tbuckley/cabot-search huggingface dataset:
Corticosteroid-dependent association between prognostic peripheral blood cell-free DNA levels and neutrophil-mediated NETosis in patients with glioblastoma
Authors: Jacob E. Till, Nicholas J. Seewald, Zachariya Yazdani, Zhuoyang Wang, Dominique Ballinger, Heather Samberg, Siri Dandu, Camilla Macia, Melinda Yin, Aseel Abdalla, Timothy Prior, Shivani Shah, Thara Patel, Emily McCoy, Maikel Mansour, Carson A. Wills, Veronica Bochenek, Jonathan Serrano, Matija Snuderl, Richard E. Phillips, Donald M. O'Rourke, Nduka M. Amankulor, Ali Nabavizadeh, Arati S. Desai, Kandace Gollomp, Zev A. Binder, Wanding Zhou, Stephen J. Bagley, Erica L. Carpenter
Journal: Clinical Cancer Research (2025)

Non-invasive prognostic biomarkers to inform clinical decision-making are an urgent unmet need for the management of patients with glioblastoma (GBM). We previously showed that higher circulating cell-free DNA concentration [ccfDNA] is associated with worse survival in GBM. However, the biology underlying this is unknown. We prospectively enrolled 129 patients with treatment-naïve GBM with blood drawn prior to initial resection (baseline) and at time of first post-radiotherapy MRI. We performed ccfDNA methylation deconvolution to determine cellular sources of ccfDNA. ELISA was performed to detect citrullinated H3 (citH3), a marker of neutrophil extracellular traps (NETs). Multiplex proteomic analysis was used to measure soluble inflammatory proteins. We found that neutrophils contributed the highest proportion of prognostic ccfDNA. The percentage of ccfDNA derived from neutrophils was correlated with total [ccfDNA], but only in patients receiving pre-operative corticosteroids. At baseline and on-therapy, [citH3] was significantly higher in the plasma of patients with GBM receiving corticosteroids compared to corticosteroid-naïve GBMs or no-cancer controls. Unsupervised hierarchical clustering of ccfDNA methylation patterns yielded two clusters, with one enriched for patients with the NETosis phenotype and who received corticosteroids. Unsupervised clustering of circulating inflammatory proteins yielded similar results. These data suggest neutrophil-mediated NETosis is the dominant source of prognostic ccfDNA in patients with GBM and may be associated with glucocorticoid exposure. If further studies show that pharmacological inhibition of NETosis can mitigate the deleterious effects of corticosteroids, these plasma markers will have important clinical utility as non-invasive correlative biomarkers.
Risk of HPV-associated precancer and cancer in women with systemic lupus erythematosus
Authors: Kanwal Zahid Siddiqi, Louise Baandrup, Louise Diederichsen, Rasmus Hertzum-Larsen, Henrik Christian Bidstrup Leffers, Søren Jacobsen, Susanne Krüger Kjær
Journal: Annals of the Rheumatic Diseases (2025)

We aimed to compare the occurrence of human papillomavirus (HPV)-associated precancer and cancer in a nationwide cohort of women with systemic lupus erythematosus (SLE) with general female population rates. In the nationwide Patient Registry, we identified all women in Denmark with a first diagnosis of SLE recorded during 1996-2021 (N = 5092). The cohort was followed up in nationwide registries for HPV-associated precancer and cancer until 2022. Standardised incidence ratios (SIRs) were computed with 95% CIs overall and stratified by age at SLE diagnosis and follow-up time. Compared with general population rates, women with SLE had increased rates of cervical (SIR, 2.3; 95% CI, 2.0-2.7), vaginal (SIR, 4.3; 95% CI, 1.1-9.5), vulvar (SIR, 3.7; 95% CI, 2.3-5.5), and anal (SIR, 4.3; 95% CI, 1.7-8.1) precancers. Increased cancer rates were observed for cervix, anus, and oropharynx, but only the SIR for oropharyngeal cancer was near statistical significance (SIR, 2.5; 95% CI, 0.9-4.9). The increased SIRs for precancers and cancers sustained throughout follow-up and were higher in women diagnosed with SLE at age <50 years compared with ≥50 years, but CIs were overlapping. Women in this nationwide SLE cohort had twice the risk of cervical precancer (vs the general population) and up to 5-fold increased risk of the individual noncervical anogenital precancers. Rates of oropharyngeal cancer and the anogenital cancers were not statistically significantly increased; however, estimates were based on few cases.
Anti-CD19 CAR T cell therapy induces antibody seroconversion and complete B cell depletion in the bone marrow of a therapy-refractory patient with ANCA-associated vasculitis
Authors: Ioanna Minopoulou, Artur Wilhelm, Fredrik Albach, Arnd Kleyer, Edgar Wiebe, Simon Schallenberg, Anja Fleischmann, Mareike Frick, Frederik Damm, Julia Gogolok, Sebastian Serve, Benjamin Nick Locher, Dominic Borie, Vincent Casteleyn, Robert Biesen, Thomas Dörner, Tobias Alexander, Jan Zernicke, Kamran Movassaghi, Marie Luise Hütter-Krönke, Eva Schrezenmeier, Adrian Schreiber, Udo Schneider, Lars Bullinger, Gerhard Krönke, Olaf Penack, David Simon
Journal: Annals of the Rheumatic Diseases (2025)
Genetic burden of lupus increases the risk of transition from normal to preclinical autoimmune conditions via antinuclear antibody development
Authors: Sehwan Chun, So-Young Bang, Ayeong Kwon, Chan Young Kim, Soojin Cha, Young-Chang Kwon, Young Bin Joo, Soo-Kyung Cho, Chan-Bum Choi, Yoon-Kyoung Sung, Ji-Young Han, Tae-Hwan Kim, Jae-Bum Jun, Dae Hyun Yoo, Hye-Soon Lee, Kwangwoo Kim, Sang-Cheol Bae
Journal: Annals of the Rheumatic Diseases (2025)

This study aimed to investigate the association between the genetic burden of systemic lupus erythematosus (SLE) and the loss of tolerance to self-nuclear antigens in the preclinical stage. We analysed genetic data from 349 Korean individuals who tested positive for autoantibodies in the preclinical stage, along with 33,596 healthy controls and 2057 patients with SLE. Genome-wide and pathway-specific polygenic risk scores (PRSs) of SLE were calculated based on 180 known non-human leukocyte antigen (non-HLA) SLE loci, HLA-DRB1 classical alleles, and predefined immune-related pathways to subsequently correlate with clinical phenotypes, particularly the presence of antinuclear antibodies (ANAs) at various titre thresholds. Individuals with preclinical autoimmune conditions exhibited significantly higher SLE PRSs than healthy controls (P = 2.99 × 10-5), with a significantly upward trend between ANA titres and PRS (P = 1.12 × 10-3). Stratification analysis revealed that preclinical-stage individuals with PRSs exceeding the means of age- and sex-matched PRSs among patients with SLE were at a significantly higher risk of ANA development (odds ratio = 2.25; P = 8.12 × 10-3 at a dilution factor of 1:80). Pathway-specific PRS analysis identified the significant enrichment of SLE-risk effects in nine pathways, such as signalling related to reactive oxygen species production, T cell receptor, B cell receptor, and cytokines, in ANA-positive preclinical individuals (Padjusted < 0.05). Our findings illustrate that the genetic burden of SLE may lead to a crucial transition from normal to preclinical autoimmune conditions prior to the pathogenic stage by increasing the susceptibility to and levels of ANAs.
Periductal fibroblasts participate in liver homeostasis, fibrosis, and tumorigenesis
Authors: Shan-Shan Wang, Jia Yuan, Xinyu Thomas Tang, Xiujuan Yin, Ke Fang, Lin Veronica Chen, Zhenggang Ren, Bo O. Zhou
Journal: The Journal of Experimental Medicine (2025)

Hepatic fibroblasts comprise groups of stromal cells in the liver that are phenotypically distinct from hepatic stellate cells. However, their physiology is poorly understood. By single-cell RNA sequencing, we identified Cd34 and Dpt as hepatic fibroblast–specific genes. Cd34-CreER labeled periportal-venous and periductal fibroblasts, but few pericentral-venous fibroblasts. Cd34+ fibroblasts generated ∼25% of myofibroblasts in periportal fibrosis and ∼40% of cancer-associated fibroblasts (CAFs) in intrahepatic cholangiocarcinoma (ICC). Myofibroblast formation by Cd34+ fibroblasts required Tgfbr2. Depletion of Cd34+ fibroblasts increased the frequency of the ductal epithelial cells under homeostasis and accelerated the progression of ICC. Dpt-CreER labeled periportal- and pericentral-venous fibroblasts, but much less periductal fibroblasts. Dpt+ cells generated ∼15% of myofibroblasts in periportal fibrosis, but few myofibroblasts in pericentral fibrosis or CAFs in ICC. Thus, an orthogonal combination of Cd34-CreER and Dpt-CreER dissected the fates of periductal, periportal-venous, and pericentral-venous fibroblasts. Both periductal and periportal-venous fibroblasts contribute to liver fibrosis. Periductal fibroblasts also contribute to ductal homeostasis and ICC progression.
Colorectal cancer incidence in steatotic liver disease (MASLD, MetALD, and ALD)
Authors: Takefumi Kimura, Nobuharu Tamaki, Shun-Ichi Wakabayashi, Naoki Tanaka, Takeji Umemura, Namiki Izumi, Rohit Loomba, Masayuki Kurosaki
Journal: Clinical Gastroenterology and Hepatology (2025)
Microalgae-based bacteria for oral treatment of ASD through enhanced intestinal colonization and homeostasis
Authors: Rongrong Yang, Li Ma, Huan Peng, Yifang Zhai, Gengyao Zhou, Linjuan Zhang, Lixia Zhuo, Wei Wu, Yuxi Guo, Jiao Han, Linlin Jing, Xinyu Zhou, Xiancang Ma, Yan Li
Journal: Theranostics (2025)

Rationale: Exogenous supplementation of beneficial intestinal bacteria can alleviate the behavioural symptoms of psychiatric disorders, such as autism spectrum disorder (ASD), through gut-brain interactions. However, the application of beneficial bacteria, such as Lactobacillus reuteri (L. reuteri), for treating ASD is hindered by limited gut colonization. Methods: Utilizing Spirulina platensis (SP) as a natural microcarrier for intestinal bacteria, a safer and more natural binding approach was employed to bind intestinal bacteria to the surface of SP to produce SP-intestinal bacteria. Due to the high adhesion efficiency and long residence time of SP in the intestines, SP-intestinal bacteria exhibit stronger intestinal colonization ability and better therapeutic effects on ASD. Results: SP is an effective carrier that can bind and deliver bacteria of different shapes and with different gram-staining properties. SP-intestinal bacteria exhibited enhanced colonization capabilities both ex vivo and in vivo. Further research showed that SP-L. reuteri had greater intestinal colonization efficiency than L. reuteri. SP-L. reuteri showed a stronger therapeutic effect on alleviating social deficits in an ASD mouse model by modulating the gut microbiota, enhancing intestinal barrier integrity, reducing lipopolysaccharide entry into the blood and mediating the neuroinflammatory response in the paraventricular thalamic nucleus. Conclusions: This study reports a microalgae-assisted intestinal bacterial delivery system for enhancing intestinal bacterial transplantation for gut-brain axis- or other intestinal-related diseases.
OASL promotes immune evasion in pancreatic ductal adenocarcinoma by enhancing autolysosome-mediated degradation of MHC-I
Authors: Xin Xing, Xia-Qing Li, Shi-Qi Yin, Hong-Tai Ma, Shu-Yu Xiao, Aziguli Tulamaiti, Yan Yang, Shu-Heng Jiang, Li-Peng Hu, Zhi-Gang Zhang, Yan-Miao Huo, Dong-Xue Li, Xiao-Mei Yang, Xue-Li Zhang
Journal: Theranostics (2025)

Rationale: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive malignancy with a global prevalence and poor prognosis, largely due to immune escape mechanisms. However, the potential reasons for the decreased infiltration of cytotoxic T lymphocytes (CTLs) in PDAC remain inadequately understood. In this study, we aimed to elucidate the molecular mechanisms contributing to the low-CTLs infiltration in patients with PDAC. Methods: Bioinformatic analyses were used to identify key factors associated with low-CTLs infiltration in PDAC and the role of oligoadenylate synthetase-like (OASL) was mainly focused in our study. Immunohistochemistry (IHC) was used to assess the relationship between the expression of OASL and the prognosis of patients. Western blotting, Flow cytometry, Co-immunoprecipitation and Immunofluorescence were applied to elucidate the molecular mechanism by which OASL mediates immune escape in PDAC. The orthotopic PDAC models were constructed to evaluate the effects of OASL-knockdown on CD8+ T cells infiltration and tumor growth in vivo. Results: OASL was found to be significantly upregulated in PDAC and negatively correlated with the major histocompatibility complex class I (MHC-I) expression, which is associated with worse patient prognosis. Notably, OASL-knockdown leads to a significant increase in CD8+ T cell infiltration and slows tumor growth in vivo. Mechanistic studies revealed that OASL -knockdown restored the total and surface MHC-I level through impairing neighbor of BRCA1 gene 1 (NBR1)-mediated autophagy-lysosomal degradation of MHC-I. Conclusions: Targeting OASL enhances the immune response in PDAC, providing a novel therapeutic strategy to improve outcomes in PDAC patients.
Edaravone-Encapsulated Agonistic Micelles Rescue Ischemic Brain Tissue by Tuning Blood-Brain Barrier Permeability: Erratum
Authors: Qu Jin, Yu Cai, Sihan Li, Haoran Liu, Xingyu Zhou, Chunqiang Lu, Xihui Gao, Jun Qian, Jun Zhang, Shenghong Ju, Cong Li
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.18219.].
Redox Regulation of Stem-like Cells Though the CD44v-xCT Axis in Colorectal Cancer: Mechanisms and Therapeutic Implications: Erratum
Authors: Huai-Qiang Ju, Yun-Xin Lu, Dong-Liang Chen, Tian Tian, Hai-Yu Mo, Xiao-Li Wei, Jian-Wei Liao, Feng Wang, Zhao-Lei Zeng, Helene Pelicano, Mitzi Aguilar, Wei-Hua Jia, Rui-Hua Xu
Journal: Theranostics (2025)

[This corrects the article DOI: 10.7150/thno.14848.].
NSUN2-mediated m<sup>5</sup>C modification drives alternative splicing reprogramming and promotes multidrug resistance in anaplastic thyroid cancer through the NSUN2/SRSF6/UAP1 signaling axis
Authors: Xiukun Hou, Qiman Dong, Jie Hao, Min Liu, Junya Ning, Mei Tao, Zhongyu Wang, Fengli Guo, Dongmei Huang, Xianle Shi, Ming Gao, Dapeng Li, Xiangqian Zheng
Journal: Theranostics (2025)

Rationale: Anaplastic thyroid carcinoma (ATC) is an extraordinarily aggressive form of thyroid cancer, frequently presenting with locally advanced infiltration or distant metastases at the time of initial diagnosis, thus missing the optimal window for surgical intervention. Consequently, systemic chemotherapy and targeted therapies are vital for improving the prognosis of ATC. However, ATC exhibits significant resistance to conventional treatments, highlighting the need to elucidate the biological mechanisms underlying this drug resistance and identify novel therapeutic targets to overcome it. Methods: We conducted a comprehensive analysis of both bulk and single-cell RNA sequencing (scRNA-seq) data from ATC samples to screen for m5C modification-related genes associated with multidrug resistance (MDR). We then performed IC50 assays, flow cytometry, and employed a spontaneous tumorigenic ATC mouse model with Nsun2 knockout to demonstrate that NSUN2 promotes MDR in ATC. To investigate the mechanisms of NSUN2-mediated drug resistance, we generated NSUN2-knockout ATC cell lines and performed transcriptomic, proteomic, and MeRIP-seq analyses. Additionally, RNA sequencing and alternative splicing analyses were conducted to determine global changes upon NSUN2 knockout. We further explored the underlying mechanisms of the NSUN2/SRSF6/UAP1 axis through glycoprotein staining, denaturing IP ubiquitination, nuclear-cytoplasmic fractionation, and PCR. Lastly, we evaluated the synergistic effects of a small-molecule NSUN2 inhibitor with anticancer agents both in vitro and in vivo. Results: Our findings reveal that NSUN2 expression correlates significantly with MDR in ATC. NSUN2 operates as a "writer" and ALYREF as a "reader" of m5C on SRSF6 mRNA, inducing alternative splicing reprogramming and redirecting the splice form of the UAP1 gene from AGX1 to AGX2. As a result, AGX2 enhances the N-linked glycosylation of ABC transporters, stabilizing them by preventing ubiquitination-mediated degradation. Furthermore, an NSUN2 inhibitor reduces NSUN2 enzymatic activity and diminishes downstream target expression, presenting a novel, promising therapeutic approach to overcome MDR in ATC. Conclusions: These findings suggest that the NSUN2/SRSF6/UAP1 signaling axis plays a vital role in MDR of ATC and identify NSUN2 as a synergistic target for chemotherapy and targeted therapy in ATC.
DLGAP5 enhances bladder cancer chemoresistance by regulating glycolysis through MYC stabilization
Authors: Zhao Deng, Fenfang Zhou, Mingxing Li, Wan Jin, Jingtian Yu, Gang Wang, Kaiyu Qian, Lingao Ju, Yi Zhang, Yu Xiao, Xinghuan Wang
Journal: Theranostics (2025)

Rationale: Bladder cancer (BLCA), one of the most lethal urological tumors, exhibits high rates of recurrence and chemoresistance, particularly to gemcitabine (GEM). Understanding the mechanisms of GEM resistance is crucial for improving therapeutic outcomes. Our study investigates the role of DLGAP5 in promoting GEM resistance through modulation of glycolysis and MYC protein stability in BLCA cells. Methods: We utilized various BLCA cell lines and clinical tissue samples to analyze the impact of DLGAP5 on GEM resistance. Through biochemical assays, protein interaction studies, and gene expression analyses, we examined how DLGAP5 interacts with USP11 and MYC, assessed the effects on MYC deubiquitination and stability. The influence of these interactions on glycolytic activity and GEM resistance was also evaluated via mouse subcutaneous xenograft model and spontaneous BLCA model. Results: Our findings indicate that DLGAP5 enhances GEM resistance by stabilizing MYC protein via deubiquitination, a process mediated by USP11. DLGAP5 was found to facilitate the interaction between USP11 and MYC, promoting MYC-driven transcription of DLGAP5 itself, thereby creating a positive feedback loop. This loop leads to sustained MYC accumulation and increased glycolytic activity, contributing to GEM resistance in BLCA cells. Conclusion: The study highlights the critical role of DLGAP5 in regulating MYC protein stability and suggests that disrupting the DLGAP5-USP11-MYC axis may provide a novel therapeutic approach to overcome GEM resistance in BLCA. DLGAP5 represents a potential target for therapeutic intervention aimed at mitigating chemoresistance in bladder cancer BLCA.
Collagen-targeted PET imaging for progressive experimental lung fibrosis quantification and monitoring of efficacy of anti-fibrotic therapies
Authors: Alexandre Magno Maneschy Dias, Olivier Burgy, Mathieu Moreau, Victor Goncalves, Lenny Pommerolle, Romain Douhard, Alan Courteau, Alex Helbling, Mélanie Guillemin, John Simonet, Alexandra Oudot, Carmen Garrido, Philippe Bonniaud, Françoise Goirand, Bertrand Collin, Pierre-Simon Bellaye
Journal: Theranostics (2025)

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by an excessive collagen deposition ultimately leading to tissue stiffening and functional decline. Beyond IPF, other progressive pulmonary fibrosis are often associated with connective tissue diseases and may develop in ∼18-32% of patients. Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression without curing it. The current lack of biomarker to accurately assess and predict disease progression and therapy efficacy for IPF remains a major clinical concern. Methods: In our study, collagen deposition was monitored in bleomycin-induced lung fibrosis in mice by in vivo molecular imaging using a collagen-targeted radiopharmaceutical, [68Ga]Ga-NODAGA-collagelin. Fibrosis progression was also monitored using computed tomography, the gold standard technique to detect lung fibrosis in patients. Results: We demonstrated that the bleomycin-induced increase in collagen lung content can be accurately quantified by [68Ga]Ga-NODAGA-collagelin PET imaging in correlation with disease stage and severity. The lung uptake of [68Ga]Ga-NODAGA-collagelin was mainly found in fibrotic areas of lungs in bleomycin-receiving mice. Most interestingly, [68Ga]Ga-NODAGA-collagelin PET imaging allowed the in vivo non-invasive monitoring of nintedanib efficacy as well as the anti-fibrotic effect of the JAK inhibitor, tofacitinib. Conclusion: Thus, collagen-targeted PET imaging appears as a promising non-invasive tool for staging, monitoring and prediction of disease progression and therapy efficacy towards personalized medicine in IPF.
Cancer-control outcomes with [<sup>177</sup>Lu]Lu-PSMA Radioligand Therapy in elderly, frail or comorbid mCRPC patients
Authors: Mike Wenzel, Carolin Siech, Cristina Cano Garcia, Clara Humke, Daniel Groener, Maximilian Kriegmair, Markus Graefen, Tobias Maurer, Georg Salomon, Severine Banek, Felix K H Chun, Philipp Mandel
Journal: Theranostics (2025)

Rationale: [177Lu]Lutetium prostate-specific membrane antigen radioligand therapy ([177Lu]Lu-PSMA) is EMA-approved for certain indications in metastatic castration resistant prostate cancer (mCRPC). However, cancer-control outcomes in specific and trial-underrepresented subgroups are scant. Methods: We relied on the FRAMCAP database to elaborate progression-free (PFS) and overall (OS) survival in elderly (≥75 yrs), frail (ECOG status ≥1) mCRPC patients or those with cardiovascular disease (CVD) treated with [177Lu]Lu-PSMA. Results: Of 312 [177Lu]Lu-PSMA mCRPC patients, 76% were ≤75 vs. 24% >75 years. Patients >75 years received [177Lu]Lu-PSMA more frequently within the first three mCRPC lines (85% vs. 62%) and harbored more frequently ECOG status ≥2 (13% vs. 4.3%, both p < 0.01). In PFS and OS analyses, no significant difference between patients aged ≤75 vs. >75 years was observed (hazard ratios [HR] 0.97 & 0.85, both p≥0.4) with median PFS of 12.7 vs. 11.7 and OS of 15.1 vs. 19.8 months. In ECOG-stratified analyses, no PFS difference was observed, with significantly better OS for ECOG 0 vs. ≥1 (HR 1.69, p < 0.01), but not after further multivariable adjustment. In CVD-stratified analyses, PFS failed to provide significant differences between CVD vs. no CVD (HR: 1.44, p = 0.051). However, in OS analyses, significant worse OS for CVD mCRPC [177Lu]Lu-PSMA patients was observed (HR: 1.93, p < 0.01). After multivariable adjustment, CVD was an independent predictor for worse PFS and OS (both p < 0.01). Conclusions: Real-world evidence suggests equally effective cancer-control outcomes in elderly and frail mCRPC patients treated with [177Lu]Lu-PSMA. However, patients with CVD are of higher risk for shorter PFS and OS.
Metabolic regulation of myeloid-derived suppressor cells in tumor immune microenvironment: targets and therapeutic strategies
Authors: Hong Wang, Fei Zhou, Wenqing Qin, Yun Yang, Xiaojiaoyang Li, Runping Liu
Journal: Theranostics (2025)

Cancer remains a major challenge to global public health, with rising incidence and high mortality rates. The tumor microenvironment (TME) is a complex system of immune cells, fibroblasts, extracellular matrix (ECM), and blood vessels that form a space conducive to cancer cell proliferation. Myeloid-derived suppressor cells (MDSCs) are abundant in tumors, and they drive immunosuppression through metabolic reprogramming in the TME. This review describes how metabolic pathways such as glucose metabolism, lipid metabolism, amino acid metabolism, and adenosine metabolism have a significant impact on the function of MDSCs by regulating their immunosuppressive activity and promoting their survival and expansion in tumors. The review also explores key metabolic targets in MDSCs and strategies to modulate MDSC metabolism to improve the tumor immune microenvironment and enhance anti-tumor immune responses. Understanding these pathways can provide insight into potential therapeutic targets for modulating MDSC activity and improving outcomes of cancer immunotherapies.