Down syndrome (DS), or trisomy 21 (T21), represents the most common genetic cause of intellectual disability worldwide and is associated with a wide range of medical, developmental, and neurodegenerative conditions, including a universal predisposition to early-onset Alzheimer's disease (AD). Since its establishment in 2014, the Trisomy 21 Research Society (T21RS) has provided a global forum for advancing DS research across disciplines and promoting translational efforts to improve health and quality of life. Every two years, T21RS hosts an international scientific meeting that brings together researchers, clinicians, self-advocates, families, and industry stakeholders. In 2024, the 5th T21RS International Conference was held in Rome, Italy, from June 5 to 8, under the theme "Promoting Research Excellence in Down Syndrome." The meeting brought together about 500 scientists from 26 countries across five continents, and more than 900 attendees overall, including families and caregivers. The scientific program featured 5 keynote lectures, 2 satellite meetings, 17 symposia, 7 nano symposia, 2 workshops, and 1 industry-focused session, totaling more than 150 oral presentations. More than 230 abstracts were presented as posters. The conference covered research across the lifespan of individuals with DS, spanning genomic and epigenetic regulation, molecular and cellular mechanisms, preclinical and experimental models, cognition and behavior, neurodevelopment, aging and neurodegeneration, co-occurring medical conditions, and therapeutic interventions. Dedicated sessions focused on capacity-building in DS research and societal engagement were established. Significantly, T21RS promoted inclusivity by supporting 60 young investigator fellowships, providing childcare awards, and organizing a two-day program for families and caregivers in collaboration with Italian DS associations. This proceeding summarizes the main scientific highlights of the 5th T21RS International Conference, reflecting the latest advances in DS biology, clinical research, biomarker development, and therapeutic innovation.
A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach was best clinical practice. This comprised seven histological patterns that had corresponding idiopathic multidisciplinary diagnoses. This classification was updated in 2013, with the addition of an eighth histological pattern. Since 2013, there have been further advances in our understanding of interstitial pneumonias, in particular relating to idiopathic versus secondary disease, advances in molecular pathology and recognition of progressive pulmonary fibrosis (PPF), which have led to a further update in 2025. This review highlights the changes relevant to pathologists reporting interstitial pneumonias. Major changes include (1) expansion beyond idiopathic interstitial pneumonias to also include secondary causes, (2) subclassification as interstitial (fibrotic vs non-fibrotic) and alveolar filling disorders, (3) expansion to include additional patterns (e.g. bronchiolocentric interstitial pneumonia), (4) improved terminology that better reflects histogenesis and (5) consideration of diagnostic confidence in biopsy evaluation. Pathologists also need to be aware of the advantages and limitations of cryobiopsy interpretation and the importance of reporting features that point towards a secondary cause rather than idiopathic disease. The 2025 classification provides a framework for a methodological approach to reporting biopsies in patients with interstitial pneumonia, which should be used prospectively for both diagnosis and research.
The accumulation of pathogenic tau protein is linked to cognitive decline and neuronal loss in Alzheimer's disease (AD), with tau oligomers identified as particularly neurotoxic. The 51 kDa FK506-binding protein (FKBP51) stabilizes these toxic tau oligomers and has been identified as a risk factor for several neurodegenerative diseases. FKBP51 levels increase with age and are especially high in AD brains, suggesting its involvement in disease progression. The development of the selective FKBP51 inhibitor, SAFit2, which can cross the blood-brain barrier, has shown promise in reducing stress hormones, improving stress responses, and mitigating protein-related pathologies in other neurodegenerative models. However, the effects of SAFit2 on tauopathies, such as those seen in AD, have not yet been investigated. Here, the effects of the FKBP51-selective inhibitor, SAFit2, were evaluated in PS19 tau transgenic mice. Mice received a 28-day regimen of SAFit2, followed by comprehensive behavioral, neuropathological, and proteomic analyses. SAFit2 demonstrated effective brain penetrance, with sex-dependent pharmacokinetics. Treatment slowed cognitive decline and depressive-like behavior, with pronounced benefits in male PS19 mice, including improved spatial memory and reduced tau oligomer burden. In females, SAFit2 promoted clearance of AT8-positive tau multimers with some benefit to recognition memory. Proteomic profiling revealed distinct molecular signatures underlying these sex-specific responses: males exhibited upregulation of RNA processing and ribosomal proteins, while females showed restoration of calcium signaling and synaptic drivers. Notably, behavioral recovery occurred independently of widespread neuroinflammation reversal. These findings provide the first in vivo evidence that FKBP51 inhibition by SAFit2 induces sex-specific remodeling of the brain proteome. This study also provides further evidence for the therapeutic benefits of targeting FKBP51 for tauopathies.
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Optimal pre-analytical management of breast tissue specimens, particularly formalin fixation, is essential for accurate immunohistochemical (IHC) biomarker assessment in invasive breast cancer. Although international guidelines suggest using 4% neutral buffered formalin with controlled fixation time, many laboratories in low-resource settings deviate from these standards. This study aimed to determine whether three pre-analytical variables - fixation duration, cold ischemia time, and fixative preparation (4% neutral buffered versus 4% non-buffered formaldehyde) - impact the preservation and evaluation of tissue biomarkers in invasive breast cancer. We conducted an exploratory, proof-of-concept, experimental study using fresh mastectomy tissue from a 34-year-old patient with invasive ductal carcinoma (pT4, hormone receptor-positive, HER2-negative, Ki67 = 40%) who had not received neoadjuvant chemotherapy. Fifty microsamples (5-15 mm in length, approximately 1 mm in diameter) were obtained using a 14-gauge core needle biopsy device and divided into four cohorts: (1) 19 samples fixed in 4% neutral buffered formaldehyde for 0.5 to 144 hours; (2) 19 samples fixed in 4% non-buffered formaldehyde for 0.5 to 144 hours; (3) 6 samples with delayed fixation (0.5 to 8 hours) then fixed in neutral buffered formaldehyde for 10 hours; (4) 6 samples with delayed fixation (0.5 to 8 hours) then fixed in non-buffered formaldehyde for 10 hours. Hormone receptors (estrogen receptor-ER, progesterone receptor-PR) and Ki67 expression were evaluated by IHC using the Allred scoring system and current international recommendations. Fixative preparation had a statistically significant, yet small, impact on biomarker evaluation. The mean percentage of ER-positive cells was 96.89 ± 0.74% with neutral buffered formaldehyde compared to 94.32 ± 1.51% with non-buffered formaldehyde (p = 0.011). Similar trends were seen for PR (94.89 ± 0.95% vs. 92.63 ± 1.67%, p = 0.027) and staining intensity. However, Allred scores remained unchanged. Fixation duration was significantly correlated with biomarker expression (Spearman ρ between -0.60 and -0.83, p ≤ 0.007), with stable values from 0.5 to 48 h and a significant decline beyond 72 h (one-way ANOVA across fixation windows: all p < 0.01). Cold ischemia time was strongly correlated with decreased biomarker expression regardless of fixative preparation. Hormone receptor expression and Ki67 remained stable with minimal Allred score changes for up to 2 hours of cold ischemia, but significantly decreased after 2 hours, with scores decreasing in proportion to the duration of ischemia (p < 0.05). In this single-specimen controlled experiment, non-buffered formaldehyde preserved tissue biomarkers with small but measurable differences relative to neutral buffered formaldehyde for IHC analysis, although these findings require validation in multi-patient studies. Consistent with current guidelines, a cold ischemia time of up to 1 hour maintained adequate biomarker preservation. These preliminary results may be relevant for pathology laboratories in resource-limited settings where neutral buffered formalin may not be easily accessible, and warrant further investigation across diverse tumor types and baseline expression levels, particularly tumors with ER-low-positive (1-10%) or heterogeneous expression.
To better characterize the genetic architecture underlying Alzheimer's disease (AD) and related dementias (ADRD), we performed a meta-analysis of European-ancestry genome-wide association studies in 128,681 cases or proxy cases of ADRD and 849,833 (proxy) controls. We identified 91 genetic loci associated with ADRD risk, of which 16 are new and 56 are specifically detected in clinically diagnosed AD cases. We also provide a list of 18 loci (15 new) requiring further external validation. A polygenic score combining the effects of ADRD loci other than APOE was primarily associated with AD rather than non-AD pathology. Individuals in the tenth decile of the score exhibited a twofold increased risk of presenting with Braak neurofibrillary tangles stage of >4 and moderate-to-severe neuritic amyloid plaque pathology at death compared to individuals in the median score group. In conclusion, our study validated a large number of loci associated with the risk of clinically diagnosed AD, while further investigations are required to confirm the impact of the other loci on AD clinical diagnosis and of each locus on AD pathology.
To evaluate whether an age < 55 years is independently associated with early urinary continence recovery after robot-assisted radical prostatectomy (RARP) in a large multi-institutional Japanese cohort. The cohort comprised 5349 patients aged < 75 years with clinically localized prostate cancer (cT1-2N0M0) who underwent RARP at Japanese tertiary care centers from August 2011 to April 2023. The primary analysis consisted of a 1:1 propensity score-matched comparison between men aged < 55 and 55-74 years. Covariates used for matching included American Society of Anesthesiologists physical status, clinical T stage, biopsy International Society of Urological Pathology grade group, prostate-specific antigen, prostate volume, nerve-sparing status, pelvic lymph node dissection, and surgical approach. Early urinary continence, biochemical recurrence-free survival, and surgical outcomes were evaluated using logistic regression and Cox proportional hazards models in the matched cohort. After propensity score matching, 158 well-balanced matched pairs were generated. A younger age (< 55 years) was significantly associated with higher odds of early continence at 1 month (odds ratio: 1.66, 95% confidence interval [CI]: 1.04-2.65) and 3 months (odds ratio: 2.22, 95% CI: 1.32-3.73). Five-year biochemical recurrence-free survival was similar between men aged < 55 and 55-74 years (86.2% vs. 84.8%). In an exploratory three-group analysis, continence recovery showed a graded age-related pattern. In this large Japanese cohort, an age < 55 years was independently associated with early urinary continence recovery after RARP without compromising oncological outcomes. These findings provide age-specific evidence to support preoperative counseling and surgical decision-making in younger patients.
This study compared the prevalence of atopic dermatitis (AD) in pediatric patients with autism spectrum disorder (ASD) versus controls and explored approaches to AD management in children with ASD. We conducted a cross-sectional analysis of the International Business Machines Explorys electronic medical records database in the United States from January 1, 2017, to December 31, 2019. The primary outcome was International Classification of Diseases-10 diagnosis of AD with asthma or allergic rhinitis, a validated algorithm for identifying true AD cases. Logistic regression compared crude prevalence and assessed associations independent of potential confounders. AD prevalence was 5.0% among patients with ASD and 3.6% among controls (crude odds ratio (OR), 1.41; 95% CI, 1.23-1.61). After adjustment for demographics and healthcare visit frequency, the OR attenuated to 1.15 (95% CI, 1.01-1.32; P = .04) and further adjustment for attention-deficit/hyperactivity disorder yielded an OR of 1.09 (95% CI, 0.95-1.25; P = .24). Visual aids and storyboards may support AD management in children with ASD. These findings highlight a modest increase in AD prevalence in this population and underscore the need for tailored strategies to improve dermatologic care in children with ASD.
Autosomal recessive cerebellar ataxias (ARCA) are clinically and genetically heterogeneous, often presenting as sporadic cases that pose a significant diagnostic challenge. The aim was to characterize the clinical and mutational landscape of ARCA in the largest Chinese cohort using whole-genome sequencing (WGS). We performed WGS on a cohort of 187 patients with suspected hereditary ataxia. Clinical severity was assessed using the Scale for the Assessment and Rating of Ataxia and the International Cooperative Ataxia Rating Scale. Pathogenicity was determined according to American College of Medical Genetics and Genomics guidelines, and variants were validated via Sanger sequencing and co-segregation analysis. We identified 109 variants across 56 genes, with a rate of 79.8% (87/109) being novel. Definitive molecular diagnoses were achieved in 21 cases across 11 distinct subtypes. SYNE1 and SETX were the most frequent genetic contributors, with SETX truncating mutations (c.22_23insTA) associated with higher clinical burden. Multisystemic features were identified, including conjunctival telangiectasia in ATM, progressive action myoclonus in SCARB2, and spastic paraplegia in CAPN1. In this study with, to date the largest Chinese cohort of ARCA, 87 novel variants were classified, which significantly expanded the genomic and phenotype landscape of ARCA in the Chinese population. © 2026 International Parkinson and Movement Disorder Society.
Type 2B von Willebrand disease (VWD) is a rare qualitative variant, accounting for approximately 5% of all VWD cases. It is characterized by increased affinity of abnormal von Willebrand factor (VWF) for the platelet glycoprotein Ibα receptor, resulting in enhanced clearance of both high-molecular-weight VWF multimers and platelets from circulation. The management of women with type 2B VWD during pregnancy and the postpartum period poses unique challenges due to complex hemostatic abnormalities, a high risk of bleeding complications, and a lack of evidence-based guidelines. A recent systematic review, international registry analysis, and global physician survey highlighted several unmet clinical needs in this population, including gaps in early diagnosis, prenatal counseling, pregnancy monitoring, and peripartum management. In response, the ISTH Scientific Subcommittees (SSCs) on von Willebrand Factor and on Women's Health Issues in Thrombosis and Haemostasis collaborated to develop consensus-based guidance for the management of type 2B VWD in pregnancy and postpartum. Using the Real-Time Delphi methodology, 14 international experts reviewed 26 initial statements on diagnosis, monitoring, and treatment. After two rounds of anonymous voting and revisions based on participants' feedback, consensus was achieved on 25 statements. These consensus statements, grounded in the best available evidence and expert opinion, aim to standardize care, guide management, and improve clinical outcomes for women with type 2B VWD during pregnancy and postpartum.
To systematically evaluate radiomic features extracted from [18F] PSMA-3Q PET/CT using 40%, 45%, and 50% SUVmax thresholds for their ability to predict post-surgical International Society of Urological Pathology (psISUP) grading and extraprostatic extension (EPE) in prostate cancer and ultimately develop an optimal threshold-based predictive model. This retrospective study included 243 prostate cancer patients undergoing [18F] PSMA-3Q PET/CT before radical prostatectomy. Patients were chronologically divided into training (n = 190) and test (n = 53) cohorts, with stratification by prostate-specific antigen density (PSAD < 0.25 vs. ≥ 0.25 ng/mL). Radiomics features were extracted using 40%, 45%, and 50% SUVmax thresholds. Nine machine learning algorithms developed integrated PET/CT radiomics-clinical models (PC40, PC45, PC50) and PET radiomics-clinical models (P40, P45, P50). Model performance was evaluated using area under the curve (AUC), sensitivity, specificity, positive and negative predictive values. Among the models constructed with 40%, 45%, and 50% SUVmax thresholds, the PC45 model (PET/CT radiomics + clinical parameters) performed best. For predicting psISUP grade ≥ 4, its test set AUC reached 0.917 (95% CI: 0.828-0.985), with 0.800 sensitivity and 0.921 specificity. For EPE prediction, the test set AUC was 0.772(95% CI: 0.633-0.883), sensitivity 0.700 and specificity 0.727. It showed stable performance across PSAD subgroups and higher net clinical benefit. The [18F] PSMA-3Q PET/CT radiomics model with a 45% SUVmax threshold may facilitate relatively accurate noninvasive prediction of psISUP grade and EPE. These findings suggest its potential value as a promising preoperative tool for precision prostate cancer management, and provide preliminary evidence supporting its stable and balanced performance as a noninvasive decision‑making aid, pending further validation in larger cohorts.
Overdiagnosis of clinically insignificant prostate cancer (International Society of Urological Pathology Grade Group 1 [ISUP GG1]) remains a concern. Many men with Prostate Imaging Reporting and Data System (PI-RADS 3) or selected PI-RADS 4 lesions have no cancer or only ISUP GG1 on biopsy. A strategy of deferred decision-making on biopsy indication using longitudinal information may reduce overdiagnosis and biopsy burden. The SPROUT trial evaluates longitudinal prostate-specific antigen density (PSAD) and magnetic resonance imaging (MRI) monitoring, triggering biopsy only upon progression while preserving safety for detecting clinically significant (ISUP GG ≥2) cancer. The SPROUT study is a phase 2, multicentre, single-arm trial across seven Dutch centres, enrolling 503 biopsy-naïve men aged >18 yr with PI-RADS 3, or PI-RADS 4 with PSAD ≤ 0.15 ng/ml/cm3. Instead of immediate biopsy, participants undergo PSA testing every 6 mo and annual MRI for up to 4 yr. If follow-up MRI shows no suspicious lesion, monitoring de-escalates to twice-yearly PSA testing alone, with MRI retriggered in the event of subsequent biochemical progression. Targeted biopsies are triggered by progression to PI-RADS 4 with PSAD >0.15 ng/ml/cm3 or PI-RADS 5. Men with persistent PI-RADS 3 or 4 lesions after 48 mo undergo an end-of-study biopsy. Image quality is assessed using a standardised scoring system for Prostate Image Quality (PI-QUAL) version 2. Primary endpoints are the proportion of avoided biopsies that would have been negative or ISUP GG1 (effectiveness), and the proportion of ISUP GG ≥ 2 cancers missed by monitoring, using the end-of-study biopsy as the reference (safety). Secondary endpoints include grade shifts, detection of ISUP GG ≥ 3, health-related quality of life (EPIC-26, short STAI-6), and cost-effectiveness. Safety will be assessed using a ≤5% noninferiority margin for missed ISUP GG ≥ 2 cancers, defined as cases detected only at end-of-study biopsy. Effectiveness will be measured by ISUP GG1 and negative biopsy rates. Strengths include the intermediate-term follow-up and MRI quality control during the study. Limitations include the nonrandomised design, which might result in selection bias. This trial was approved by the Medical Research Ethics Committee Utrecht (ClinicalTrials.gov, NCT07180381). Not all prostate cancers require treatment. This study focuses on men with an intermediate risk of harbouring aggressive prostate cancer, based on PSA blood levels and MRI findings. Instead of undergoing immediate prostate biopsy, participants are closely monitored with PSA testing every 6 mo and MRI annually over a 4-yr period. A biopsy is performed only if there are signs of disease progression. If no biopsy has been performed during the study but a lesion remains visible on the final MRI, end-of-study biopsies will be conducted to assess any potentially missed aggressive cancers. This approach aims to reduce unnecessary biopsies and avoid overdiagnosis of nonaggressive prostate cancers, while still ensuring timely detection of cancers that require treatment.
Significant interindividual differences exist in the efficacy of immunotherapy for hepatocellular carcinoma (HCC), and reliable biomarkers for predicting therapeutic response are lacking. Immunogenic cell death (ICD) participates in regulating the tumor immune microenvironment (TME) through the release of damage-associated molecular patterns (DAMPs), thereby possessing the potential to reshape the TME. DAMPs are essential for the occurrence of ICD. This study aims to address the lack of systematic evaluation of ICD-related molecular subtypes in HCC by constructing a DAMP-related molecular classification system and risk scoring model, as well as identifying hub genes regulating ICD in HCC for prognosis assessment and prediction of immunotherapy response. Transcriptomic data and clinical information from multiple cohorts, including The Cancer Genome Atlas (TCGA)-LIHC dataset, the Gene Expression Omnibus (GEO) GSE14520 dataset, and the International Cancer Genome Consortium (ICGC)-LIRI dataset, were integrated. Unsupervised consensus clustering analysis of 40 DAMP-related genes was performed to identify molecular subtypes of HCC, followed by functional analyses and identification of activated signaling pathways in each subtype. Prognosis-related genes were screened from differentially expressed genes using univariate Cox regression analysis, and a DAMP scoring model was established through least absolute shrinkage and selection operator (LASSO) regression and stepwise Cox regression analyses. The ESTIMATE algorithm was used to evaluate TME characteristics, and the CIBERSORT algorithm was applied to analyze immune cell infiltration levels in HCC. Time-dependent receiver operating characteristic (ROC) curve analysis was used to evaluate the prognostic predictive performance of the DAMP score and compare it with clinical characteristics and previously published messenger RNA (mRNA) biomarkers. Weighted gene co-expression network analysis (WGCNA) was used to identify hub genes associated with the DAMP score. Immunohistochemistry (IHC) staining was performed to validate differential expression of hub genes between tumor and normal tissues. In vitro experiments, including cell counting kit-8 (CCK-8) assays and wound-healing assays, were conducted to investigate the role of hub genes in HCC. Flow cytometry was used to detect apoptosis levels and evaluate sensitivity to the ICD inducer 5-fluorouracil (5-FU). Unsupervised consensus clustering analysis showed that HCC patients could be classified into 2 subgroups, namely low-DAMP-score and high-DAMP-score groups, based on the expression profiles of DAMP-related genes. Patients in the low-DAMP-score group had longer overall survival and exhibited higher immune cell infiltration, particularly CD8⁺ T-cell infiltration (all P<0.05). The DAMP score demonstrated stable prognostic stratification capability across multiple independent cohorts, with poorer survival outcomes observed in the high-DAMP-score group (all P<0.05). Time-dependent ROC analysis demonstrated high accuracy of the DAMP score in predicting 1-year and 3-year survival, outperforming commonly used clinical characteristics and 53 previously published mRNA biomarkers. Functional analyses revealed that pathways activated in the high-DAMP-score group were mainly enriched in cell proliferation-related pathways, whereas the low-DAMP-score group was associated with immune activation and metabolism-related pathways. In addition, the DAMP score was significantly negatively correlated with immune cell infiltration levels, and the proportions of multiple immune cell types differed significantly between the high- and low-DAMP-score groups (all P<0.05). The DAMP-score-related hub gene TRIP13 was significantly upregulated in HCC tissues and promoted proliferation and migration of HCC cells (all P<0.05). Silencing TRIP13 expression in HCC cells increased sensitivity to the ICD inducer 5-FU and was accompanied by increased apoptosis levels (all P<0.05). The prognostic risk scoring model constructed based on DAMP-related genes can effectively stratify HCC patients and is closely associated with characteristics of the tumor immune microenvironment. The DAMP scoring model established in this study may be used for prognostic evaluation and prediction of immunotherapy efficacy in HCC and demonstrated stable predictive performance across multiple cohorts. As a hub gene in this DAMP scoring model, TRIP13 exerts oncogenic effects in HCC and regulates tumor cell sensitivity to the ICD inducer 5-FU. The DAMP-score-based subtype classification system and TRIP13-targeted therapy provide new molecular evidence for individualized treatment of HCC. 目的: 肝细胞癌(hepatocellular carcinoma，HCC)的免疫治疗效果存在显著的个体差异，缺乏可靠的生物标志物用于疗效预测。免疫原性细胞死亡(immunogenic cell death，ICD)通过激活损伤相关分子模式(damage-associated molecular pattern，DAMP)参与调控肿瘤免疫微环境，其具有改变免疫抑制性肿瘤微环境(tumor microenvironment，TME)的潜力。DAMP对ICD的发生至关重要。本研究旨在针对HCC中ICD相关的分子分型缺乏系统评估的问题，构建基于DAMP相关基因的分型系统及风险评分模型，并识别在HCC中调控ICD的枢纽基因，以用于预后评估及免疫治疗反应预测。方法: 整合癌症基因组图谱(The Cancer Genome Atlas，TCGA)-LIHC数据集、基因表达综合数据库(Gene Expression Omnibus，GEO)的GSE14520数据集及国际癌症基因组联盟(International Cancer Genome Consortium，ICGC)-LIRI数据集等多队列的转录组数据及临床信息，对40个DAMP相关基因进行无监督共识聚类分析，识别HCC分子亚型，进行功能分析，并识别各个亚型中被激活的信号通路。采用单因素Cox回归分析法从差异表达基因中筛选预后相关基因，并通过最小绝对收缩与选择算子(least absolute shrinkage and selection operator，LASSO)回归及逐步Cox回归分析法建立DAMP评分模型。采用ESTIMATE算法评估TME特征，CIBERSORT算法分析HCC的免疫细胞浸润水平。采用时间依赖性的受试者操作特征曲线(receiver operator characteristic curve，ROC)分析DAMP评分的预后预测能力，并与临床特征及既往发表的信使RNA(messenger RNA，mRNA)标志物进行比较。利用加权基因共表达网络分析(weighted gene co-expression network analysis，WGCNA)筛选与DAMP评分相关的枢纽基因。通过免疫组织化学(immunohistochemistry，IHC)染色验证枢纽基因在肿瘤组织和正常组织中的表达差异，并结合体外实验[包括细胞计数试剂盒-8(cell counting kit-8，CCK-8)和细胞划痕试验]探讨枢纽基因在HCC中的作用，同时采用流式细胞术检测细胞凋亡水平，以评估枢纽基因对ICD诱导剂5-氟尿嘧啶(5-fluorouracil，5-FU)的敏感性。结果: 无监督共识聚类分析结果表明，基于DAMP相关基因的表达特征，HCC患者可分为低DAMP评分和高DAMP评分2个亚组。其中低DAMP评分组的总生存期更长，且具有高免疫细胞浸润特征(尤其是CD8+ T细胞)(均P<0.05)。DAMP评分在多个独立队列中均表现出稳定的预后分层能力，高DAMP评分组的生存结局较差(均P<0.05)。时间依赖性ROC分析显示，DAMP评分在1年和3年生存预测中具有较高准确性，其预测效能优于常用的临床特征及53个已发表的mRNA标志物。功能分析表明，高DAMP评分组中被激活的通路主要富集于细胞增殖相关通路，而低DAMP评分组则与免疫激活及代谢有关通路相关。同时，DAMP评分与免疫细胞浸润水平呈显著负相关，高DAMP评分组与低DAMP评分组相比，多种免疫细胞的比例均显著改变(均P<0.05)。DAMP评分相关的枢纽基因TRIP13在HCC组织中显著上调，并可促进HCC细胞的增殖和迁移(均P<0.05)。沉默HCC细胞中TRIP13的表达可增加对ICD诱导剂5-FU的敏感性，并伴随细胞凋亡水平的升高(均P<0.05)。结论: 基于DAMP相关基因构建的预后风险评分模型能够对HCC患者进行有效分层，并与肿瘤免疫微环境特征密切相关。本研究建立的DAMP评分模型可用于HCC的预后评估及免疫治疗的效果预测，并在多队列中显示出稳定的预测性能。TRIP13作为该模型中的枢纽基因，在HCC中发挥促癌作用，并调控肿瘤细胞对ICD诱导剂5-FU的敏感性。基于DAMP评分的亚型分型系统和TRIP13靶向治疗为HCC的个体化治疗提供了新的分子依据。.
This approaches, for inducing knee osteoarthritis (KOA) in rabbit and rodent models. It also summarizes data study evaluates surgical, mechanical, chemical, genetic, and diet-induced methods, as well as combination-based on post-intervention time points for KOA development, the duration required for osteophyte formation, KOA scoring systems, and relevant histopathological findings. A systematic search of PubMed, Scopus, and Web of Science (from 1970 to February 2025) was conducted using the PICO framework, focusing on animal models (rabbits and rodents), osteoarthritis induction methods, comparative efficacy, and relevant outcomes. Extracted variables included model characteristics, interventions, and KOA-related findings. The risk of bias was assessed using the Cochrane risk-of-bias tool and the ROBINS-I tool. After screening 5,702 records, 98 studies met the inclusion criteria. Surgical (n = 34), chemical (n = 15), genetic (n = 13), mechanical (n = 19), and high-fat diet-induced (n = 6) models, as well as combination approaches, were reviewed. Among surgical techniques, anterior cruciate ligament transection (ACLT) and medial meniscus destabilization (DMM) were the most frequently used, whereas monosodium iodoacetate (MIA) was the predominant chemical inducer. Genetic models primarily involved gene deletions or mutations in C57BL/6 mice. Mechanical induction methods included joint loading, treadmill running, and immobilization. Histological evaluation-most commonly using the Mankin and Osteoarthritis Research Society International (OARSI) scoring systems-was the predominant approach for KOA assessment, while micro-computed tomography (micro-CT) was employed in selected studies. Osteophyte formation was prominent in surgical and specific chemical models and was typically observed within 8 weeks post-intervention. Additionally, each induction method exhibited a distinct time course for osteophyte development and the establishment of KOA. Each approach offers distinct advantages for replicating KOA pathology and for facilitating research into disease mechanisms and therapeutic interventions.
Colorectal cancer is the third most common cancer worldwide, with increasing incidence and mortality expected in the coming decades. In Ghana, its burden is growing, and this has been addressed through training skilled colorectal surgeons and adopting international protocols. This study aimed to evaluate adherence to the American Society of Colon and Rectal Surgeons preoperative colorectal cancer checklist and its association with postoperative outcomes in two teaching hospitals in Ghana. A cross-sectional study was conducted on rectal cancer patients treated at two major teaching hospitals in Ghana. Chart reviews were done retrospectively to assess the completion of checklist items and their relationship with 30-day morbidity and mortality, comparing patients who completed the median number or more items to those who completed fewer. Fifty-two rectal cancer cases were included. Males (53. 9%) were the majority, with a mean age of 56 years. Most patients were diagnosed at stage III (69. 2%). The median number of completed checklist items was 6, with no patient completing all 10 items. The checklist items with the highest completion rates were clinical tumor staging (100%) and pathology review (100%). Assessments of family history, stool continence, sexual function, and stoma site marking were the least frequently completed. There was a significant difference in checklist completion between the two hospitals (p = 0.030). Checklist adherence was not significantly linked to postoperative morbidity or mortality. Adherence to the preoperative checklist provides a systematic approach to patient evaluation in preparation for surgery, though it did not influence morbidity or mortality in this study. Establishing dedicated colorectal units is a key step toward improving surgical outcomes and overall patient survival.
This study uses bibliometric analysis and knowledge mapping methods to systematically explore the emerging research frontiers and development trajectories of focused ultrasound (FUS) technology in the treatment of Alzheimer's disease (AD), and provides new clues and research directions for future research by exploring hotspots and new topics. A comprehensive literature search was conducted through the Science Citation Index Expanded Core Collection (WoSCC) database to identify relevant articles and reviews published between January 2014 and 2025 on the application of FUS technology in AD. For data analysis and visualization, we used VOSviewer software, CiteSpace, and the R package "bibliometrix" to conduct rigorous bibliometric analysis and build knowledge domain maps. A total of 1531 papers involving 9220 contributors were identified between 2014 and 2025. The field demonstrated consistent growth (R2=0.9272), peaking in 2025 with 225 publications. China led in total output (475 papers), while the United States achieved the highest academic impact (12,965 citations, H-index: 56). The Chinese Academy of Sciences was the most prolific institution, whereas Harvard Medical School recorded the highest citation impact. The Journal of Alzheimer's Disease and Scientific Reports emerged as the leading publication venues, while Theranostics and Alzheimer's & Dementia provided high-prestige platforms. Tianfu Wang and Baiying Lei were the most productive authors, though Isabelle Aubert garnered the highest total citations. International collaboration analysis revealed a robust, multi-centric network anchored by the USA, China, Canada, and Italy. Co-citation analysis identified Leinenga G (2015) as the foundational study for ultrasound-mediated amyloid-beta clearance. Lipsman N (2018) marked a critical clinical inflection point, exhibiting a strong citation burst (17.3) that catalyzed a shift from preclinical models to human safety trials. Recent bursts extending into 2025 focus on multicenter clinical validation and long-term efficacy. Keywords analysis confirms that non-invasive blood-brain barrier (BBB) opening via microbubble-enhanced focused ultrasound (FUS) is the central research paradigm. Emerging frontiers have shifted from basic technical validation toward neuroinflammation, oxidative stress, tau pathology, and deep-learning-assisted diagnostics, reflecting an evolving focus on molecular mechanisms and precision neurosurgery. Focused ultrasound technology has made significant progress in the field of Alzheimer's disease research and has become a research frontier with considerable therapeutic potential. With ongoing technological progress, the clinical translation of FUS is expected to bring new breakthroughs in AD treatment.
To identify prenatal predictors of tuberous sclerosis complex (TSC) in fetuses with one or more cardiac rhabdomyomas (CR), evaluate an integrated multimodal diagnostic workflow using fetal magnetic resonance imaging (MRI) and trio whole-exome sequencing (trio-WES) and characterize perinatal outcomes. This was a retrospective cohort study of 80 fetuses that were diagnosed prenatally with one or more CR between February 2016 and December 2024 at a single tertiary center and that received a definitive TSC diagnosis either prenatally (via genomic or clinical criteria) or by postnatal pathological verification. All fetuses underwent routine high-resolution echocardiography. Those in which a CR was suspected were then offered the option of further investigation via fetal brain MRI and trio-WES, to identify pathogenic variants in TSC1/TSC2 genes. A definitive prenatal TSC diagnosis was assigned based on genetic testing or the presence of two major clinical features. Clinical, imaging, genetic and perinatal data were retrieved and compared between the TSC-positive and TSC-negative groups. Postnatal or postmortem verification was only required in cases that lacked a definitive prenatal diagnosis. Performance metrics, including sensitivity, specificity and positive (PPV) and negative (NPV) predictive values, were calculated to evaluate the diagnostic utility of tumor multiplicity and fetal brain MRI in prediction of TSC. Forty-eight (60.0%) fetuses were diagnosed with TSC and 32 (40.0%) were TSC-negative. Tumor multiplicity had a sensitivity of 87.5% (95% CI, 74.8-95.3%) but low specificity (50.0%; 95% CI, 31.9-68.1%) for the prediction of TSC. Seventy fetuses underwent brain MRI. Among these, MRI achieved a specificity of 100.0% (95% CI, 89.1-100.0%) and identified central nervous system lesions in 89.4% of those with TSC that underwent the MRI examination, of which 81.0% were occult on ultrasound examination. Trio-WES was performed in 31 cases. Among these, pathogenic variants were identified in 20 cases, with 85.0% of these affecting the TSC2 gene. Trio-WES identified pathogenic variants in five TSC-positive cases that presented with normal fetal brain MRI, demonstrating its essential additive value for fetuses with occult imaging phenotypes, while MRI detected structural lesions in four trio-WES-negative cases. TSC2 variants were associated with more severe phenotypes, including subependymal giant cell astrocytoma, whereas TSC1 variants typically presented with milder manifestations. Sixty-two fetuses underwent termination of pregnancy (TOP); the TOP rate was 87.5% in the TSC-positive group and 62.5% in the TSC-negative group. Eighteen fetuses were liveborn (six TSC-positive and 12 TSC-negative). The TSC-positive infants had significantly lower birth weight compared with the TSC-negative infants (median, 3050 g vs 3500 g; P = 0.025), despite the two groups having a similar gestational age at delivery. All liveborn TSC-positive infants developed postnatal epilepsy. Multiple CR at screening ultrasound examination and a major lesion at fetal brain MRI are key prenatal predictors of TSC, but accurate diagnosis requires not only MRI but also trio-WES, to overcome the developmental limitations imposed by the late appearance of some fetal anomalies associated with TSC and genetic limitations inherent in standard molecular analysis. Given the severe perinatal outcomes associated with TSC observed in this study, including high termination rates and postnatal epilepsy in all liveborn infants, definitive prenatal diagnosis is essential for accurate risk stratification, parental counseling and proactive neurological management. © 2026 The Author(s). Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Decades of immunological and genetic studies highlight CD4+ T cells as initiators of central nervous system (CNS) pathology in individuals who develop multiple sclerosis (MS). A low-frequency CD4+ T-cell population termed T helper 17.1 (Th17.1) has been argued to play a central role during MS onset due to differences in abundance, yet little is known about their functional heterogeneity and distinctive mode of action in MS. Features that distinguished Th17.1 from Th17 and Th1 cells in the blood were explored using spectral flow cytometry. We focused on the brain-homing properties of Th17.1 in MS by analysing paired blood and cerebrospinal fluid (CSF) as well as blood before and after natalizumab treatment. Identified Th17.1 effector signatures were further analysed using purified subsets for single-cell transcriptomics and corresponding in vitro stimulation assays. Our screens reveal an CCR5high Th17.1 cluster that is enriched in CSF, but also selectively reduced in post-versus pre-natalizumab blood samples from people with MS. The phenotypical and transcriptional signature of this Th17.1 cluster matched and pointed to a highly receptive and pre-cytotoxic state. Indeed, particularly CCR5high Th17.1 cells upregulated cytolytic proteins by strongly responding to IL-12, while secretion of these proteins was only found when adding both IL-12 and IL-18 in vitro. We show that low-frequency, circulating Th17.1 cells harbour a unique MS-associated CCR5high cluster with enhanced cytotoxic and CNS-infiltrating potential. This CD4+ cytotoxic T-cell precursor could be a promising target for future research aimed at monitoring disease-relevant immune perturbations for precision medicine in MS. ZonMw (09150171910036), Stichting MS Research (19-1075 MS, 23-490 g MS), European Union's Horizon Europe Research and Innovation Actions (101137235; BEHIND-MS) and the Swiss State Secretariat for Education, Research and Innovation (SERI), Erasmus MC Foundation (10502/02).
Immune checkpoint inhibitors (ICIs) are now standard of care for most advanced solid tumors. While effective, they are associated with immune-related adverse events (irAEs), including rare autonomic complications. We present a patient with metastatic lung adenocarcinoma receiving nivolumab and ipilimumab who developed reflex syncope with reproducible complete heart block (CHB) triggered by swallowing and food proximity. Barium esophagram revealed esophageal dysmotility, a small hiatal hernia, and distal esophageal narrowing. ICI therapy was held, and a dual-chamber pacemaker resolved the syncopal episodes. The overlap between structural esophageal pathology, possible ICI-associated autonomic dysregulation, and situational syncope complicates diagnosis and management. Clinicians should maintain vigilance for autonomic manifestations, especially new-onset bradyarrhythmias or syncope, in patients on immunotherapy.
To validate the predictive value of Total Tumor Load (TTL), based on Cytokeratin 19 (CK19) mRNA copy number measured by OSNA in sentinel lymph nodes (SLNs), and to establish an optimal cut-off for identifying HR + /HER2- breast cancer (BC) patients at high risk of ≥ 4 metastatic lymph nodes (LNs), eligible for adjuvant abemaciclib therapy. A retrospective, international, multicenter study pooling data from six studies conducted between 2000 and 2016 in adult BC patients with SLN biopsies analyzed by OSNA. Variables were TTL (CK19 mRNA copies/µL) in SLNs, number of LNs removed, and number of metastatic ones. We constructed receiver operating characteristics (ROC) curves to determine optimal TTL values and multivariate logistic regression models to identify relevant prognostic factors for predicting ≥ 4 LN metastases. We included 3804 patients with HR + /HER2- tumors of any histological type, complete axillary LN dissection, and > 4 LNs removed; 608 (16.0%) had ≥ 4 metastatic LNs and 439 had lobular BC. At cut-offs of 99,500 and 101,000 copies/µL, TTL had a 32.3% and 32.4% PPV. In lobular BC, cut-offs between 92,305 and 108,700 copies/µL reached a 40% PPV. In lobular HR + /HER2- BC, a multivariate model including tumor grade, TTL, and lymphovascular invasion reached a 49% PPV for predicting ≥ 4 metastatic LNs, yielding a nomogram and an online calculator for use in routine practice. TTL measured using OSNA predicts ≥ 4 metastatic LNs in patients with luminal-like BC, with a proposed optimal threshold of 100,000 copies/µL. Not applicable.