Search Results (1,066)

Background/Objectives: DNA methylation (DNAm)-based aging measures are increasingly being used in biological aging, disease vulnerability, and cancer-related risk. However, it remains unclear whether these measures capture a single generalized aging process or separable biological domains relevant to cancer-relevant biological vulnerability. Methods: Using data from the Family and Community Health Study (FACHS), we examine whether blood-based DNAm scores capture two distinct biological domains relevant to cancer susceptibility: a replication/mitotic domain, indexed by CellDRIFT, EpiTOC2, and MiAge, and an early-life systemic dysregulation domain, indexed by DunedinPACE, GrimAgeV2, and PhenoAge. Results: Regression results showed clear domain specificity. CRP, BMI, alcohol methylation, and AHRR/cg05575921 were positively associated with the early-life systemic dysregulation domain but showed weak or null associations with the replication/mitotic domain. Cross-domain tests confirmed significantly stronger associations for the early-life systemic dysregulation domain for CRP, BMI, and alcohol methylation, with a marginal difference for AHRR/cg05575921. In contrast, telomere-related methylation and immune-cell composition showed a different pattern. DNAmTL was inversely associated with both domains and did not differ significantly across domains. Conclusions: These findings suggest that blood-based DNAm aging measures do not reflect a single aging process. Instead, they distinguish at least two cancer-relevant methylation domains: one reflecting replication-driven mitotic aging and hematopoietic cell-turnover biology, and another reflecting early-life systemic dysregulation vulnerability linked to inflammation, metabolic risk, smoking methylation, and alcohol-related methylation. This two-domain framework may help clarify how blood DNAm profiles capture complementary biological processes relevant to cancer susceptibility and guide future studies of methylation-based cancer risk. Full article

OS is the most common primary malignant bone tumor, predominantly affecting children, adolescents, and young adults. Despite advances in multimodal treatment, patient outcomes have remained largely unchanged over the past decades, particularly in cases of metastatic or recurrent disease. Increasing evidence highlights the pivotal role of the tumor microenvironment (TME) in OS progression, metastasis, immune evasion, and therapeutic resistance. The OS TME comprises a complex and dynamic network of tumor cells, immune cells, cancer-associated fibroblasts, mesenchymal stromal cells, endothelial cells, extracellular matrix components, and soluble factors that collectively regulate tumor behavior. This review summarizes the current understanding of the OS TME, highlighting the interactions between malignant cells and their surrounding microenvironment and their contribution to tumor growth, angiogenesis, invasion, metastatic dissemination, and treatment response. Moreover, here we discuss the strengths and limitations of the most relevant preclinical models currently used to investigate OS biology and evaluate novel therapeutic strategies. Three-dimensional (3D) culture systems, including spheroids, organoids, and biomimetic scaffold-based models, today are considered the models able to best recapitulate the structural, mechanical, and cellular complexity of the native tumor microenvironment than conventional two-dimensional cultures. In addition, patient-derived xenograft (PDX) models are reviewed for their ability to preserve the histopathological, molecular, and genetic characteristics of the original tumors, making them valuable platforms for translational research, biomarker discovery, and personalized medicine. Full article

Colorectal cancer (CRC) exhibits substantial metabolic heterogeneity, but the organization of sphingolipid remodeling remains incompletely understood. In this exploratory single-center study, we integrated patient-matched tissue lipidomics, systemic oxidative stress profiling, and independent transcriptomic analyses. Tumor tissue, adjacent non-neoplastic mucosa, and preoperative serum were collected from 40 patients with CRC, with serum obtained from 23 hospitalized non-cancer controls. Sphingolipids were quantified by UHPLC–MS/MS, while total antioxidant capacity, total oxidant status, and oxidative stress index characterized systemic redox status. Paired lipidomics revealed coordinated remodeling with increased S1P-associated measures, selective ceramide depletion, and elevated S1P-to-ceramide ratios. Multivariate analyses did not identify stable discrete lipidomic subgroups and revealed variation consistent with a continuum-like organization within the measured sphingolipid feature space. In separate principal component analyses, ratio-derived variables showed a more concentrated low-dimensional covariance structure than absolute lipid concentrations. Circulating sphingolipids showed limited correspondence with tumor-local remodeling, whereas oxidative stress markers showed strong apparent discrimination between CRC and hospitalized non-cancer controls, although this finding may be affected by residual confounding. TCGA–GTEx analyses provided complementary pathway-level transcriptomic context, while anatomically resolved analysis of 374 TCGA tumors identified 3376 genes significantly associated with colorectal anatomical position, including six sphingolipid-related genes. Overall, these exploratory findings support a conceptual CRC Metabolic Continuum while requiring validation in larger, independent cohorts. Full article

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal malignancies worldwide, with limited improvements in long-term survival despite significant progress in systemic therapy. This review focuses predominantly on pancreatic ductal adenocarcinoma (PDAC), the most common and best-studied pancreatic malignancy, while referencing other pancreatic neoplasms only where directly relevant to intrapancreatic fat biology. Obesity has emerged as a major modifiable risk factor for PDAC. In addition, increasing attention has focused on ectopic fat depots, particularly intrapancreatic fat, as potential mediators linking metabolic disease to pancreatic carcinogenesis. This narrative review summarizes the classification and epidemiology of PDAC, the relationship between obesity and pancreatic cancer risk, the biology of intrapancreatic fat, as well as putative mechanisms by which intrapancreatic fat may promote pancreatic carcinogenesis. In addition, we will review current diagnostic approaches, therapeutic and preventive considerations, and key unanswered questions for future research on the relevance of intrapancreatic fat deposits. Collectively, available evidence supports intrapancreatic fat as a biologically plausible and potential mediator of pancreatic cancer risk, warranting further prospective investigation. Full article

Hyperbaric oxygen therapy (HBOT) increases tissue oxygen availability through the administration of near-pure oxygen under elevated atmospheric pressure. Although HBOT is clinically established for several hypoxia-related conditions and selected radiation-induced tissue injuries, its role in oncology remains controversial. This review evaluates HBOT as a context-dependent modulator of tumor and normal-tissue biology by integrating evidence on hypoxia-inducible factor signaling, redox homeostasis, tumor metabolism, vascular remodeling, immune regulation, extracellular matrix organization, cancer stemness, and treatment sensitivity. Available preclinical and clinical evidence does not support the historical assumption that HBOT universally accelerates tumor growth, recurrence, or metastasis, but current evidence is also insufficient to support HBOT as a broadly applicable standalone anticancer therapy. The strongest clinical evidence concerns late radiation-induced normal-tissue injury, particularly radiation cystitis, whereas evidence for direct antitumor activity or treatment sensitization remains predominantly preclinical and context-dependent. Selected experimental models suggest that transient reoxygenation may attenuate hypoxia-dependent signaling, alter redox and metabolic adaptation, and enhance sensitivity to radiotherapy or systemic anticancer treatment, while other models demonstrate increased proliferation or vascular responses. Future studies should incorporate standardized HBOT protocols, direct or surrogate measurements of tumor oxygenation, mechanistic biomarkers, patient stratification based on measurable tumor characteristics such as baseline hypoxia, redox phenotype, and microenvironmental features, and precise treatment scheduling. HBOT may ultimately be most relevant as a biomarker- and timing-guided pharmacodynamic reoxygenation strategy in tumors in which a transient reoxygenation window can be therapeutically exploited. Full article

Pancreato-hepatobiliary (HPB) malignancies—pancreatic ductal adenocarcinoma (PDAC), hepatocellular carcinoma (HCC), and the biliary tract cancers (BTC) comprising intrahepatic, perihilar and distal cholangiocarcinoma, gallbladder carcinoma, and ampullary adenocarcinoma—together constitute one of the heaviest and fastest-growing burdens in global oncology. Liver cancer is the third leading cause of cancer death worldwide, and pancreatic cancer, with a mortality-to-incidence ratio approaching unity, is projected to become the second leading cause of cancer death in high-income countries. This narrative review synthesises PubMed-indexed evidence across the full clinical arc of all three disease families, organised around epidemiology and risk; diagnosis, staging and biomarkers; surgical and multimodal management; and the rapidly evolving systemic therapy landscape, with survival and prognosis integrated throughout. Three cross-cutting narratives emerge. First, HPB cancers are united by late presentation, biological aggressiveness, and dependence on a background of organ dysfunction (cirrhosis in HCC, biliary obstruction in BTC and PDAC, and chronic pancreatitis as a major predisposing background in PDAC) that constrains therapy. Second, their trajectories are diverging: HCC has achieved the largest proportional survival gain of any solid tumour, driven by surveillance and immunotherapy in the subset of patients who reach specialist care; BTC has entered a nascent precision-oncology era in which FGFR2, IDH1, HER2, and BRAF alterations are druggable and immune-chemotherapy is first-line standard, although absolute survival gains remain modest and access to comprehensive molecular profiling is uneven; whereas PDAC has improved only incrementally, its immunosuppressive stroma and near-universal KRAS driver remaining formidable barriers. Third, molecular profiling, multidisciplinary care, and surgical centralisation are now non-negotiable structural determinants of outcome. We conclude that HPB oncology has entered a phase of real but unevenly distributed progress: long-term survival remains poor for most patients globally, and translating these advances into population-level gains will require earlier detection, broader access to molecular profiling and novel therapies, and biology-driven innovation. Full article

Liquid biopsy enables minimally invasive detection and longitudinal monitoring of tumor-derived material in blood and urine. In genitourinary cancers, most applications have focused on genomic alterations in circulating tumor DNA (ctDNA), together with circulating tumor cells (CTCs), extracellular vesicles (EVs), and cell-free RNAs. These measurements are clinically informative but are often interpreted as isolated, predominantly descriptive biomarkers and therefore incompletely represent the adaptive processes that determine progression and treatment response. We propose circulating tumor function (CTF) as a systems biology framework for integrating tumor-derived and host-derived genomic, regulatory, metabolic, redox, and immune signals obtained through serial liquid biopsy. CTF is not a single analyte or assay; rather, it is an inference model intended to generate interpretable functional states, including proliferative activity, immune evasion, metastatic potential, metabolic stress, and therapeutic adaptation. We review the contributions and limitations of ctDNA, ncRNA networks, EV-mediated signaling, redox biomarkers, and tumor–host crosstalk in prostate, bladder, renal, and testicular cancers. We also outline the analytical and clinical validation required to determine whether integrated CTF models provide incremental value over established single-analyte approaches. This framework may help reposition liquid biopsy from molecular detection toward functional precision oncology. Full article

Molecular residual disease (MRD) testing approaches with plasma next-generation sequencing (NGS) testing to identify circulating tumor DNA (ctDNA) in resectable-stage non-small cell lung cancer (NSCLC) are evolving. The MRD concept is to better guide perioperative systemic treatment and identify recurrent NSCLC before symptomatic radiographic recurrences. Multiple tumor-informed assays are available with technology driving lower levels of ctDNA detection. However, it remains unclear that individual patients derive survival outcome benefit from MRD testing. NSCLC tumor biology of spatial heterogeneity, early parallel metastases, and recurrence clonal evolution can impact tumor-informed approaches irrespective of specific assay level of ctDNA detection. Clinical decision making guided by tumor-informed MRD testing to date have been limited by recurrence risks of up to 20% when landmark MRD-negative, improved outcomes benefit of adjuvant treatment even when landmark MRD-negative, and lead times with longitudinal MRD-positive conversion of several months or longer before overt radiographic recurrences with no proven strategy of survival benefit with intervening treatment. Cautionary tumor biology and clinical issues remain in the clinical utility of tumor-informed MRD testing in resected NSCLC. These need to be clarified with certainty before MRD testing should step beyond a technology-driven prognostic recurrence risk indicator before becoming an absolute clinical guide to meaningfully impact individual patient management and outcomes. Full article

Liver transplantation (LT) has evolved from a contraindicated procedure for malignancy into an established oncologic therapy for selected primary and secondary hepatic cancers. Advances in tumor biology, molecular profiling, immunotherapy, and peri-transplant management have expanded transplant indications beyond hepatocellular carcinoma (HCC) to include perihilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, colorectal liver metastasis (CRLM), neuroendocrine liver metastasis (NELM), and rare hepatic malignancies. The 2024 TransMet randomized controlled trial, demonstrating a 5-year overall survival (OS) of 73% with LT plus chemotherapy versus 9% with chemotherapy alone for unresectable CRLM, established the first Level 1 evidence supporting transplantation as a curative oncologic intervention in metastatic disease. These advances necessitate a modern framework for clinical trial design and research prioritization in transplant oncology. This manuscript proposes a comprehensive framework for future transplant oncology trials addressing endpoint selection, biomarker-driven patient selection, trial methodology, immunosuppression optimization, surveillance strategies, and ethical organ allocation. OS and transplant benefit are emphasized as the preferred primary endpoints for CRLM and NELM, whereas recurrence-free survival is recognized as retaining distinct clinical and prognostic value in HCC, underscoring that endpoint selection should be disease-specific rather than universally standardized. Emerging biomarkers—including circulating tumor DNA, AFP dynamics, and molecular and functional imaging profiling—are stratified into established, prospectively validated, and investigational categories to clarify their current clinical applicability. Randomized controlled trials, adaptive platform and enrichment designs, biomarker-stratified randomization, registry-based trials, and prospective registries are presented as complementary strategies tailored to disease prevalence and feasibility, alongside explicit consideration of how graft source—particularly the predominance of living donor liver transplantation in Asia versus deceased donor systems elsewhere—shapes trial design and interpretation. The manuscript further examines tumor biology-based immunosuppression, immune checkpoint inhibitor integration, and management of post-transplant recurrence. A precision medicine vision is proposed in which transplant candidacy is determined by biologic behavior and molecular signatures rather than morphology alone, with proposed trial frameworks offering an actionable research agenda for the next decade of transplant oncology. Full article

Epithelial ovarian cancer (EOC) comprises biologically and immunologically distinct histotypes and frequently develops within a chronically inflamed tumor microenvironment, particularly in advanced disease with malignant ascites. This narrative review revisits translational observations from the 1990s–2000s showing impaired lymphomonocyte proliferation, altered Fas/CD25 signaling, and abundant cytokine release in ovarian cancer effusions. These findings are interpreted as direct evidence of dysfunctional immune activation, but not as retrospective proof of T-cell exhaustion according to contemporary molecular, transcriptional, epigenetic, or functional definitions. Modern single-cell and spatial studies provide independent evidence that malignant ascites is a dynamic ecosystem containing heterogeneous T-cell and macrophage states and that immune architecture differs across anatomical compartments and histotypes. Within this framework, cytokine signaling, macrophage plasticity, iron/redox biology, ferroptosis susceptibility, adipocyte–tumor crosstalk, and systemic metabolic dysfunction are considered at different levels of evidentiary strength, with ovarian cancer-specific data distinguished from pan-cancer or preclinical extrapolation. Clinical experience with immune-checkpoint inhibitors further illustrates the distinction between immune-cell presence and effective immunity: single-agent activity has generally been modest, whereas the phase III ENGOT-ov65/KEYNOTE-B96 trial demonstrates that clinically meaningful benefit can emerge in an appropriate therapeutic and biomarker-selected context. We propose that “inflammation without effective immunity” is best viewed as an overarching, histotype- and context-dependent immunometabolic framework rather than a uniform ovarian cancer phenotype. The concept remains hypothesis-generating and requires prospective validation before biomarker or therapeutic implementation. Full article

Ubiquitin-related modifier 1 (URM1) defines a distinctive ubiquitin-like system in which URM1 functions both as a covalent protein modifier and a sulfur carrier required for wobble uridine (U34) thiolation of cytosolic tRNAs. This dual role places URM1 signaling at the intersection of protein post-translational modification and codon-sensitive translational control. Although URM1 remains less well characterized than ubiquitin and other ubiquitin-like modifiers, accumulating evidence links URM1-associated processes to oxidative-stress tolerance, proteostasis, and tumorigenesis. In this review, we summarize the molecular architecture and biochemical regulation of URM1 signaling, distinguish the biological significance of protein URMylation from URM1-dependent tRNA U34 thiolation, and evaluate evidence connecting these pathways to cancer biology. Notably, stress-inducible protein URMylation has been demonstrated in mammalian cells, although endogenous mammalian URM1 substrates and their cancer-relevant functions remain incompletely defined to date. In parallel, URM1-dependent tRNA thiolation has been linked to selective translational programs that support metastatic progression and adaptation to targeted therapy. We further discuss emerging therapeutic opportunities associated with redox and translational dependencies, as well as the potential limitations and challenges of pathway selectivity, biomarker development, and normal-tissue toxicity. Together, these studies position URM1 signaling as a context-dependent stress-adaptive network with emerging relevance to cancer biology and precision oncology. Full article

Replicating the complex physiology of human skin in vitro remains a challenge for cutaneous oncology. Although several three-dimensional (3D) skin and melanoma models have been developed, reproducible skin equivalent systems that enable direct and standardized comparisons between healthy and melanoma-containing skin remain valuable experimental tools. This study aimed to optimize and characterize skin equivalents containing either melanocytes or melanoma cells and to evaluate their utility as platforms for investigating melanoma-associated skin biology and UVB-induced responses in vitro. To achieve this, 3D skin equivalents containing fibroblasts, keratinocytes, and either melanocytes or melanoma cells were reconstructed on a polystyrene scaffold to generate healthy (mc) and melanoma (mm) models. Morphological characteristics were compared with clinically verified human tissue sections, and functional responses to UVB irradiation were assessed with a focus on the kynurenine pathway. The models demonstrated a distinct dermal–epidermal architecture and distinguishable melanoma-associated features, including epidermis-confined melanoma cell clusters, in mm constructs. UVB exposure induced differential responses between models, including significant differences in kynurenine pathway regulation. These findings suggest that the developed skin equivalents provide a reproducible in vitro platform for studying melanoma-associated skin biology and treatment-related metabolic responses and may support future mechanistic studies of skin cancer progression. Full article

Extracellular vesicles (EVs), including exosomes and microvesicles, are nanoscale membrane-enclosed particles that transfer proteins, lipids, mRNAs, and microRNAs between cells. The same communication system is now being developed in two apparently opposing settings: mesenchymal stem/stromal cell (MSC)-derived EVs are explored as cell-free regenerative therapeutics, whereas tumor-derived EVs can promote metastasis, immune evasion, and treatment resistance while also serving as liquid-biopsy biomarkers. Rather than treating these studies separately, this review compares them along shared mechanistic axes: producer-cell identity and state, luminal cargo, membrane and surface composition (including the biomolecular corona), dose and administration route, biodistribution, and recipient-cell context. This cross-field perspective shows that angiogenesis, immunomodulation, matrix remodeling, and tissue tropism are not intrinsically regenerative or oncogenic; their consequences depend on where, how, and to which cells EV signals are delivered. We review EV biology and MISEV2023-aligned nomenclature, examine bidirectional regenerative and cancer-associated functions, and survey engineering strategies for cargo loading and surface modification together with plant-derived exosome-like nanovesicles. We further compare EVs with lipid nanoparticles, adeno-associated viruses, polymers, and virus-like particles, and discuss how engineering can improve potency and targeting while increasing manufacturing and characterization complexity. Finally, we address tumor-related safety considerations for regenerative EVs and the unresolved biological, technical, manufacturing, and regulatory questions that must be addressed for clinical translation. Full article

Microgravity research has emerged as a rapidly evolving field at the intersection of space medicine, genomics, biotechnology, and precision medicine. Exposure to the space environment induces complex physiological and molecular adaptations that affect multiple biological systems, including immune regulation, metabolism, musculoskeletal function, and gene expression. Recent advances in genomics, multi-omics technologies, artificial intelligence, and bioengineering have substantially improved our understanding of biological adaptation to spaceflight and expanded opportunities for translational biomedical research. This review summarizes recent advances in genetic and biomedical research under microgravity conditions, with particular emphasis on molecular mechanisms, omics technologies, genome editing, microbiome research, regenerative medicine, and personalized healthcare approaches. Major experimental platforms, landmark spaceflight studies, and translational applications in infectious diseases, cancer biology, aging, tissue engineering, and pharmaceutical development are discussed. The review also highlights Saudi Arabia’s emerging contributions to genomic medicine and space biosciences through initiatives such as the Saudi Human Genome Program, the Saudi Pangenome Project, the Saudi Space Agency, and the BioGravity Initiative. Recent Saudi participation in human spaceflight and microgravity-associated biomedical research is discussed within the context of Vision 2030 and national investments in biotechnology and precision medicine. Collectively, advances in microgravity research are expected to contribute to the advancement of precision medicine and facilitate the development of innovative diagnostic and therapeutic strategies with significant implications for both human space exploration and terrestrial healthcare. Full article

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer deaths worldwide. Mutations of the RAS and BRAF genes and the location of the primary tumor determine the choice of systemic therapy. Panitumumab—a fully human anti-EGFR monoclonal antibody—is well-established in the treatment of patients with wild-type RAS and BRAF and left-sided tumor localization. The aim of this review is to summarize the role and potential of targeted therapies for colorectal cancer with monoclonal antibodies such as panitumumab or cetuximab, to provide current evidence on the position of panitumumab in the treatment of mCRC, and to discuss biomarkers and qualification strategies for targeted therapy, including the role of ctDNA in disease monitoring and rechallenge. The work is based on a narrative review of literature from the PubMed, Scopus, Web of Science and Google Scholar databases, including publications available until May 2026. The efficacy of panitumumab was confirmed in phase III studies: first-line (PRIME: prolongation of OS by 5.6 months) and second-line treatment. A key condition for eligibility is complete RAS and BRAF genotyping, assessment of MSI/dMMR status, HER2 amplification, and tumor location. ctDNA analysis enables monitoring of tumor clonal evolution and qualification for rechallenge—the CHRONOS study showed 30% objective responses with liquid biopsy-based selection. Associations with BRAF/MEK and KRAS G12C inhibitors and modulation of the immune microenvironment via the CCL5/CCR5 axis remain promising directions. Panitumumab occupies an important position in the treatment of patients with mCRC, but increasingly precise molecular stratification and dynamic monitoring of disease with ctDNA are becoming the basis for the effective and rational use of the drug. Unlike reviews that selectively focus on individual aspects of anti-EGFR therapy, the following work integrates all aspects: from molecular biology and biomarkers used to qualify patients to clinical data on panitumumab and new strategies in the fight against mCRC. Further development of next-generation sequencing methods and standardization of ctDNA panels will be crucial for the widespread deployment of targeted therapies in everyday clinical practice. The role of panitumumab is well established in appropriately selected patients with RAS wild-type, particularly left-sided, metastatic colorectal cancer (mCRC). Combining panitumumab with immune checkpoint inhibitors warrants further investigation, particularly in patients with MSS/pMMR mCRC. The observed activity of panitumumab in combination with nivolumab and ipilimumab provides a rationale for further clinical evaluation and monitoring. Full article