Search Results (1,951)

We present a family case study of Phelan–McDermid syndrome (PMS), a neurodevelopmental disorder caused by haploinsufficiency of the SHANK3 gene, in which two of three siblings were clinically diagnosed with PMS. Sanger sequencing identified a novel heterozygous deletion in exon 20 of SHANK3 (c.3679del, p.Ala1227Profs*168), predicted to introduce a premature stop codon and truncate the protein; this variant was absent in the unaffected sibling. Auditory steady-state responses (ASSRs) were recorded at 16, 27, and 40 Hz. The 40 Hz ASSR was markedly reduced in both affected siblings, reaching statistical significance in the younger child and remaining non-significant in the older sibling, while it was preserved in the unaffected sibling. These findings suggest that the 40 Hz ASSR is particularly sensitive to SHANK3-related cortical inhibitory dysfunction during childhood and adolescence, with reduced sensitivity in early adulthood. The results highlight the potential of the 40 Hz ASSR as an electrophysiological biomarker in PMS and underscore the need for age-stratified normative control datasets to enable robust individual-level interpretation and support its use in biomarker development, clinical trial stratification, and monitoring of treatment response. Full article

Ovarian cancer (OC) is a particularly lethal gynecological malignancy with few treatment options due to its late-stage diagnosis, extensive genetic heterogeneity, and frequent development of resistance to existing therapies. Immunotherapy has revolutionized the management and clinical outcome of numerous solid tumors, but its clinical benefit for OC has been limited, in part due to an extremely immunosuppressive tumor microenvironment (TME) and diverse, overlapping immune evasion mechanisms. In this review, we present a comprehensive and timely synthesis of next-generation immunotherapeutic approaches for ovarian cancer, emphasizing strategies that overcome the immunosuppressive tumor microenvironment and improve clinical responsiveness. We describe the emerging molecular mechanisms of immune evasion in OC, including altered antigen presentation, inhibition of T-cell activation (e.g., via immunological checkpoints, metabolic reprogramming), polarization of tumor-associated macrophages (TAMs), and dysfunction of natural killer (NK) cells. We also critically examine several emerging therapeutic approaches, including combination immune checkpoint blockade (ICB), bispecific T-cell engagers (BiTEs), neoantigen-based vaccines, chimeric antigen receptor (CAR)-T- and CAR-NK-cell therapies, oncolytic viruses (OVs), and nanoparticle-mediated immunomodulation. In addition, we highlight recent advances in tumor microenvironment–targeted therapies for ovarian cancer, focusing on strategies that modulate non-lymphoid components such as cancer-associated fibroblasts (CAFs), hypoxia-driven signaling, and the PI3K/AKT/mTOR axis to enhance antitumor immune responsiveness. Finally, we discuss how predictive biomarkers, multi-omics systems, and patient-derived organoid models are accelerating the development and deployment of precision immunotherapies for OC. We would like to highlight the translational promise of next-generation immunotherapies and identify novel molecular targets that may be leveraged to achieve durable responses in OC. Full article

This review highlights the rapidly evolving role of artificial intelligence (AI) in transforming lung cancer care, with a specific focus on its integrated applications across diagnosis, biomarker discovery, and drug development. The novelty of this work lies in its holistic examination of how AI bridges these traditionally separate domains, from radiology and pathology to genomics and clinical trials, to create a more cohesive and personalized oncology pipeline. We detail how AI algorithms significantly enhance early detection by improving the accuracy and efficiency of pulmonary nodule characterization on computed tomography scans and enable precise cancer subtyping via computational pathology. In biomarker discovery, AI-driven analysis of radiomic features and genomic data facilitates the non-invasive prediction of tumor genotype, PD-L1 expression, and immunotherapy response, moving beyond invasive tissue biopsies. Furthermore, AI is accelerating the drug development lifecycle by identifying novel therapeutic targets and optimizing patient selection for clinical trials. The review also explores AI’s critical role in personalizing treatment regimens, including predicting outcomes for radiotherapy and immunotherapy, thereby tailoring therapy to individual patient profiles. We critically address the challenges of clinical translation, including model interpretability, data standardization, and ethical considerations, which are pivotal for real-world implementation. Finally, we contend that the future of lung cancer management hinges on robust, multi-institutional validation of AI tools and the development of trustworthy, explainable systems. Full article

Immunotherapy has significantly reshaped the management of malignant pleural mesothelioma (MPM), offering new therapeutic opportunities after decades in which platinum–pemetrexed chemotherapy represented the only systemic option. However, clinical benefit remains markedly heterogeneous, with outcomes strongly influenced by histologic subtype, patient characteristics, and real-world treatment conditions. Evidence from monotherapy trials has been inconsistent, whereas combination approaches—particularly nivolumab plus ipilimumab—have demonstrated improved survival compared with chemotherapy, mainly in non-epithelioid tumors. Nevertheless, real-world data consistently show lower efficacy and higher toxicity than registrational studies, especially among elderly and unselected populations. Recent translational work has highlighted the relevance of the tumor microenvironment and recurrent genomic alterations such as BAP1, NF2, and CDKN2A in shaping immune activity and potentially modulating response to immune checkpoint inhibitors. Transcriptomic signatures and circulating biomarkers—including soluble mesothelin-related peptide—have shown prognostic associations but no validated predictive value. Overall, current evidence suggests that sensitivity to immunotherapy in MPM arises from a complex interplay of genomic, immunologic, and clinical factors, and that no biomarker is yet suitable for guiding treatment decisions. Prospective studies integrating molecular and immune profiling will be essential to refine patient selection and advance toward a more rationally personalized use of immunotherapy Full article

Background: Immune checkpoint blockade (ICB) has revolutionized lung adenocarcinoma (LUAD) therapy, yet predictive bio-markers remain suboptimal. We hypothesized that BCL2A1 expression in CD8⁺ T cells may reflect immune endurance and complement PD-L1 in predicting ICB response. Methods: Integrating bulk and single-cell RNA-seq across multiple LUAD cohorts, this study performed differential expression, survival, and pathway analyses in a discovery cohort (n = 60) and validated findings across five independent cohorts (n = 126). Results: Single-cell profiling identified BCL2A1 enrichment in tissue-resident memory and proliferating subsets that appeared preferentially expanded in responders; cell–cell communication analysis revealed that BCL2A1^high CD8⁺ T cells exhibited significantly enhanced outgoing signaling capacity (p = 0.0278), with proliferating subsets serving as intra-CD8⁺ coordination hubs and MIF pathway interactions achieving the highest intensity among all axes examined. BCL2A1 was significantly upregulated in responders (FDR < 0.05) and associated with improved ICB survival (HR = 0.43, p < 0.05), but not in non-ICB settings, suggesting treatment-specific prognostic relevance. A tri-marker model integrating BCL2A1, PD-L1 (CD274), and a 27-gene HOT score demonstrated favorable predictive performance (AUC = 0.826 discovery; macro-AUC = 0.774 validation), outperforming PD-L1 alone (AUC = 0.706) and established signatures including TIDE, IPS, TIS, and IFNG. Cross-platform simulations suggested high reproducibility (ρ = 0.982–0.993). Conclusions: These findings suggest BCL2A1 may serve as a bio-marker of CD8⁺ T-cell survival and enhanced intercellular coordination, and its integration with PD-L1 and immune activation markers may yield a reproducible ICB response predictor, pending clinical validation. Full article

Single-cell transcriptomics has redefined our understanding of cancer by exposing the complexity of tumor ecosystems and their therapeutic vulnerabilities. scRNA-seq studies have identified lineage hierarchies, immune evasion programs, and resistance-associated states across solid and liquid tumors, informing biomarker development and drug discovery. Advanced computational frameworks integrate these data with longitudinal profiling, RNA velocity, and network diffusion to prioritize targets and predict therapeutic response. Emerging multi-omics approaches further expand the scope of precision oncology by linking genetic alterations, protein-level markers, and spatial context to functional states. This narrative review aims to synthesize current applications of single-cell transcriptomics for target discovery, highlight computational frameworks that translate high-dimensional data into actionable insights, and explore how multi-omics integration is shaping future directions. By bridging molecular complexity with target prioritization, these approaches hold promise for translating single-cell insights into clinically actionable biomarkers and therapeutic strategies for personalized cancer treatment and rational drug development. Full article

Cervical cancer is strongly associated with persistent infection by high-risk human papillomavirus (HPV). Recent advances in immunotherapy have redefined the therapeutic landscape of this disease. We aim to review the biological rationale, clinical evidence, and biomarker standardization supporting the use of immune checkpoint inhibitors (ICIs) in cervical cancer. A comprehensive review of recent literature and pivotal phase II–III clinical trials was performed, focusing on the PD-1/PD-L1 and CTLA-4 pathways, mechanisms of immune evasion, and predictive biomarkers. Persistent HPV infection leads to immune dysregulation and PD-L1 upregulation through E6/E7-mediated activation of the PI3K/AKT/mTOR and JAK/STAT pathways. ICIs have demonstrated significant improvements in overall survival, progression-free survival, and objective response rates in advanced and recurrent disease. PD-L1 immunohistochemistry using standardized assays such as 22C3 pharmDx and SP263 remains the key biomarker for treatment selection, while emerging molecular markers (TMB, MSI, HLA-I expression) are under investigation. Immunotherapy represents a major step forward in cervical cancer management, integrating molecular diagnostics and immune modulation into clinical practice. Continued efforts to refine biomarkers, optimize combination strategies, and expand global access will be essential to achieve equitable outcomes and disease elimination goals. Full article

Colorectal cancer (CRC) is one of the leading causes of mortality worldwide, with rising cases in individuals under 50 years old, classified as early-onset CRC (EO-CRC). EO-CRC is characterized by having clinical features related to a worse prognosis and outcome. This underscores the critical need for early detection biomarkers. ncRNAs emerge as potential biomarkers for diagnosis, prognosis, and treatment response in other types of cancers. Sequencing data from the NCBI Bioproject PRJNA787417 were analyzed to identify differentially expressed miRNAs in early- and late-onset colorectal cancer (EO-CRC and LO-CRC). Differential expressions were assessed with a log fold change threshold of 1 and an adjusted p-value of 0.05. Predicted mRNA targets were identified via ENCORI and analyzed for pathway enrichment using the SHINYGO algorithm. RNA-seq analysis identified a 25-ncRNA EO-CRC signature, including hsa-miR-195 (downregulated) and hsa-miR-549a (upregulated), with enrichment analyses suggesting associations with MAPK, PI3K, VEGF, and KRAS pathways commonly linked to angiogenesis, migration, and invasion. This preliminary report highlights a 25-gene deregulated signature in EO-CRC, in which hsa-miR-195 and hsa-miR-549a emerge as biomarkers of clinical relevance, regulating key genes involved in angiogenesis, migration, and invasion. Their dysregulation could contribute to the aggressive clinical features and poor outcomes observed in EO-CRC. Full article

Metastatic urothelial carcinoma (mUC) is a lethal cancer with limited therapeutic options. Advances in genomic and transcriptomic research have deepened the understanding of mUC biology, leading to the identification of clinically relevant molecular alterations that represent potential actionable targets. This has broadened the treatment landscape of the disease to include novel agents, such as antibody–drug conjugates (e.g., enfortumab vedotin) and targeted therapies, including the pan-fibroblast growth factor receptor (FGFR) inhibitor erdafitinib. Genomic alterations in FGFR3 are well-established oncogenic drivers in bladder cancer and represent predictive biomarkers of response to FGFR-targeted therapies. The phase III THOR trial demonstrated the clinical benefit of erdafitinib in previously treated mUC patients harboring FGFR3 alterations and supported its subsequent approval by the European Medicines Agency. In this context, accurate molecular profiling is essential to guide patient selection for FGFR inhibitor therapy. Equally important is the standardization and timely implementation of FGFR3 testing in clinical practice to optimize treatment planning. This review addresses key considerations in FGFR3 testing in mUC and discusses how it can be routinely incorporated into clinical practice. Full article

Background: The FLT3-ITD mutation is associated with a poor prognosis in acute myeloid leukemia (AML), particularly in relapsed or refractory (R/R) cases. Although Gilteritinib has been approved for the treatment of R/R AML with FLT3-ITD mutation, the emergence of resistance in clinical settings remains a major challenge. Homoharringtonine (HHT), a plant-derived alkaloid with antitumor properties, has also been used in AML treatment. However, the combination effects of HHT and gilteritinib have not been investigated. Methods: The cell viability and apoptosis of MV4-11 and MOLM-13 cells in the treatment of HHT, gilteritinib and the combination were assessed by CCK-8 assay and flow cytometry, respectively. Combination index (CI) values were calculated using CompuSyn 1.0. Western blotting was used to investigate the molecule mechanisms of HHT and gilteritinib mediated anti-leukemia effects in time- and dose-dependent experiments. To investigate the role of p53 status in drug responses, MV4-11-p53R248W and MV4-11-p53WT subclones were isolated and MV4-11-p53knockout cells was established through CRISPR/Cas9 system. The cell viability and apoptosis of MV4-11 cells with various p53 status were compared. Moreover, RNA-seq analysis was performed in MV4-11 cells treated with or without HHT. RT-qPCR and Western blotting were conducted to verify the mechanism underlying HHT-induced p53 upregulation. Results: HHT and gilteritinib exerted a significant synergistic effect on cell viability and apoptosis in MV4-11 and MOLM-13 cells, which was markedly diminished in the cells with the p53-R248W muta-tion or without p53. Mechanistically, HHT and gilteritinib both suppressed FLT3 signaling. Interestingly, HHT mediated the upregulation of p53 through HSPA8 downregulation, while gilteritinib downregulated the p53 level. The combination enhanced the p53 expression. Conclusions: Our findings elucidate the mechanism underlying this synergistic interaction and underscore the potential of p53 status as a predictive biomarker for identifying patients most likely to benefit from HHT and gilteritinib combination therapy. Full article

Sub-internal limiting membrane (sub-ILM) hemorrhage is a distinct preretinal bleeding entity in which blood accumulates between the ILM and the retinal nerve fiber layer (RNFL), forming a sharply confined compartment. The ILM’s low permeability and lack of immune cell access create a stagnant microenvironment in which erythrocyte lysis leads to the accumulation of hemoglobin, heme, and iron, promoting the generation of reactive oxygen species. This oxidative burden poses a direct risk to retinal ganglion cells and Müller cell endfeet. Spectral-domain optical coherence tomography (SD-OCT) enables precise identification of sub-ILM blood through its characteristic dome-shaped elevation and hyperreflective contents, distinguishing it from subhyaloid and vitreous hemorrhage. Management options include observation, neodymium-doped yttrium–aluminum–garnet (Nd: YAG) laser membranotomy, pneumatic displacement, and pars plana vitrectomy (PPV). While small, extrafoveal hemorrhages may resolve spontaneously, prolonged blood entrapment is associated with increased retinal toxicity, tractional changes, and proliferative vitreoretinopathy (PVR). Early intervention generally results in faster clearance and improved visual outcomes, particularly for dense or foveal bleeding. Major gaps remain regarding cellular stress responses, biomarkers that predict irreversible damage, and the optimal timing of intervention. Standardized imaging criteria and evidence-based management algorithms are needed to guide individualized treatment. Full article

Background: Lung adenocarcinoma (LUAD) remains a leading cause of cancer-related mortality. The prognostic significance and functional role of sodium overload-induced necrosis (a novel form of regulated cell death driven by disrupted sodium homeostasis, hereafter abbreviated as NECSO) in LUAD are largely unexplored. Methods: A prognostic model was constructed utilizing the NECSO key gene TRPM4 and analyzed through Cox, LASSO, and multivariate Cox regression analyses. LUAD patients were stratified into high- and low-risk groups. The model’s predictive performance was evaluated using time-dependent ROC curves and nomograms. Functional enrichment analysis elucidated underlying biological disparities. The tumor immune microenvironment was characterized using ESTIMATE, ssGSEA, CIBERSORTx, and TIDE algorithms, with results corrected for multiple testing. Drug sensitivity to chemotherapeutic and targeted agents was predicted. The functional role of a key gene, DENND1C, was validated in vitro. Its association with immunotherapy survival outcomes was assessed in a real-world cohort. Results: The NECSO-based prognostic signature demonstrated robust performance in risk stratification across training and independent validation cohorts. Patients in the high-risk group exhibited significantly shorter overall survival. Functional enrichment revealed associations with processes related to plasma membrane integrity, cell death, metabolism, and immune response. Multi-algorithm immunogenomic analyses consistently identified an immunosuppressive microenvironment in high-risk patients. The risk score was predictive of differential sensitivity to therapeutics, including taxanes and EGFR inhibitors. In vitro experiments confirmed DENND1C as a tumor suppressor, inhibiting LUAD cell proliferation, invasion, and migration. Furthermore, high DENND1C expression was associated with improved survival in patients receiving immunotherapy. Conclusions: This study establishes and validates a novel NECSO-based prognostic model for LUAD. DENND1C is identified as a key tumor suppressor and a potential biomarker for immunotherapy, offering insights for personalized treatment strategies in LUAD. Full article

Rheumatoid arthritis (RA) is triggered by dysregulated cytokine networks, but the distributional association of conventional synthetic (csDMARDs) and biologic DMARDs (bDMARDs) with circulating mediators has not been fully described. In this study, we aimed to investigate the treatment-associated modulation of TNF-α, IL-17, IL-13, and soluble CTLA-4 (sCTLA-4) in 64 RA patients (untreated, n = 14; csDMARD, n = 32; bDMARD ± csDMARD, n = 18) and 20 controls. ELISA was used to determine the serum levels, and Kruskal–Wallis tests and false discovery rate correction were used to determine the differences between groups, accompanied by DAS28- and CRP-adjusted quantile regression. Group-level analysis demonstrated that the levels of IL-17 were higher in patients treated with csDMARDs and bDMARDs than in the controls (FDR-adjusted p = 0.0009 and <0.0001, respectively), and the levels of IL-13 were higher in patients treated with bDMARDs than in the controls (p = 0.026). However, quantile regression did not reveal consistent treatment-related associations, suggesting that long-term pathway-specific immune responses and context-dependent regulation may be involved. Smoking independently predicted higher IL-13 at lower quantiles (β = 35.5; p < 0.0001), while TNF-α showed treatment-related increases only at the upper quantile in CRP-adjusted models (β = 323.7; p = 0.049). On the other hand, sCTLA-4 had the largest and most significant treatment-based increase (p < 0.0001), regardless of disease activity, and constant effects across mid-quantiles. Taken together, these findings suggest that sCTLA-4 shows therapy-responsive distributional changes, supporting its potential utility as a biomarker of biological efficacy. In contrast, the observed increases in IL-17 and IL-13 reflect ongoing immune activity and possible environmental influences. Distribution-sensitive biomarker profiling provides a nuanced approach to capturing immune response diversity in RA and may enhance precision in monitoring procedures. Full article

The evolving tumor microenvironment (TME) plays a critical role in breast cancer tumorigenesis, growth, and metastatic potential. This study focuses on two key components of the TME: tumor-associated neutrophils (TANs) and the desmoplastic reaction (DR). We will analyze their multifaceted functions, emphasizing the significant mutual relationships among them, which dramatically affect disease outcomes and the effectiveness of treatments. TANs can either suppress or promote tumors, demonstrating notable functional flexibility in response to signals from their immediate environment. Concurrently, the proliferation of myofibroblasts and the extensive deposition of extracellular matrix (ECM), which characterize the DR, substantially alter the tumor’s physical properties, increasing its stiffness. This increased stiffness significantly obstructs immune system cells from accessing the tumor, ultimately limiting the effectiveness of therapies and contributing to a more clinically aggressive tumor behavior. A comprehensive understanding of the interactions among TANs, the desmoplastic stroma, and other elements of the TME is critical for developing new predictive biomarkers and establishing more effective targeted therapies. Full article

Depression is a heterogeneous neuropsychiatric disorder with variable clinical presentation and response to treatment. This variability has motivated interest in neuroimaging biomarkers capable of disease characterization and therapeutic prediction. Positron emission tomography (PET) enables in vivo assessment of cerebral glucose utilization, neurochemical targets, inflammatory markers, and cerebral blood flow. This narrative review synthesizes PET studies conducted predominantly in adults with major depressive disorder diagnosed using DSM-based criteria, with bipolar disorder included only when imaging was performed during a depressive episode. Studies were identified through a structured, non-systematic literature search of major databases. Depression is consistently associated with regionally specific PET alterations within cortico-limbic and cortico-striatal circuits; studies most frequently report reduced glucose-derived PET measures in prefrontal and anterior cingulate regions at baseline, with treatment responders showing relative increases or redistribution of these measures following interventions. Neurochemical PET studies demonstrate altered receptor, transporter, or enzyme-related binding in serotonergic, dopaminergic, and noradrenergic systems, while neuroinflammatory and perfusion studies reveal regionally increased PET signals in subsets of patients. Overall, PET findings indicate convergent, region-specific and neurochemical alterations associated with depressive episodes and treatment response. Interpretation is constrained by methodological and clinical heterogeneity, underscoring the need for harmonized, longitudinal PET studies. Full article