tbuckley/cabot-search huggingface dataset:
Transcriptomic profiling of the airway epithelium in COPD links airway eosinophilia to type 2 inflammation and corticosteroid response
Authors: Clarus Leung, Hye Yun Park, Xuan Li, Graeme J. Koelwyn, Josie Tuong, Seyed Milad Vahedi, Fernando Sergio Leitao Filho, Julia S. Yang, Rachel L. Eddy, Stephen Milne, Min Hyung Ryu, Hiroto Takiguchi, Kentaro Akata, Seung Won Ra, Ji-Yong Moon, Hyun Kuk Kim, Yuji Cho, Kei Yamasaki, Stephan F. van Eeden, Tawimas Shaipanich, Stephen Lam, Janice M. Leung, Don D. Sin
Journal: European Respiratory Journal (2025)

Background A subset of COPD patients have high levels of eosinophils in the distal airways (“airway eosinophilia”). Objectives To compare the gene expression of type 2 inflammation in airway epithelial brushings of COPD patients with and without airway eosinophilia and to investigate the changes after inhaled corticosteroids (ICS). Methods Post-hoc analyses of the DISARM randomised controlled trial investigated the expression of airway inflammation (type 1, 2, and 17), IL-13, and mast cell gene signatures at baseline and after 12-week ICS treatment. Gene signatures were generated from RNA sequencing of airway epithelial brushings. Airway eosinophilia was defined as eosinophils&gt;1% of the total leukocyte count in bronchoalveolar lavage. Gene set enrichment analyses identified upregulated canonical pathways in airway eosinophilia. Results Among 58 COPD patients, 38% had airway eosinophilia at baseline. Patients with airway eosinophilia had more severe airflow obstruction and more radiographic emphysema than the non-eosinophilia group. Patients with airway eosinophilia showed a higher epithelial expression of type 2 airway inflammation and IL-13 and mast cell activation at baseline, but the expression of type 1 and type 17 airway inflammation was similar to patients without airway eosinophilia. The airway eosinophilia group showed an upregulation of canonical pathways related to type 2 immune response and asthma. Treatment with ICS for 12 weeks reduced the epithelial expression of type 2 inflammation and mast cell gene signatures in patients with airway eosinophilia, while this change was not significant in patients without airway eosinophilia. Conclusions Airway eosinophilia marks a subset of COPD patients with increased airway epithelial expression of type 2 inflammation and a response to ICS treatment.
<i>HMCN1</i> variants aggravate epidermolysis bullosa simplex phenotype
Authors: Shir Bergson, Ofer Sarig, Moshe Giladi, Janan Mohamad, Mariana Mogezel-Salem, Karina Smorodinsky-Atias, Ofir Sade, Bar Manori, Sari Assaf, Kiril Malovitski, Yarden Feller, Mor Pavlovsky, Stefan Hainzl, Thomas Kocher, Julia I. Hummel, Noy Eretz Kdosha, Lubna Gazi Khair, Roland Zauner, Josefina Pinon Hofbauer, Ruby Shalom-Feuerstein, Verena Wally, Ulrich Koller, Liat Samuelov, Yoni Haitin, Uri Ashery, Rotem Rubinstein, Eli Sprecher
Journal: The Journal of Experimental Medicine (2025)

Epidermolysis bullosa simplex (EBS) refers to a heterogeneous group of inherited skin disorders characterized by blister formation within the basal cell layer. The disease is characterized by marked variations in phenotype severity, suggesting co-inheritance of genetic modifiers. We identified three deleterious variants in HMCN1 that co-segregated with a more severe phenotype in a group of 20 individuals with EBS caused by mutations in KRT14, encoding keratin 14 (K14). HMCN1 codes for hemicentin-1. Protein modeling, molecular dynamics simulations, and functional experiments showed that all three HMCN1 variants disrupt protein stability. Hemicentin-1 was found to be expressed in human skin above the BMZ. Using yeast-2-hybrid, co-immunoprecipitation, and proximity ligation assays, we found that hemicentin-1 binds K14. Three-dimensional skin equivalents grown from hemicentin-1–deficient cells were found to spontaneously develop subepidermal blisters, and HMCN1 downregulation was found to reduce keratin intermediate filament formation. In conclusion, hemicentin-1 binds K14 and contributes to BMZ stability, which explains the fact that deleterious HMCN1 variants co-segregate with a more severe phenotype in KRT14-associated EBS.
Salvage treatment after covalent BTKi failure: An unmet need in clinical practice in Waldenstrom macroglobulinemia
Authors: Anna Maria Frustaci, Arianna Zappaterra, Andrea Galitzia, Andrea Visentin, Michele Merli, Rita Rizzi, Isacco Ferrarini, Simone Ferrero, Vanessa Innao, Claudia Baratè, Pierluigi Zinzani, Benedetta Puccini, Francesco Autore, Monica Tani, Angela Ferrari, Gioacchino Catania, Maura Nicolosi, Raffaella Pasquale, Marina Motta, Roberta Murru, Silvia Gambara, Francesca Rezzonico, Marzia Varettoni, Emanuele Cencini, Enrico Lista, Nicolò Danesin, Bianca Maria Granelli, Marina Deodato, Francesco Piazza, Alessandra Tedeschi
Journal: HemaSphere (2025)
Timing of circulating tumor DNA analysis aimed at guiding adjuvant treatment in colorectal cancer
Authors: Tenna V. Henriksen, Christina Demuth, Amanda Frydendahl, Jesper Nors, Marijana Nesic, Mads H. Rasmussen, Ole H. Larsen, Claudia Jaensch, Uffe S. Løve, Per V. Andersen, Thomas Kolbro, Ole Thorlacius-Ussing, Alessio Monti, Jeppe Kildsig, Peter Bondeven, Nis H. Schlesinger, Lene H. Iversen, Kåre A. Gotschalck, Claus L. Andersen
Journal: Clinical Cancer Research (2025)

Abstract Background: Multiple clinical trials investigate circulating tumor DNA (ctDNA) to guide adjuvant chemotherapy (ACT) in colorectal cancer. Timely ACT initiation necessitates early ctDNA testing, but the impact of postoperative cell-free DNA (cfDNA) and ctDNA dynamics remains unclear, particularly with cost-reducing input caps employed in some assays. This study investigates ctDNA detection at day14 versus day30, comparing whole-sample analysis with capping the cfDNA input, and evaluates single and dual timepoint assessments for ACT allocation. Patients and methods: In 2019-2023, 611 stage I-III colorectal cancer patients were enrolled. Blood was collected preoperatively, and postoperatively ~day14 and ~day30. The cfDNA levels were assessed using digital PCR, and ctDNA using tumor-informed digital PCR or targeted sequencing analyzing all cfDNA from 8mL of plasma. Results: Despite elevated cfDNA in 85% of day14 samples, performance was comparable between the two timepoints (sensitivity 31% vs 32%; specificity both 98%). A 50ng cfDNA input cap reduced ctDNA detection probability, impacting 78% of day14 samples and 65% of day30 samples. At both timepoints, ctDNA detection was prognostic of recurrence (day14: HR=9.0, 95%CI 5.5-14.8; day30: HR=12.5, 95%CI 7.6-20.4). In 74% of ctDNA-positive recurrence patients, both samples had ctDNA detected. An increase in ctDNA level from day14 to day30 was associated with shorter time to recurrence (Pearson R=-0.63, P=0.003). Combining the timepoints would increase sensitivity (36%) and allow earlier ACT start in 80% of patients. Conclusion: Early ctDNA sampling is feasible and highly prognostic. Supplemental later testing may improve sensitivity while allowing early ACT initiation for most ctDNA positive patients.
Tannic acid‑cerium nanoenzymes serve as broad-spectrum antioxidants to alleviate acute kidney injury by modulating macrophage polarization, mitophagy and endoplasmic reticulum stress
Authors: Huayu Fu, Yanhui Wang, Bangqi Huang, Zonghao Liang, Yumin Li, Zhong Cao, Jun Wu, Yi Zhao
Journal: Journal of Controlled Release (2025)
Corrigendum
Authors: Henry E Wiley, Ramaprasad Srinivasan, Jodi K Maranchie, Jay Chhablani, Ane Bundsbæk Bøndergaard Iversen, Anders Kruse, Eric Jonasch, Dan S Gombos, Tobias Else, Hakan Demirci, Benjamin L Maughan, M Elizabeth Hartnett, Hanna R Coleman, Wei Fu, Rodolfo F Perini, Yanfang Liu, W Marston Linehan, Emily Y Chew
Journal: Ophthalmology (2025)
Outcomes of patients with Richter transformation who received no prior chemoimmunotherapy for their CLL
Authors: Adam S. Kittai, Ying Huang, Sarah Miller, John N. Allan, Seema A. Bhat, David A. Bond, Danielle M. Brander, John C. Byrd, Julio C. Chavez, Elise Chong, Matthew S. Davids, Alexey V. Danilov, Wei Ding, Mark R. Dowling, Kaitlyn Dvorak-Kornaus, Hannah Freedman, Paul J. Hampel, Carrie Ho, Steven R. Hwang, Prioty Islam, Nikita Malakhov, Matthew Matasar, Cecelia Miller, Zulfa Omer, Sameer A. Parikh, Erin Parry, Kari G. Rabe, Philipp W. Raess, Manoj Rai, Lindsey Roeker, Joanna Rhodes, Kerry A. Rogers, Aditi Saha, Jake Schade, Hamish W. Scott, Mazyar Shadman, Geoffrey Shouse, Alan Skarbnik, Stephen Spurgeon, Deborah M. Stephens, Meghan C. Thompson, Philip A. Thompson, Yucai Wang, Max Yano, Jennifer A. Woyach
Journal: Blood Cancer Journal (2025)
stDyer enables spatial domain clustering with dynamic graph embedding
Authors: Ke Xu, Yu Xu, Zirui Wang, Xin Maizie Zhou, Lu Zhang
Journal: Genome biology (2025)

Spatially resolved transcriptomics (SRT) data provide critical insights into gene expression patterns within tissue contexts, necessitating effective methods for identifying spatial domains. We introduce stDyer, an end-to-end deep learning framework for spatial domain clustering in SRT data. stDyer combines Gaussian Mixture Variational AutoEncoder with graph attention networks to learn embeddings and perform clustering. Its dynamic graphs adaptively link units based on Gaussian Mixture assignments, improving clustering and producing smoother domain boundaries. stDyer's mini-batch strategy and multi-GPU support facilitate scalability to large datasets. Benchmarking against state-of-the-art tools, stDyer demonstrates superior performance in spatial domain clustering, multi-slice analysis, and large-scale dataset handling.
High WEE1 expression is independently linked to poor survival in multiple myeloma
Authors: Anish K. Simhal, Ross S. Firestone, Jung Hun Oh, Viswatej Avutu, Larry Norton, Malin Hultcrantz, Saad Z. Usmani, Kylee H. Maclachlan, Joseph O. Deasy
Journal: Blood Cancer Journal (2025)

Current prognostic scores in multiple myeloma (MM) currently rely on disease burden and a limited set of genomic alterations. Some studies have suggested gene expression panels may predict clinical outcomes, but none are presently utilized in clinical practice. The tyrosine kinase WEE1 is a critical cell cycle regulator during the S-phase and G2M checkpoint. Abnormal WEE1 expression has been implicated in multiple cancers including breast, ovarian, and gastric cancers, but its prognostic signal in MM has not been thoroughly reported. We, therefore, analyzed the MMRF CoMMpass dataset (N = 659) and identified a high-risk group (top tertile) and a low-risk group (bottom tertile) based on WEE1 expression sorted in descending order. PFS was significantly different (p < 1e-9) between the groups, which was validated in two independent microarray gene expression profiling (GEP) datasets from the Total Therapy 2 (N = 341) and 3 (N = 214) trials. Our results show that WEE1 expression is prognostic independent of known biomarkers, differentiates outcomes associated with known markers, is upregulated independently of its interacting neighbors, and is associated with dysregulated P53 pathways. This suggests that WEE1 expression levels may have clinical utility in prognosticating outcomes in newly diagnosed MM and may support the application of WEE1 inhibitors to MM preclinical models. Determining the causes of abnormal WEE1 expression may uncover novel therapeutic pathways.
Laparoscopic versus open parenchymal preserving liver resections in the posterosuperior segments (ORANGE Segments): a multicentre, single-blind, randomised controlled trial
Authors: Jasper P Sijberden, Christoph Kuemmerli, Francesca Ratti, Mathieu D'Hondt, Robert P Sutcliffe, Roberto I Troisi, Mikhail Efanov, Robert S Fichtinger, Rafael Díaz-Nieto, Giuseppe M Ettorre, Aali J Sheen, Krishna V Menon, Marc G Besselink, Zahir Soonawalla, Somaiah Aroori, Rebecca Marino, Celine De Meyere, Ravi Marudanayagam, Giuseppe Zimmitti, Bram Olij, Zina Eminton, Lloyd Brandts, Clarissa Ferrari, Ronald M van Dam, Luca A Aldrighetti, Siân Pugh, John N Primrose, Mohammed Abu Hilal
Journal: The Lancet Regional Health - Europe (2025)
catGRANULE 2.0: accurate predictions of liquid-liquid phase separating proteins at single amino acid resolution
Authors: Michele Monti, Jonathan Fiorentino, Dimitrios Miltiadis-Vrachnos, Giorgio Bini, Tiziana Cotrufo, Natalia Sanchez de Groot, Alexandros Armaos, Gian Gaetano Tartaglia
Journal: Genome biology (2025)

Liquid-liquid phase separation (LLPS) enables the formation of membraneless organelles, essential for cellular organization and implicated in diseases. We introduce catGRANULE 2.0 ROBOT, an algorithm integrating physicochemical properties and AlphaFold-derived structural features to predict LLPS at single-amino-acid resolution. The method achieves high performance and reliably evaluates mutation effects on LLPS propensity, providing detailed predictions of how specific mutations enhance or inhibit phase separation. Supported by experimental validations, including microscopy data, it predicts LLPS across diverse organisms and cellular compartments, offering valuable insights into LLPS mechanisms and mutational impacts. The tool is freely available at https://tools.tartaglialab.com/catgranule2 and https://doi.org/10.5281/zenodo.14205831 .
Mechanisms of astrocyte aging in reactivity and disease
Authors: Holly K. Gildea, Shane A. Liddelow
Journal: Molecular Neurodegeneration (2025)

Normal aging alters brain functions and phenotypes. However, it is not well understood how astrocytes are impacted by aging, nor how they contribute to neuronal dysfunction and disease risk as organisms age. Here, we examine the transcriptional, cell biology, and functional differences in astrocytes across normal aging. Astrocytes at baseline are heterogenous, responsive to their environments, and critical regulators of brain microenvironments and neuronal function. With increasing age, astrocytes adopt different immune-related and senescence-associated states, which relate to organelle dysfunction and loss of homeostasis maintenance, both cell autonomously and non-cell autonomously. These perturbed states are increasingly associated with age-related dysfunction and the onset of neurodegeneration, suggesting that astrocyte aging is a compelling target for future manipulation in the prevention of disease.
Chronic subthalamic nucleus deep brain stimulation reduces pathological TrkB aggregates in a Parkinson’s disease rat model
Authors: Tobias Petschner, Katarina Hofman, Jia Zhi Chen, Thomas Andreska, Daniel Wolf, Susanne Knorr, Robert Blum, Muthuraman Muthuraman, Uwe Gbureck, Jens Volkmann, Michael Sendtner, Chi Wang Ip
Journal: Translational Neurodegeneration (2025)
Hippocampal P2X7 and A2A purinoceptors mediate cognitive impairment caused by long-lasting epileptic seizures
Authors: Meng-Juan Sun, Wen-Jing Ren, Ya-Fei Zhao, Xuan Li, Muhammad Tahir Khan, Xin-Yi Cheng, Hai-Yan Yin, Alexei Verkhratsky, Tobias Engel, Patrizia Rubini, Yong Tang, Peter Illes
Journal: Theranostics (2025)

Rationale: Cognitive impairment and depression are salient comorbidities of mesial temporal lobe epilepsy; it is still unclear whether this frequently drug resistant disease is a cause or consequence of hippocampal damage and its interplay with long-lasting seizure activity (status epilepticus; SE). Thus, a major therapeutic advance in this field is badly needed. Methods: We modeled enduring behavioral and electroencephalographic (EEG) seizures in mice by the intraperitoneal injection of kainic acid (KA), and measured the dynamics of the intracellular Ca2+ signals in the hippocampal CA1 area by fiber photometry. Learning and memory were controlled by the Morris Water-Maze and Novel Object Recognition tests on whole animals and by the induction of long-term potentiation in CA1 pyramidal neurons in brain slices. Depressive-like reactions were evaluated by the Tail Suspension, Forced Swim, and Sucrose Preference tests. Results: The intraperitoneal injection of the blood-brain permeable, highly selective, P2X7 and A2A receptor (R) antagonists, JNJ-47965567, and KW6002/SCH58261, respectively, counteracted the effects of KA-induced SE both on seizure activity and the increase of Ca2+ signals (as a measure of changes in the intracellular Ca2+ concentration) in neurons and astrocytes of the hippocampal CA1 area. In addition, these drugs also prevented the impairment of the hippocampus-dependent spatial and non-spatial learning abilities by KA-SE. The knockdown of P2X7Rs in CA1 astrocytes, but not neurons prevented the cognitive deterioration, suggesting that the release of astrocytic signaling molecules onto neighboring neurons might be the cause of this effect. In accordance with our observations, in hippocampal slices prepared from mice which underwent KA-SE, a selective sensitivity increases to the prototypic P2X7R agonist dibenzoyl-ATP (Bz-ATP) manifested in CA1 neurons. This sensitivity increase appeared to be due to a postsynaptic interference between P2X7Rs and the release of excitatory neurotransmitters during SE. In spite of a P2X7 and A2AR-mediated increase of Ca2+ signaling in the medial prefrontal cortex, no similar change was noted after KA-SE in depressive-like reactions or the open-field behavior. Conclusions: SE induced the release of ATP and adenosine from the hippocampus and in consequence decreased the cognitive abilities of mice. The pharmacological blockade of P2X7 and A2ARs prevented the SE-induced seizure activity and cognitive deterioration, but not depressive-like behavior.
Engineered Probiotic-Based Biomaterials for Inflammatory Bowel Disease Treatment
Authors: Guangze Sang, Bingkai Wang, Yujie Xie, Yu Chen, Feng Yang
Journal: Theranostics (2025)

Inflammatory bowel disease (IBD) is a chronic condition affecting the intestines, marked by immune-mediated inflammation. This disease is known for its recurrent nature and the challenges it presents in treatment. Recently, probiotic have gained attention as a promising alternative to traditional small molecular drugs and monoclonal antibody chemotherapies for IBD. Probiotic, recognized as a "living" therapeutic agent, offers targeted treatment with minimal side effects and the flexibility for biological modifications, making them highly effective for IBD management. This comprehensive review presents the latest advancements in engineering probiotic-based materials, ranging from basic treatment mechanisms to the modification techniques used in IBD management. It delves deep into how probiotic produces therapeutic effects in the intestinal environment and discusses various strategies to enhance probiotic's efficacy, including genetic modifications and formulation improvements. Additionally, the review addresses the challenges, practical application conditions, and future research directions of probiotic-based therapies in IBD treatment, providing insights into their feasibility and potential clinical implications.
7-nm Mn<sub>0.5</sub> Zn<sub>0.5</sub>Fe<sub>2</sub>O<sub>4</sub> superparamagnetic iron oxide nanoparticle (SPION): a high-performance theranostic for MRI and hyperthermia applications
Authors: Joo Young Lee, Yi Rang Na, Chul Min Na, Pyung Won Im, Hyung Woo Park, Min Kyu Kim, Yona Kim, Ji Hyeon You, Dong Su Kang, Hyo Eun Moon, Hye Ran Park, Min Gyu Kim, Pilhan Kim, Sung Hye Park, Hye Won Youn, Young Don Son, Yasushi Takemura, Chang Won Song, Daishun Ling, Yuanzhe Piao, Sun Ha Paek
Journal: Theranostics (2025)

Superparamagnetic iron oxide nanoparticles (SPIONs) are promising contrast agents for imaging-guided cancer therapies. However, challenges such as the requirement for a high alternating magnetic field (AMF), dosage limitations, and suboptimal imaging contrast have hindered their practical applications. Methods: First, the optimal doping ratio of Mn and Zn in MnxZn1-xFe2O4 nanoparticles synthesized using a modified high-temperature thermal decomposition method (mHTTD) was determined. Then, the magnetic and physical properties of the optimal 7-nm Mn0.5Zn0.5Fe2O4 SPIONs were systematically and comprehensively characterized via hysteresis measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM), X-ray diffraction (XRD), X-ray absorption fine structure (XAFS) spectroscopy, and X-ray absorption near edge structure (XANES) spectroscopy. Next, the stability, biosafety, biocompatibility, and theranostic performance of 7-nm Mn0.5Zn0.5Fe2O4 SPIONs in magnetic hyperthermia therapy (MHT) were evaluated by in vivo and in vitro studies involving mouse models, magnetic resonance imaging (MRI), and bioassays. The results were then compared with those for conventional SPIONs. Results: Under an AMF of 140 Oe at 100 kHz, 7-nm Mn0.5Zn0.5Fe2O4 SPIONs demonstrated significantly higher heat production than conventional SPIONs. Following surface modification with methoxy-PEG-silane, PEGylated 7-nm Mn0.5Zn0.5Fe2O4 SPIONs showed excellent monodispersity and magnetic properties, with an exceptionally high T2 relaxivity (r2). Conclusions: The high in vitro and in vivo theranostic performance of PEGylated 7-nm Mn0.5Zn0.5Fe2O4 SPIONs as efficient and stable contrast agents for treating glioblastoma, encompassing strengthened magnetic hyperthermia, activated anti-tumor immunity, and remarkable T2 contrast enhancement, underscores the potential of precisely designed ferrites to concurrently enhance the T2 contrast and magnetocaloric properties for optimal theranostic outcomes. Our study provides a compelling rationale for the development of tailored magnetic nanoprobes for improved glioblastoma theranostics.
The TMBIM1-YBX1 axis orchestrates MDSC recruitment and immunosuppressive microenvironment in pancreatic cancer
Authors: Xuhui Tong, Mingming Xiao, Jing Yang, Jin Xu, Wei Wang, Xianjun Yu, Si Shi
Journal: Theranostics (2025)

Background: Pancreatic ductal adenocarcinoma (PDAC) is notorious for its profoundly immunosuppressive nature. The complex crosstalk between diverse immune cell types and heterogeneous tumor cell populations shapes this challenging tumor immune microenvironment (TIME). In this study, the role of transmembrane BAX inhibitor motif-containing 1 (TMBIM1) in modulating the TIME and its potential as a therapeutic target in PDAC were investigated. Methods: RNA sequencing was used to assess differential gene expression between PANC-1 cells with TMBIM1 knockdown and control cells. Single-cell RNA sequencing further validated the role of TMBIM1 in modulating the expression of CCL2 and PD-L1. Mechanistic insights were gained through chromatin immunoprecipitation, ELISA, real-time quantitative PCR, and flow cytometry experiments. To evaluate the impact of TMBIM1 on immune cell dynamics, we employed an in vitro chemotaxis assay and an in vivo C57BL/6J mouse xenograft model to examine CD8+ T-cell activation and myeloid-derived suppressor cell (MDSC) infiltration. Additionally, the therapeutic potential of TMBIM1 knockdown combined with anti-PD-1 antibody treatment was investigated in PDAC animal models. Results: TMBIM1 was significantly upregulated in pancreatic cancer tissues and cell lines, driving pancreatic cancer cell proliferation, growth, and migration both in vitro and in vivo. Elevated TMBIM1 expression induced high infiltration of MDSCs and fostered an immunosuppressive tumor microenvironment. Mechanistically, TMBIM1 binds to the transcription factor Y box binding protein 1 (YBX1), which in turn increases the affinity of YBX1 for the PD-L1 and CCL2 gene promoters. This interaction results in their upregulation, leading to increased MDSC infiltration, thereby facilitating the immunosuppressive TIME in PDAC. Notably, the combination of TMBIM1 knockdown with anti-PD-1 therapy had a more potent antitumor effect than anti-PD-1 therapy alone. Conclusions: Our study reveals that the TMBIM1/YBX1 axis is a key driver of immune evasion in PDAC and shapes the immunosuppressive TIME through the upregulation of CCL2 and PD-L1 expression. These findings highlight TMBIM1 as a potential therapeutic target to sensitize PDAC to immunotherapy.