Search Results (480)

Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer-related mortality worldwide. Although screening has reduced CRC in older adults, cases in younger individuals are rising, highlighting the need for early biomarkers. Emerging research highlights the role of estrogen metabolism in CRC progression, with enzymes such as hydroxysteroid (17-beta) dehydrogenase (HSD17B) being increasingly implicated. In this study, we performed a bioinformatics analysis using publicly available datasets, including The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort and two independent Gene Expression Omnibus (GEO) cohorts (GSE40967 and GSE41258), to investigate the role of HSD17B enzymes in CRC. Our results suggest that HSD17B2 is frequently downregulated in precancerous lesions and early-stage CRC, which may contribute to elevated estradiol levels and a tumor-promoting microenvironment. In advanced stages, higher HSD17B2 expression levels are associated with poorer survival outcomes in retrospective cohorts. Other HSD17B enzymes also exhibit significant expression changes, further complicating the hormonal landscape of CRC. In addition, estrone, traditionally considered a weaker estrogen, emerges as a potential driver of CRC progression. Our in-silico analyses indicate that HSD17B2 and HSD17B11 warrant further investigation as candidate biomarkers for distinguishing CRC from benign and precancerous conditions, with the combination showing strong discriminatory power in Receiver Operating Characteristic (ROC) analyses. Overall, these findings highlight the potential role of estrogen metabolism in CRC and suggest that HSD17B enzymes may hold value as candidate prognostic and diagnostic indicators, though their clinical utility remains hypothetical at this stage. Experimental and clinical validation is strictly required to confirm these in silico observations and to clarify their mechanisms in CRC. Full article

Gastric cancer is one of the malignancies with the highest incidence and mortality worldwide. Helicobacter pylori (H. pylori) infection is the primary driving factor in its development. The progression of gastric mucosal malignancy follows the Correa cascade model: “chronic non-atrophic gastritis → chronic atrophic gastritis (CAG) → intestinal metaplasia (IM) → dysplasia (Dys) → gastric cancer.” Currently, clinical management faces major challenges, including increasing antibiotic resistance in H. pylori, limited pharmacological options for gastric precancerous lesions, and treatment resistance and toxicity in established gastric cancer. This review synthesizes current evidence on BBR, COP, EPI, PAL, and JAT and organizes their reported actions into a three-tier intervention framework. At the first tier, etiologic and inflammatory interception, individual alkaloids suppress H. pylori persistence through direct antibacterial injury, urease inhibition, and modulation of bacterial virulence and antibiotic susceptibility, while attenuating infection-driven inflammatory and immune responses. At the second tier, modulation of precancerous mucosal progression, preclinical studies indicate that these compounds can ameliorate gastric glandular injury and may attenuate biological processes associated with progression toward intestinal metaplasia and dysplasia. At the third tier, antitumor and adjunctive intervention in established gastric cancer, alkaloids inhibit proliferation, induce cell-cycle arrest and apoptosis, suppress invasion and metastasis, and regulate non-coding RNA and epigenetic networks; BBR-centered preclinical studies further suggest potential chemosensitizing and supportive effects. This review integrates the five alkaloids BBR, COP, EPI, PAL, and JAT and systematically elucidates their mechanisms of action across the pathological continuum from H. pylori infection and chronic inflammation to precancerous lesions and ultimately gastric cancer. It establishes a stage-oriented, compound-specific analytical framework to clarify the pharmacological positioning of these compounds, identify priorities requiring further validation, and guide future mechanistic and translational research. Full article

Human papillomavirus (HPV) infection is a necessary but insufficient cause of cervical cancer (CC) and reflects a long-standing host–virus equilibrium shaped by immune control, viral persistence, and latency. The transition from cytology-based screening to primary high-risk HPV testing has substantially improved early detection of cervical precancerous lesions but has also introduced new clinical challenges related to fluctuating test results, overdiagnosis, overtreatment, and patient anxiety, whose magnitude may vary across countries depending on screening organization and access to prevention services. This narrative review provides a clinically oriented overview of HPV-based CC screening in the context of evolving knowledge on HPV natural history, persistence, and immune interaction, and discusses the implications for the interpretation of test results and risk stratification. New emerging screening and triage approaches, including molecular biomarkers, exosome-based biomarkers, and artificial-intelligence-supported risk assessment, are reshaping CC prevention strategies by enabling more precise identification of women at risk for clinically significant disease. These tools may be particularly relevant in self-sampling-based screening pathways, where molecular triage strategies can reduce the need for additional clinician-collected samples and improve management of HPV-positive women. At the same time, improved understanding of viral latency and host-related determinants of progression supports a shift from binary test interpretation toward longitudinal and individualized risk assessment. Integrating biological insight with technological innovation may facilitate personalized screening strategies that maintain high sensitivity while reducing unnecessary interventions. An evolutionary-informed and risk-adapted approach to HPV-related disease management is essential to optimize prevention outcomes and preserve the benefits of population-based screening programs. Full article

Cervical cancer (CC) affects women worldwide, and more than 95% of cases are caused by persistent infection with high-risk human papillomavirus (HR-HPV), such as type 16, which promotes the progression of precancerous lesions to cancer. This study aimed to identify differentially expressed proteins (DEPs) in biopsies from patients with HPV16+ low-grade squamous intraepithelial lesions (LSILs) and from patients with HPV16+ squamous cell carcinoma (SCC) compared with those from HPV-negative normal cervical tissue (NCT HPV−) controls. The samples were analyzed by high-performance liquid chromatography–tandem mass spectrometry (HPLC-MS/MS) using a data-independent acquisition (DIA) approach. Data processing and differential protein expression analysis were performed with the DIA-NN software (Data-Independent Acquisition Neural Networks), followed by bioinformatics analyses, including Venn diagrams, pathway enrichment, functional interactome, The Cancer Genome Atlas (TCGA)-SCC data integration, and Western blot detection. In total, 1607 DEPs associated with cell adhesion and extracellular matrix proteins were identified in LSILs, whereas 1516 DEPs associated with catalytic and transport activities were identified in SCC; the proteins overexpressed in LSILs (332) were enriched in processes such as metabolism, immune response activation, and stress and cell death responses. In contrast, proteins overexpressed in SCC (205) were associated with the cell cycle, DNA damage, drug metabolism, proteasome degradation, methylation, and immune response. Interaction analyses highlighted proteins related to early proteins 1,5,6 and 7 (E1, E5, E6, and E7). In terms of the two DEPs, S100 calcium binding protein A10 (S100A10/p11) and thymidine phosphorylase (TYMP) were detected in patients with LSIL, HSIL, and SCC at the protein level, consistent with their higher transcript levels in public datasets. Given the small, exploratory cohort, these findings are hypothesis-generating, and validation in a larger, balanced, independent cohort is required. In conclusion, this study identified DEPs associated with the progression of premalignant lesions to SCC that may represent candidate biomarkers and therapeutic targets warranting further investigation. Full article

Gynecological malignancies and breast cancer impose substantial health and economic burdens. This review examines how local and systemic microbiota may affect epithelial integrity, inflammation, estrogen metabolism, and immunity. The vaginal ecosystem is the most extensively studied female microbial niche. Cervical cancer serves as the most illustrative clinical example: loss of stable Lactobacillus crispatus dominance and increased prevalence of anaerobic bacteria (anaerobic dysbiosis) are associated with persistent HPV infection, which directly elevates the risk of cervical precancerous lesions. The estrobolome is particularly relevant in endometrial cancer, where intestinal bacterial beta-glucuronidase activity may increase estrogen reabsorption, particularly in obesity and metabolic disease. In ovarian cancer, microbiota is being studied as a possible risk modifier in BRCA1 carriers, but the evidence remains exploratory. In breast cancer, intratumoral bacteria may shape the immune microenvironment, particularly in triple-negative disease. The primary limitation of current research is methodological heterogeneity. Low-biomass samples, such as those from the ovary or endometrium, are highly susceptible to technical contamination. Most studies are cross-sectional and cannot establish causality. Current evidence supports microbiota as a modifier, not a standalone marker or a substitute for standard diagnosis and treatment. Its most plausible near-term role is in multiparameter risk or response models, pending standardized prospective validation. Full article

Intratumor heterogeneity (ITH) of premalignant colorectal lesions is an important area of research for understanding the diverse biological behavior of colorectal cancer (CRC). Accurate assessment of ITH depends substantially on the sampling strategy used. We present a novel methodological approach termed whole tumor heterogeneity topography (WTHT) and compare it with three previously described sampling strategies: whole tumor homogenization, macrodissection of selected tumor regions, and multisampling. A cohort of 184 advanced precancerous colorectal lesions was processed into paraffin blocks, and the entire tumor mass was systematically divided into equally sized samples (~10 mm³). DNA was isolated from each sample separately and analyzed for hotspot mutations in APC, KRAS, BRAF, PIK3CA, and TP53. ITH was quantified using mutation variance and a newly introduced Heterogeneity Grade (HG). Results obtained by WTHT were statistically and graphically compared with three other modeled sampling strategies. Significant differences were observed among the analyzed sampling approaches. Macrodissection showed the greatest deviation from WTHT, indicating substantial sampling bias, whereas multisampling produced the closest results. WTHT enabled precise quantification and spatial mapping of mutational clones across the entire lesion. WTHT combined with HG provides a robust and reproducible framework for comprehensive assessment of ITH in colorectal adenomas. Full article

Intraductal papillary mucinous neoplasm (IPMN) of the pancreas is among the most clinically relevant and conceptually intricate precancerous lesions encountered in modern gastroenterology. First identified in the early 1980s as a “mucin-producing tumor,” IPMN has since undergone a profound redefinition: from an obscure and poorly classified entity to a well-established precursor of pancreatic ductal adenocarcinoma (PDAC), shaped by characteristic molecular alterations such as KRAS, GNAS, and RNF43 mutations. Over the past two decades, the reported incidence of IPMN has risen sharply, a trend largely attributable to the widespread use of high-resolution cross-sectional imaging rather than a genuine increase in disease prevalence. IPMNs are categorized anatomically into main-duct (MD-IPMN), branch-duct (BD-IPMN), and mixed-type forms and histologically into gastric, intestinal, pancreatobiliary, and oncocytic subtypes, each associated with distinct malignant potential and prognostic implications. International consensus guidelines (Sendai 2006; Fukuoka 2012; Fukuoka revision 2017; Kyoto 2024) have progressively refined strategies for risk stratification and surgical decision-making. Nevertheless, significant debate persists regarding optimal surveillance intervals, thresholds for resection, and the management of low-risk branch-duct lesions. This review offers a comprehensive and critically evaluated synthesis about IPMN, spanning its historical recognition, molecular pathogenesis, epidemiology, clinical manifestations, diagnostic evaluation, pathological features, differential diagnosis, surveillance paradigms, long-term complications, associated conditions, therapeutic options, and future directions. Particular attention is given to longstanding “myths” that have influenced clinical practice and to emerging “realities” grounded in contemporary molecular and clinical evidence. Our aim is to provide physicians with a clear and updated framework for navigating the complexities of IPMN management in current practice. Full article

Photodynamic therapy (PDT) is a cornerstone non-invasive modality for keratinocytic precancers and non-melanoma skin cancer (NMSC), leveraging selective photosensitizer accumulation, light activation, and reactive oxygen species (ROS) generation. This narrative review synthesized literature from major databases (2010–2025) to comprehensively evaluate PDT’s molecular mechanisms, innovative optimization protocols, and clinical efficacy across actinic keratosis (AK), field cancerization, Bowen’s disease (BD), basal cell carcinoma (BCC), and invasive squamous cell carcinoma (cSCC). The evidence highlights frontline clinical maturity and excellent cosmetic outcomes for superficial lesions (AK, field cancerization, superficial BCC, and BD), with daylight PDT offering a virtually painless alternative for widespread dysplasia. However, therapeutic reliability decreases in thick nodular, pigmented, or high-risk lesions due to optical barriers and tissue hypoxia. To overcome these limitations, advanced physical and chemical enhancements—such as ablative fractional lasers, iron chelators, epigenetically enhanced PDT (ePDT), and targeted nanocarriers—are actively reshaping drug delivery and cellular susceptibility. Furthermore, cyclic PDT serves as an indispensable tissue-sparing intervention for organ transplant recipients and Gorlin syndrome patients. In conclusion, while PDT is highly effective for superficial neoplasias, precise histopathological stratification and the integration of nanomedicine are critical to overcoming current biological barriers in aggressive dermatological malignancies. Full article

Background/Objectives: Gastric precancerous conditions and early gastric cancer represent a heterogeneous disease spectrum with variable malignant potential and complex management pathways. Despite well-established international guidelines, discrepancies remain between recommended strategies and routine clinical practice, particularly regarding endoscopic diagnosis, risk stratification, therapeutic selection, and follow-up. This review aims to synthesize current evidence and provide practice-oriented, question-based guidance for the management of gastric precancerous lesions and early gastric cancer. Methods: A comprehensive review of the literature was conducted using PubMed and Google Scholar, focusing on endoscopic diagnosis, histological risk assessment, therapeutic options, and surveillance strategies for gastric precancerous lesions and early gastric cancer. Key areas of clinical uncertainty and controversy were identified and translated into focused, practice-oriented clinical questions designed to reflect and possibly help to improve real-world gastroenterological practice. Results: Clinical questions were formulated to cover the entire management pathway, from endoscopic detection and characterization to therapeutic decision-making and post-treatment surveillance. Topics include high-quality endoscopic diagnosis, biopsy strategies, histological staging system, selection between endoscopic and surgical therapy, and follow-up according to individual risk profile. For each question, current evidence is summarized into concise, actionable recommendations. Conclusions: Management of gastric precancerous lesions and early gastric cancer requires a structured and individualized approach, integrating high-quality endoscopy, accurate histological risk stratification, and evidence-based therapeutic and surveillance strategies. Organizing available evidence into practice-oriented clinical questions may help harmonize clinical practice, reduce unwarranted variability, and support gastroenterologists in delivering optimal patient-centered care. Full article

Gastric cancer is a globally prevalent malignancy, with early detection being pivotal for improving patient survival. While endoscopy remains the diagnostic gold standard, it frequently faces challenges such as missed lesions and operator dependency. Artificial intelligence (AI) has emerged as a powerful tool to address these limitations. This narrative review synthesizes recent evidence from PubMed and Web of Science, focusing on four core functional domains of AI-assisted gastric endoscopy: lesion detection and characterization, margin delineation, invasion depth prediction, and blind-spot monitoring. Furthermore, we summarize current limitations, including single-center data biases and algorithmic “black-box” issues, and discuss future directions such as multimodal data integration and real-time video analysis systems. Ultimately, carefully validated AI represents a vital clinical adjunct that holds great potential to significantly enhance diagnostic accuracy and patient outcomes. Full article

Background/Objectives: Heavy metals are environmental hazards that are recognized as neurotoxic agents that may impair olfactory pathways in susceptible individuals. This study aimed to determine the concentrations of cadmium (Cd), arsenic (As), lead (Pb), chromium (Cr), manganese (Mn), nickel (Ni), copper (Cu), zinc (Zn), iron (Fe), and mercury (Hg) in the nasal mucosa and secretions of patients diagnosed with nasal septal deviation, nasal polyposis, or chronic rhinosinusitis, and to investigate their associations with olfactory function, nasal airflow, and pathohistological changes in the nasal mucosa. Methods: This prospective study included 97 adult patients who underwent nasal surgery. We used the Smell Diskettes Olfaction Test to assess olfactory function and rhinomanometry to evaluate nasal airflow resistance. Nasal mucosal tissue samples were collected intraoperatively. Heavy metal concentrations were analyzed using inductively coupled plasma mass spectrometry and atomic absorption spectrometry. Results: Preoperative olfactometry scores in patients with olfactory dysfunction differed to those in patients without olfactory dysfunction (3.4 ± 1.3 vs. 4.1 ± 1.2). Inferential analysis of heavy metals and olfactometry revealed that Cr, Fe, and Pb concentrations were negatively associated with olfactory performance before exposure (Cr: β = −0.12, p = 0.018; Fe: β = −0.08, p = 0.009; Pb: β = −0.10, p = 0.048). Rhinomanometry parameters showed positive associations with olfactory function, independently of age, sex, and groups of patients with or without olfactory dysfunction (R1: β = 0.45, p < 0.001; R2: β = 0.30, p = 0.003). Stepwise regression identified Fe, Pb, and Cr as the strongest predictors of olfactory dysfunction. The adverse effects of Fe and Pb exposure were significantly amplified with age. MANOVA revealed significant differences in heavy metal concentrations across pathohistological categories (Wilks’ Lambda = 0.038, p < 0.001). Carcinoma tissue exhibited significantly higher Cr concentrations, whereas precancerous lesions exhibited increased Cd concentrations. Conclusions: Cr, Fe, and Pb accumulation in nasal mucosa secretion is significantly associated with impaired olfactory function and pathohistological changes. Prolonged exposure to environmental heavy metals may affect olfactory function in the elderly population. Full article

Background: Chronic atrophic gastritis (CAG) is a prevalent precancerous gastric disorder characterized by persistent inflammation, glandular atrophy, and progressive mucosal damage, for which effective multi-target therapeutic strategies remain insufficient. The Lian-Huo-Hua-Zhuo formula (LHHZ), a traditional Chinese herbal prescription, has demonstrated potential anti-inflammatory and gastrointestinal protective effects in clinical practice; however, its active constituents and mechanisms of action against CAG remain undefined. This study aimed to clarify the absorbed bioactive components of LHHZ and explore its therapeutic mechanism for CAG. Methods: Ultra-high-performance liquid chromatography coupled with quadrupole Orbitrap high-resolution mass spectrometry was employed to identify the absorbed components of LHHZ in the gastric and intestinal tissues of mice. The therapeutic effects of LHHZ on CAG were assessed through histopathological staining, ultrastructural observation, and evaluation of serum and gastric functional indicators. Network pharmacology, molecular docking, and molecular dynamics simulations were integrated to predict the core targets and key signaling pathways, while the regulatory effects on the interleukin-17 (IL-17) signaling pathway were further validated by immunofluorescence staining, real-time quantitative polymerase chain reaction, and Western blotting. Additionally, 16S ribosomal RNA gene sequencing and targeted metabolomics were applied to investigate the effects of LHHZ on gut microbiota composition and short-chain fatty acid (SCFA) metabolism. Results: The results revealed that 55 and 48 absorbed components were identified in the gastric and intestinal tissues, respectively, predominantly derived from Coptis chinensis Franch. and Pogostemon cablin (Blanco) Benth. LHHZ significantly alleviated gastric mucosal lesions, reduced intestinal metaplasia, restored the ultrastructure of gastric mucosal cells, improved gastric functional indicators including pepsinogen I (PG I), pepsinogen II (PG II), and gastrin-17 (GAS-17), and decreased the levels of pro-inflammatory cytokines. Network pharmacology combined with in vitro and in vivo experiments demonstrated that the core bioactive components of LHHZ can target and regulate interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α), attenuate activation of the IL-17 signaling pathway, and suppress the secretion of downstream pro-inflammatory factors. Furthermore, LHHZ enhanced the alpha diversity of gut microbiota, reduced the Firmicutes to Bacteroidetes (F/B) ratio, restored the abundance of SCFA-producing bacteria such as Bacteroidales and Oscillospirales, and normalized the aberrant levels of eight SCFAs. Significant correlations were also observed between gut microbiota composition and SCFA metabolism. Conclusions: These findings suggest that LHHZ alleviates CAG by inhibiting inflammation via the IL-17 signaling pathway and by modulating the gut microbiota–SCFA axis, thereby providing preclinical evidence supporting its further investigation and development for multi-target therapeutic strategies against CAG. Full article

Chronic atrophic gastritis (CAG) is a pivotal precancerous condition in gastric carcinogenesis, with progression typically following the classic Correa cascade. Although Helicobacter pylori (H. pylori) infection is widely recognized as the principal etiological factor, the persistence of gastric cancer (GC) risk in a subset of patients after successful eradication suggests that gastric microbiota dysbiosis may also contribute to CAG progression. In recent years, high-throughput sequencing technologies have revealed distinct microbial restructuring in patients with CAG, characterized by decreased microbial diversity, depletion of commensal taxa, and enrichment of opportunistic pathogens. These compositional changes are accompanied by metabolic dysfunction, activation of inflammatory signaling pathways, and disruption of immune homeostasis, which may contribute to a microenvironment permissive for precancerous transformation of the gastric mucosa. Probiotics and related microbiome-based therapeutics, including prebiotics, synbiotics, and postbiotics, have emerged as promising adjunctive strategies for H. pylori eradication and disease management. Their beneficial effects are mediated through multiple mechanisms, including remodeling of the microbial community, inhibition of pathogen colonization, modulation of host immune responses, and restoration of mucosal barrier integrity. However, whether these interventions can reverse established atrophic or metaplastic lesions remains unclear. In addition, how strain specificity, dose dependency, and interindividual heterogeneity influence clinical efficacy has yet to be fully elucidated. In this review, we summarize the compositional and functional features of gastric microbiota dysbiosis in patients with CAG, as well as the mechanisms and clinical applications of microbiome-based interventions. We further highlight current limitations in the field and discuss future directions for precision microecological therapies integrating multi-omics approaches, engineered probiotics, and artificial intelligence. These advances may provide a theoretical framework and practical guidance for the diagnosis and management of CAG and the prevention of GC. Full article

Oral squamous cell carcinoma (OSCC) frequently develops within chronically injured oral mucosa and may be preceded by clinically recognizable oral potentially malignant disorders (OPMDs), which provide an important window for cancer interception. This review examines how etiological exposures, persistent inflammation, and lesion-specific epithelial–stromal–immune interactions cooperate during the transition from mucosal injury to dysplasia, carcinoma in situ, and invasive OSCC. Major carcinogenic exposures, including tobacco, alcohol, and areca nut, are considered together with context-dependent contributors such as microbial dysbiosis, viral infection, and immune-mediated epithelial injury. At the molecular level, inflammation-driven oral carcinogenesis involves cytokine and chemokine amplification, oxidative and nitrosative stress, NF-κB and STAT3 activation, the COX-2/PGE₂ axis, genomic instability, field cancerization, epithelial–stromal crosstalk, angiogenesis, immune dysregulation, and epigenetic and non-coding RNA-mediated reprogramming. Emerging tools such as molecular risk assessment, liquid biopsy, optical imaging, spatially resolved profiling, and artificial intelligence-assisted models may improve identification of high-risk lesions, although most biomarkers require further prospective validation. Prevention should therefore integrate exposure control, biopsy-based diagnosis, local treatment when indicated, long-term surveillance, and trial-based precision strategies according to lesion risk, intervention window, and safety profile. This review supports a shift from lesion-centered management toward risk-adapted precision prevention in inflammation-driven oral carcinogenesis. Full article

Background: Modifiable lifestyle factors may contribute additively to colorectal cancer (CRC) risk in individuals who already have non-modifiable risk factors, such as prior colorectal neoplasia or significant family history of CRC. However, the impact of multicomponent lifestyle interventions (such as dietary modification, physical activity, and counselling) on behavioural modification, risk of colorectal neoplasia, and quality of life (QoL) in this population has not yet been systematically reviewed. Aims: The primary aim was behavioural change (change in body weight, diet, physical activity, sedentary lifestyle, smoking, and alcohol consumption). The secondary aim was colorectal neoplasia outcomes, including the incidence of precancerous lesions and/or cancer and CRC mortality/survival, and QoL, including specific domains. Methods: This review was conducted following the Cochrane guidelines for Systematic Reviews of Interventions. Both randomised and non-randomised studies assessing the effect of multicomponent lifestyle interventions on behavioural modification, risk of colorectal neoplasia, mortality, and quality of life in people at above-average risk of CRC were included. Medline/Ovid, Cochrane Library, Web of Science, and Scopus were searched. Screening, data extraction, and risk of bias assessment were independently performed by two reviewers using the revised Cochrane Risk of Bias (RoB) tools. Results: Of the 4174 studies screened, 10 interventional studies were eligible for inclusion, which had outcomes for behavioural change or quality of life. No interventions assessed neoplasia risk or mortality outcomes. Multicomponent lifestyle interventions mainly targeting diet and physical activity, delivered via a telephone-based or health coaching approach, showed positive effects on healthy behaviours and quality of life compared with usual care, although some studies reported inconsistent results. Conclusions: There is emerging evidence that multicomponent lifestyle interventions may offer beneficial effects on practicing healthy behaviours and improving QoL for individuals at above-average risk for CRC and undergoing colonoscopy surveillance. Full article