tbuckley/cabot-search huggingface dataset:
Soluble cerebral Aβ protofibrils link Aβ plaque pathology to changes in CSF Aβ42/Aβ40 ratios, neurofilament light and tau in Alzheimer’s disease model mice
Authors: Emelie Andersson, Nils Lindblom, Shorena Janelidze, Gemma Salvadó, Eleni Gkanatsiou, Linda Söderberg, Christer Möller, Lars Lannfelt, Junyue Ge, Jörg Hanrieder, Kaj Blennow, Tomas Deierborg, Niklas Mattsson-Carlgren, Henrik Zetterberg, Gunnar Gouras, Oskar Hansson
Journal: Nature Aging (2025)

Abstract The Aβ 42 /Aβ 40 ratio in the cerebrospinal fluid (CSF) and the concentrations of neurofilament light (NfL) and total tau (t-tau) are changed in the early stages of Alzheimer’s disease (AD) 1 , but their neurobiological correlates are not entirely understood. Here, we used 5xFAD transgenic mice to investigate the associations between these CSF biomarkers and measures of cerebral Aβ, including Aβ 42 /Aβ 40 ratios in plaques, insoluble fibrillar deposits and soluble protofibrils. A high Aβ 42 /Aβ 40 ratio in soluble protofibrils was the strongest independent predictor of low CSF Aβ 42 /Aβ 40 ratios and high CSF NfL and t-tau concentrations when compared to Aβ 42 /Aβ 40 ratios in plaques and insoluble fibrillar deposits. Furthermore, the Aβ 42 /Aβ 40 ratio in soluble protofibrils fully mediated the associations between the corresponding ratio in plaques and all the investigated CSF biomarkers. In App NL-G-F/NL-G-F knock-in mice, protofibrils fully mediated the association between plaques and the CSF Aβ 42 /Aβ 40 ratio. Together, the results suggest that the Aβ 42 /Aβ 40 ratio in CSF might better reflect brain levels of soluble Aβ protofibrils than insoluble Aβ fibrils in plaques in AD. Furthermore, elevated concentrations of NfL and t-tau in CSF might be triggered by increased brain levels of soluble Aβ protofibrils.
Preeclampsia risk prediction from prenatal cell-free DNA screening
Authors: Mohamed Adil, Teodora R. Kolarova, Anna-Lisa Doebley, Leah A. Chen, Cara L. Tobey, Patricia Galipeau, Sam Rosen, Michael Yang, Brice Colbert, Robert D. Patton, Thomas W. Persse, Erin Kawelo, Jonathan B. Reichel, Colin C. Pritchard, Shreeram Akilesh, Christina M. Lockwood, Gavin Ha, Raj Shree
Journal: Nature Medicine (2025)

Preeclampsia is characterized by placental dysfunction and results in significant morbidity, but reliable early prediction remains challenging. We investigated whether clinically obtained prenatal cell-free DNA (cfDNA) screening (PDNAS) using whole-genome sequencing (WGS) data can be leveraged to predict preeclampsia risk early in pregnancy (≤16 weeks). Using 1,854 routinely collected clinical PDNAS samples (median, 12.1 weeks) with low-coverage (0.5×) WGS data, we developed a framework to quantify maternal and fetal tissue signatures using nucleosome accessibility, revealing early placental and endothelial dysfunction. These signatures informed a prediction model for preeclampsia risk, which achieved a validation performance of 0.85 area under the receiver operating characteristic curve (AUC) (81% sensitivity at 80% specificity) for preterm phenotypes several months prior to disease onset in a separate cohort of 831 consecutively collected samples, and subsequently confirmed in an external cohort of 141 samples (AUC 0.84, 79% sensitivity). We demonstrate that assessment of cfDNA nucleosome accessibility from early-pregnancy cfDNA sequence data enables the detection of early placental and endothelial-tissue aberrations and may aid in the determination of preeclampsia risk. Using 1,854 routinely collected clinical samples from early in pregnancy, with validation in an external cohort, low-coverage cfDNA sequence data identified distinctive features among those who developed preeclampsia.
Automated longitudinal treatment response assessment of brain tumors: a systematic review
Authors: Tangqi Shi, Aaron Kujawa, Christian Linares, Tom Vercauteren, Thomas C Booth
Journal: Neuro-Oncology (2025)

Abstract Background Longitudinal assessment of tumor burden using imaging helps to determine whether there has been a response to treatment both in trial and real-world settings. From a patient and clinical trial perspective alike, the time to develop disease progression, or progression-free survival, is an important endpoint. However, manual longitudinal response assessment is time-consuming and subject to interobserver variability. Automated response assessment techniques based on machine learning (ML) promise to enhance accuracy and reduce reliance on manual measurement. This paper evaluates the quality and performance accuracy of recently published studies. Methods Following PRISMA guidelines and the CLAIM checklist, we searched PUBMED, EMBASE, and Web of Science for articles (January 2010-November 2024). Our PROSPERO-registered study (CRD42024496126) focused on adult brain tumor automated treatment response assessment studies using ML methodologies. We determined the extent of development and validation of the tools and employed QUADAS-2 for study appraisal. Results Twenty (including seventeen retrospective and three prospective) studies were included. Data extracted included information on the dataset, automated response assessment including pertinent steps within the pipeline (index tests), and reference standards. Only limited conclusions are appropriate given the high bias risk and applicability concerns (particularly regarding reference standards and patient selection), and the low-level evidence. There was insufficient homogenous data for meta-analysis. Conclusion The study highlights the potential of ML to improve brain tumor longitudinal treatment response assessment. Interpretation is limited due to study bias and limited evidence of generalizability. Prospective studies with external datasets validating the latest neuro-oncology criteria are now required.
Establishment of interpretable cytotoxicity prediction models using machine learning analysis of transcriptome features
Authors: You Wu, Ke Tang, Chunzheng Wang, Hao Song, Fanfan Zhou, Ying Guo
Journal: Acta Pharmaceutica Sinica B (2025)

Cytotoxicity, usually represented by cell viability, is a crucial parameter for evaluating drug safety in vitro. Accurate prediction of cell viability/cytotoxicity could accelerate drug development in the early stage. In this study, by integrating cellular transcriptome and cell viability data using four machine learning algorithms (support vector machine (SVM), random forest (RF), extreme gradient boosting (XGBoost), and light gradient boosting machine (LightGBM)) and two ensemble algorithms (voting and stacking), highly accurate prediction models of 50% and 80% cell viability were developed with area under the receiver operating characteristic curve (AUROC) of 0.90 and 0.84, respectively; these models also showed good performance when utilized for diverse cell lines. Concerning the characterization of the employed Feature Genes, the models were interpreted, and the mechanisms of bioactive compounds with a narrow therapeutic index (NTI) can also be analyzed. In summary, the models established in this research exhibit superior capacity to those of previous studies; these models enable accurate high-safety substance screening via cytotoxicity prediction across cell lines. Moreover, for the first time, Cytotoxicity Signature (CTS) genes were identified, which could provide additional clues for further study of mechanisms of action (MOA), especially for NTI compounds.
Author correction to “PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism” [Acta Pharmaceutica Sinica B 13 (2023) 157-173]
Authors: Mingming Sun, Leilei Li, Yujia Niu, Yingzhi Wang, Qi Yan, Fei Xie, Yaya Qiao, Jiaqi Song, Huanran Sun, Zhen Li, Sizhen Lai, Hongkai Chang, Han Zhang, Jiyan Wang, Chenxin Yang, Huifang Zhao, Junzhen Tan, Yanping Li, Shuangping Liu, Bin Lu, Min Liu, Guangyao Kong, Yujun Zhao, Chunze Zhang, Shu-Hai Lin, Cheng Luo, Shuai Zhang, Changliang Shan
Journal: Acta Pharmaceutica Sinica B (2025)
Response to luspatercept can be predicted and improves overall survival in the real‐life treatment of LR‐MDS
Authors: Angela Consagra, Luca Lanino, Najla H. Al Ali, Luis Aguirre, Zhuoer Xie, Onyee Chan, Gloria Andreossi, Marco G. Raddi, Luca Rigodanza, Alessandro Sanna, Giorgio Mattiuz, Elena Tofacchi, Cristina Amato, Michele Tanturli, Sven De Pourcq, Alison Walker, Andrew Kuykendall, Jeffrey Lancet, Eric Padron, David A. Sallman, Francesco Restuccia, Alessandra Perego, Marta Ubezio, Bruno Fattizzo, Marta Riva, Giulia Maggioni, Alessia Campagna, Matteo G. Della Porta, Valeria Santini, Rami S. Komrokji
Journal: HemaSphere (2025)

Abstract We explored the impact of luspatercept therapy on overall survival (OS) and possible predictors of response in low‐risk (LR) myelodysplastic syndrome (MDS) patients. We evaluated 331 anemic patients treated with luspatercept. Hematological response (HI) was defined as (i) hemoglobin (Hb) increase of ≥1.5 g/dL in nontransfusion‐dependent (NTD) patients, and (ii) red blood cell (RBC) transfusion independence (TI) with a concomitant Hb increase of ≥1.5 g/dL, or RBC‐TI without an Hb increase of 1.5 g/dL, or &gt;50% reduction in RBC transfusion burden (TB) for TD patients. Response was observed in 166 patients (50.2%), with significantly higher response in NTD and low TB versus high TB patients ( p &lt; 0.001). A significant correlation between lower Molecular International Prognostic Scoring System (IPSS‐M) risk scores and response was observed. No statistically significant difference in HI was found in SF3B1‐ mutated versus wild‐type MDS patients (53.8% vs. 40.1%, respectively). SF3B1 mut hotspots (K700E vs. others) and variant allele frequencies (VAFs; &lt;38% VAF vs. ≥38% VAF) did not impact on HI. SF3B1‐ mutated MDS with del5q showed inferior HI compared to other LR‐MDS ( p = 0.046). The median treatment duration overall was 35 weeks (20.86–90.29), the median time to response was 11 weeks (8.71–21.86), and the median duration of response was 65 weeks (26.5–114). After a median follow‐up of 13 months, median OS was not reached (NR) for responders and 24 months for nonresponders (hazard ratio [HR] 0.25, 95% confidence interval 0.14–0.44, p &lt; 0.001). This analysis of 331 luspatercept real‐life‐treated LR‐MDS patients demonstrated a significant OS benefit upon luspatercept response. Low baseline RBC‐TB and lower risk IPSS‐M scores correlated with higher HI and could constitute predictive markers of response.
Risk of Invasive Meningococcal Disease in people with Sickle Cell Disease: a Systematic Review
Authors: Catherine Isitt, Helen Campbell, Catherine A Cosgrove, Mary E Ramsay, Paul T Heath, Ray Borrow, Shamez N Ladhani
Journal: Journal of Infection (2025)

BackgroundAsplenia and splenic dysfunction is associated with an increased risk of severe and fatal infections, especially due to encapsulated bacteria including Streptococcus pneumoniae, Haemophilus influenzae serotype b (Hib) and Neisseria meningitidis. People with sickle cell disease (SCD) develop recurrent splenic infarcts rendering them functionally asplenic. Consequently, additional vaccination against these three pathogens is recommended. There is robust evidence of an increased risk for invasive pneumococcal (IPD) and Hib disease, in people with SCD, but for not invasive meningococcal disease (IMD).MethodsWe conducted a systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) recommendations. Studies published in any language before June 2024 and including people with SCD of all ages and from all geographical locations were included. Studies were included if they documented bacterial culture and/or PCR in patients with SCD with suspected infection. The primary outcome was to estimate IMD risk in people with SCD. Secondary outcomes included estimating the risk of IMD and Hib disease in people with SCD.FindingsWe identified 3,804 publications and included 86 in the final analyses. Among 74 cohort studies published during 1971-2023, there were three IMD cases among 26,404 persons with SCD compared with 570 IPD and 113 Hib cases. Eight case-control studies published during 1983-2022 reported one IMD case among 1,021 people with SCD (0.1%) compared to 118 IMD cases among 7,143 people without SCD (1.65%). In contrast, there were 112 IPD cases (112/1021, 11.0%) in people with SCD compared to 530 (530/7143, 7.4%) in those without SCD. For Hib, the rates were 28/1021 (2.7%) and 205/7143 (2.9%), respectively. After including all published studies, we identified five IMD cases in people with SCD across studies published worldwide during 1965-1995 and all five survived their infection.InterpretationWe found no evidence of any increased risk of IMD in people with SCD. This has important implications for policymakers in countries and organisations that currently recommend meningococcal vaccination for people with SCD.FundingNone
Single‐cell DNA and surface protein characterization of high hyperdiploid acute lymphoblastic leukemia at diagnosis and during treatment
Authors: Margo Aertgeerts, Sarah Meyers, Olga Gielen, Jochen Lamote, Barbara Dewaele, Mercedeh Tajdar, Johan Maertens, Jolien De Bie, Kim De Keersmaecker, Nancy Boeckx, Lucienne Michaux, Anne Uyttebroeck, Sofie Demeyer, Heidi Segers, Jan Cools
Journal: HemaSphere (2025)

Abstract High hyperdiploid (HeH) B‐cell acute lymphoblastic leukemia (B‐ALL) is the most prevalent subtype of childhood ALL. This leukemia is characterized by trisomies and tetrasomies of specific chromosomes and additional point mutations. Here, we used single‐cell targeted DNA and antibody sequencing to determine the clonal evolution of HeH B‐ALL during development and chemotherapy treatment. Chromosomal copy number changes were mostly stable over all the leukemia cells, while mutations were typically subclonal. Within all 13 cases, at least one RAS mutant ( KRAS or NRAS ) subclone was detected (range: 1 to 4 subclones with RAS mutations), indicating the importance of RAS signaling in HeH B‐ALL development. NSD2 mutations were detected in 4 out of 13 cases and always in a subclone with RAS signaling mutations. Single‐cell DNA sequencing detected residual leukemia cells during chemotherapy treatment, and analysis of chromosomal copy number changes aided in the accurate detection of these cells. Our single‐cell data demonstrate that chromosomal changes are acquired prior to additional mutations and that RAS signaling mutations are present in all HeH cases, often as subclonal mutations. This single‐cell multi‐omics study enabled us to extensively characterize the genetic and surface protein heterogeneity in patients with HeH B‐ALL.
High-throughput in vitro drug screening and in vivo studies identify fenretinide as a brain-penetrant DMG therapeutic
Authors: Dannielle H Upton, Jie Liu, Sandra M George, Santosh Valvi, Caitlin Ung, Benjamin S Rayner, Anjana Gopalakrishnan, Ruby Pandher, Aaminah Khan, Pooja Venkat, Chelsea Mayoh, Holly Holliday, Nicole Yeung, Hieu Nguyen, Laura Franshaw, Anahid Ehteda, Han Shen, Giovanna Farruggia, Isabella Orienti, C Patrick Reynolds, Maria Tsoli, David S Ziegler
Journal: Neuro-Oncology (2025)

Abstract Background Diffuse midline glioma, characterised by H3K27 alteration (DMG), is the predominant high-grade glioma in children. It commonly originates in the brainstem, yet effective treatments for these patients remain elusive. Methods To identify novel therapies for DMG, we conducted high-throughput drug screens (HTS) using biologically active, clinically approved compounds against DMG neurospheres. Multiple primary DMG cultures were utilised in conjunction with in vitro cytotoxicity and clonogenic assays to validate the efficacy of top compounds. Molecularly diverse patient-derived and transgenic DMG orthotopic models were employed to assess therapeutic efficacy alongside pharmacokinetic and immunohistochemical analyses. Mechanistic studies, including RNA sequencing, western blotting, and flow cytometry, were conducted to elucidate the antitumour efficacy of the most promising compound, fenretinide, in DMG cells. Results Through HTS, six compounds were identified and validated for their potent cytotoxic activity. However, most of these compounds failed to improve survival in an orthotopic Diffuse Midline Glioma (DMG) model due to limited blood-brain barrier (BBB) penetration. In contrast, fenretinide exhibited effective BBB penetration, significantly enhancing the survival of tumour-bearing animals. Mechanistic studies revealed that fenretinide increased reactive oxygen species (ROS) generation and induced apoptosis by inhibiting PDGFRα. RNA-sequencing further elucidated that fenretinide upregulates the Unfolded Protein Response (UPR) and endoplasmic reticulum (ER) stress pathways while downregulating neurogenesis. The in vivo antitumour efficacy of two fenretinide formulations was demonstrated in PDGFRα-amplified and transgenic DMG models. Conclusion This comprehensive study has identified new DMG therapeutic vulnerabilities and highlights fenretinide as a brain-penetrant, anti-DMG agent.
Incidence of RSV-related Hospitalizations for ARIs, including CAP: Data from the German Prospective ThEpiCAP Study
Authors: Caihua Liang, Elizabeth Begier, Stefan Hagel, Juliane Ankert, Liz Wang, Claudia Schwarz, Lea J. Bayer, Christof von Eiff, Qing Liu, Jo Southern, Jeffrey Vietri, Sonal Uppal, Bradford D. Gessner, Christian Theilacker, Mathias Pletz
Journal: Journal of Infection (2025)

Highlights•RSV incidence is underestimated due to infrequent testing and low-test sensitivity•We estimated RSV hospitalization incidence, accounting for undiagnosed cases•RSV-related ARI hospitalization incidence among those ≥60 years was 401.6/100,000•There is a substantial burden of RSV among adults in Germany•36.4% of RSV hospitalizations in older adults had associated cardiovascular eventsAbstractBackgroundRSV is a leading cause of ARI, including CAP, in older adults. Data available often underestimate RSV ARI incidence. We estimated RSV-related ARI hospitalization incidence from a prospective CAP study, adjusting for undiagnosed RSV infections due to nasopharyngeal/nasal swab testing only.MethodsActive surveillance of adult CAP hospitalizations in Germany was conducted between 2021–2023. Nasopharyngeal/nasal swabs were RSV-tested, and age-group specific proportions were applied to calculate RSV-related CAP incidence. This was divided by the CAP proportions among RSV-related ARI hospitalizations (from multispecimen study) to extrapolate RSV-related ARI rates.ResultsAmong 1,040 radiologically confirmed CAP cases, 3.7% tested RSV-positive via nasopharyngeal/nasal swab, corresponding to 7.8% after adjusting for underdetection. For 18–59 and ≥60 years, adjusted RSV-related CAP hospitalization rates (95% CI) were 4.9 (1.8–10.9) and 115.6 (78.8–163.6). Adjusted RSV-related ARI hospitalization rates were 19.8 (6.8–50.1) and 401.6 (260.7–609.3) per 100,000, respectively. Within 30 days of an RSV-related CAP admission, 18.2% of those ≥65 years died, and 11.1% and 36.4% had cardiovascular events among those 18–64 and ≥65 years, respectively.ConclusionsOlder adults in Germany experience a high burden of RSV-related ARI hospitalizations, including CAP, underscoring RSV vaccination's potential utility for this population.
Immunotherapy targeting a leader sequence cathepsin G-derived peptide
Authors: Chunhua Shi, Ze Tian, Jun Yan, Mao Zhang, Pariya Sukhumalchandra, Edward Chang, Guojun Yang, Junping You, Meng Cui, Qing Shi, Celine Kerros, Anne Philips, Na Qiao, Hiroki Torikai, Sathvik Patchametla, Anna Sergeeva, Lisa St. John, Helen He, Dmitri Wiederschain, Benjamin H. Lee, Geraldine L. C. Paulus, Dongxing Zha, Jeffrey Molldrem, Gheath Alatrash
Journal: Leukemia (2025)

Myeloid azurophil granules provide a rich source of intracellular leukemia antigens. Cathepsin G (CG) is a serine protease that has higher expression in acute myeloid leukemia (AML) blasts in comparison to normal myeloid progenitors. Based on the unique biology of HLA-A*0201 (HLA-A2), in which presentation of leader sequence (LS)-derived peptides is favored, we focused on the LS-CG-derived peptide CG1 (FLLPTGAEA). We previously detected CG1/HLA-A2 complexes on the surface of primary HLA-A2+ AML blasts and cell lines, and immunity targeting CG1/HLA-A2 in leukemia patients. T cell receptor (TCR)-mimic (m) antibodies are immunotherapeutic antibodies that target peptide-HLA (pHLA) complexes. Here we report on the engineering, preclinical efficacy, and safety evaluation of a novel CG1/HLA-A2-targeting, T cell-engager, bispecific antibody (CG1/A2xCD3). CG1/A2xCD3 showed high binding affinity to CG1/HLA-A2 monomers, CD3-Fc fusion protein, and to AML and T cells, with potent killing of HLA-A2+ primary AML and cell lines in vitro and in vivo. This correlated with both tumor- and CG1/A2xCD3-dependent T cell activation and cytokine secretion. Lastly, CG1/A2xCD3 had no activity against normal bone marrow. Together, these results support the targeting of LS-derived peptides and the continued clinical development of CG1/A2xCD3 in the setting of AML.
In Situ Assembled Metal‐Phenolic Nanozyme Biointerfaces Revitalize Stem Cells and Optimize Diabetic Implant Osseointegration
Authors: Xinxiao Chen, Weijia Wang, Yuhan Hu, Jiao Sun, Liguo Zhang, Yi Chen, Jin Liu, Yang Yu, Jianhua Li, Shaohua Ge
Journal: Advanced Healthcare Materials (2025)

Abstract The hyperglycemic microenvironment of diabetes inevitably leads to the accumulated reactive oxygen species (ROS) and impairs the function of stem cells, thereby impeding the process of osseointegration after implant placement. In this study, a self‐assembled metal‐phenolic nanozyme coating is presented for alleviating diabetic oxidative stress and improving osseointegration at implant interfaces. The antioxidant‐like enzyme activity is induced by phenolic ligand−metal charge transfer (LMCT) during the coordination of epigallocatechin‐3‐gallate (EGCG) with copper phosphate nanosheets (Cu NS). The metal‐phenolic nanozyme biointerfaces exhibits scavenging activity against a range of free radicals and facilitated the adhesion, migration, and osteogenic differentiation of stem cells, thereby enhancing the osseointegration of implants in diabetic rats. Additionally, the nanozyme coating strategy inhibits bacterial invasion and supports the adhesion of soft tissue cells. This study provides a prospective approach for surface modification to safeguard and enhance the osseointegration of implants in diabetic subjects.
Urine‐Stable Aptamer‐Conjugated Gold Nanorods for the Early Detection of High‐Grade Bladder Cancer Residual Disease
Authors: Chiara Venegoni, Silvia Tortorella, Alessandra Caliendo, Irene Locatelli, Alessia Di Coste, Erica Locatelli, Filippo Capancioni, Emanuela Bua, Simona Camorani, Andrea Salonia, Francesco Montorsi, Jithin Jose, Marco Moschini, Laura Cerchia, Mauro Comes Franchini, Massimo Alfano
Journal: Advanced Healthcare Materials (2025)

Abstract The limitations of current diagnostic imaging techniques and therapies for bladder cancer are associated with and responsible for the recurrence and progression of residual disease, with an impact on social costs and quality of life of patients. This study delivers a cost‐effective solution for the detection of bladder cancer residual disease, which is represented by the early detection of bladder cancer lesions &lt; 1 mm. Urine‐stable 34‐mer SH‐terminated 2′F‐Py‐RNA aptamer that recognizes the integrin α5β1, expressed by 81% of human high‐grade non‐muscle invasive bladder cancer, is developed. The intravesical instillation of aptamer‐conjugated gold nanorods as contrast agent for photoacoustic imaging is validated in a preclinical model of orthotopic bladder cancer expressing the integrin α5β1. The photoacoustic signal of gold nanorods remains on the tumor surface for 3 h and allows early detection of cancer lesions &lt; 1 mm. The aptamer is internalized into lysosomes, an opportunity that paves the way for lysosomal‐mediated drug release in tumor cells. This study highlights the potential of urine‐stable aptamer for the delivery of a solution to target the residual high‐grade bladder cancer disease.