Molecular Diagnosis & Therapy最新文献

{"title":"Multiplex RT-PCR-Based Sequencing Assay to Detect Kidney Cancer-Specific Splice Variants in Tumor Tissues and Plasma Cell-Free RNAs.","authors":"Kapil K Avasthi, Kendrick H Yim, Youngchul Kim, Paola M Ramos Echevarria, Liz M Darst, Nicholas Abreu, Kelly P Zea, Mitchell T Hayes, Aram Vosoughi, Brandon J Manley, Liang Wang","doi":"10.1007/s40291-026-00865-2","DOIUrl":"10.1007/s40291-026-00865-2","url":null,"abstract":"<p><strong>Background: </strong>Clear cell renal cell carcinoma (ccRCC) lacks sensitive molecular biomarkers for early detection of disease recurrence and monitoring. Recurrent splice variants (SVs) offer promising diagnostic potential for capturing tumor-specific signals in circulating blood. In this study, we report a multiplex reverse transcription-polymerase chain reaction sequencing assay to quantify ccRCC-specific SVs in tumor tissue and plasma samples.</p><p><strong>Methods: </strong>A 56-target reverse transcription-polymerase chain reaction panel was designed to amplify 27 previously identified ccRCC-associated SVs, 24 matched wild-type transcripts, and five housekeeping genes. Endogenous SVs were validated in ccRCC cell lines using nanopore long‑read sequencing. Analytical sensitivity was assessed using synthetic oligos, and translational potential of these SVs was evaluated in 47 prospectively collected matched tumor-plasma pairs from patients undergoing curative surgery. Normalized SV counts were analyzed for tumor-plasma detectability, agreement, bootstrap stability, and depth robustness.</p><p><strong>Results: </strong>Long-read sequencing confirmed multiple SVs and demonstrated cell line-specific isoform patterns. The serial dilution of synthetic oligos demonstrated strong analytical performance, including linear quantification over 4 orders of magnitude (R² > 0.99) and a limit of detection of approximately 100 molecules. Principal component analysis demonstrated distinct global expression patterns between tumor tissue RNA and plasma cell‑free RNA, consistent with differences in sample origin. Several SVs exhibited high tumor-to-plasma concordance, including TTCB-SV, MVK-beta-SV, MVK-alpha-SV, and MCCC-SV, with positive percent agreement that ranged from 0.87 to 0.98. Downsampling analyses showed strong depth stability, with leading SVs retaining most detectability at 0.25× plasma sequencing depth (TTCB-SV = 0.99, MVK-beta-SV = 1.00, MVK-alpha-SV = 0.87, MCCC-SV = 0.93). A composite ranking of agreement, stability, prevalence, and robustness consistently identified a core set of highly reliable circulating SVs suitable for future clinical development.</p><p><strong>Conclusions: </strong>This multiplex reverse transcription-polymerase chain reaction sequencing assay enables sensitive detection of ccRCC-associated SVs from both tumor RNA and plasma cell-free RNA. Its high analytical fidelity, strong tumor-plasma concordance, and depth robustness support advancement of a focused SV panel for non-invasive molecular profiling, with potential applicability to longitudinal monitoring in ccRCC.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"821-832"},"PeriodicalIF":5.8,"publicationDate":"2026-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148399677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative Omics of Eosinophils in Asthma and COPD: Deciphering Molecular Signatures for Targeted Therapy.","authors":"Jun Miyata, Keeya Sunata, Hisashi Sasaki, Shotaro Chubachi, Yoshinori Hasegawa, Yusuke Kawashima, Makoto Arita, Koichi Fukunaga","doi":"10.1007/s40291-026-00877-y","DOIUrl":"https://doi.org/10.1007/s40291-026-00877-y","url":null,"abstract":"<p><p>Eosinophils are central effector and regulatory cells in asthma and eosinophilic respiratory disease, and a clinically relevant subset in a proportion of patients with chronic obstructive pulmonary disease (COPD) and asthma-COPD overlap. While eosinophil counts are established biomarkers to guide corticosteroid and biologic therapy, they do not capture the molecular heterogeneity of eosinophil activation across these conditions. Advances in integrative omics now permit comprehensive profiling of eosinophils at the transcriptomic, proteomic, and lipidomic levels. In this narrative review we summarize eosinophil-focused single-omics and multi-omics studies in asthma and COPD, with an emphasis on severe eosinophilic asthma and eosinophilic COPD. Multi-omics analysis of blood eosinophils in severe asthma has revealed IL-5-dominated pathways that coexist with IL-4 and microbe-responsive programs. In contrast, eosinophils in asthma-COPD overlap and eosinophilic COPD exhibit prominent interferon-γ, tumor necrosis factor-α, and IL-33 signatures. Mechanistic studies further demonstrate that IL-4/IL-13 enhances eosinophil responsiveness to IL-33 and that IL-33 induces extracellular trap formation (ETosis). We discuss how these disease- and context-specific molecular programs may refine biomarker interpretation and inform the rational selection of biologics targeting IL-5/IL-5R, IL-4Rα, TSLP, and IL-33/ST2 in asthma and COPD.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circulating MicroRNAs as Diagnostic and Prognostic Biomarkers for Neuroblastoma: A Systematic Review and Exploratory Re-analysis.","authors":"Kashif Daud, Mubariz Maqsood, Sahill Bajwa, Nicholas Coleman, Matthew J Murray","doi":"10.1007/s40291-026-00873-2","DOIUrl":"https://doi.org/10.1007/s40291-026-00873-2","url":null,"abstract":"<p><p>Neuroblastoma is a leading cause of pediatric cancer deaths. Accurate and early risk stratification is crucial; however, current approaches rely on invasive biopsies. MicroRNAs have shown promise as non-invasive biomarkers. PubMed and EMBASE were systematically searched for studies evaluating circulating microRNAs in patients with neuroblastoma until April 2025. Eligible studies were included in a narrative synthesis. If raw expression data were available, a standardized re-analysis was performed to assess diagnostic and prognostic performance using differential expression, receiver operating characteristic (ROC) curve, and Cox regression analyses. Nine studies comprising 385 patients were included. Narrative synthesis identified four microRNAs consistently associated with high-risk disease: miR-375, miR-124-3p, miR-218-5p, and miR-490-5p. In our re-analysis, the findings were largely driven by a single cohort of 185 patients, with limited contributions from smaller studies, and should therefore be interpreted as exploratory. We identified nine microRNAs that were associated with poor prognosis. MiR-9-3p demonstrated the most promising performance for identifying high-risk disease (sensitivity = 0.95; specificity = 0.89) and the strongest association with poor overall survival (hazard ratio [HR] = 14.80). In multivariable analyses, miR-9-3p remained an independent predictor of poor survival (HR = 5.48) after controlling for MYCN amplification (HR = 2.08), metastatic disease (HR = 1.62), and age ≥ 18 months at diagnosis (HR = 2.30). While miR-9-3p may serve as a promising candidate biomarker for high-risk disease, there are several limitations to this study. Prospective multicenter validation is required before clinical implementation.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148800708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bile Cell-Free DNA as a Tumor-Proximal Source for Molecular Profiling of Biliary Tract Cancer: A Systematic Review and Meta-Analysis.","authors":"Jun-Ha Jang, Gi Yeon Lee, Jung Won Chun, Sang-Jae Park, Seung-Kwon Myung, Sun-Young Kong","doi":"10.1007/s40291-026-00870-5","DOIUrl":"https://doi.org/10.1007/s40291-026-00870-5","url":null,"abstract":"<p><strong>Background: </strong>Molecular profiling is increasingly required for treatment selection in advanced biliary tract cancer, yet tumor tissue is often insufficient and plasma circulating tumor DNA has limited yield. Because bile directly contacts the biliary epithelium and is obtainable during routine biliary interventions, bile cell-free DNA (cfDNA) may provide a tumor-proximal molecular profiling source.</p><p><strong>Objective: </strong>We systematically reviewed and quantitatively synthesized bile cfDNA detection and profiling in biliary tract cancer.</p><p><strong>Methods: </strong>PubMed, EMBASE, and the Cochrane Library were searched from inception to 13 October, 2025 for studies that included at least ten patients with suspected or confirmed biliary tract cancer and extractable bile cfDNA outcomes. Pooled proportions were estimated using random-effects models with Freeman-Tukey double-arcsine transformation. Bile-versus-plasma detection was compared using pooled log risk ratios. Heterogeneity was quantified by I², with a 95% prediction interval for the primary conservative estimate. Risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool.</p><p><strong>Results: </strong>Eight studies including 271 patients with biliary tract cancer were included. After excluding two cohorts with 100% detection, the conservative pooled bile cfDNA molecular detection rate was 59.1% (95% confidence interval [CI] 49.0-68.7; I² = 50.4%) with a 95% prediction interval of 33.3-82.5%. Bile cfDNA showed higher molecular detection than plasma cfDNA in within-study comparisons (risk ratio 1.58, 95% CI 1.19-2.10; I² = 0%), with directionally higher allele fractions in bile. Bile-tissue concordance was 82.7% (95% CI 69.1-93.5; I² = 43.7%). Among patients with non-diagnostic biliary cytology, incremental molecular detection yield was 36.6% (95% CI 26.9-46.9; I² = 0%). Potentially actionable FGFR2 fusions, IDH1 mutations, and ERBB2 alterations were reported across five studies but were summarized descriptively because actionability definitions and reporting units varied.</p><p><strong>Conclusions: </strong>Bile cfDNA showed higher molecular detection than plasma cfDNA and supported molecular profiling when tumor tissue was insufficient, but detection and endpoint heterogeneity limit its use as a stand-alone diagnostic test. Its role is best defined as opportunistic molecular profiling during indicated biliary procedures, pending prospective multicenter validation with standardized protocols.</p><p><strong>Protocol registration: </strong>PROSPERO CRD420251250742 (registered prospectively prior to study conduct).</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148765395","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mapping the Synaptome in Neurodegeneration: Emerging Clinical Applications of SV2A PET Imaging.","authors":"Luca Filippi, Susanna Nuvoli, Angela Spanu, Barbara Palumbo","doi":"10.1007/s40291-026-00871-4","DOIUrl":"https://doi.org/10.1007/s40291-026-00871-4","url":null,"abstract":"<p><p>Synaptic loss is a core pathological feature of neurodegenerative disorders and closely relates to cognitive and functional decline. Positron emission tomography (PET) targeting synaptic vesicle glycoprotein 2A (SV2A) has recently emerged as a promising tool for the indirect assessment of presynaptic alterations in the living human brain. This leading article discusses the evolving clinical landscape of SV2A PET across the neurodegenerative spectrum, emphasizing its translational trajectory and emerging applications. Current evidence spans Alzheimer's disease (AD), other dementias, movement disorders, Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS). The literature is currently dominated by PET with [¹¹C]UCB-J, while [¹⁸F]-labeled tracers, particularly [¹⁸F]SynVesT-1, are expanding clinical feasibility through longer half-life and broader distribution potential. Across disorders, PET consistently detected SV2A reductions that frequently correlated with cognition, disease severity, and complementary biomarkers, including amyloid, tau, glucose metabolism, and dopaminergic imaging. Although the field remains limited by small cohorts, heterogeneous quantification strategies, and incomplete longitudinal validation, SV2A PET is rapidly evolving into a promising translational tool for studying synaptopathies and monitoring disease progression.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cost-Effectiveness of a Host-Response Point-of-Care Assay for Early Sepsis Diagnosis in UK Emergency Departments.","authors":"Erika P Plata-Menchaca, Enrique Hernández-Jiménez, Queralt Caus-Capdevila, Judit Cubedo, Eduard Guerrero, Ignasi Azagra, Joan Vieyra, Francisco Eduardo Dardón-Fierro, Jia Louise, Kate Zhang, Cheryl McDade, Christopher Knight, David Price, Bob Jarman, Ricard Ferrer","doi":"10.1007/s40291-026-00860-7","DOIUrl":"https://doi.org/10.1007/s40291-026-00860-7","url":null,"abstract":"<p><strong>Background: </strong>Early recognition of sepsis in emergency departments (EDs) improves outcomes and reduces healthcare resource use. However, current clinical practice (CCP), largely based on the National Early Warning Score 2 (NEWS2) and clinical judgement, has limited diagnostic sensitivity at presentation. Consequently, some patients with early sepsis are not promptly identified, resulting in delayed treatment, disease progression, and increased use of high-cost care. Rapid point-of-care host-response diagnostics may complement clinical assessment by identifying patients at risk who do not initially meet conventional clinical thresholds.</p><p><strong>Objective: </strong>To estimate the cost-effectiveness of adding a rapid LPS-induced TNF-α release point-of-care assay (TARA) to current clinical practice, compared with procalcitonin (PCT) plus CCP and CCP alone, from the UK National Health Service (NHS) and Personal Social Services perspective, in line with NICE reference case methods.</p><p><strong>Methods: </strong>A decision-analytic model simulated diagnostic classification, timing of sepsis recognition (early, delayed, late), initiation of antibiotic treatment, hospital admission (general ward or intensive care unit [ICU]), discharge, and readmission among adults presenting to UK EDs with suspected sepsis without shock. Model inputs included diagnostic accuracy, clinical outcomes, health-related quality of life, and costs derived from published literature and UK-relevant sources. The base-case time horizon was lifetime, to fully capture the QALY consequences of prevented deaths and long-term sequelae (ESRD, amputation); a 6-month scenario analysis was also conducted. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty.</p><p><strong>Results: </strong>In the deterministic base-case analysis, TARA plus CCP was associated with lower total costs and higher quality-adjusted life-years (QALYs) compared with both comparator strategies. Cost savings were approximately £370 per patient versus PCT plus CCP and £1,822 per patient versus CCP alone, with incremental QALY gains of 0.0834 and 0.0836, respectively. In the probabilistic analysis, mean cost savings were £391 versus PCT plus CCP and £1,835 versus CCP alone. Benefits were driven primarily by reductions in false-negative diagnoses, leading to earlier treatment, lower ICU use, and reduced downstream hospital costs.</p><p><strong>Conclusions: </strong>Integrating a rapid host-response point-of-care assay into ED sepsis pathways in the UK was associated with lower total costs (savings of approximately £370 per patient versus PCT plus CCP and £1,822 per patient versus CCP alone) and marginally higher quality-adjusted life-years (QALY gains of 0.0834 and 0.0836, respectively), driven by reductions in missed diagnoses and downstream use of high-cost care.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148708377","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Non-Invasive Prenatal Testing in Donor-Oocyte Pregnancies: Biological Determinants, Algorithmic Limitations and Clinical Implications.","authors":"Michele Miscia, Irene Pesaresi, Benedetta Dini, Danila Morano, Paolo Ivo Cavoretto, Antonio Farina","doi":"10.1007/s40291-026-00866-1","DOIUrl":"https://doi.org/10.1007/s40291-026-00866-1","url":null,"abstract":"<p><p>Non-invasive prenatal testing (NIPT) based on circulating cell-free DNA (cfDNA) has transformed prenatal screening for common aneuploidies, but its interpretation is less straightforward in pregnancies conceived with donor oocytes. In this setting, fetal chromosomal risk is largely donor-driven, whereas cfDNA interpretability is shaped mainly by the recipient and the placenta. Donor-oocyte pregnancies are enriched for advanced maternal age, obesity, hypertensive and immunologic complications, low-molecular-weight heparin exposure, multiple gestation, vanishing twin, and placental dysfunction - all factors that can destabilize the cfDNA signal. Fetal fraction should therefore be read not only as a technical quality metric but also as a biological marker of placental performance. Analytical platform behavior also matters; counting-based and single-nucleotide polymorphism-based approaches may behave differently in biologically complex samples, particularly for sex chromosome findings and in the setting of maternal confounding. In donor-oocyte pregnancies, a no-call result may be clinically informative rather than neutral. Pre-test counseling, explicit communication with the laboratory, availability of fetal-fraction reporting, and integration with first-trimester ultrasound are essential. Donor-oocyte pregnancy should be regarded as a biologically distinct model for cfDNA screening, one that exposes the limits of generic NIPT algorithms and argues for more tailored interpretation.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148698242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Unfolded Protein Response Pathways in Cancer: Mechanisms, Tumor Biology and Therapeutic Opportunities.","authors":"Mercilena Benjamin, Surender Kumar Sharawat, Anita Chopra","doi":"10.1007/s40291-026-00869-y","DOIUrl":"https://doi.org/10.1007/s40291-026-00869-y","url":null,"abstract":"<p><p>Endoplasmic reticulum (ER) is a multifunctional organelle essential for maintaining proteostasis, lipid and carbohydrate metabolism, and calcium homoestasis. Rapidly dividing cancer cells driven by oncogenes, elevated translational output, increased metabolic demands, and a hostile tissue microenvironment overwhelm the protein-folding machinery of ER, leading to massive accumulation of unfolded proteins within the ER's lumen leading to chronic ER stress. This activates the unfolded protein response (UPR), a conserved signaling network mediated by three principal sensors: protein kinase R-like endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1-alpha (IRE1α), and activating transcription factor 6 (ATF6), which functions to restore proteostasis or induce apoptosis under unresolved ER stress. Accumulating evidence indicates that malignant cells hijack the pro-adaptive function of the UPR pathway not only to thrive but also to promote cancer progression by invasion and metastasis. UPR activation modulates transcriptional and translational programs that contribute to angiogenesis, invasion, metastasis, immune escape, and chemoresistance. In this review, we dissect how cells balance this tightrope between adaptation and cell death in the context of cancer. We also explore how UPR signaling drives angiogenesis, metastasis, immune-evasion, and chemoresistance before finally discussing its therapeutic potential.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":""},"PeriodicalIF":5.8,"publicationDate":"2026-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148686515","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Why are Some Tissues More Vulnerable? Revisiting Tissue Specificity in Hereditary Cancer Syndromes.","authors":"Vanessa N Kozak, Jaqueline C Oliveira, Daniela F Gradia, Carolina Mathias, Enilze M S F Ribeiro","doi":"10.1007/s40291-026-00845-6","DOIUrl":"10.1007/s40291-026-00845-6","url":null,"abstract":"&lt;p&gt;&lt;p&gt;The genomic era revolution has significantly enhanced our understanding of hereditary cancer predisposition syndromes (HCPSs). However, despite the identification of pathogenic variants in cancer predisposition genes such as RB1, TP53, BRCA1, and BRCA2 and mismatch repair genes as the molecular explanations for familial clustering of specific cancer types, the biological basis behind the striking tissue preference for cancer development in these conditions remains unclear. Although the cancer spectra for each HCPS are widely recognized and routinely used to inform clinical strategies, most cancer predisposition genes are ubiquitously expressed and have DNA damage repair functions that would be expected to impact any tissue involved by loss (or gain, for oncogenes) of function. This narrative review aims to provide a comprehensive overview of the literature on the tissue specificity of HCPSs, integrating insights from molecular biology and epigenetics and discussing the evolving landscape of multi-omics. A structured literature search was conducted in PubMed (March 2023-September 2025) using predefined keywords related to tissue specificity and hereditary cancer, with additional screening of reference lists to identify relevant studies. While isolated mechanisms, including higher proliferation rates and organ-specific sequential patterns of mutation acquisition during carcinogenesis, have been proposed, the marked heterogeneity in tumor spectra across syndromes, together with their intrinsic complexity, suggest that no single mechanism is likely to fully explain tissue specificity. In support of this view, recent literature proposes that germline defects interact with the distinct epigenetic landscape of each cell type, which is inherently multifactorial. The epigenetic \"hardwiring\" prior to malignant transformation would include differential expression of genes that interact with the causal gene, and the presence of redundant compensatory pathways in unaffected organs. In parallel, the combined effects of inherited DNA repair defects and tissue-specific endogenous or exogenous genotoxic exposures, including hormone-mediated oxidative stress or ultraviolet radiation, further shape organ vulnerability. Experimental models reinforce the complexity, demonstrating that loss of tumor suppressor function is tolerated in certain cellular contexts but triggers cell death in others, suggesting that differential thresholds for genomic instability-induced apoptosis versus malignant transformation can delineate target tissues. Additionally, emerging evidence implicates microRNAs and regulatory variants in modifying cancer risk and organ tropism within hereditary syndromes. Collectively, the tissue specificity in HCPSs likely reflects the convergence of the germline defect with tissue-specific epigenetic architecture, regulatory networks, and environmental exposures, rather than a single causative mechanism. A better understanding of these factors could ","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"615-628"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147943624","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles in Beta-Thalassemia: Phenotype-Specific Profiles and Potential Clinical Associations.","authors":"Sirichai Srichairatanakool, Siriporn C Chattipakorn, Adisak Tantiworawit, Nipon Chattipakorn, Sirinart Kumfu","doi":"10.1007/s40291-026-00852-7","DOIUrl":"10.1007/s40291-026-00852-7","url":null,"abstract":"<p><p>Βeta-thalassemia is one of the most common genetic disorders worldwide, characterized by ineffective erythropoiesis (IE), which leads to a wide spectrum of heterogeneous disease-related complications. Extracellular vesicles (EVs) have emerged as having important roles in β-thalassemia complications; however, phenotype-specific differences and their relevance to clinical outcomes remain incompletely defined. This review addresses the knowledge gap with regards to the difference in  EV profiles between transfusion-dependent β-thalassemia (TDT) and nontransfusion-dependent β-thalassemia (NTDT), and how these may contribute to distinct disease manifestations. The evidence indicates that EVs derived from platelets, erythrocytes, leukocytes, and endothelial cells are elevated in β-thalassemia, with phenotype-specific patterns. TDT is predominantly characterized by EV profiles associated with transfusion exposure and iron overload, whereas NTDT shows EV alterations linked to IE, chronic hemolysis, and endothelial activation. These processes have been implicated in thrombosis, pulmonary hypertension (PHT), vascular injury, and various organ dysfunctions. These findings are also supported by functional in vitro studies that thalassemic EVs can induce endothelial activation, oxidative stress, and altered cellular proliferation. Moreover, splenectomy emerges as an important modifier of EV profiles, with splenectomized patients consistently demonstrating higher levels of procoagulant EVs, potentially contributing to increased thrombotic risk. However, heterogeneity in study design, transfusion exposure, and therapeutic interventions complicates interpretation. Overall, this review highlights phenotype-specific differences in EVs between TDT and NTDT and summarizes proposed mechanisms linking EVs to clinical complications. For future perspective, well-characterized cohort studies incorporating rigorous EV isolation, quantitative synthesis, and longitudinal design are needed to clarify the clinical utility of EVs in β-thalassemia.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":" ","pages":"651-680"},"PeriodicalIF":5.8,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148007271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}