tbuckley/cabot-search huggingface dataset:
First-in-Human Phase 1 study of a CD16A bispecific innate cell engager, AFM24, targeting EGFR-expressing solid tumors
Authors: Anthony El-Khoueiry, Omar Saavedra, Jacob Thomas, Claire Livings, Elena Garralda, Gabriele Hintzen, Laura Kohlhas, Dessislava Vanosmael, Joachim Koch, Erich Rajkovic, Paulien Ravenstijn, Paolo Nuciforo, Todd A. Fehniger, Mark Foster, Melissa M. Berrien-Elliott, Susanne Wingert, Sina Stäble, Daniela Morales-Espinosa, Delcia Rivas, Michael Emig, Juanita Lopez
Journal: Clinical Cancer Research (2025)

Abstract Purpose: Innate immune cell-based therapies have shown promising antitumor activity against solid and hematologic malignancies. AFM24, a bispecific innate cell engager, binds CD16A on natural killer (NK) cells/macrophages and EGFR on tumor cells, redirecting antitumor activity towards tumors. The safety and tolerability of AFM24 was evaluated in this Phase 1/2a dose escalation/dose expansion study in patients with recurrent or persistent, advanced solid tumors known to express EGFR. Methods: The main objective in Phase 1 was to determine the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). The primary endpoint was the incidence of dose-limiting toxicities (DLTs) during the observation period. Secondary endpoints included the incidence of treatment emergent adverse events and pharmacokinetics. Results: In the dose escalation phase, 35 patients received AFM24 weekly across seven dose cohorts (14–720 mg). One patient experienced a DLT of Grade 3 infusion-related reaction (IRR). IRRs were mainly reported after the first infusion; these were manageable with premedication and a gradual increase in infusion rate. Pharmacokinetics were dose-proportional and CD16A receptor occupancy on NK cells approached saturation between 320–480 mg. Paired tumor biopsies demonstrated activation of innate and adaptive immune responses within the tumor. Best objective response was stable disease in 10/35 patients; four had stable disease for 4.3–7.1 months. Conclusions: AFM24 was well tolerated with 480 mg established as the RP2D. AFM24 could be a novel therapy for patients with EGFR-expressing solid tumors with suitable tolerability and appropriate pharmacokinetic properties for further development in combination with other immuno-oncology therapeutics.
Intratumoral or Subcutaneous MK-2118, a Non-Cyclic Dinucleotide STING Agonist, With or Without Pembrolizumab for Advanced or Metastatic Solid Tumors or Lymphomas
Authors: Jason J. Luke, Randy F. Sweis, J. Randolph. Hecht, Reva Schneider, Mark N. Stein, Talia Golan, Timothy A. Yap, Anuradha Khilnani, Mo Huang, Runchen Zhao, Thomas Jemielita, Sandip Pravin. Patel
Journal: Clinical Cancer Research (2025)

We evaluated the non-cyclic dinucleotide stimulator of interferon genes agonist MK-2118 ± pembrolizumab in patients with advanced solid tumors or lymphomas. This first-in-human study (NCT03249792) enrolled patients with refractory, advanced solid tumors or lymphomas. Patients received intratumoral (IT) MK-2118 100-20,000 µg (arm 1), IT MK-2118 900-15,000 µg plus intravenous (IV) pembrolizumab 200 mg every 3 weeks (Q3W; arm 2), or subcutaneous (SC) MK-2118 5000-150,000 µg plus IV pembrolizumab 200 mg Q3W (arm 4); arm 3 (visceral injection of MK-2118) was not pursued. IT dosing used an accelerated titration design and modified toxicity probability interval method; SC dosing (arm 4) was started subsequent to arms 1 and 2. Primary objectives were safety/tolerability. MK-2118 pharmacokinetics were a secondary endpoint; objective responses and biomarkers were exploratory endpoints. 140 patients were enrolled (arm 1, n=27; arm 2, n=57; arm 4, n=56). Grade 3/4 treatment-related adverse events occurred in 22%, 23%, and 11% of patients, respectively, but no maximum tolerated dose was identified up to MK-2118 20,000, 15,000, and 150,000 µg across the 3 arms. Dose-dependent increases in MK-2118 systemic exposure were observed following IT and SC administration. Objective responses were seen in 0%, 6%, and 4% of patients, respectively. IT MK-2118 led to dose-dependent changes in STING-based blood RNA expression levels, interferon-gamma, interferon-gamma‒induced protein 10, and interleukin-6; SC MK-2118 did not generate dose-related immune responses. IT MK-2118 ± pembrolizumab and SC MK-2118 plus pembrolizumab had manageable toxicity and limited antitumor activity. IT but not SC administration demonstrated systemic immune effects.
Salt‐Compact Albumin as a New Pure Protein‐based Biomaterials: From Design to In Vivo Studies
Authors: Eya Aloui, Jordan Beurton, Claire Medemblik, Ludivine Hugoni, Igor Clarot, Ariane Boudier, Youri Arntz, Marcella De Giorgi, Jérôme Combet, Guillaume Fleith, Eric Mathieu, Naji Kharouf, Leyla Kocgozlu, Benoît Heinrich, Damien Favier, Michael Brender, Fouzia Boulmedais, Pierre Schaaf, Benoît Frisch, Philippe Lavalle
Journal: Advanced Healthcare Materials (2025)

Current biodegradable materials are facing many challenges when used for the design of implantable devices because of shortcomings such as toxicity of crosslinking agents and degradation derivatives, limited cell adhesion, and limited immunological compatibility. Here, a class of materials built entirely of stable protein is designed using a simple protocol based on salt-assisted compaction of albumin, breaking with current crosslinking strategies. Salt-assisted compaction is based on the assembly of albumin in the presence of high concentrations of specific salts such as sodium bromide. This process leads, surprisingly, to water-insoluble handable materials with high preservation of their native protein structures and Young's modulus close to that of cartilage (0.86 MPa). Furthermore, these materials are non-cytotoxic, non-inflammatory, and in vivo implantations (using models of mice and rabbits) demonstrate a very slow degradation rate of the material with excellent biocompatibility and absence of systemic inflammation and implant failure. Therefore, these materials constitute promising candidates for the design of biodegradable scaffolds and drug delivery systems as an alternative to conventional synthetic degradable polyester materials.
Helicobacter pylori and gastric cancer: mechanisms and new perspectives
Authors: Yantao Duan, Yonghu Xu, Yi Dou, Dazhi Xu
Journal: Journal of Hematology & Oncology (2025)

Gastric cancer remains a significant global health challenge, with Helicobacter pylori (H. pylori) recognized as a major etiological agent, affecting an estimated 50% of the world's population. There has been a rapidly expanding knowledge of the molecular and pathogenetic mechanisms of H. pylori over the decades. This review summarizes the latest research advances to elucidate the molecular mechanisms underlying the H. pylori infection in gastric carcinogenesis. Our investigation of the molecular mechanisms reveals a complex network involving STAT3, NF-κB, Hippo, and Wnt/β-catenin pathways, which are dysregulated in gastric cancer caused by H. pylori. Furthermore, we highlight the role of H. pylori in inducing oxidative stress, DNA damage, chronic inflammation, and cell apoptosis—key cellular events that pave the way for carcinogenesis. Emerging evidence also suggests the effect of H. pylori on the tumor microenvironment and its possible implications for cancer immunotherapy. This review synthesizes the current knowledge and identifies gaps that warrant further investigation. Despite the progress in our previous knowledge of the development in H. pylori-induced gastric cancer, a comprehensive investigation of H. pylori's role in gastric cancer is crucial for the advancement of prevention and treatment strategies. By elucidating these mechanisms, we aim to provide a more in-depth insights for the study and prevention of H. pylori-related gastric cancer.
Emerging targets of α-synuclein spreading in α-synucleinopathies: a review of mechanistic pathways and interventions
Authors: Grace Kuo, Ramhari Kumbhar, William Blair, Valina L. Dawson, Ted M. Dawson, Xiaobo Mao
Journal: Molecular Neurodegeneration (2025)

Abstract α-Synucleinopathies constitute a spectrum of neurodegenerative disorders, including Parkinson’s disease (PD), Lewy body dementia (LBD), Multiple System Atrophy (MSA), and Alzheimer’s disease concurrent with LBD (AD-LBD). These disorders are unified by a pathological hallmark: aberrant misfolding and accumulation of α-synuclein (α-syn). This review delves into the pivotal role of α-syn, the key agent in α-synucleinopathy pathophysiology, and provides a survey of potential therapeutics that target cell-to-cell spread of pathologic α-syn. Recognizing the intricate complexity and multifactorial etiology of α-synucleinopathy, the review illuminates the potential of various membrane receptors, proteins, intercellular spreading pathways, and pathological agents for therapeutic interventions. While significant progress has been made in understanding α-synucleinopathy, the pursuit of efficacious treatments remains challenging. Several strategies involving decreasing α-syn production and aggregation, increasing α-syn degradation, lowering extracellular α-syn, and inhibiting cellular uptake of α-syn are presented. The paper underscores the necessity of meticulous and comprehensive investigations to advance our knowledge of α-synucleinopathy pathology and ultimately develop innovative therapeutic strategies for α-synucleinopathies. Graphical Abstract
Improved Black Phosphorus Nanocomposite Hydrogel for Bone Defect Repairing: Mechanisms for Advancing Osteogenesis
Authors: Ailin Wu, Gaoqiang Ma, Yanhua Chen, Houda Gui, Baiyu Sun, Bing Zhang, Yingxue Liu, Sen Zhang, Guixue Lian, Dawei Song, Dongjiao Zhang
Journal: Advanced Healthcare Materials (2025)

Bone defects caused by fractures and diseases often do not heal spontaneously. They require external agents for repair and regeneration. Bone tissue engineering is emerging as a promising alternative to traditional therapies like autografts and allografts. Nanobiomaterials enhance osteoblast resistance to harsh environments by promoting cell differentiation. Black phosphorus (BP), a novel 2D material in biomedicine, displays unique osteogenic and antimicrobial properties. However, BP nanosheets still face clinical limitations like rapid degradation and high-dose cytotoxicity. To address these, the introduction of amino-silicon phthalocyanine (SiPc-NH2) is investigated to see if it can enhance BP dispersion, reduce BP oxidation, and improve stability and safety for better osteogenesis and antibacterial effects through noncovalent interactions (van der Waals, π-π stacking and electrostatic interactions). Here, the self-healing hydrogel is successfully designed using a step-by-step co-assembly of BP and SiPc-NH2. SiPc-NH2 as a "structural stabilizer" of BP nanosheets reconstructed well-dispersed BP-SiPc-NH2 nanosheets, which improves the biocompatibility of BP, reduces oxidation and enhances photothermal conversion, guaranteeing osteogenic and antimicrobial properties. Furthermore, findings show BP-SiPc-NH2-induced mitochondrial changes support osteogenesis by regulating the crosstalk between Hippo and Wnt signaling pathways-mediated mitochondrial homeostasis, and boosting cellular bioenergetics. Overall, this mitochondrial morphology-based BP-SiPc-NH2 strategy holds great promise for bone repair applications.
Endogenous Protein‐Modified Gold Nanorods as Immune‐Inert Biomodulators for Tumor‐Specific Imaging and Therapy
Authors: Chunyan Fang, Yueming Cai, Cui He, Ying Li, Lei He, Xiaoyan Wang, Yong Lu
Journal: Advanced Healthcare Materials (2025)

Abstract Engineered modifications of nanomaterials inspired by nature hold great promise for disease‐specific imaging and therapies. However, conventional polyethylene glycol modification is limited by immune system rejection. The manipulation of gold nanorods (Au NRs) modified by endogenous proteins (eP@Au) is reported as an engineered biomodulator for enhanced breast tumor therapy. The results show that eP@Au NRs neither activate inflammatory factors in vitro nor elicit rejection of immune responses in vivo. Tumor‐specific eP@Au NRs exhibit a dual‐modal imaging capability and trigger a mild photothermal effect under near‐infrared light irradiation, enabling highly efficient imaging and therapy of tumors. Transcriptome sequencing and confirmatory experiments reveal that the antitumor effect is mainly attributed to the repression of PI3K‐Akt/MAPK signaling pathways at the molecular level. This powerful and surprising in situ eP‐regulated biomodulation demonstrates the advantages of convenient fabrication, inert immunogenicity, and biocompatibility, providing an alternative strategy for biomedical imaging and therapy.
Adhesive and Conductive Fibrous Hydrogel Bandages for Effective Peripheral Nerve Regeneration
Authors: Subin Jin, Hyunjin Jung, Jihyang Song, Sumin Kim, Subeen Yoon, Jung Hyun Kim, Jung Seung Lee, Yong Jun Kim, Donghee Son, Mikyung Shin
Journal: Advanced Healthcare Materials (2025)

Abstract Peripheral nerve injury is a common disease resulting in reversible and irreversible impairments of motor and sensory functions. In addition to conventional surgical interventions such as nerve grafting and neurorrhaphy, nerve guidance conduits are used to effectively support axonal growth without unexpected neuroma formation. However, there are still challenges to secure tissue‐mimetic mechanical and electrophysiological properties of the conduit materials. Herein, the phenylborate‐tethered hydrogel‐assisted doping effect is elucidated on conductive polymers, enhancing peripheral nerve regeneration when used as a sutureless bandage on the injured nerve. The adhesive and conductive nerve bandage consists of biocompatible hyaluronic acid hydrogel microfibers produced by electrospinning, followed by in situ conductive polypyrrole polymerization on the fibrous mat. Particularly, phenylborate groups enable high adsorption of pyrrole without mechanical crack on the hydrogel network and allow tissue‐like stretchability and on‐nerve adhesiveness. In a rat crushed nerve injury model, the nerve bandage can effectively promote nerve regeneration through stable sutureless wrapping followed by great electrical transmission on the defect region, showing anatomical and functional recovery of the nerve tissues and preventing muscular atrophy. Such hydrogel fibrous bandages will be a promising surgical dressing to be combined with versatile biomedical devices/materials for peripheral nerve repair.
Systemic IFN-I combined with topical TLR7/8 agonists promotes distant tumor suppression by c-Jun-dependent IL-12 expression in dendritic cells
Authors: Martina Sanlorenzo, Philipp Novoszel, Igor Vujic, Tommaso Gastaldi, Martina Hammer, Ourania Fari, Cristiano De Sa Fernandes, Alina D. Landau, Bilge V. Göcen-Oguz, Martin Holcmann, Babak Monshi, Klemens Rappersberger, Agnes Csiszar, Maria Sibilia
Journal: Nature Cancer (2025)

Abstract Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8 + T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors.
NEDD4–Mediated GSNOR Degradation Aggravates Cardiac Hypertrophy and Dysfunction
Authors: Xin Tang, Xiameng Liu, Xinqi Sha, Yan Zhang, Yan Zu, Qiyao Fan, Lulu Hu, Shixiu Sun, Zhiren Zhang, Feng Chen, ChengHui Yan, Xin Chen, Yueyue Xu, Wen Chen, Yongfeng Shao, Jiaxi Gu, Jun Pu, Bo Yu, Yaling Han, Liping Xie, Yi Han, Yong Ji
Journal: Circulation Research (2025)

BACKGROUND: The decrease in S-nitrosoglutathione reductase (GSNOR) leads to an elevation of S-nitrosylation, thereby exacerbating the progression of cardiomyopathy in response to hemodynamic stress. However, the mechanisms under GSNOR decrease remain unclear. Here, we identify NEDD4 (neuronal precursor cell expressed developmentally downregulated 4) as a novel molecule that plays a crucial role in the pathogenesis of pressure overload–induced cardiac hypertrophy, by modulating GSNOR levels, thereby demonstrating significant therapeutic potential. METHODS: Protein synthesis and degradation inhibitors were used to verify the reasons for the decrease in GSNOR. Mass spectrometry and database filtering were used to uncover NEDD4, the E3 Ub (ubiquitin) ligase, involved in GSNOR decrease. NEDD4 cardiomyocyte-specific deficiency mice were used to evaluate the role of NEDD4 and NEDD4–induced ubiquitination of GSNOR in cardiac hypertrophy in vivo. Both IBM, a highly specific NEDD4 inhibitor, and indole-3-carbinol, a NEDD4 inhibitor currently undergoing phase 2 clinical trial, were used to effectively suppress the NEDD4/GSNOR axis. RESULTS: GSNOR protein levels were reduced, while mRNA levels remained unchanged in myocardium samples from hypertrophic patients and transverse aortic constriction–induced mice, indicating GSNOR is regulated by ubiquitination. NEDD4, an E3 Ub ligase, was associated with GSNOR ubiquitination, which exhibited significantly higher expression levels in hypertrophic myocardial samples. Moreover, either the NEDD4 enzyme-dead mutant or GSNOR nonubiquitylated mutant decreased GSNOR ubiquitination and inhibited cardiac hypertrophic growth. Cardiomyocyte-specific NEDD4 deficiency inhibited cardiac hypertrophy in vitro and in vivo. NEDD4 inhibitor IBM effectively suppressed GSNOR ubiquitination and cardiac hypertrophy. Clinically, indole-3-carbinol, a NEDD4 inhibitor in phase II clinical trials used as an antitumor drug, demonstrated comparable efficacy. CONCLUSIONS: Our findings showed that upregulated NEDD4 leads to GSNOR ubiquitination and subsequent degradation, thereby facilitating the progression of cardiac hypertrophy. NEDD4 inhibitors may serve as a potential therapeutic strategy for the treatment of cardiac hypertrophy and heart failure.
Placental Hypoxia-Induced Ferroptosis Drives Vascular Damage in Preeclampsia
Authors: Chanho Park, Sruthi Alahari, Jonathan W. Ausman, Ruizhe Liu, Frederik Nguyen, Julien Sallais, Martin Post, Isabella Caniggia
Journal: Circulation Research (2025)

BACKGROUND: Iron is an essential micronutrient for cell survival and growth; however, excess of this metal drives ferroptosis. Although maternal iron imbalance and placental hypoxia are independent contributors to the pathogenesis of preeclampsia, a hypertensive disorder of pregnancy, the mechanisms by which their interaction impinge on maternal and placental health remain elusive. METHODS: We used placentae from normotensive and preeclampsia pregnancy cohorts, human H9 embryonic stem cells differentiated into cytotrophoblast-like cells, and placenta-specific Phd2 −/− preeclamptic mice. Lipid peroxidation and iron cargo of placenta-derived small extracellular vesicles (sEVs) isolated from the maternal circulation of control and preeclampsia individuals were examined by mass spectrometry, flow cytometry, and colorimetry. Human microvascular endothelial cells’ angiogenic capacity and function were examined after exposure to control and pathological sEVs. RESULTS: Placentae from preeclampsia pregnancies contain increased ferrous iron and lipid peroxidation byproduct, malondialdehyde. Antioxidant capacity is significantly lower in preeclampsia placentae, with decreased glutathione content, and GPx4 (glutathione peroxidase 4) expression and activity. Hypoxia triggers the occurrence of ferroptosis in human trophoblast cells and mouse Phd2 − /− placentae. Disrupted placental iron homeostasis in preeclampsia is accompanied by improper extrusion of iron through sEVs mediated by the pentaspan protein prominin-2. Heightened lipid peroxidation content was found in villous explants and maternal circulating sEVs of preeclampsia individuals. Exposure of human microvascular endothelial cells to preeclampsia-derived placental sEVs results in endothelial activation and impaired angiogenesis, which is rescued by treatment with hinokitiol, a compound known to restore tissue iron balance. CONCLUSIONS: In pregnancy, iron and oxygen work synergistically to conserve an operative antioxidant system to maintain iron homeostasis and protect the placenta from ferroptotic death. Hindrance to this system due to hypoxia results in heightened ferroptosis rates and sEV-mediated extrusion of harmful lipid peroxides from trophoblast cells into the circulation thereby contributing to maternal endothelial dysfunction characterizing preeclampsia.
Propagation of pathologic α-synuclein from kidney to brain may contribute to Parkinson’s disease
Authors: Xin Yuan, Shuke Nie, Yingxu Yang, Congcong Liu, Danhao Xia, Lanxia Meng, Yue Xia, Hua Su, Chun Zhang, Lihong Bu, Min Deng, Keqiang Ye, Jing Xiong, Liam Chen, Zhentao Zhang
Journal: Nature Neuroscience (2025)
Utility of loop diuretics as a marker of risk in clinical trials of heart failure with preserved ejection fraction: Analysis from the Swedish Heart Failure Registry
Authors: Fouad Chouairi, Marat Fudim, Gianluigi Savarese, Barna Szabo, Ulf Dahlström, Camilla Hage, Federica Guidetti, Lina Benson, Lars H. Lund
Journal: European Journal of Heart Failure (2025)
Leveraging Epigenetic Alterations in Pancreatic Ductal Adenocarcinoma for Clinical Applications
Authors: Jorg Tost, Secil Ak-Aksoy, Daniele Campa, Chiara Corradi, Riccardo Farinella, Alejandro Ibanez-Costa, Juan Dubrot, Julie Earl, Emma Barreto Melian, Agapi Kataki, Georgina Kolnikova, Gjorgji Madjarov, Marija Chaushevska, Jan Strnadel, Miljana Tanić, Miroslav Tomas, Peter Dubovan, Maria Urbanova, Verona Buocikova, Bozena Smolkova
Journal: Seminars in Cancer Biology (2025)
Canagliflozin reduces oral loop diuretic intensification in patients with type 2 diabetes: A participant‐level pooled analysis of the <scp>CANVAS</scp> and <scp>CREDENCE</scp> trials
Authors: Safia Chatur, Muthiah Vaduganathan, Robert A. Fletcher, Vlado Perkovic, Hiddo Heerspink, Clare Arnott, Carol Pollock, Kenneth W. Mahaffey, Bruce Neal, Meg Jardine, Scott D. Solomon, Brendon L. Neuen
Journal: European Journal of Heart Failure (2025)