tbuckley/cabot-search huggingface dataset:
Inhibition of AXL ameliorates pulmonary fibrosis<i>via</i>attenuation of M2 macrophage polarization
Authors: Dong Ha Kim, Kyungtaek Im, In-Jeoung Baek, Yun Jung Choi, Hyeonjeong Lee, Da-Som Kim, Chae Won Lee, JaeYi Jeong, Kyosun Ban, Sang-Yeob Kim, Wonjun Ji, Jae Cheol Lee, Hyun-Yi Kim, Yoonji Lee, Yeongin Yang, Miyong Yun, Ho Cheol Kim, Chang Min Choi, Jin Kyung Rho
Journal: European Respiratory Journal (2025)

Rationale Although a relationship between the Gas6/AXL pathway and pulmonary fibrosis (PF) has been suggested, the precise mechanisms and clinical implications of the AXL pathway in idiopathic pulmonary fibrosis (IPF) are still unclear. Methods Constitutive and conditional AXL-knockout mice were generated and injected with bleomycin (BLM) to induce pulmonary fibrosis. The expression of AXL and macrophage subtypes in BLM-injected mice and patients with IPF was analysed using flow cytometry. The therapeutic effects of the AXL inhibitors were examined. Results AXL-deficient mice were resistant to BLM-induced pulmonary fibrosis and had a lower degree of M2-like macrophage differentiation than wild-type mice. Interestingly, AXL expression in monocytes was enhanced according to the progression of BLM-induced pulmonary fibrosis (PF), and these results were especially prominent in Ly6C high monocytes. Gene silencing or inhibitor treatment with AXL inhibited the differentiation of M2-like macrophages during bone marrow-derived macrophage (BMDMs) differentiation. These results were confirmed through experiments using AXL fl/fl LysMCre+ mice and systems with depletion and reconstitution of macrophages. In line with these results, patients with severe IPF had higher AXL expression in monocytes, high GAS6 levels, and an enhanced population of M2-like macrophages than those with mild IPF. Lastly, treatment with AXL inhibitors ameliorated BLM-induced PF and improved survival rate. Conclusions The AXL pathway in classical monocytes contributed to PF progression through the induction of M2-like macrophage differentiation. Therefore, targeting AXL may be a promising therapeutic option for PF.
Peptide-based PET/CT imaging visualizes PD-L1-driven radioresistance in glioblastoma
Authors: Yong Wang, Zhiguo Liu, Yang Li, Kelin Wang, Chunhui Yuan, Jian Shi, Jiazhong Ren, Shijie Wang, Jinping Wang, Miaoqing Zhao, Man Hu
Journal: Drug Resistance Updates (2025)
Pre-biologic disease trajectories are associated with morbidity burden and biologic treatment response in severe asthma
Authors: Marianne Baastrup Soendergaard, Frederikke Hjortdahl, Susanne Hansen, Anne-Sofie Bjerrum, Anna von Bülow, Ole Hilberg, Barbara Bonnesen Bertelsen, Claus Rikard Johnsen, Sofie Lock-Johansson, Roxana Vijdea, Linda Makowska Rasmussen, Johannes Martin Schmid, Charlotte Suppli Ulrik, Celeste Porsbjerg, Kjell Erik Julius Håkansson
Journal: European Respiratory Journal (2025)

Background Biologics can induce remission in some patients with severe asthma, however, little is known about pre-biologic disease trajectories and their association with outcomes from biological treatment. We aimed to identify long-term trajectories of disease progression in patients initiating biologics and investigate trajectory associations with disease burden and impact on biologic therapy efficacy. Methods Patients in the Danish Severe Asthma Registry initiating biologic therapy between 2016–2022 were included and followed retrospectively in prescription databases starting 1995. We performed sequence analysis for inhaled corticosteroid (ICS) treatment intensity over time combined with unsupervised trajectory clustering. Results In total, 755 patients were included and three pre-biologic disease trajectories were identified: Chronic severe asthma (26%), Gradual onset severe asthma (35%), Recent, sudden onset severe asthma (39%). Chronic severe asthma patients were older, had the longest disease duration (35 years), the most impaired pulmonary function, the highest comorbidity prevalence and the lowest employment rate. Recent, sudden onset severe asthma patients were younger, had shorter disease duration (5 years), more tobacco exposure and the least impaired lung function. Gradual onset severe asthma had an intermediate burden of disease. The Chronic severe asthma cluster demonstrated the lowest prevalence of remission (17%) compared to the Gradual onset severe asthma (29%) and Recent onset severe asthma (32%) clusters. Conclusions Three pre-biologic disease trajectories were identified, with increased disease duration and activity associating with asthma- and comorbidity burden. Early intervention may be key to prevent irreversible adverse outcomes for patients with severe asthma.
Autoimmune Tubulopathies
Authors: Pascal Houillier, Caroline Prot-Bertoye
Journal: Journal of the American Society of Nephrology (2025)

Abstract The renal tubule and collecting duct express a large number of proteins, all having putative immunoreactive motives. Therefore, all can be the target of pathogenic autoantibodies. However, autoimmune tubulopathies seem to be rare and we hypothesize that they are underdiagnosed. This review summarizes the current knowledge on autoimmune tubulopathies. We elected to classify tubulopathies according to the segment that is targeted, because this determines, at least in part, the phenotypic presentation. In the proximal tubule, autoantibodies can cause anti-brush border antibody disease, renal Fanconi syndrome, renal proximal tubular acidosis or tubulointerstitial nephritis and uveitis syndrome. Autoantibodies targeting the thick ascending limb of the loop of Henle can cause either acquired Bartter’s syndrome or hypomagnesemia with hypercalciuria, whereas autoantibodies targeting the distal convoluted tubule can cause acquired Gitelman’s syndrome. Finally, renal distal tubular acidosis or nephrogenic diabetes insipidus can be caused by autoantibodies targeting the collecting duct. In most instances, the characterization of the autoantibodies remains incomplete and the pathogenesis of the disease obscure. We believe it is important to increase the awareness of the physicians regarding autoantibodies-mediated tubular diseases in order to have a better estimation of the prevalence and to improve the care to patients. A research effort to increase the understanding of the pathogenesis of autoantibodies-mediated tubular diseases is also hoped for.
Loss of Cpt1a results in elevated glucose-fueled mitochondrial oxidative phosphorylation and defective hematopoietic stem cells
Authors: Jue Li, Jie Bai, Vincent T. Pham, Michihiro Hashimoto, Maiko Sezaki, Qili Shi, Qiushi Jin, Chenhui He, Amy Armstrong, Tian Li, Mingzhe Pan, Shujun Liu, Yu Luan, Hui Zeng, Paul R. Andreassen, Gang Huang
Journal: Journal of Clinical Investigation (2025)

Hematopoietic stem cells (HSCs) rely on self-renewal to sustain stem cell potential and undergo differentiation to generate mature blood cells. Mitochondrial fatty acid β-oxidation (FAO) is essential for HSC maintenance. However, the role of Carnitine palmitoyl transferase 1a (CPT1A), a key enzyme in FAO, remains unclear in HSCs. Using a Cpt1a hematopoietic specific conditional knock-out (Cpt1aΔ/Δ) mouse model, we found that loss of Cpt1a leads to HSC defects, including loss of HSC quiescence and self-renewal, and increased differentiation. Mechanistically, we find that loss of Cpt1a results in elevated levels of mitochondrial respiratory chain complex components and their activities, as well as increased ATP production, and accumulation of mitochondrial reactive oxygen species (mitoROS) in HSCs. Taken together, this suggests hyperactivation of mitochondria and metabolic rewiring via upregulated glucose-fueled oxidative phosphorylation (OXPHOS). In summary, our findings demonstrate a novel role for Cpt1a in HSC maintenance and provide insight into the regulation of mitochondrial metabolism via control of the balance between FAO and glucose-fueled OXPHOS.
NXP800 activates the unfolded protein response, altering AR and E2F function to impact castration-resistant prostate cancer growth
Authors: Jonathan Welti, Denisa Bogdan, Ines Figueiredo, Ilsa Coleman, Juan Jiménez Vacas, Kate Liodaki, Franziska Weigl, Lorenzo Buroni, Wanting Zeng, Ilona Bernett, Claudia Bertan, Theodoros I. Roumeliotis, Amandeep Bhamra, Jan Rekowski, Bora Gurel, Antje J. Neeb, Jian Ning, Dapei Li, Veronica S. Gil, Ruth Riisnaes, Susana Miranda, Mateus Crespo, Ana Ferreira, Nina Tunariu, Elisa Pasqua, Nicola Chessum, Matthew Cheeseman, Robert te Poele, Marissa Powers, Suzanne Carreira, Jyoti Choudhary, Paul Clarke, Udai Banerji, Amanda Swain, Keith Jones, Wei Yuan, Paul Workman, Peter S. Nelson, Johann S. de Bono, Adam Sharp
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Advanced prostate cancer (PCa) is invariably fatal with the androgen receptor (AR) being a major therapeutic target. AR signaling inhibitors have improved overall survival for men with advanced PCa, but treatment resistance is inevitable and includes reactivation of AR signaling. Novel therapeutic approaches targeting these mechanisms to block tumor growth is an urgent unmet clinical need. One attractive strategy is to target heat shock proteins critical to AR functional activity. Experimental Design: We first did transcriptome analysis on multiple castration-resistant PCa (CRPC) cohorts to correlate the association between the GO Cellular Response to Heat gene expression signature and overall survival. Next, we analyzed the impact of targeting the heat shock factor 1 (HSF1) pathway, with an inhibitor in clinical development, namely NXP800, in models of treatment-resistant PCa. Finally, we confirmed our mechanistic and phenotypic findings using an NXP800-resistant model and an in-vivo model of CRPC. Results: We report that in multiple CRPC transcriptome cohorts the GO Cellular Response to Heat gene expression signature associates with AR signaling and worse clinical outcome. We demonstrate the effects of targeting the HSF1 pathway, central to cellular stress, with an inhibitor in clinical development, namely NXP800 (formerly CCT361814), in PCa. Targeting the HSF1 pathway with the inhibitor NXP800 decreases HSP72 expression, activates the unfolded protein response, and inhibits AR- and E2F-mediated activity, inhibiting the growth of treatment-resistant PCa models. Conclusions: Overall, NXP800 has anti-tumor activity against treatment-resistant PCa models, including molecular subtypes with limited treatment options, supporting its consideration for PCa-specific clinical development.
Pushing the boundaries: future directions in the management of spinal muscular atrophy
Authors: Fiona Moultrie, Laura Chiverton, Isabel Hatami, Charlotte Lilien, Laurent Servais
Journal: Trends in Molecular Medicine (2025)

Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival. These therapies - with distinct mechanisms, routes of administration, dosing schedules, side effect profiles, and financial costs - have dramatically altered the clinical phenotypes of this condition and have presented fresh challenges for patient care. In this review article we discuss potential strategies to maximise clinical outcomes through early diagnosis and treatment, optimised dosing, use of therapeutic combinations and state-of-the-art physiotherapy techniques, and the development of innovative therapies targeting alternative mechanisms.
Robot-assisted Kidney Transplantation: The 8-year European Experience
Authors: Angelo Territo, Luca Afferi, Mireia Musquera, Josep Maria Gaya Sopena, Alessio Pecoraro, Riccardo Campi, Andrea Gallioli, Begoña Etcheverry, Thomas Prudhomme, Joris Vangeneugden, Milla Ortved, Andreas Røder, Philip Zeuschner, Alessandro Volpe, Rodrigo Garcia-Baquero, Burak Kocak, Idu Mirza, Michael Stockle, Erdem Canda, Paolo Fornara, Malene Rohrsted, Nicolas Doumerc, Karel Decaestecker, Sergio Serni, Francesc Vigues, Antonio Alcaraz, Alberto Breda
Journal: European Urology (2025)
Trastuzumab-Pertuzumab Plus Eribulin or Taxane as First-Line Chemotherapy for Human Epidermal Growth Factor 2–Positive Locally Advanced/Metastatic Breast Cancer: The Randomized Noninferiority Phase III EMERALD Trial
Authors: Toshinari Yamashita, Shigehira Saji, Toshimi Takano, Yoichi Naito, Michiko Tsuneizumi, Akiyo Yoshimura, Masato Takahashi, Junji Tsurutani, Tsuguo Iwatani, Masahiro Kitada, Hiroshi Tada, Natsuko Mori, Toru Higuchi, Tsutomu Iwasa, Kazuhiro Araki, Kei Koizumi, Hiroki Hasegawa, Yohei Uchida, Satoshi Morita, Norikazu Masuda
Journal: Journal of Clinical Oncology (2025)

PURPOSE Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC. METHODS In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.gov identifier: NCT03264547 /UMIN000027938), patients were randomly assigned (1:1) to receive eribulin 1.4 mg/m 2 once daily on days 1 and 8 (eribulin group) or a taxane (docetaxel 75 mg/m 2 once on day 1 or paclitaxel 80 mg/m 2 once daily on days 1, 8, and 15; taxane group) intravenously in a 21-day cycle, each with HP on day 1. The primary end point was progression-free survival (PFS; intention-to-treat population). Secondary end points included objective response rate, overall survival (OS), patient-reported quality of life (QoL), and safety. Noninferiority was tested using the stratified Cox proportional hazards model to estimate hazard ratios (HRs) for PFS events, with a noninferiority HR margin of 1.33. RESULTS Between August 2017 and June 2021, 446 patients (median age, 56.0 years) were enrolled. The median PFS was 14.0 and 12.9 months in the eribulin group (n = 224) and taxane group (n = 222 [docetaxel/paclitaxel, n = 186/36]), respectively (HR, 0.95 [95% CI, 0.76 to 1.19]), which confirmed the noninferiority of the study regimen. The median OS was 65.3 months in the taxane group but has not been reached in the eribulin group. Median time to QoL deterioration was numerically longer with eribulin than with taxane. Adverse event (AE) rates were similar, despite the longer duration of eribulin use. Infusion reaction, skin-related AEs, diarrhea, and edema were more common with taxane, whereas neutropenia was more common with eribulin. CONCLUSION The results suggested that eribulin + HP is an option for first-line treatment of locally advanced/metastatic HER2+ BC.
Adhesive and injectable hydrogel microspheres for NRF2-mediated periodontal bone regeneration
Authors: Yu Wang, Shanshan Jin, Yaru Guo, Yilong Lu, Xuliang Deng
Journal: International Journal of Oral Science (2025)

Abstract Regenerating periodontal bone defect surrounding periodontal tissue is crucial for orthodontic or dental implant treatment. The declined osteogenic ability of periodontal ligament stem cells (PDLSCs) induced by inflammation stimulus contributes to reduced capacity to regenerate periodontal bone, which brings about a huge challenge for treating periodontitis. Here, inspired by the adhesive property of mussels, we have created adhesive and mineralized hydrogel microspheres loaded with traditional compound cordycepin (MMS-CY). MMS-CY could adhere to the surface of alveolar bone, then promote the migration capacity of PDLSCs and thus recruit them to inflammatory periodontal tissues. Furthermore, MMS-CY rescued the impaired osteogenesis and ligament-forming capacity of PDLSCs, which were suppressed by the inflammation stimulus. Moreover, MMS-CY also displayed the excellent inhibitory effect on the osteoclastic activity. Mechanistically, MMS-CY inhibited the premature senescence induced by the inflammation stimulus through the nuclear factor erythroid 2-related factor (NRF2) pathway and reducing the DNA injury. Utilizing in vivo rat periodontitis model, MMS-CY was demonstrated to enhance the periodontal bone regeneration by improving osteogenesis and inhibiting the osteoclastic activity. Altogether, our study indicated that the multi-pronged approach is promising to promote the periodontal bone regeneration in periodontitis condition by reducing the inflammation-induced stem cell senescence and maintaining bone homeostasis.
Clinical evaluation of long-read sequencing-based episignature detection in developmental disorders
Authors: Mathilde Geysens, Benjamin Huremagic, Erika Souche, Jeroen Breckpot, Koenraad Devriendt, Hilde Peeters, Griet Van Buggenhout, Hilde Van Esch, Kris Van Den Bogaert, Joris Robert Vermeesch
Journal: Genome Medicine (2025)

A subset of developmental disorders (DD) is characterized by disease-specific genome-wide methylation changes. These episignatures inform on the underlying pathogenic mechanisms and can be used to assess the pathogenicity of genomic variants as well as confirm clinical diagnoses. Currently, the detection of these episignature requires the use of indirect methylation profiling methodologies. We hypothesized that long-read whole genome sequencing would not only enable the detection of single nucleotide variants and structural variants but also episignatures. Genome-wide nanopore sequencing was performed in 40 controls and 20 patients with confirmed or suspected episignature-associated DD, representing 13 distinct diseases. Following genomic variant and methylome calling, hierarchical clustering and dimensional reduction were used to determine the compatibility with microarray-based episignatures. Subsequently, we developed a support vector machine (SVM) for the detection of each DD. Nanopore sequencing-based methylome patterns were concordant with microarray-based episignatures. Our SVM-based classifier identified the episignatures in 17/19 patients with a (likely) pathogenic variant and none of the controls. The remaining patients in which no episignature was identified were also classified as controls by a commercial microarray assay. In addition, we identified all underlying pathogenic single nucleotide and structural variants and showed haplotype-aware skewed X-inactivation evaluation directs clinical interpretation. This proof-of-concept study demonstrates nanopore sequencing enables episignature detection. In addition, concurrent haplotyped genomic and epigenomic analyses leverage simultaneous detection of single nucleotide/structural variants, X-inactivation, and imprinting, consolidating a multi-step sequential process into a single diagnostic assay.
Adverse impact of metabolic dysfunction on fibrosis regression following direct-acting antiviral therapy: A multicenter study for chronic hepatitis C
Authors: Tom Ryu, Young Chang, Soung Won Jeong, Jeong-Ju Yoo, Sae Hwan Lee, Sang Gyune Kim, Young Seok Kim, Hong Soo Kim, Seung Up Kim, Jae Young Jang
Journal: Clinical and Molecular Hepatology (2025)

Background/Aims: Direct-acting antivirals (DAAs) effectively eradicate hepatitis C virus (HCV).This study investigated whether metabolic dysfunction influences the likelihood of fibrosis regression after DAA treatment in patients with chronic hepatitis C (CHC).Methods: This multicenter, retrospective study included 8,819 patients diagnosed with CHC who were treated with DAAs and achieved a sustained virological response (SVR) between January 2014 and December 2022.Fibrosis regression was defined as a 20% reduction in noninvasive surrogates for liver fibrosis, such as liver stiffness (LS) measured by vibrationcontrolled transient elastography (VCTE) and the fibrosis-4 (FIB-4) score.Hypercholesterolemia (h-TC) were defined as >200 mg/dL. Results:The median age of the study population was 59.6 years, with a predominance of male patients (n = 4,713, 57.3%).Genotypes 1, 2, and others were confirmed in 3,872 (46.2%), 3,487 (41.6%), and 1,024 (12.2%) patients, respectively.Diabetes mellitus (DM) was present in 1,442 (17.2%) patients and the median LS was 7.50 kPa (interquartile range, 5.30-12.50).Multivariate analysis revealed that the presence of DM and pre-DAA h-TC were independently associated with a decreased probability of fibrosis regression by VCTE Additionally, pre-DAA h-TC was independently associated with a decreased probability of fibrosis regression by the FIB-4. Conclusions: Metabolic dysfunction has an unfavorable influence on fibrosis regression inpatients with CHC who achieve SVR after DAA treatment.
Global Epidemiology of Alcohol-Related Liver Disease, Liver Cancer, and Alcohol Use Disorder, 2000–2021
Authors: Pojsakorn Danpanichkul, Luis Antonio Díaz, Kanokphong Suparan, Primrose Tothanarungroj, Supapitch Sirimangklanurak, Thanida Auttapracha, Hanna L. Blaney, Banthoon Sukphutanan, Yanfang Pang, Siwanart Kongarin, Francisco Idalsoaga, Eduardo Fuentes-López, Lorenzo Leggio, Mazen Noureddin, Trenton M. White, Alexandre Louvet, Philippe Mathurin, Rohit Loomba, Patrick S. Kamath, Jürgen Rehm, Jeffrey V. Lazarus, Karn Wijarnpreecha, Juan Pablo Arab
Journal: Clinical and Molecular Hepatology (2025)

Alcohol represents a leading burden of disease worldwide, including alcohol use disorder (AUD) and alcohol-related liver disease (ALD). We aim to assess the global burden of AUD, ALD, and alcohol-attributable primary liver cancer between 2000-2021. We registered the global and regional trends of AUD, ALD, and alcohol-related liver cancer using data from the Global Burden of Disease 2021 Study, the largest and most up-to-date global epidemiology database. We estimated the annual percent change (APC) and its 95% confidence interval (CI) to assess changes in age-standardized rates over time. In 2021, there were 111.12 million cases of AUD, 3.02 million cases of ALD, and 132,030 cases of alcohol-attributable primary liver cancer. Between 2000 and 2021, there was a 14.66% increase in AUD, a 38.68% increase in ALD, and a 94.12% increase in alcohol-attributable primary liver cancer prevalence. While the age-standardized prevalence rate for liver cancer from alcohol increased (APC: 0.59%, 95% confidence interval [CI] 0.52 to 0.67%) over these years, it decreased for ALD (APC: -0.71%, 95% CI -0.75 to -0.67%) and AUD (APC: -0.90%, 95% CI -0.94 to -0.86%). There was significant variation by region, socioeconomic development level, and sex. During the last years (2019-2021), the prevalence, incidence, and death of ALD increased to a greater extent in females. Given the high burden of AUD, ALD, and alcohol-attributable primary liver cancer, urgent measures are needed to prevent them at both global and national levels.
Burden of RSV infections among young children in primary care: a prospective cohort study in five European countries (2021–23)
Authors: Sarah F Hak, Valérie D V Sankatsing, Joanne G Wildenbeest, Roderick P Venekamp, Beatrice Casini, Caterina Rizzo, Mathieu Bangert, Daan Van Brusselen, Elizabeth Button, María Garcés-Sánchez, César García Vera, Rolf Kramer, Simon de Lusignan, Marc Raes, Adam Meijer, John Paget, Jojanneke van Summeren
Journal: The Lancet Respiratory Medicine (2025)
Efficacy, safety, and target engagement of dazukibart, an IFNβ specific monoclonal antibody, in adults with dermatomyositis: a multicentre, double-blind, randomised, placebo-controlled, phase 2 trial
Authors: David Fiorentino, Aaron R Mangold, Victoria P Werth, Lisa Christopher-Stine, Alisa Femia, Myron Chu, Amy C M Musiek, Jason C Sluzevich, Lauren V Graham, Anthony P Fernandez, Rohit Aggarwal, Kerri Rieger, Karen M Page, Xingpeng Li, Craig Hyde, Natalie Rath, Abigail Sloan, Barry Oemar, Anindita Banerjee, Mikhail Salganik, Christopher Banfield, Srividya Neelakantan, Jean S Beebe, Michael S Vincent, Elena Peeva, Ruth Ann Vleugels
Journal: The Lancet (2025)