A principal challenge in modern biology and biomedical research is the comprehensive elucidation of the molecular and cellular mechanisms that underpin human disease, with the ultimate aim of identifying novel and effective therapeutic targets. Embryogenesis represents a paradigm of tightly regulated biological complexity, orchestrated by elaborate networks of signaling pathways and transcriptional programs. This highly dynamic process, which initially unfolds within a seemingly disordered and heterogeneous microenvironment, is progressively structured through the establishment of intricate molecular equilibriums mediated by a diverse array of regulatory factors. Perturbations of these homeostatic balances at later stages frequently precipitate the emergence of various pathological conditions. Raf kinase inhibitor protein (RKIP) and Yin Yang 1 (YY1) are pleiotropic regulatory molecules implicated in a broad range of fundamental cellular processes, including proliferation, differentiation, migration, invasion, and epithelial-mesenchymal transition. Although these factors have conventionally been examined as discrete entities, emerging evidence indicates that RKIP and, YY1 may engage in significant molecular cross-talk that not only influences embryonic development but also contributes to the pathogenesis of diverse diseases, including cancer, autoimmune disorders, and immunological dysfunctions. Focusing on the pivotal developmental process of embryogenesis, this review explores the individual regulatory functions of RKIP and YY1, while emphasizing their potential points of convergence within signaling networks during both physiological development and pathological states.

Pancreatic cancer, primarily pancreatic ductal adenocarcinoma (PDAC), is one of the leading causes of cancer-related death, largely due to its late diagnosis and highly aggressive nature. Although precursors such as pancreatic intraepithelial neoplasia (PanIN), often harboring KRAS mutations, are commonly detected in adults; PanIN rarely progresses to invasive PDAC. The molecular mechanisms that govern this PanIN-to-PDAC transition remain poorly understood. Peroxisome proliferator-activated receptor delta (PPARδ), a ligand-activated nuclear transcription factor, plays critical roles in lipid metabolism, inflammation and tumorigenesis across multiple cancer types. In this brief review, we summarize recent advances and emerging evidence implicating PPARδ activation in oncogenic KRAS-initiated pancreatic tumorigenesis and progression, with emphasis on mechanisms such as metabolic reprogramming and immune suppression. These integrated insights underscore PPARδ as a potential therapeutic target in this lethal malignancy.

Cadmium exposure through smoking, occupational exposure, and pollution is linked to lung damage and cancer risk; however, most mechanistic studies remain limited to in vitro transformation and animal studies rather than large human cohorts. However, there are few clinically applicable biomarkers for early detection, risk assessment, and therapeutic monitoring. This review, centered on mechanisms, provides a summary and critical analysis of multi-omics biomarker evidence related to cadmium (Cd)-induced lung toxicity and carcinogenesis, with a particular focus on diagnostic laboratory medicine. We combine genomic and epigenomic signals (mutational signatures, cfDNA/ctDNA, methylation, and miRNA profiles) with proteomic and metabolomic readouts that represent inflammation, oxidative stress, extracellular matrix remodeling, and altered energy metabolism. In matrices (blood, urine, sputum, bronchoalveolar lavage, and extracellular vesicles), we emphasize key pre-analytical variables affecting measurements (collection tubes, processing delays, hemolysis, storage temperature, freeze-thaw cycles, and batch effects) rather than providing comprehensive experimental validation of the assays. Where appropriate, we comment on representative requirements for analytical performance and common pitfalls (limit of detection, precision, interference, calibration/traceability, and external quality assessment) of candidate biomarker classes; however, a comprehensive discussion of quantitative clinical performance measures (sensitivity, specificity, AUC, prospective validation) for most markers is lacking. Finally, we suggest a practical, stepwise translation pathway that emphasizes mechanistically informed multi-analyte panels, documented differences between exposure and effect biomarkers, future validation in exposed cohorts, and clinically relevant endpoints (reduction in lung function, incidence of malignancy, and response to treatment) to facilitate routine laboratory implementation. To demonstrate the clinical relevance and economic viability of controlling confounders and establishing decision limits, standard reporting of methods, rigorous control of confounders (particularly smoking and co-exposures), and explicit derivation of decision limits based on specific targeted applications (such as screening, surveillance, or monitoring of responses) should be prioritized over current evidence base achievements.

Human epidermal growth factor receptor 2 (HER2)-targeted therapies have been investigated for therapeutic benefit in RAS/BRAF wild-type/HER2+ metastatic colorectal cancer (mCRC). Unlike HER2+ breast and gastric cancer, there are no regulatory criteria for determining HER2 overexpression in patients with mCRC. This systematic literature review describes unmet needs for patients with HER2+ mCRC in relation to testing and treatment, highlights the importance of early HER2 testing at mCRC diagnosis, and discusses the evolving treatment landscape. We utilised PubMed and EMBASE databases up to November 2023 to identify journal articles and published congress abstracts relating to the HER2+ disease and treatment landscape, HER2 testing in mCRC, and HER2-targeted treatments in mCRC. Many studies have demonstrated the utility of immunohistochemistry, in situ hybridisation, and next-generation sequencing (tissue- and circulating tumour DNA-based) for detecting HER2 overexpression/amplification in mCRC and have attempted to establish consolidated criteria like those used for breast and gastric cancer. The value of HER2-targeted treatments in patients with HER2+ mCRC has been evidenced by clinical trials and meta-analyses, with strong evidence from MOUNTAINEER and DESTINY-CRC01 which supports the use of tucatinib + trastuzumab or trastuzumab deruxtecan, respectively, among this patient population. However, real-world analyses have confirmed that patients with HER2+ mCRC are not routinely tested for HER2 overexpression. Strong evidence and clinical guidelines support the value of HER2-targeted treatment among patients with HER2+ mCRC. There is a need for increased awareness and earlier uptake of HER2 testing among patients with mCRC to broaden treatment options and optimise outcomes for this patient population.

Hepatobiliary malignancies remain a major clinical challenge because they are highly aggressive and resistant to therapy. In eukaryotes, N6-methyladenosine (m6A), the most prevalent internal RNA modification, regulates post-transcriptional gene expression. Insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1/2/3) act as pivotal m6A readers, stabilizing coding and non-coding RNAs to modulate cancer-related signaling networks. In hepatobiliary cancers, dysregulated IGF2BP expression is associated with proliferation, metastasis, metabolic adaptation, and immune evasion, underscoring its potential as a biomarker and therapeutic targets. This review provides a comprehensive overview of IGF2BP-mediated regulatory mechanisms and explores their translational potential in precision diagnostics and targeted interventions.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related mortality worldwide, owing to its molecular complexity and limited therapeutic options. Three-dimensional (3D) in vitro models more accurately recapitulate in vivo conditions than traditional two-dimensional (2D) models, due to their ability to accurately reproduce the tumor microenvironment (TME). Among these models, HepG2 cell-derived spheroids have become an important tool for drug screening, toxicity assessment, and liver cancer research. This review highlights the advantages and limitations of currently available 3D culture systems. In particular, special attention is given to the multifaceted role of leucine-rich repeat kinase 2 (LRRK2), a gene traditionally associated with neurological disorders but increasingly implicated in cancer, a kinase, which emerges as a promising therapeutic target in HCC since it regulates oxidative stress, lipid metabolism, and treatment responses, all of which contribute to tumor progression. Finally, we explore future directions, including organ-on-chip technologies and co-culture systems, which hold considerable promise for improving precision medicine and translational research in HCC.

Colorectal cancer (CRC) is a globally prevalent malignancy with rising incidence and mortality rates over the past decades. N6-methyladenosine (m6A) is the most abundant internal RNA modification in eukaryotes, and plays a pivotal role in post-transcriptional regulation. m6A is dynamically modulated by three core components, namely methyltransferases (writers), demethylases (erasers), and binding proteins (readers), which together govern the transcription, processing, translation, decay, and stability of mRNA. There has been accumulating evidence for the association of dysregulated m6A modification with CRC pathogenesis, metastasis, and therapeutic resistance. This review summarizes the biogenesis of m6A modification and its regulatory mechanisms, and discusses the dysregulation of m6A-related factors in CRC and the functional impacts. Most importantly, the review highlights the key roles of m6A modification in mediating CRC resistance to chemotherapy, targeted therapy, and immunotherapy. These insights may facilitate the development of novel therapeutic strategies for CRC.

Aberrant DNA methylation patterns are increasingly recognized as contributors to a wide range of conditions, including metabolic, oncogenic, and neurodevelopmental disorders. Nutritional factors, such as choline, can shape methylation potential via methyl group donation. The purpose of this narrative review is to synthesize current evidence on the DNA methylation landscapes underlying health and disease paradigms, with a focus on the role of choline as a compelling target for modulating epigenetic states. A comprehensive literature review search was conducted in PubMed to identify relevant studies, with additional articles retrieved from review papers.

Chondromyxoid fibroma (CMF) is a rare benign cartilaginous neoplasm that most frequently occurs in the metaphysis of long bones in adolescents and young adults. The most common symptom is pain and/or swelling in the affected area. Radiographs typically show a well-defined, eccentric lytic lesion with sclerotic margins and scalloped or lobulated borders. Unlike other cartilaginous neoplasms, matrix calcification is uncommon. On magnetic resonance imaging (MRI), CMF usually exhibits low to intermediate signal intensity on T1-weighted sequences and heterogenous high signal intensity on T2-weighted sequences. Contrast-enhanced MRI demonstrates intense homogeneous, heterogeneous or peripheral enhancement. Histologically, CMF is composed of lobules of stellate to spindle-shaped cells in a myxoid background. The periphery of the lobules is generally hypercellular, imparting a characteristic zonal architecture. Recent molecular studies have identified alteration of glutamate metabotropic receptor 1 (GRM1) gene, and GRM1 positivity by immunohistochemistry has emerged as a reliable surrogate marker for this molecular event. Curettage or en bloc resection is the treatment of choice, with a non-negligible risk for local recurrence. This review provides an updated overview of the clinical, radiological, histological, immunohistochemical and molecular genetic features of CMF and discusses the differential diagnosis of this unusual neoplasm.

Melanoma, colorectal cancer (CRC), and hepatocellular cancer (HCC) overexpress the PD-1/PD-L1 pathway to evade the immune response. Immune Checkpoint Inhibitors (ICIs) suppress this mechanism but lack specificity, leading to immune-related adverse events (irAEs). Small-interfering RNA (siRNA) offers precise gene suppression but requires a protective delivery vector. Attenuated Salmonella, with tumor-targeting and immunomodulatory properties, is a promising carrier.

Cholangiocarcinoma (CCA), a subset of biliary tract cancers, remains a therapeutically challenging malignancy with poor long-term survival despite recent advances in targeted therapies. Recent data suggest that IDH1-mutated CCA exhibits unique mitochondrial vulnerabilities. In this report, we discuss the emerging role of mitochondrial metabolism as a target in IDH1-mutated CCA, including preclinical evidence supporting the inhibition of the tricarboxylic acid (TCA) cycle, glutamine metabolism, and potential combination approaches. We aim to highlight the growing need to integrate mitochondrial-targeted strategies into future clinical investigations.

Hepatocellular carcinoma (HCC) represents one of the most prevalent malignancies worldwide and poses a critical public health challenge due to difficulties in early diagnosis, therapy resistance, and high mortality rates. The complex tumor microenvironment (TME) of HCC plays a pivotal role in tumor progression, immune evasion, metastasis, and treatment resistance. Single-cell sequencing (scRNA-seq) has emerged as a revolutionary tool for resolving the intricacies and cellular heterogeneity of the TME, with its applications in advancing therapeutic research attracting considerable attention. As the primary battleground for antitumor immune responses, the HCC tumor TME warrants comprehensive analysis of immune cell subsets at distinct developmental and functional states to elucidate the complexity of tumor immunology. This review synthesizes extensive research on TME immune cellular subpopulations, in order to summarize mainstream classifications of immune subsets at single-cell resolution and analyze their functional significance and therapeutic value through biomarker gene profiling.

The apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) family was first defined as an innate antiviral defense system, but the APOBEC3 subfamily (APOBEC3s) is now recognized as a major endogenous source of somatic mutagenesis in cancer. APOBEC3s enzymes, particularly APOBEC3A and APOBEC3B, generate characteristic mutation patterns that promote genomic instability, clonal evolution, and adaptation to therapy. Beyond driving tumor evolution, APOBEC3 activity reshapes antitumor immunity in solid cancers. APOBEC3-induced mutations increase tumor mutational burden and create neoantigens that can enhance CD8+ T-cell infiltration and interferon signaling. However, sustained APOBEC activation may also reinforce immunosuppressive circuits: through chronic inflammation and PD-1/PD-L1-interferon signaling, tumors can induce T-cell dysfunction, immune escape, and resistance to immune checkpoint blockade. This functional ambivalence has sparked debate over whether APOBEC3s should be inhibited to limit genomic instability, leveraged to enhance tumor immunogenicity, or modulated dynamically in a context-dependent manner. This review outlines the immune landscape and biochemical characteristics of the APOBEC3 family and situates these features within broader cancer-related disease contexts. APOBEC3-mediated mutagenesis is discussed as a mechanistic link between genomic instability and tumor-immune crosstalk in solid tumors, with emphasis on its relationships to immunoediting, immune checkpoint pathways, and therapeutic responses. Context-dependent associations of APOBEC3 activity with immune activation or immune evasion are also considered, together with their implications for strategies that modulate this pathway.

In indolent small B-cell lymphomas, autoimmune cytopenia and histologic transformation pose important diagnostic and management challenges. MYD88 and MYC abnormalities are rarely reported in splenic marginal zone lymphoma (SMZL), and their role in immune dysregulation and transformation remains unclear. We describe a 44-year-old man with a small B-cell lymphoma highly suspicious for SMZL, who presented with severe warm autoimmune hemolytic anemia, massive splenomegaly, and lymphocytosis. He harbored both MYD88 L265P mutation and MYC copy-number gain within a complex karyotype, in the absence of splenic histology. This case, together with a review of the literature, suggests that such "clinically indolent but genetically high-risk" SMZL-like lymphomas may carry a non-negligible risk of progression and transformation and therefore require close longitudinal monitoring. Further accumulation of similar cases and molecular data is needed to clarify the prognostic and biological impact of MYD88 and MYC alterations in this setting.

Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs characterized by covalently closed loop structures, which confer high stability and evolutionary conservation. Beyond their well-known role as microRNA sponges, circRNAs can directly interact with proteins to modulate protein stability, activity, subcellular localization, and transcriptional or epigenetic regulation. These circRNA-protein interactions play critical roles in cancer progression by influencing tumor cell proliferation, metastasis, stemness, metabolic reprogramming, cell death, and therapy resistance. Moreover, they can shape the tumor immune microenvironment, affecting immune cell infiltration, immune evasion, and responses to immunotherapy. Understanding the mechanisms and functional consequences of circRNA-protein interactions provides new insights into tumor biology and offers promising avenues for cancer diagnosis, prognosis, and therapeutic intervention.

Glioblastoma (GBM) is an aggressive tumor with limited therapeutic options. Zika virus (ZIKV) has demonstrated activity against GBM; however, the cellular pathways behind this interaction remain unclear. We systematically reviewed open-access primary studies assessing differentially expressed genes (DEGs) in GBM models infected with wild-type or engineered ZIKV using transcriptomic approaches (inclusion criteria); reviews, restricted-access studies, commentaries, preprints, abstracts, and articles lacking data or not meeting these conditions were excluded (PROSPERO CRD420251077092). We performed a pathway analysis of reported DEGs. PubMed and Google Scholar were searched up to 5 March 2025; 139 records were identified and 5 met the eligibility criteria. Risk of bias was evaluated using an adapted ToxRTool for in vitro experiments and the SYRCLE RoB tool for in vivo models. Altogether, 4360 genes were reported as upregulated and 2072 as downregulated; 12 genes (DNAJB9, SESN2, PMAIP1, PPP1R15A, KLF4, ATF3, IFNB1, IFNL1, ANKRD33B, ZC3HAV1, OASL, and CCL5) were consistently upregulated, none were consistently downregulated. Pathway analysis of the studies providing complete DEG lists identified 23 commonly enriched pathways mostly related to interferon signaling. These findings may help guide future research in this field; nevertheless, methodological heterogeneity limits comparability, reinforcing the need for standardized protocols. Funding: ITpS, CNPq, and FAPEMIG.

Human epidermal growth factor receptor 2 (HER2)-low breast cancer is a clinically relevant subgroup defined by low but detectable HER2 protein expression, immunohistochemistry (IHC) score of 1+ or 2+ with negative in situ hybridization findings, positioned at the interface between traditional HER2-positive and HER2-negative disease. The recent introduction of antibody-drug conjugates (ADCs) has increased the clinical significance of borderline HER2 expression and exposed important diagnostic challenges, particularly in cases with very low levels of membrane staining, including the emerging HER2-ultralow category. Background and Objectives: This review summarizes the pathological and biological framework of HER2-low and HER2-ultralow breast cancer and critically appraises the magnitude, direction, and determinants of HER2 variability under systemic therapy. Particular focus is placed on treatment-associated shifts after chemotherapy, intratumoral heterogeneity, and pre-analytical and analytical factors that can influence HER2 assessment, with direct implications for therapeutic stratification and biomarker reassessment. Materials and Methods: A narrative literature review was conducted using PubMed, Scopus, and Web of Science, focusing on studies published within the last five years. Eligible publications included clinical trials, retrospective cohorts, and translational or molecular studies that reported paired HER2 assessment in breast cancer and were interpreted according to American Society of Clinical Oncology/College of American Pathologists-aligned criteria. Results: Across major cohorts, HER2-low appeared to be the most dynamic category, with variability frequently observed following systemic therapy. Beyond treatment-related effects, shifts in HER2 status may be attributable to intratumoral heterogeneity and technical variability, with the greatest impact observed at the IHC 0-1+ interface. Conclusions: Given the clinical relevance of low-level HER2 expression, standardized testing and transparent reporting are essential, and HER2 reassessment may be justified in selected clinical scenarios to optimize access to HER2-directed therapies.

G3BP2 is an important RNA-binding protein that belongs to the mammalian Ras-GAP SH3 domain-binding protein (G3BP) family. Its structure enables it to bind to RNA or proteins, regulate nuclear-cytoplasmic shuttling, and participate in various functions, including cell growth, differentiation, migration, and RNA and protein metabolism. Studies have found that G3BP2 is involved in the occurrence and development of various human diseases, such as high expression across multiple tumor diseases, including gastric cancer, breast cancer, non-small-cell lung cancer, esophageal squamous cell carcinoma, colorectal cancer, and pancreatic ductal adenocarcinoma, driving the occurrence of human tumors, participating in tumor progression, and playing an essential role in promoting the proliferation, invasion, and migration of tumor cells. Additionally, G3BP2 is closely associated with various non-tumor diseases, including viral infections, as well as cardiovascular and cerebrovascular diseases. This review elucidates the role of G3BP2 in the development and progression of various diseases, identifying biomarkers and therapeutic targets for clinical diagnosis and treatment based on G3BP2.

T-cell lymphoblastic lymphoma (T-LBL) is an aggressive malignancy of immature T-cells accounting for a substantial proportion of pediatric non-Hodgkin lymphoma cases. Current chemotherapeutic regimens achieve five-year event-free survival rates of 80-90%, yet relapse occurs in approximately 20% of patients and remains a major therapeutic challenge. This underscores the need for improved, molecularly informed treatment strategies. Recent genomic profiling has highlighted the central role of NOTCH1 signaling in T-LBL pathogenesis. NOTCH1, a transmembrane receptor critical for T-cell differentiation and maturation, requires tightly regulated activation during normal thymocyte development. Dysregulated signaling disrupts this balance, driving aberrant proliferation and impaired differentiation, characteristics of malignant transformation. While activating mutations have long been recognized as key oncogenic events, the recent identification of recurrent NOTCH1 translocations, associated with adverse outcomes, reveals an additional mechanism of pathway activation. These findings reinforce NOTCH1 as a pivotal oncogenic hub in T-cell malignancies and a compelling target for therapeutic intervention. This review synthesizes current insights into the molecular landscape of pediatric T-LBL, with a focus on the biological and clinical implications of NOTCH1 mutations and translocations. Furthermore, we examine emerging approaches to therapeutically exploit aberrant NOTCH1 signaling for the more precise and effective treatment of this disease and formulate outstanding research questions.

Colibactin, a genotoxin produced by pks+E. coli, imprints highly specific mutational signatures SBS88 and ID18 in colorectal cancer (CRC) and even in normal colonic crypts. Population-scale analyses show these signatures are enriched in early-onset CRC, vary geographically, and are imprinted early during tumor evolution, where probabilistic attribution indicates that colibactin contributes to a measurable fraction of APC driver mutations in colibactin-positive cancers. Beyond colibactin, Fusobacterium nucleatum exerts clade-specific effects on tumor ecology and therapy response, with data supporting both chemoresistance and sensitization to anti-PD-1 in microsatellite stable (MSS) CRC. This article covers mechanistic, genomic, and molecular epidemiology evidence, outlines analytic standards for signature detection (whole-genome sequencing (WGS)/whole-exome sequencing (WES), single-sample fitting, and limits at low mutation counts), and charts translational paths spanning noninvasive screening (stool metagenomics + mutational signatures in tissue/circulating tumor DNA (ctDNA)), risk stratification, and microbial-targeted interventions (antibiotics, phages, ClbP inhibitors). Framing microbiome-genome crosstalk as a tractable axis enables testable clinical hypotheses for precision oncology.