Search Results (13,257)

The C-terminal binding protein 1 (CTBP1) is a transcriptional corepressor with a major role in nervous system growth and development. There are only 20 published cases with CTBP1 mutations, displaying a phenotype of Hypotonia, Ataxia, Developmental Delay and Tooth enamel defect Syndrome (HADDTS). Histochemical evidence of decreased mitochondrial respiratory chain activity has been previously reported, but comprehensive data on the metabolic phenotype assessed by various cellular respiration parameters are still missing. We present a 10-year-old female with typical HADDTS features, harboring the most reported de novo heterozygous CTBP1 mutation c.991C>T. To elucidate her metabolic phenotype, we quantified mitochondrial respiration in peripheral blood mononuclear cells (PBMCs) utilizing an analyzer for assessing mitochondrial function (Seahorse XFp). Real-time metabolic assays revealed profound mitochondrial dysfunction with significantly attenuated maximal respiration and spare respiratory capacity compared to neurotypical controls. Following mitochondria-targeted nutritional support for one-year measurable bioenergetic improvements and reduced number of respiratory infections were registered. However, neurological recovery and new skill acquisition were not observed. We present a novel case of CTBP1-related neurodevelopmental disorder and demonstrate, for the first time, the application of non-invasive, real-time mitochondrial functional assessment in this setting, providing additional evidence for mitochondrial dysfunction in HADDTS. Full article

Oncogenic driver mutations in non-small cell lung cancer (NSCLC) activate defined signaling pathways that sustain tumor growth and influence the immune landscape. Yet, how coordinated interactions among diverse cell populations within the tumor immune microenvironment (TIME) contribute to this process remains largely unresolved. To address this, we profiled approximately 200,000 single cells from 45 treatment-naïve NSCLC patients representing seven major driver mutations. This analysis uncovered five multicellular modules (CM1–5) with distinct functional properties, each linked to specific malignant regulatory programs. Among them, CM2 and CM5 exhibited pronounced invasive features and were associated with unfavorable clinical outcomes. CM2 was predominantly observed in EGFR- and MET-driven brain metastases and was defined by strong crosstalk between astrocytes and myofibroblasts. Factors such as SPP1, PTN, and PSAP, together with metabolic alterations, contributed to a microenvironment supportive of metastatic colonization in the brain. By contrast, CM5 was enriched in ROS1-, KRAS-, and EGFR-mutant tumors and consisted of diverse myeloid and endothelial subsets characterized by immunosuppressive and pro-angiogenic signaling, including MIF, GALECTIN, and RETN, collectively facilitating immune escape and vascular remodeling. We further constructed and validated a driver mutation-specific prognostic signature (DMSP.sig) model integrating receptor–ligand interactions and core transcription factors, which effectively stratified patient survival. Leveraging this model, we also identified potential therapeutic candidates linked to these prognostic features, highlighting opportunities for clinical intervention. In summary, our study delineates how oncogenic drivers give rise to distinct TIME architectures, providing a framework for prognostic assessment and precision immunotherapy in high-risk NSCLC. Full article

Oral squamous cell carcinoma (OSCC) remains a major cause of cancer-related morbidity and mortality, and reliable biomarkers for early diagnosis and risk stratification are still lacking. Long non-coding RNAs (lncRNAs) and microRNAs (miRNAs) can regulate gene expression through competing endogenous RNA (ceRNA) interactions, but OSCC-specific ceRNA axes with clinical relevance are still poorly defined. We integrated lncRNA, miRNA, and mRNA expression data from six OSCC-related datasets in the Gene Expression Omnibus with in silico interaction predictions to construct an OSCC-focused ceRNA network and examine its association with survival. The resulting network comprised 8 mRNAs, 22 miRNAs, and 12 lncRNAs. Within this network, we identified a previously unrecognized XIST–miRNA–ZNF662 axis that has not been characterized in OSCC. ZNF662 was consistently downregulated in tumors, and higher ZNF662 expression was associated with improved survival in an independent head and neck squamous cell carcinoma cohort. Components of the XIST–miRNA–ZNF662 axis also showed excellent diagnostic performance for distinguishing OSCC from normal samples across (Gene Expression Omnibus) GEO datasets, highlighting a ceRNA module with promising diagnostic and prognostic potential that could be explored further in non-invasive biofluids. Full article

Background: The AptoDetect™-Lung assay is an aptamer-based test designed for risk assessment in patients with pulmonary nodules, but its potential role in predicting lung cancer stage has not been evaluated. We investigated whether the assay could predict advanced-stage disease beyond conventional diagnostic modalities. Methods: This multicenter prospective cohort study enrolled 1672 patients with Lung-RADS 3–4 pulmonary nodules across ten university-affiliated hospitals in South Korea between June 2023 and December 2024. Among them, 934 patients with histologically confirmed lung cancer were retrospectively selected, and 852 patients were included in the final analysis after exclusions. The AptoDetect™-Lung assay was performed before invasive diagnostic procedures. Results: Among the 852 patients, 450 (52.8%) had advanced-stage disease. The AptoDetect™-Lung score was significantly higher in advanced-stage than in early-stage lung cancer (median, 6.2 vs. 2.8, p < 0.001). In a multivariable logistic regression analysis, a high AptoDetect™-Lung score (≥5) was independently associated with advanced disease (odds ratio 1.99, 95% confidence interval 1.35–2.95, p < 0.001). The AptoDetect™-Lung assay showed moderate discrimination of advanced-stage disease (area under the curve [AUC] 0.696) and in non–small cell lung cancer (AUC 0.720), whereas its discriminative ability was limited in small cell lung cancer (AUC 0.561). A combined prediction model incorporating the AptoDetect™-Lung assay, serum CEA, and radiologic findings demonstrated improved discriminative performance (AUC 0.821). Conclusions: The AptoDetect™-Lung assay score was independently associated with advanced-stage lung cancer and could provide clinically useful information for early risk stratification before definitive diagnosis and staging are available. Full article

Background/Objectives: Aging is increasingly recognized as a key determinant of changes in human tissue and cellular function. Women’s age, in particular, has been associated with reduced oocyte quality and negatively correlated with the expression of genes involved in endometrial decidualization and cellular function. The ability of endometrial cells to interact and allow the invasion of the growing embryo is defined as endometrial receptivity. Investigating age-related differences in human endometrial receptivity may expand our understanding of factors contributing to infertility. Methods: Stromal cells were isolated and cultured from endometrial pipelle biopsies (n = 28) obtained from female donors at the proliferative phase of the menstrual cycle. Protein and mRNA expression of the receptivity modulators OPN, CD44, and HOXA10 were analyzed by Western blot and real-time PCR, respectively. Results: Data presented a linear decrease in mRNA expression of OPN and HOXA10 (p = 0.0066, R² = 0. and p = 0.0036, R² = 0.529, respectively) with women’s increasing age, and a similar trend was evident at the protein level (OPN, p < 0,05; HOXA10, p < 0,01). Further analysis of the data included separating the samples into three age groups: 25–35 years, 36–40 years, and 41–46 years. ANOVA revealed a significant decrease in OPN and HOXA10 mRNA expression (p = 0.03158 and p = 0.02578, respectively). CD44 expression did not differ with age. Conclusions: OPN and HOXA10 are negatively correlated with increasing maternal age. These findings suggest that age-related alterations in key endometrial receptivity modulators may contribute to impaired implantation and could represent potential targets for diagnostic or therapeutic strategies in human implantation failure. Full article

Triple-negative breast cancer (TNBC) is one of the most aggressive and clinically challenging subtypes of breast cancer, defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. The lack of actionable molecular targets contributes to limited therapeutic options, frequent recurrence, and a high propensity for distant metastasis. Metastatic dissemination remains the principal cause of mortality in patients with TNBC and is driven by complex molecular mechanisms involving multiple interconnected signaling networks. This review summarizes current knowledge of the molecular mechanisms underlying metastatic progression in TNBC, with particular emphasis on signaling pathways that regulate tumor invasion, migration, and colonization of distant organs. We discuss the roles of key pathways, including PI3K/Akt, TGF-β, Wnt/β-catenin, NF-κB, and Rho/ROCK signaling, in the regulation of epithelial–mesenchymal transition, cytoskeletal remodeling, cancer stem cell phenotypes, and tumor–microenvironment interactions. A deeper understanding of these signaling networks may facilitate the identification of novel therapeutic targets and support the development of more effective strategies to limit metastatic disease in TNBC. Full article

Photodynamic therapy (PDT) is a minimally invasive treatment choice whose clinical success in dermatology relies on the interaction between a photosensitizer, light of an appropriate wavelength, and tissue oxygen, leading to reactive oxygen species generation and selective cytotoxicity. This narrative review summarizes contemporary mechanisms and clinical evidence supporting PDT across neoplastic, inflammatory, infectious, and esthetic indications. A comprehensive literature search included randomized trials when available, systematic reviews, meta-analyses, and guideline and consensus documents, complemented by mechanistic and translational studies relevant to clinical outcomes. In premalignant and neoplastic disease, strongest evidence supports field-directed PDT for actinic keratosis and high efficacy in Bowen’s disease, with favorable cosmetic outcomes and acceptable recurrence patterns. PDT plays a more selective role in basal cell carcinoma, particularly superficial and selected nodular lesions, while its routine use as monotherapy in squamous cell carcinoma remains limited by higher recurrence. Beyond oncology, PDT shows expanding utility in acne via sebomodulatory and immunomodulatory effects, and in infectious dermatoses through broad antimicrobial activity and biofilm disruption with low resistance potential. Cosmetic applications, including photorejuvenation, benefit from protocol tailoring and combination strategies that enhance penetration and remodeling. Overall, PDT is evolving into an adaptable therapeutic framework best positioned within mechanism-oriented, multimodal algorithms. Full article

Tumor-associated macrophages (TAMs) are among the most abundant immune cell populations in breast cancer and have emerged as central regulators of tumor progression, metastatic dissemination, immune evasion, and therapeutic resistance. While TAMs were historically described using a simplified M1/M2 polarization framework, accumulating evidence indicates that TAMs in breast cancer comprise a continuum of phenotypic and functional states shaped by ontogeny (tissue-resident vs monocyte-derived), spatial localization (including hypoxic, perivascular, and invasive niches), tumor-intrinsic programs, and therapy-induced selective pressures. In breast cancer, mechanistic studies integrating lineage tracing, intravital imaging, single-cell and spatial profiling, and clinical analyses have established that TAMs actively coordinate rate-limiting steps of the metastatic cascade. These include promotion of angiogenesis and vascular permeability, orchestration of tumor cell invasion and TMEM-mediated intravasation, facilitation of metastatic seeding and niche formation, and suppression of anti-tumor immunity. TAMs also critically influence therapeutic response by modulating chemotherapy efficacy and limiting the activity of immune checkpoint blockade. Therapeutic strategies targeting TAMs in breast cancer have evolved from depletion approaches (CSF1/CSF1R blockade) to inhibition of monocyte recruitment (CCL2/CCR2 axis), functional reprogramming (CD40 agonism, PI3Kγ inhibition), and macrophage-directed checkpoint modulation (CD47–SIRPα axis). Early clinical studies demonstrate clear pharmacodynamic activity but highlight the need for context-specific and combination-based approaches. This review focuses on TAM biology in breast cancer progression and metastasis, synthesizing key mechanistic and translational evidence and proposing a framework in which spatially and functionally defined macrophage states act as rate-limiting regulators of dissemination and therapy response. We further outline principles for rational TAM-targeting strategies that integrate tumor stage, metastatic niche, and treatment context. Full article

Colorectal cancer (CRC) remains one of the leading causes of cancer-related mortality worldwide, with prognosis critically dependent on the stage at diagnosis. Traditional tissue biopsy presents well-known limitations, including tumor heterogeneity and invasiveness. Liquid biopsy, encompassing the analysis of circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and other cell-free biomarkers, has emerged as a transformative approach for non-invasive tumor profiling. This comprehensive narrative review outlines the recent evidence published on the current state and future perspectives of liquid biopsy in CRC, with a focused emphasis on the role of artificial intelligence (AI), machine learning (ML), and deep learning (DL) in data analysis and clinical translation. Methods: A narrative review of the literature was conducted by searching PubMed/MEDLINE, EMBASE, and ClinicalTrials.gov for articles published between January 2020 and January 2026, using a predefined Boolean search string combining terms related to liquid biopsy biomarkers, colorectal cancer, and artificial intelligence methodologies. Filters were applied to include only English-language human studies. Additional relevant sources were consulted to ensure comprehensive coverage of the available literature. Liquid biopsy platforms, particularly ctDNA sequencing and methylation profiling, demonstrate increasing clinical utility across the CRC care continuum from population screening to post-surgical minimal residual disease (MRD) detection and real-time therapy monitoring. AI-driven analytical frameworks, including Random Forest, Convolutional Neural Networks, LSTM models, and more recently Large Language Models (LLMs), substantially augment the sensitivity and specificity of liquid biopsy interpretation, enabling multimodal data integration. The convergence of liquid biopsy technology and AI-driven analytics represents a paradigm shift toward precision oncology in CRC. Remaining challenges include analytical standardization, model explainability, regulatory harmonization, and equitable access. Future integration of federated learning frameworks and LLM-based clinical decision support tools will be essential for responsible clinical translation. Full article

Backgrounds/Objectives: Non-small cell lung cancer (NSCLC) exhibits substantial prognostic heterogeneity that is not fully captured by conventional anatomical staging, highlighting the need for individualized risk assessment. Radiomics enables non-invasive characterization of tumor phenotype, yet high dimensionality and inter-feature correlations often limit model stability and interpretability. Methods: To address these challenges, we developed a multimodal late-fusion framework integrating radiomic, clinical, and demographic information to predict patient-specific absolute risk in the Lung1 cohort (N = 398). Radomic features (N = 107) were extracted from primary tumor volumes and refined using a Group Lasso–penalized Cox model, preserving biological coherence and producing a parsimonious imaging signature. This signature was combined with clinical and demographic variables using five different late-fusion strategies: weighted averaging, Cox regression, logistic stacking, Random Survival Forests (RSF), and XGBoost. Model performance was evaluated using 5-fold cross-validation based on discrimination, calibration, and risk stratification metrics. Results: Using 5-fold cross validation, the radiomics-only model outperformed conventional clinical staging in patients’ risk prediction (C-index 0.5717 vs. 0.5350) and accuracy, demonstrating the prognostic value of imaging biomarkers. All fusion strategies improved risk prediction performance, with the Cox fusion model slightly better than other fusion methods with C-index of 0.58, time-dependent AUC of 0.60, and the distinct risk stratification with log-rank χ² of 22.85. Conclusions: These findings suggest that multimodal late fusion may provide robust and interpretable risk estimates with potential clinical relevance, supporting personalized risk prediction for informed decision-making in NSCLC. Full article

The membrane fusion process, mediated by the entry fusion complex (EFC) of the monkeypox virus (MPXV), is crucial for host cell invasion. Apolipoprotein B mRNA Editing Catalytic Polypeptide-like 3 (APOBEC3)-driven mutation bias is a key factor in MPXV’s adaptive evolution during its global spread. However, how these mutations affect the structure and function of EFC proteins remains poorly understood. To address this, we performed genomic mutation analysis on globally circulating MPXV clades Ib and IIb, combined with protein monomer, binary, and quaternary complex structure modeling based on AlphaFold 3 and experimental validation by ELISA. We first delineated the mutational spectra of all 11 EFC proteins, revealing that although EFC proteins in clade Ib are highly conserved, lineage IIb B exhibits extensive APOBEC3-driven mutations and the G9 M142I mutation is identified as a lineage-associated APOBEC3-type mutation of lineage IIb B. Structural predictions revealed that while the M142I mutation does not alter G9 monomer folding, it induces a conformational shift in the G9/A16 subcomplex. Furthermore, within the predicted G9/A16/A56/K2 quaternary complex, this mutation enlarges the interfacial gap and reduces docking stability between the G9/A16 subcomplex and A56/K2. Experimental validation demonstrated that the M142I mutation significantly reduces the binding affinity of G9 for A16 and impairs the recruitment of A56/K2 to the quaternary complex, confirming the computationally predicted mechanism of interface destabilization. These findings highlight a dynamic interplay between APOBEC3-driven evolution and EFC protein structure, demonstrating that the M142I mutation alters EFC complex assembly dynamics and may shift the regulatory balance of the membrane fusion system. These structural changes provide molecular insights into MPXV lineage differentiation, though direct functional assays are required to determine the net effect on viral entry efficiency. Full article

Background/Objectives: Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), also known as protein tyrosine phosphatase non-receptor type 6, functions as a tumor suppressor in breast, hepatocellular, and prostate cancers and an oncogene in glioblastoma and cervical cancer. A previous analysis of The Cancer Genome Atlas (TCGA) dataset revealed that lower SHP-1 transcript levels in bladder tumors were associated with poorer overall survival. Methods: This study aimed to evaluate the role of SHP-1 in bladder cancer and to assess the functional impact of its forced expression and knockdown in bladder carcinoma cell lines. SHP-1 expression was assessed in 19 bladder cancer cell lines and 26 bladder tissues. Lentiviral transduction was used to knock down or overexpress SHP-1 in four cell lines, followed by Western blot analysis of SHP-1 and pAkt/Akt protein expression. Results: SHP-1 protein levels were significantly lower in highly invasive cell lines (p < 0.001) and muscle-invasive tumors (p < 0.05). Functional studies demonstrated that SHP-1 modulation influenced the epithelial–mesenchymal transition (EMT) phenotype. SHP-1 expression was positively correlated with E-cadherin expression (p < 0.001) and negatively correlated with N-cadherin (p < 0.01) and Vimentin (p < 0.05) expression. Alteration of SHP-1 expression in bladder cancer cell lines affected proliferation, invasion, and migration (p < 0.05). RNA-seq analysis of the transduced cell lines revealed enrichment of gene sets related to EMT and signaling pathways involving MYC, PI3K, Akt, and mTOR. Furthermore, SHP-1 alteration impacted pAkt/Akt ratios (p < 0.05). Conclusions: Collectively, lower SHP-1 protein expression correlated with more aggressive phenotypes in bladder cancer cell lines and bladder tumors. In our limited dataset, reduced SHP-1 expression correlated with muscle-invasive disease, suggesting a potential link to more advanced tumor biology, consistent with TCGA associating reduced SHP-1 transcript expression to poorer survival rates. Our data provide preliminary functional evidence that SHP-1 may modulate Akt signaling in bladder cancer. Together, these results support further investigation of SHP-1 as a possible tumor suppressor, candidate prognostic biomarker, and potential therapeutic target in bladder cancer. Full article

Background: Cardiolipin (CL) is a phospholipid composed of a glycerol linked with two phosphatidate moieties that constitutes an integral part of the human inner mitochondrial membrane under physiological conditions. It is also vital for bacterial membrane transport and key bacterial functions associated with cell division and infection. CL is released in the cytosol or into the extracellular milieu upon cell death and during inflammation. We therefore tested the ability of CL to activate and expand tumor infiltrating lymphocytes (TIL) from patients with epithelial cancer. Methods: TIL were isolated from gastrointestinal tumor tissues and expanded in vitro in the presence of CL. The role of the NLRP3 inflammasome was evaluated using the specific inhibitor MCC950 and siRNA-mediated silencing of NLRP3. Phenotypic changes and T-cell potency were assessed via CXCL9/10 expression levels. To characterize the immune repertoire, deep TCR sequencing was performed to compare the TCR Vα and Vβ CDR3 regions between TIL and the corresponding tumor tissue. Recognition of autologous tumor cells and tumor-specific mutations, including mutations in KRAS and mitochondrial UQCRFS1 (D145V), was assessed using MHC class I and II restriction assays. Results: CL-expanded TIL exhibited increased CXCL9/10 expression, which is associated with increased potency of tissue invasion. CL-TIL exhibited broader recognition of frequently occurring KRAS mutations, and this effect could be blocked with an inhibitor (MCC950) of the NLRP3 pathway, a multiprotein inflammatory complex associated with danger signaling. TIL exhibited an enriched TCR Vα and Vβ CDR3 repertoire compared to tumor tissue, as defined by deep TCR sequencing. TCR αβ+ TIL recognized autologous tumor tissue in an MHC class I– and class II–restricted fashion, including the mutant HLA-DP–restricted mitochondrial protein associated with the electron respiratory chain complex III (UQCRFS1 D145V) presented by autologous tumor cells. Conclusions: CL activates the NLRP3 inflammasome pathway in TIL from patients with GI cancer and increases CXCL9/CXCL10 expression in TIL, resulting in enhanced recognition of mutant cancer–associated target epitopes, including a mitochondrial protein. CL may provide a danger signal: that facilitates TIL expansion via CL-activated pathways. Full article

Craniofacial and corneal neuropathic pain are disabling conditions characterized by persistent pain that is frequently refractory to conventional pharmacologic and interventional therapies. These disorders arise from complex interactions between peripheral nerve injury, neuroinflammation, and maladaptive central sensitization within trigeminal pathways, features that span neuropathic and nociplastic pain mechanisms as defined by the International Association for the Study of Pain, thus emphasizing the need for mechanism-based, patient-stratified treatment strategies. Regenerative medicine offers a paradigm shift from symptom suppression toward structural nerve repair and functional restoration. This narrative review examines the pathophysiological mechanisms underlying craniofacial and corneal neuropathic pain and critically evaluates emerging regenerative therapies, including autologous biologics (autologous serum tears and platelet-rich plasma), mesenchymal stem cells and their derivatives, exosomes and extracellular vesicles, and neurotrophic peptides. Particular emphasis is placed on corneal neuropathic pain as a translational model, given the cornea’s dense sensory innervation and the ability to non-invasively quantify nerve regeneration using in vivo confocal microscopy as an objective biomarker of treatment response. Clinical evidence across regenerative modalities varies by indication: cenegermin has demonstrated robust efficacy and regulatory approval for neurotrophic keratitis, while platelet-rich plasma shows growing evidence in temporomandibular disorders, myofascial pain, and occipital neuralgia. Cell-based and cell-free therapies demonstrate strong preclinical promise but remain limited by heterogeneous protocols and a paucity of large-scale randomized trials. Key barriers to translation include regulatory uncertainty, lack of standardized outcome measures, and workforce and implementation challenges. Advancing regenerative therapies for craniofacial and corneal neuropathic pain will require rigorous clinical trials, biomarker-driven patient selection, and multidisciplinary collaboration. Sex as a biological variable remains underexplored across all regenerative modalities and represents a priority for future research. Full article

Background/Objectives: Clear-cell renal cell carcinoma (ccRCC) represents the predominant histologic subtype of renal cancer and poses persistent diagnostic challenges, particularly in the evaluation of small renal masses, where conventional imaging and biopsy have relevant limitations. Molecular imaging targeting carbonic anhydrase IX (CAIX) has emerged as a promising non-invasive alternative. This narrative review aims to summarize the biological rationale, diagnostic performance, and potential clinical applications of [⁸⁹Zr]Zr-girentuximab positron emission tomography-computed tomography (girentuximab PET-CT) in ccRCC, as well as to discuss its current limitations and future directions. Methods: A narrative synthesis of published phase 1–3 clinical trials, post hoc analyses, and early clinical series evaluating girentuximab PET-CT was performed, focusing on diagnostic accuracy, clinical impact in localized and metastatic disease, and emerging theranostic applications. Results: The phase 3 ZIRCON trial demonstrated high diagnostic accuracy of girentuximab PET-CT for indeterminate renal masses ≤7 cm, with a sensitivity of 85% and specificity of 87%, as well as performance exceeding 96% for lesions <2 cm. Early studies suggest that this modality may influence clinical decision-making by supporting active surveillance, avoiding biopsy, and refining surgical or ablative strategies, although evidence remains limited by small cohorts and lack of long-term outcome data. Exploratory data indicate improved lesion detection in metastatic ccRCC, but the absence of systematic histopathologic confirmation restricts routine staging use. Conclusions: Girentuximab PET-CT is a highly accurate, CAIX-targeted molecular imaging technique with the potential to transform the diagnostic pathway of ccRCC. While current evidence supports its use in selected localized settings, broader clinical adoption will require prospective validation of its impact on patient outcomes and management strategies. Full article