in recent decades. Their growing consumption has coincided with a rising global burden of cancer, including marked increases in several cancers diagnosed before age 50 years. In this comprehensive review, we summarize trends in ultra-processed food consumption and the sociodemographic, psychological, and behavioral characteristics associated with higher intake. We further review the epidemiological evidence linking ultra-processed foods with cancer incidence and mortality, with particular attention to the limited but emerging evidence relevant to early-onset cancer. Potential mechanisms linking ultra-processed foods to cancer include unfavorable nutrient displacement, changes in body composition and fat deposition, and increased exposure to additives, processing by-products, and other chemicals. These influences may converge on a range of biological pathways, including metabolic dysfunction, chronic inflammation, immune dysregulation, gut microbiome disruption, DNA damage and genomic instability, and epigenetic alterations. Substantial uncertainties remain, including heterogeneous exposure definitions and classification practices, limitations in dietary assessment and temporal exposure capture, residual confounding, and the complexity of putative biological mechanisms. We conclude by highlighting key research challenges and future directions, along with considerations related to policy, regulation, and industry practices.

Ultra-processed foods↗