Early breast cancer may induce a systemic immune response before abundant tumor-derived material reaches the circulation, creating a potential source of amplified liquid-biopsy biomarkers. However, the extent to which host-response signatures can support early detection or population screening before diagnosis remains uncertain. This structured narrative review examines the biological basis, analytical platforms, evidence, clinical roles, and translational requirements of circulating autoantibodies, leukocyte transcriptomic and epigenetic profiles, immune-cell phenotypes, adaptive immune-receptor repertoires, soluble mediators, extracellular vesicles, and integrated multi-omics. PubMed/MEDLINE and citation networks were searched through August 31, 2026 using a predefined diagnostic review framework. Evidence was organized by intended use, sample timing, comparator spectrum, and validation maturity, with appraisal informed by established diagnostic-accuracy and prediction-model standards. Proof-of-concept estimates include a mean area under the curve of 0.96 for a machine-learning T-cell receptor model in 98 women, 80.8% sensitivity and 61.6% specificity for a 28-autoantibody panel, and an external-validation area under the curve of 0.951 for a 20-analyte proteome-metabolome model involving 662 participants. These estimates are not directly comparable: most derive from retrospective case-control or diagnostic cohorts with established cancer, healthy or benign comparators, post-diagnosis sampling, data-driven thresholds, and limited independent validation. Consequently, discrimination between known cases and controls must not be equated with detection of occult disease or population screening utility. Breast-specific prediagnostic evidence and screening validation remain sparse. Host-response signatures are therefore best considered investigational, complementary biological sensors rather than replacements for mammography. Their most plausible future roles include triage after equivocal imaging, enrichment for supplemental imaging, and longitudinal surveillance in high-risk populations. Translation requires prospective prediagnostic cohorts, representative benign and inflammatory controls, locked algorithms, high-specificity performance, calibration at screening prevalence, external validation, subgroup fairness, reproducibility, and evidence that testing improves cancer yield or stage distribution without unacceptable false-positive procedures, overdiagnosis, cost, or inequity.

Alpha-fetoprotein (AFP) is widely used as a serum biomarker in the evaluation of hepatocellular carcinoma and nonseminomatous germ cell tumors, but persistent AFP elevation may occasionally occur without demonstrable malignancy or active liver disease. We report a 54-year-old asymptomatic man in whom routine health screening showed persistently elevated AFP values in the 200-400 ng/mL range. Liver biochemistry was normal; viral hepatitis and human immunodeficiency virus (HIV) testing were negative; AFP-L3, protein induced by vitamin K absence or antagonist II (PIVKA-II), carcinoembryonic antigen, and carbohydrate antigen 19-9 (CA 19-9) were not elevated; and targeted imaging, including abdominal ultrasonography, triple-phase contrast-enhanced computed tomography, testicular ultrasonography, and whole-body positron emission tomography/computed tomography, revealed no evidence of malignancy. Incidental simple hepatic cysts were identified, but they lacked suspicious imaging features; cyst-fluid cytology was negative, and cyst-fluid AFP was not elevated. Over 6 years of serial follow-up, AFP remained elevated. After exclusion of hepatocellular carcinoma, germ-cell tumor, active hepatic injury, and other occult malignancy, hereditary persistence of AFP or idiopathic persistent AFP elevation was considered the most plausible explanation. This case highlights the importance of confirming persistence, excluding common malignant and hepatic causes in a stepwise manner, and avoiding repeated invasive or high-burden investigations when the patient remains clinically stable.

The success of trastuzumab deruxtecan (T-DXd) has expanded the therapeutic relevance of human epidermal growth factor receptor 2 (HER2) expression beyond the traditional HER2-positive population. This has led to evolving concepts such as HER2-low, HER2-ultralow, and HER2-null. Accurately and reproducibly distinguishing HER2 immunohistochemistry (IHC) scores 0, 0+, and 1+ remains challenging because of intratumoral heterogeneity and interobserver variability. This review discusses the challenges in HER2 assessment.

The evolution of HER2 testing and recent guideline updates were reviewed. The implications of HER2-low and HER2-ultralow breast cancers for HER2 testing were discussed.

Challenges in HER2 assessment include interobserver variability and intratumoral heterogeneity. Potential strategies for accurately and reproducibly distinguishing all HER2 IHC categories, especially HER2 IHC 0 from HER2 IHC 0+, are also discussed. Significant discordance has been reported in interpreting low-level HER2 expression. Revisiting HER2 testing guidelines, improving HER2 assessment, and developing sensitive, objective, and reproducible detection methods may reduce variability. No alternative method has been validated as a companion diagnostic for determining eligibility for T-DXd or other HER2-targeted antibody–drug conjugates. Consequently, HER2 immunohistochemistry, supplemented by reflex in situ hybridization testing for equivocal cases, remains the standard despite its limitations at the HER2-low threshold. Digital pathology, quantitative image analysis, artificial intelligence-assisted interpretation, molecular profiling, and other emerging technologies may provide more objective, sensitive, and reproducible approaches to HER2 assessment.

The evolving concepts of HER2-low, HER2-ultralow, and HER2-null emphasize the need to accurately and reproducibly distinguish HER2 IHC categories. Further research and technological advances are needed to better classify HER2 status.

The huge burden of type 1 diabetes mellitus (T1DM) has been a source of concern globally since the Industrial Revolution in the 18th–19th centuries. To this end, studies have shown that certain environmental changes that accompanied the Revolution may have increased the risk and burden of the disease in genetically predisposed individuals. However, documented studies that synthesize these environmental triggers are scarce. As a result, the current study was conceived to synthesize the environmental triggers of T1DM to boost public awareness. Relevant information was retrieved from reputable academic databases; namely, Scopus, PubMed, SpringerLink, and Embase. The results showed that chemical exposure, viral infection, gut microbiome disruption, vitamin and mineral deficiencies, inadequate or exclusive breastfeeding, as well as early exposure to infant feeding formulas could increase the risk and burden of T1DM in genetically predisposed individuals. As a consequence, these triggers could compromise the expression of certain genes involved in insulin synthesis and immune function, such as the human leukocyte antigen (HLA), insulin (INS), cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and protein tyrosine phosphatase non-receptor type 22 (PTPN22) genes. This would result in a dysfunctional immune system in which immune cells, such as T-cells and B-cells and molecules, such as cytokines would attack self-tissues, thus causing autoimmunity of the pancreatic beta cells. Environmental triggers could also induce the T1DM pathophysiology by modifying the epigenome of the mentioned genes. Furthermore, some epigenetic changes could be reversed, which would infer that treatment procedures that would include the pathophysiology of the environmental triggers could be more effective.

Emerging evidence suggests that RNA-binding motif (RBM) proteins are involved in hepatocarcinogenesis and act either as oncogenes or tumor suppressors. The objective of this study was to investigate the role of RBM34, an RBM protein, in hepatocellular carcinoma (HCC).

We first examined the expression of RBM34 across cancers. The correlation of RBM34 with clinicopathological features and the prognostic value of RBM34 for HCC was then investigated. Functional enrichment analysis of RBM34-related differentially expressed genes (DEGs) was performed to explore its biological function. RNA sequencing (RNA-seq) was applied to identify downstream genes and pathways affected upon RBM34 knockout. The correlation of RBM34 with immune characteristics was also analyzed. The oncogenic function of RBM34 was examined in in vitro and in vivo experiments.

RBM34 was highly expressed in hepatocellular carcinoma and correlated with poor clinicopathological features and prognosis. RBM34 was positively associated with tumor immune cell infiltration, biomarkers of immune cells, and immune checkpoint expression. A positive correlation was also observed between RBM34, T cell exhaustion, and regulatory T cell marker genes. Knockout of RBM34 significantly inhibited cell proliferation, migration, and xenograft tumor growth, and sensitized HCC cells to sorafenib treatment. RBM34 inhibition reduced FGFR2 expression and affected PI3K-AKT pathway activation in HCC cells.

Our study suggests that RBM34 may serve as a new prognostic marker and therapeutic target of HCC.

Naringenin is an anti-inflammatory flavonoid that has been studied in chronic liver disease. The mechanism specific to its antifibrosis activity needs further investigation This study was to focused on the cyclic guanosine monophosphate-adenosine monophosphate synthase (cGAS) pathway in hepatic stellate cells and clarified the antifibrosis mechanism of naringenin.

The relationship between the cGAS-stimulator of interferon genes (STING) pathway and liver fibrosis was analyzed using the Gene Expression Omnibus database. Histopathology, immunohistochemistry, fluorescence staining, Western blotting and polymerase chain reaction were performed to assess gene and protein expression levels associated with the cGAS pathway in clinical liver tissue samples and mouse livers. Molecular docking was performed to evaluate the relationship between naringenin and cGAS, and western blotting was performed to study the expression of inflammatory factors downstream of cGAS in vitro.

Clinical database analyses showed that the cGAS-STING pathway is involved in the occurrence of chronic liver disease. Naringenin ameliorated liver injury and liver fibrosis, decreased collagen deposition and cGAS expression, and inhibited inflammation in carbon tetrachloride (CCl4)-treated mice. Molecular docking found that cGAS may be a direct target of naringenin. Consistent with the in vivo results, we verified the inhibitory effect of naringenin on activated hepatic stellate cells (HSCs). By using the cGAS-specific agonist double-stranded (ds)DNA, we showed that naringenin attenuated the activation of cGAS and its inflammatory factors affected by dsDNA. We verified that naringenin inhibited the cGAS-STING pathway, thereby reducing the secretion of inflammatory factors by HSCs to ameliorate liver fibrosis.

Interrupting the cGAS-STING pathway helped reverse the fibrosis process. Naringenin has potential as an antihepatic fibrosis drug.