tbuckley/cabot-search huggingface dataset:
Leucine-rich α-2 glycoprotein 1 (LRG1) during inflammatory complications after allogeneic stem cell transplantation and CAR-T cell therapy
Authors: Sarah Mertlitz, Katarina Riesner, Martina Kalupa, Nora Uhlig, Steffen Cordes, Lydia Verlaat, Mina Jamali, Ningyu Li, Hadeer Mohamed Elsayed Rasheed Mohamed, Lars Bullinger, Stephen Moss, John Greenwood, Jerome Jatzlau, Petra Knaus, Pedro Vallecillo-Garcia, Olaf Penack
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Previous data indicated that the leucine-rich α-2 glycoprotein 1 (LRG1) pathway contributes to vascular dysfunction during cancer growth. Therapeutic targeting of LRG1 normalized tumor vessel dysfunction and enhanced the efficacy of anti-cancer adoptive T cell therapy. A major clinical problem after allogeneic hematopoietic stem cell transplantation (alloHSCT) and after chimeric antigen receptor (CAR) T-cell therapy is the induction of hyperinflammatory side effects, which are typically associated with severe endothelial dysfunction. Methods We investigated LRG1 in preclinical models and in patient samples. Results In prospective studies, we found elevated LRG1 serum levels in patients with cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome after CAR-T-cell therapy as well as in patients with acute graft-versus-host disease (aGVHD) after alloHSCT. In preclinical models of aGVHD, we found vasculature-associated LRG1 upregulation as well as LRG1 pathway gene upregulation. The genetic deletion of LRG1 in alloHSCT donors and in alloHSCT recipients led to reduced clinical and histological aGVHD. In line with this, LRG1 deletion led to clinically and histologically reduced disease severity in experimental inflammatory models of colitis (dextran sulfate sodium colitis) and paw edema. LRG1 deletion reduced inflammation-related vascular leakiness, endothelial cell proliferation, and migration. Conclusions The current data support the hypothesis that LRG1 is an attractive therapeutic target after alloHSCT and after CAR-T cell therapy for cancer because of its role in dysfunctional tumor vessels as well as in inflammatory complications.
Targeting NAT10 attenuates homologous recombination via destabilizing DNA:RNA hybrids and overcomes PARP inhibitor resistance in cancers
Authors: Zhu Xu, Mingming Zhu, Longpo Geng, Jun Zhang, Jing Xia, Qiang Wang, Hongda An, Anliang Xia, Yuanyuan Yu, Shihan Liu, Junjie Tong, Wei-Guo Zhu, Yiyang Jiang, Beicheng Sun
Journal: Drug Resistance Updates (2025)
Targeting cTRIP12 counteracts ferroptosis resistance and augments sensitivity to immunotherapy in pancreatic cancer
Authors: Hongyi Lin, Shuncang Zhu, Yinhao Chen, Jinpeng Lu, Chengke Xie, Chengyu Liao, Xiaoxiao Huang, Ge Li, Yongding Wu, Zhiyuan Li, Jianfei Hu, Xinquan Lin, Yifeng Tian, Qiaowei Li, Zuwei Wang, Shi Chen
Journal: Drug Resistance Updates (2025)

Current therapeutic strategies for pancreatic ductal adenocarcinoma (PDAC) have limited efficacy in increasing patient survival rates, largely due to ferroptosis resistance and immunosuppression. The aim of this study is to identify molecular mechanisms associated with ferroptosis resistance and immunosuppression in PDAC tumour cells. Circular RNA sequencing (circRNA-seq) was performed on clinical samples to identify potential circRNAs that mediate ferroptosis resistance. C11-BODIPY staining, FerroOrange staining, the glutathione ratio, malondialdehyde quantification, and transmission electron microscopy were employed to assess ferroptosis. RNA pulldown, mass spectrometry, RNA immunoprecipitation, and coimmunoprecipitation assays were conducted to investigate the molecular mechanisms involved. A HuNSG mouse xenograft tumour model was utilized to validate therapeutic agents. A circRNA derived from TRIP12 (cTRIP12) was identified in PDAC samples resistant to ferroptosis. cTRIP12 knockdown increased the sensitivity of PDAC cells to ferroptosis and immunotherapy. Subsequent mechanistic studies revealed that cTRIP12 specifically binds to the O-linked N-acetylglucosamine transferase (OGT) protein and increases intracellular O-GlcNAcylation levels, leading to increased protein levels of ferritin heavy chain (FTH) and PD-L1 in tumour cells. Notably, high cTRIP12 expression suppressed ferroptosis sensitivity and increased immune resistance in PDAC cells by functioning as a protein scaffold through its interaction with OGT and protein kinase R-like endoplasmic reticulum kinase (PERK). cTRIP12 inhibition induced ferroptosis in PDAC cells by reducing FTH and PD-L1 expression and synergistically increased the immunotherapy efficacy. In vivo animal experiments confirmed that the triple therapy consisting of GSK2656157, erastin, and anti-CTLA-4 effectively suppressed the progression of PDAC in tumours with high cTRIP12 expression. We elucidated the molecular mechanisms underlying the simultaneous occurrence of ferroptosis resistance and immune suppression in PDAC patients. Our study provides a novel therapeutic strategy that could promote ferroptosis in tumour cells and increase immunotherapy efficacy.
Thermoresistant flagellin-adjuvanted cancer vaccine combined with photothermal therapy synergizes with anti-PD-1 treatment
Authors: Jayalakshmi Thiruppathi, Veena Vijayan, Hye Suk Hwang, Yong Jun Bang, Vandara Loeurng, Seol Hee Hong, Aravindkumar Sundaram, In-Kyu Park, Shee Eun Lee, Joon Haeng Rhee
Journal: Journal for ImmunoTherapy of Cancer (2025)

Background Cancer immunotherapy, leveraging the immune system to target and eradicate cancer cells, has transformed cancer treatment paradigms. Immune checkpoint inhibitors (ICIs) are used in a wide array of cancers, but only a limited fraction of patients are responding. Cancer vaccines could elicit antigen-specific immune responses and establish long-term immune memory, preventing recurrence and metastasis. Despite their promising profiles, ICIs and cancer vaccines by themselves are often insufficient to overcome the immunosuppressive tumor microenvironment (TME) and recurrence/metastasis. Addressing these challenges is crucial for improving cancer immunotherapy outcomes. Methods The targeted liposomal formulation (TLIF), displaying Cyclic RGD (cRGD) peptide on the surface and encapsulating ICG and thermoresistant flagellin (FlaB) inside, was used for photothermal therapy (PTT), which was designed to induce robust immunogenic cell death (ICD) and release tumor antigens (TAs). We employed a mouse breast cancer model amenable to PTT. Utilizing a bilateral DD-Her2/neu tumor implantation model, we evaluated local and abscopal effects of combinatorial approaches employing PTT, FlaB-adjuvanted peptide vaccine (FlaB-Vax), and anti-PD-1 treatment. FlaB-Vax was designed to trigger tumor-associated antigen (TAA)-specific immune responses, which will trigger specific anti-tumor immunity. TLIF-PTT aimed to reduce tumor burden and induce ICD-mediated TA liberation for epitope spreading. Sustained anti-tumor immune memory was assessed by orthotopic rechallenging cured mice with the DD-Her2/neu tumor cells. Results The combination of TLIF-PTT and FlaB-Vax provided significantly enhanced primary tumor suppression, with strong abscopal effects and long-lasting immune memory. The addition of anti-PD-1 therapy further improved long-term relapse-free survival, highlighting the potential of this combinatorial approach to induce durable antitumor immunity and sustainably prevent cancer recurrence and metastasis. Conclusion This study demonstrates that the combination of TLIF-PTT and FlaB-Vax synergistically induced synergistic anti-tumor immune responses, which were efficaciously potentiated by anti-PD-1 treatment for recurrence-free long-term survival.
Osteoarthritis increases the risk of inflammatory arthritis due to immune checkpoint inhibitors associated with tissue-resident memory T cells
Authors: Matthieu Paiola, Daniel M Portnoy, Luke Yi Hao, Shoiab Bukhari, Robert J Winchester, Brian S Henick, Adam Mor, Yevgeniya Gartshteyn
Journal: Journal for ImmunoTherapy of Cancer (2025)

Objective Immune checkpoint inhibitors (ICIs) have significantly advanced cancer treatment, but they can also lead to immune-related adverse events (irAEs), including inflammatory arthritis. Understanding the risk factors and underlying mechanisms of irAE pathogenesis is crucial for optimal patient management. Increasing evidence suggests that ICI-mediated activation of tissue-resident memory T cells (T RM ) significantly eliminates cancer cells and is associated with irAE-related colitis and dermatitis. However, it remains unknown why the development of these irAEs is restricted to a subset of patients. We hypothesized that osteoarthritis (OA) associated tissue damage and chronic inflammation lead to the recruitment and differentiation of joint T RM cells, predisposing individuals to ICI-induced arthritis. Methods Using a comprehensive approach, we compared the prevalence of OA in patients with irAE-arthritis to those with irAE non-arthritis and those without irAEs. Additionally, we used advanced immunophenotyping techniques to characterize T-cell populations in the blood and synovial fluid of patients with OA and irAE-arthritis. Results Our findings revealed a significantly higher prevalence of OA in patients who developed irAE-arthritis than controls. Furthermore, the multivariable analysis identified OA, body mass index, and smoking as independent risk factors for the development of irAE-arthritis. T RM cells expressing programmed cell death protein-1 (PD-1) were the predominant synovial T cells in OA joints. These cells were directly targeted by ICIs, resulting in an inflammatory immune response and the transition from OA to irAE-arthritis. Conclusion This study, the first of its kind, identifies OA as a significant risk factor for irAEarthritis. It reveals a potential mechanism by which ICIs activate PD-1-positive T RM cells in OA joints, resulting in tissue inflammation and irAE-arthritis. This research could significantly enhance the management and treatment of patients with cancer receiving ICIs.
Beneficial effects of vascular endothelial growth factor B gene transfer in the aged heart
Authors: Nivethitha Manickam, Ibrahim Sultan, Josefine Panthel, Haris Kujundzic, Ariane Fischer, Katja Schmitz, Mariano Ruz Jurado, David Rodriguez Morales, David John, Simone-Franziska Glaser, Kathrin A Stilz, Pedro Felipe Malacarne, Ralf Peter Brandes, Thomas Braun, Carolin Lerchenmüller, Fynn Betge, Wesley T Abplanalp, Kari Alitalo, Stefanie Dimmeler, Julian U G Wagner
Journal: Cardiovascular Research (2025)

Abstract Aim Members of the VEGF family are crucial modulators of vascular and neural function. While VEGFA signaling has been shown to mitigate several aging-related cardiac phenotypes and prolong survival in aged mice, the role of VEGFB in cardiac aging remains underexplored. In this study, we identify a significant decline in Vegfb expression, particularly of its soluble isoform Vegfb186, in aged mouse and human hearts. To assess the therapeutic potential of VEGFB in aging-associated cardiac pathologies, we used AAV9-mediated gene transfer to overexpress Vegfb186 in 18-month-old male C57Bl/6J mice. Method and results VEGFB is known to exhibit vascular and neuroprotective effects that we assessed in the ageing heart. In the aged heart, doses of Vegfb186 overexpression that had only a modest effect on the vascular endothelium prevented age-induced diastolic dysfunction and fibrosis. Vegfb186 treatment additionally restored sympathetic and sensory nerve fiber density and increased heart rate variability. Although Vegfb186 overexpression induced cardiac hypertrophy, our findings indicated that this hypertrophy was compensatory rather than pathological as Vegfb186 overexpression corrected the elevated cardiomyocyte length-to-width-ratio observed in aged hearts, a metric typically indicative of pathological remodeling. Cardiac single-nucleus RNA sequencing of the hearts and in vitro analysis of the cardiomyocytes indicated upregulation of the STAT3 signal transduction pathway as a potential contributor of VEGFB-induced cardiac hypertrophy. Conclusions Our findings demonstrate that Vegfb186 overexpression partially reverses age-related cardiac pathologies such as diastolic dysfunction and fibrosis. This work highlights VEGFB as a potential therapeutic target for combating cardiac aging and its associated dysfunctions.
INCREASED RISK OF CUTANEOUS SQUAMOUS CELL CARCINOMAS IN PATIENTS WITH SÉZARY SYNDROME: A NATIONWIDE MULTICENTER RETROSPECTIVE STUDY
Authors: Louise Guillon, Caroline Ram-Wolff, Serge Boulinguez, Marie Beylot-Barry, Michel D'incan, Henri Adamski, Sarah Faiz, Yannick Le Corre, Stéphane Dalle, Florent Amatore, Axelle Cornillault, Guillaume Chaby, Anne-Benedicte Duval-Modeste, Sophie Dalac, Saskia Oro, Henri Montaudié, Charlene Nardin, Cedric Lenormand, Eve Maubec, Pierre-Emmanuel Stoebner, Olivier Dereure
Journal: Journal of the American Academy of Dermatology (2025)
Metal‐Organic Frameworks for the Therapy of Inflammatory Diseases
Authors: Heng Zhao, Christian Serre, Nathalie Steunou
Journal: Advanced Healthcare Materials (2025)

Inflammation is a natural immune response triggered by harmful external or internal stimuli. However, when inflammation fails to resolve and restore basal homeostasis, it can lead to various inflammatory diseases such as rheumatoid arthritis (RA), inflammatory bowel disease (IBD), and diabetic chronic wound (DCW). The modulation of inflammation follows a highly complex mechanism, and monotherapy is often insufficient for treating such conditions. Therefore, developing next-generation nanocarriers for anti-inflammatory drug delivery and multi-target combination therapies is critical. Metal-organic frameworks (MOFs), a class of porous coordination polymers with large surface areas and adaptable porosity, have emerged as promising drug delivery systems (DDS) due to their biodegradability, high drug loading capacity, stimuli-responsive drug release, and ease of functionalization. Over the past five years, MOFs have shown significant promise in treating inflammatory diseases, either as DDS or as intrinsic anti-inflammatory and anti-oxidative agents. Additionally, hybrid MOFs, which combine MOFs with nanozymes, offer a multifunctional anti-inflammatory platform with great potential. This review intends to provide a comprehensive review of the recent development of MOF-based nanomedicines for the therapy of inflammatory diseases. The challenges and future directions of research into the use of MOFs in the treatment of these diseases will also be discussed.
Recognition of glycine versus non‐glycine citrulline motifs dictates the <scp>HLA</scp> class <scp>II</scp> association of anti‐citrullinated protein antibodies ‐ insights from autoantibody profiling of 6900 Scandinavian rheumatoid arthritis patients
Authors: Linda Mathsson Alm, Helga Westerlind, Isabel Gehring, Monika Hansson, Nasim Ghasemzadeh, Jessica Rojas‐Restrepo, Saedis Saevarsdottir, Joe Sexton, Siri Lillegraven, Espen Haavardsholm, Bente Glintborg, Hilde Berner Hammer, Tore K. Kvien, Merete Lund Hetland, Leonid Padyukov, Johan Askling, Caroline Grönwall
Journal: Arthritis & Rheumatology (2025)

Rheumatoid arthritis (RA) associated anti-citrullinated protein antibodies (ACPA) target various antigens by binding short citrulline-amino acid motifs, resulting in heterogeneous ACPA-profiles among patients. Here we analyzed ACPA-patterns by recognized citrulline-motifs in relation to the RA risk factors HLA-DRB1 shared epitope (SE) alleles and history of smoking. Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (CCP2) isotypes, 15 anti-Cit- and four anti-Carb/Acet-peptide-IgG, were centrally measured in 6,907 patients from five Scandinavian RA cohorts using fluoroenzyme immunoassay and a custom-made multiplex solid-phase microarray. HLA-DRB1 SE alleles were imputed from SNP genotyping data. Single-citrulline peptides derived from four multi-citrulline peptides (Cit Fibα36-50, Cit Fibβ60-74, Cit TNC5, Cit Vim60-75) showed differential binding patterns, supporting recognition of citrulline-motifs rather than long peptides. Four citrulline-peptides (Cit Fibβ36-52, Cit Fibβ60-74-Cit3, Cit Fil307-324, Cit Vim60-75-Cit1) captured 97% of IgG anti-CCP2+ patients. Patient subsets based on ACPA, anti-Carb/Acet, and RF displayed differences in ACPA composition and disease activity, but not comorbidities. Different ACPA overlapped, but when dichotomizing patients based on high reactivity to peptide citrulline-motifs, only ACPA to non-glycine citrulline-motif associated with HLA-SE alleles. In IgG anti-CCP2+ patients, 90% of those with only high non-glycine ACPA were HLA-SE allele carriers, compared to 67% in the group with glycine-motif only ACPA (OR=4.5). Smoking status associated with IgA and glycine-motif ACPA. While citrulline-glycine-motifs are prevalent ACPA-targets, our data reveals that HLA-SE alleles are primarily associated with ACPA to non-glycine citrulline-motifs, providing insight in ACPA T-cell dependance. Yet, the etiological significance of ACPA targeting different protein structures remains unknown.
Impact of postpartum physical activity on maternal anthropometrics: a systematic review and meta-analysis
Authors: Matthew J Gervais, Stephanie-May Ruchat, Muhammad Usman Ali, Talia Sjwed, Brittany A Matenchuk, Sarah Meyer, Michelle F Mottola, Kristi B Adamo, Allison Sivak, Margie H Davenport
Journal: British Journal of Sports Medicine (2025)

This systematic review and meta-analysis examined the relationship between postpartum exercise and maternal postpartum anthropometrics. Systematic review with random-effects meta-analysis and meta-regression. Online databases were searched from database inception until 12 January 2024. Randomised controlled trials (RCTs) written in any language were eligible if they contained information on the population (postpartum women and people); intervention (frequency, intensity, duration, volume or type of exercise, alone ('exercise-only') or in combination with other interventions (eg, dietary; 'exercise+cointervention')); comparator (no exercise) and outcomes (anthropometric measures including weight, postpartum weight retention (PPWR), body mass index (BMI), fat mass, lean body mass (LBM), body fat percentage, waist circumference, hip circumference or waist-hip ratio). 64 RCTs (n=12 684 participants) from 20 countries were included. Moderate to high certainty of evidence showed that exercise-only interventions reduced weight by 1.34 kg (18 studies, n=771; 95% CI -2.06 to -0.61, I2 0%), BMI by 0.73 kg/m2 (14 studies, n=662; 95% CI -1.21 to -0.25, I2 60%) and fat mass by 1.55 kg (5 studies, n=135; 95% CI -3.01 to -0.09, I2 0%) compared with no exercise. The duration of the exercise interventions ranged from 3 months to 3 years. Dose-response analysis found 560 MET-min/week of exercise (eg, 120 min/week of brisk walking) was associated with 1 kg/m2 reduction in BMI. Low certainty of evidence showed that exercise-only interventions had no effect on LBM (5 RCTs, n=135; standardised mean difference -0.13; 95% CI -0.48, 0.21, I2 0%) compared with no exercise. These findings highlight physical activity as an effective intervention to improve postpartum anthropometrics and reduce PPWR. CRD42022359282.
On the probability of reaching high peaks in fitness landscapes by adaptive walks
Authors: Yang Li, Jianzhi Zhang
Journal: Molecular Biology and Evolution (2025)

Abstract Adaptive evolution can be described by an uphill walk in a fitness landscape. However, climbing the global peak in a multi-peak landscape is improbable because of the high chance of being trapped at a local peak. Nonetheless, over three-quarters of simulated adaptive walks in the fitness landscape of the Escherichia coli dihydrofolate reductase (DHFR) gene were reported to end at the highest 14% of peaks, suggesting that biological systems may be substantially more evolvable than commonly thought. To investigate the cause and generality of this observation, we estimate in empirical and theoretical fitness landscapes the probability of reaching high peaks by adaptive walks (PHP), where high peaks refer to the highest 1, 5, 14, or 25% of all peaks. We find that (1) PHP varies substantially among landscapes, (2) PHP in empirical landscapes is generally comparable to or smaller than that in same-size Rough Mount Fuji landscapes of similar ruggedness, and (3) lowering landscape ruggedness boosts PHP. As observed in DHFR, we find in every examined landscape a positive correlation between the fitness of a peak and its basin size, which is the number of genotypes that can reach the peak through adaptive walks. Yet, this correlation does not guarantee a large PHP because of the influences of other factors. We conclude that evolvability depends on the specific fitness landscape and that the large PHP in the DHFR landscape is not a general property of empirical or theoretical fitness landscapes.
Steroid acne: fluorescence under ultraviolet light
Authors: Lin Wang, Cheng Tan
Journal: British Journal of Dermatology (2025)

A 22-year-old female with a history of allergic bronchopulmonary aspergillosis, treated with glucocorticoids and itraconazole, developed monomorphic perifollicular eruptions on her face, diagnosed as steroid acne. The skin examination revealed comedones and papules, with Wood’s light examination confirming Cutibacterium acnes colonization. After discontinuing glucocorticoids, the rash improved within two months.
SWI/SNF complexes govern ontology-specific transcription factor function in MYC-subtype atypical teratoid rhabdoid tumor
Authors: Cody L Nesvick, Liang Zhang, Yuqian Yan, Alexander Q Wixom, Feda H Hamdan, Jizhi Ge, Jacob B Anderson, Alexandre Gaspar-Maia, Steven A Johnsen, David J Daniels
Journal: Neuro-Oncology (2025)

Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is a deadly central nervous system embryonal tumor caused by loss of SMARCB1, a core subunit of SWI/SNF chromatin remodeling complexes. SMARCB1-deficient cancers are defined by loss of cell differentiation-associated enhancers, but how SWI/SNF interacts with other arbiters of cell differentiation (specifically lineage-specific transcription factors (TFs)) remains poorly understood. Methods We leveraged a multi-omics approach, patient-derived ATRT cells and patient-derived orthotopic xenografts to investigate the interplay of SWI/SNF with lineage-specific TFs in a clinically relevant setting. Results We observe that an activating protein 1 (AP-1)-dependent transcriptional regulatory network is lost in ATRT, and AP-1 and lineage-specific TFs TEAD1 and ZIC2 require SMARCB1 for enhancer binding. SMARCB1-dependent SWI/SNF integrates transcriptional functions of lineage-specific TFs into a core regulatory circuit that depends on the AP-1 subunit cJUN, whose expression is determined by a SMARCB1-dependent super enhancer that is lost in ATRT-MYC. In the absence of SMARCB1, lineage-specific TFs are sequestered to promoters, where they maintain core transcriptional programs necessary for cell survival. Targeting residual, promoter-proximal TF activity by a protein degrader of the SWI/SNF ATPase SMARCA4 or small molecule inhibitors that indirectly inhibit AP-1 and TEAD activity abrogates expression of these networks, reducing cell viability in vitro and prolonging survival in an orthotopic patient-derived xenograft model. Conclusions These results demonstrate SWI/SNF complexes are critical for lineage-specific TF binding and activity at both promoters and enhancers. In the context of ATRT, these findings reveal a previously underappreciated therapeutic vulnerability in targeting residual promoter-proximal TF function in ATRT.
Towards Epigenetic-based Subtyping of Bladder Cancer: DNA Methylation Predicts Molecular Subtypes of Non–muscle-invasive Bladder Cancer
Authors: Minghao Yu, Anshita Goel, Benjamin Tura, Celina M Whalley, Kar Keung Cheng, Maurice P Zeegers, Nicholas D James, Lars Dyrskjøt, Douglas G Ward, Richard T Bryan, Roland Arnold
Journal: European Urology (2025)