tbuckley/cabot-search huggingface dataset:
The first-in-class bispecific antibody IBI318 (LY3434172) targeting PD-1 and PD-L1 in patients with advanced tumors: a phase Ia/Ib study
Authors: Dan-Yun Ruan, Xiao-Li Wei, Fu-Rong Liu, Xi-Chun Hu, Jian Zhang, Dong-Mei Ji, Ding-Zhi Huang, Yan-Qiu Zhao, Hong-Min Pan, Wang-Jun Liao, Kun-Yu Yang, Nong Xu, Xiao-Xiao Lu, Yu-Ling Chen, Wen Zhang, Hui Zhou, Hong-Yun Zhao, Rui-Hua Xu
Journal: Journal of Hematology & Oncology (2024)

There is an unmet clinical need to enhance the response rate and safety of anti-PD-1/PD-L1-based cancer immunotherapy (IO). Herein, we presented the clinical study of IBI318 (LY3434172), a first-in-class bispecific antibody (bsAb) targeting PD-1 and PD-L1, in patients with advanced tumors. In this open-label, multicenter Phase Ia/Ib study of IBI318, the Phase Ia involved dose escalation and a safety dose expansion, while the Phase Ib focused on preliminary safety and efficacy evaluation in non-small cell lung cancer (NSCLC) and nasopharyngeal carcinoma (NPC). In Phase Ia, patients with advanced tumors received IBI318 doses ranging from 0.3 to 1200 mg every two weeks (Q2W) to determine the recommended Phase 2 dose (RP2D). In Phase Ib, NSCLC or NPC patients from five cohorts with varying treatment histories received IBI318 at the RP2D. The primary endpoint was safety and the secondary endpoints included efficacy assessed by investigators according to RECIST v1.1, pharmacokinetics, immunogenicity, and pharmacodynamics. From February 11, 2019, to January 25, 2022, a total of 103 eligible patients were enrolled (Phase Ia, n = 55; Phase Ib, n = 48). The median follow-up was 10.1 months (range 0.7–28.6). The RP2D was determined to be 300 mg Q2W. Treatment-related adverse events (TRAEs) of any grades occurred in 88 patients (85.4%), while 10 patients (9.7%) experienced grade ≥ 3 TRAEs. The objective response rate (ORR) was 15.5% and the disease control rate (DCR) was 49.5% in all patients. In Phase Ib, the confirmed ORR was 45.5% in treatment-naïve NSCLC patients and 30.0% in IO-naïve NPC patients who had failed or were intolerant to platinum-based treatments. IBI318 demonstrated a favorable safety profile and preliminary efficacy in treatment-naïve NSCLC and IO-naïve NPC patients. Further clinical studies are needed to assess the full therapeutic potential of PD-1/PD-L1 dual inhibition with bsAbs.
PD-1/PD-L1 immune checkpoint blockade in breast cancer: research insights and sensitization strategies
Authors: Menglei Jin, Jun Fang, Junwen Peng, Xintian Wang, Ping Xing, Kunpeng Jia, Jianming Hu, Danting Wang, Yuxin Ding, Xinyu Wang, Wenlu Li, Zhigang Chen
Journal: Molecular Cancer (2024)

Immunotherapy targeting programmed cell death-1 (PD-1) and PD-L1 immune checkpoints has reshaped treatment paradigms across several cancers, including breast cancer. Combining PD-1/PD-L1 immune checkpoint blockade (ICB) with chemotherapy has shown promising efficacy in both early and metastatic triple-negative breast cancer, although only a subset of patients experiences durable responses. Identifying responders and optimizing immune drug selection are therefore critical. The effectiveness of PD-1/PD-L1 immunotherapy depends on both tumor-intrinsic factors and the extrinsic cell-cell interactions within the tumor microenvironment (TME). This review systematically summarizes the key findings from clinical trials of ICBs in breast cancer and examines the mechanisms underlying PD-L1 expression regulation. We also highlight recent advances in identifying potential biomarkers for PD-1/PD-L1 therapy and emerging evidence of TME alterations following treatment. Among these, the quantity, immunophenotype, and spatial distribution of tumor-infiltrating lymphocytes stand out as promising biomarkers. Additionally, we explore strategies to enhance the effectiveness of ICBs in breast cancer, aiming to support the development of personalized treatment approaches tailored to the unique characteristics of each patient's tumor.
An optimal antibiotic selection framework for Sepsis patients using Artificial Intelligence
Authors: Philipp Wendland, Christof Schenkel-Häger, Ingobert Wenningmann, Maik Kschischo
Journal: npj Digital Medicine (2024)

Abstract In this work we present OptAB, the first completely data-driven online-updateable antibiotic selection model based on Artificial Intelligence for Sepsis patients accounting for side-effects. OptAB performs an iterative optimal antibiotic selection for real-world Sepsis patients focussing on minimizing the Sepsis-related organ failure score (SOFA-Score) as treatment success while accounting for nephrotoxicity and hepatotoxicity as serious antibiotic side-effects. OptAB provides disease progression forecasts for (combinations of) the antibiotics Vancomycin, Ceftriaxone and Piperacillin/Tazobactam and learns realistic treatment influences on the SOFA-Score and the laboratory values creatinine, bilirubin total and alanine-transaminase indicating possible side-effects. OptAB is based on a hybrid neural network differential equation algorithm and can handle the special characteristics of patient data including irregular measurements, a large amount of missing values and time-dependent confounding. OptAB’s selected optimal antibiotics exhibit faster efficacy than the administered antibiotics.
Mechanisms and cross-talk of regulated cell death and their epigenetic modifications in tumor progression
Authors: Ruimin He, Yifan Liu, Weijie Fu, Xuan He, Shuang Liu, Desheng Xiao, Yongguang Tao
Journal: Molecular Cancer (2024)

Cell death is a fundamental part of life for metazoans. To maintain the balance between cell proliferation and metabolism of human bodies, a certain number of cells need to be removed regularly. Hence, the mechanisms of cell death have been preserved during the evolution of multicellular organisms. Tumorigenesis is closely related with exceptional inhibition of cell death. Mutations or defects in cell death-related genes block the elimination of abnormal cells and enhance the resistance of malignant cells to chemotherapy. Therefore, the investigation of cell death mechanisms enables the development of drugs that directly induce tumor cell death. In the guidelines updated by the Cell Death Nomenclature Committee (NCCD) in 2018, cell death was classified into 12 types according to morphological, biochemical and functional classification, including intrinsic apoptosis, extrinsic apoptosis, mitochondrial permeability transition (MPT)-driven necrosis, necroptosis, ferroptosis, pyroptosis, PARP-1 parthanatos, entotic cell death, NETotic cell death, lysosome-dependent cell death, autophagy-dependent cell death, immunogenic cell death, cellular senescence and mitotic catastrophe. The mechanistic relationships between epigenetic controls and cell death in cancer progression were previously unclear. In this review, we will summarize the mechanisms of cell death pathways and corresponding epigenetic regulations. Also, we will explore the extensive interactions between these pathways and discuss the mechanisms of cell death in epigenetics which bring benefits to tumor therapy.
Assessing advances in three decades of clinical antiretroviral therapy on the HIV-1 reservoir
Authors: Irene González-Navarro, Víctor Urrea, Cristina Gálvez, Maria del Carmen Garcia-Guerrero, Sara Morón-López, Maria C. Puertas, Eulàlia Grau, Beatriz Mothe, Lucía Bailón, Cristina Miranda, Felipe García, Lorna Leal, Linos Vandekerckhove, Vincent C. Marconi, Rafick P. Sekaly, Bonaventura Clotet, Javier Martinez-Picado, Maria Salgado
Journal: Journal of Clinical Investigation (2024)

BACKGROUND. Antiretroviral therapy (ART) has improved the clinical management of HIV-1 infection. However, little is known about how the latest ART recommendations affect the heterogeneity of HIV-1 reservoir size.
Carcinogenicity of hydrochlorothiazide, voriconazole, and tacrolimus
Authors: Vincent J Cogliano, Emanuela Corsini, Agnès Fournier, Heather H Nelson, Consolato M Sergi, Alexandra M M Antunes, Elizabeth K Cahoon, Guosheng Chen, Talita Duarte-Salles, Eric Engels, Jingqi Fu, Dori Germolec, Reza Ghiasvand, Blánaid Hicks, Bertrand J Jean-Claude, Gopabandhu Jena, Catharina M Lerche, Xilin Li, Angela Lupattelli, Thomas P Ong, Libia Vega, Diana R Withrow, Alistair B A Boxall, Lamia Benbrahim-Tallaa, Aline de Conti, Andrew Kunzmann, Elisa Pasqual, Roland Wedekind, Xiaobei Deng, Yahya Mahamat-Saleh, Azam Majidi, Laia Peruchet-Noray, Julia Rezende Da Silva, Eero Suonio, Susana Viegas, Yue Zhai, Heidi Mattock, Caterina Facchin, Mary K Schubauer-Berigan, Federica Madia
Journal: The Lancet Oncology (2024)
Global trends and regional differences in mortality of cardiovascular disease and its impact on longevity, 1980-2021: age-period-cohort analyses and life expectancy decomposition based on the Global Burden of Disease study 2021
Authors: Xue Xia, Xue Tian, Qin Xu, Yijun Zhang, Xiaoli Zhang, Jing Li, Anxin Wang
Journal: Ageing Research Reviews (2024)
Eosinophilic Esophagitis Drives Tissue Fibroblast Regenerative Programs Towards Pathologic Dysfunction
Authors: Medet Jumabay, Edsel M Abud, Kevin Okamoto, Paramita Dutta, Austin W T Chiang, Haining Li, Mario Manresa, Yanfang P Zhu, Dana Frederick, Richard Kurten, Ben Croker, Nathan E Lewis, Joshua L Kennedy, Ranjan Dohil, Michael Croft, Ferhat Ay, Joshua B Wechsler, Seema S Aceves
Journal: Journal of Allergy and Clinical Immunology (2024)
Current Burden of Steatotic Liver Disease and Fibrosis among Adults in the United States, 2017-2023
Authors: Donghee Kim, Pojsakorn Danpanichkul, Karn Wijarnpreecha, George Cholankeril, Rohit Loomba, Aijaz Ahmed
Journal: Clinical and Molecular Hepatology (2024)

Multi-society experts proposed the adoption of new terminology, metabolic dysfunction-associated steatotic liver disease (MASLD) and steatotic liver disease (SLD). We studied the current prevalence of SLD and its subcategories in the US. Using the recent National Health and Nutrition Examination Survey from 2017 to 2023, we analyzed data from 12,199 participants (≥18 years) who completed transient elastography. SLD and its subcategories, including MASLD, metabolic and alcohol-related liver disease (MetALD), and alcohol-related liver disease (ALD), were categorized according to consensus nomenclature. The age-adjusted prevalence of SLD (cut-off: 285 dB/m) was 35.0% (95% confidence interval [CI]: 33.4-36.7). Within this category, the age-adjusted prevalence for MASLD was 31.9% (95% CI: 30.4-33.4), MetALD 2.2% (95% CI: 1.8-2.6), and ALD 0.8% (95% CI: 0.6-1.1). The prevalence of SLD and MASLD showed a statistically insignificant decrease during COVID-19, while ALD increased without significance. In contrast, the prevalence of advanced fibrosis in SLD was significantly higher during the COVID-19 era, at 9.8% for 285 dB/m and 7.8% for 263 dB/m, compared to 7.4% (P=0.039) and 6% (P=0.041) in the pre-COVID-19 era. The proportion of advanced fibrosis and cirrhosis in individuals with ALD was two-fold higher than MASLD and MetALD, largely due to increases during the COVID-19 era. While the prevalence of SLD and its subcategories remained stable, there was a significant increase in advanced fibrosis among SLD individuals during the COVID-19 era, with ALD having a proportion of advanced fibrosis and cirrhosis that was twice as high as MASLD and MetALD.
Bioinspired micro‐ and nanostructured systems for cancer therapy
Authors: Rui Yang, Bing Zhang, Xiawei Fei, Shanshan Cong, Shaojie Zhao, Tao Zhou, Yanting Shen
Journal: MedComm (2024)

Abstract Numerous organisms in nature have demonstrated enhanced biocompatibility, precise tumor targeting capabilities, and efficient tissue traversal within the human body. Drawing inspiration from these organisms, researchers have employed bioengineering, bioconjugation, and micro‐ or nanotechnology to fabricate bioinspired micro‐ and nanostructured systems. These systems play a crucial role in addressing the limitations of conventional anticancer drugs and nanomaterials concerning biocompatibility, effective penetration of physiological barriers, as well as selective tumor targeting, thereby leading to improved therapeutic efficacy while minimizing nonspecific adverse effects on healthy cells. Consequently, extensive exploration of these bioinspired micro‐ and nanostructured systems has been undertaken across various cancer treatment modalities with some progressing into preclinical or clinical stages. However, our understanding of this field remains limited which may impede research progress, clinical translation efforts, and practical applications. Therefore, this study presents a systematic classification of bioinspired micro‐ and nanostructured systems for cancer therapy that comprehensively elucidates their sources of inspiration and design principles. Furthermore, it extensively discusses the current status of clinical translation efforts while identifying prevailing challenges and exploring future prospects. This work will establish a robust theoretical framework and serve as a valuable reference to facilitate advancements in research and clinical application within this field.
Near‐Infrared Two‐Photon J‐Aggregation‐Induced Organic Fluorescent Dots with Large Stokes‐Shift for Ratiometric Imaging of Hypochlorous Acid in Living Cells and Brains of AD Mice
Authors: Rui Huang, Ziwei Zhang, Zhen Shi, Yumeng Yang, Junyong Sun, Feng Gao
Journal: Advanced Healthcare Materials (2024)

Abstract Alzheimer's disease (AD) is characterized by multiple toxicity from various biomarkers, and it is very important to monitor the fluctuation of biomarker level in brain tissues to track its early onset, illness progression, and therapeutic effect. Hypochlorous acid (HOCl) is confirmed to be a reliable biomarker to extend the scope of diagnosis. However, the practical applications of the developed conjugated small molecule fluorescent probes for detecting HOCl are often restricted to a large extent by their low solubility, aggregation‐caused quenching (ACQ), unsatisfactory fluorescence brightness, small Strokes‐shift, and lack of self‐correcting ratiometric emitters. In this study, a J‐aggregation‐induced organic fluorescent dot (PBT dots), is reported which is facilely developed by co‐assembling newly designed organic molecule PBT with polymer DSPE‐PEG, for ClO − imaging in living brain‐derived Endothelial (bEnd.3) cells and brain tissues of AD mice. The developed two‐photon PBT dots show NIR emission at 715 nm, large Stokes‐shift of 245 nm, quick response within 2 s, ratiometric sensing properties, and favorable blood‐brain barrier (BBB) penetrate ability. The results demonstrate that HOCl level is elevated in AD mouse brain, and PBT dot holds promise as an imaging probe to understand and reveal AD pathologies.
Localized Hydrogel Microspheres for Osteoarthritis Treatment: Recruitment and Differentiation of Stem Cells
Authors: Qiming Pang, Zhuolin Chen, Jingdi Zhan, Jiacheng Liu, Junyan Liu, Weikang Zhao, Wei Huang, Lili Dong
Journal: Advanced Healthcare Materials (2024)

Osteoarthritis (OA) represents a common degenerative joint disorder marked by progressive cartilage degradation, necessitating innovative therapeutic approaches beyond symptom management. Here, this study introduces a novel strategy leveraging the regenerative capabilities of mesenchymal stem cells (MSCs) by utilizing a bioactive extracellular matrix (ECM) derived from IFN-γ-stimulated MSCs, encapsulated within aldehyde- and methacrylic anhydride-modified hyaluronic acid hydrogel microspheres (AH). This engineered scaffold effectively mimics the native cartilage microenvironment, promoting targeted adhesion and retention at damaged sites via spontaneous Schiff base reactions. Notably, the IFN-γ-ECM@AH microspheres facilitate the localized release of key chemokines, such as CXCL12, enhancing endogenous stem cell recruitment, and bioactive factors (e.g., TGF-βI and TGF-β3) to drive chondrogenic differentiation. Additionally, the scaffold possesses binding sites for cellular integrins, further augmenting the regenerative potential of stem cells. Collectively, the approach presents a dual-action mechanism that supports efficient cartilage repair and regeneration, positioning this engineered microenvironment as a promising therapeutic avenue for OA and potentially other degenerative conditions.
Organoids of Musculoskeletal System for Disease Modeling, Drug Screening, and Regeneration
Authors: Weicheng Chen, Dachuan Liu, Kai Lu, Mengping Xu, Di Li, Wei Yan, Song Chen, Bin Li
Journal: Advanced Healthcare Materials (2024)

Abstract Musculoskeletal diseases have emerged as the leading cause of disability worldwide, with their prevalence increasing annually. In light of this escalating health challenge, organoids, an emerging technology in tissue engineering, offer promising solutions for disease modeling, drug screening, regeneration, and repair processes. The successful development of musculoskeletal organoids represents a significant breakthrough, providing a novel platform for studying musculoskeletal diseases and facilitating the discovery of new treatments. Moreover, organoids serve as valuable complements to traditional 2D culture methods and animal models, offering rich insights into musculoskeletal biology. This review provides an overview of organoid technology, outlining the construction processes of various musculoskeletal organoids and highlighting their similarities and differences. Furthermore, the challenges associated with organoid technology in musculoskeletal systems are discussed and insights into future perspectives are offered.
Defining the features and structure of neutralizing antibody targeting the silent face of the SARS‐CoV‐2 spike N‐terminal domain
Authors: Zhaoyong Zhang, Yuanyuan Zhang, Yuting Zhang, Linling Cheng, Lu Zhang, Qihong Yan, Xuesong Liu, Jiantao Chen, Jun Dai, Yingying Guo, Peilan Wei, Xinyi Xiong, Juxue Xiao, Airu Zhu, Jianfen Zhuo, Ruoxi Cai, Jingjun Zhang, Haiyue Rao, Bin Qu, Shengnan Zhang, Jiaxin Feng, Jinling Cheng, Jingyi Su, Canjie Chen, Shu Li, Yuanyuan Zhang, Lei Chen, Yingkang Jin, Yonghao Xu, Xiaoqing Liu, Yimin Li, Jingxian Zhao, Yanqun Wang, Qiang Zhou, Jincun Zhao
Journal: MedComm (2024)

Abstract Research on virus/receptor interactions has uncovered various mechanisms of antibody‐mediated neutralization against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). However, understanding of neutralization by antibodies targeting the silent face, which recognize epitopes on glycan shields, remains limited, and their potential protective efficacy in vivo is not well understood. This study describes a silent face neutralizing antibody, 3711, which targets a non‐supersite on the N‐terminal domain (NTD) of the spike protein. Cryo‐EM structure determination of the 3711 Fab in the spike complex reveals a novel neutralizing epitope shielded by glycans on the spike's silent face. Antibody 3711 inhibits the interaction between the receptor‐binding domain (RBD) and human angiotensin‐converting enzyme 2 (hACE2) through steric hindrance and exhibits superior in vivo protective effects compared to other reported NTD‐targeted monoclonal antibodies (mAbs). Competition assays and antibody repertoire analysis indicate the rarity of antibodies targeting the 3711‐related epitope in SARS‐CoV‐2 convalescents, suggesting the infrequency of NTD silent face‐targeted neutralizing antibodies during SARS‐CoV‐2 infection. As the first NTD silent face‐targeted neutralizing antibody against SARS‐CoV‐2, the identification of mAb 3711, with its novel neutralizing mechanism, enhances our understanding of neutralizing epitopes on glycan shields and elucidates epitope‐guided viral mutations that evade specific antibodies.
Antecedent viral immunization and efficacy of immune checkpoint blockade: an extensive serum antibody profile to predict outcomes in non-small cell lung cancer
Authors: Filippo G Dall'Olio, Wael Salem Zrafi, Quentin Blampey, Francois-Xavier Danlos, Matthieu Roulleaux-Dugage, Gabriel Roman, Charles Naltet, Paul-Henry Cournède, Daniel Gautheret, Mihaela Aldea, David Planchard, Fabrice Barlesi, Aurelien Marabelle, Tyler Hulett, Nathalie Chaput-Gras, Benjamin Besse
Journal: Journal for ImmunoTherapy of Cancer (2024)

Immune checkpoint blockers (ICBs) revolutionized the treatment of patients with advanced non-small cell lung cancer (NSCLC) but only a fraction of them obtain a response, and clinical benefit from these treatments is often difficult to predict. The aim of our study is to unveil the potential implications of antibody response to previous viral infections in predicting response to ICBs in patients with NSCLC. Sera from patients treated with ICBs alone, chemotherapy (CT) or a combination of CT-ICBs were analyzed with VirScan (CDI Labs, USA), a high-throughput method that comprehensively analyzes epitope-level antiviral IgG antibodies via programmable phage display and immunoprecipitation sequencing.Total number of unique positive peptides (tUP) was defined as the total number of non-overlapping positive "is a hit" peptides for each patient. Overall, 387 patients were included. Of them, 129 were treated with ICBs alone, 66 with CT-ICBs and 195 with CT alone. 90 out of 129 patients treated with ICBs alone received ICBs as a subsequent line of treatment, while CT-ICBs and CT were administered as upfront therapies.A higher tUP was correlated with improved overall survival in patients treated with ICBs, and confirmed in the multivariate model (HR 0.43, 95% CI 0.24, 0.79, p=0.006), while it was not in those treated with CT-ICBs (p=0.8) and CT alone (p=0.1).tUP was not correlated with programmed death-ligand 1 (PD-L1) expression, while at the transcriptome level it was correlated with several immune-related pathways, particularly involving B cells. A higher number of viral peptides recognized by serum antibodies might reflect increased immune fitness, resulting in improved outcomes in ICBs treated patients with NSCLC.
Programmed cell death: molecular mechanisms, biological functions, diseases, and therapeutic targets
Authors: Shen'er Qian, Yao Long, Guolin Tan, Xiaoguang Li, Bo Xiang, Yongguang Tao, Zuozhong Xie, Xiaowei Zhang
Journal: MedComm (2024)

Programmed cell death represents a precisely regulated and active cellular demise, governed by a complex network of specific genes and proteins. The identification of multiple forms of programmed cell death has significantly advanced the understanding of its intricate mechanisms, as demonstrated in recent studies. A thorough grasp of these processes is essential across various biological disciplines and in the study of diseases. Nonetheless, despite notable progress, the exploration of the relationship between programmed cell death and disease, as well as its clinical application, are still in a nascent stage. Therefore, further exploration of programmed cell death and the development of corresponding therapeutic methods and strategies holds substantial potential. Our review provides a detailed examination of the primary mechanisms behind apoptosis, autophagy, necroptosis, pyroptosis, and ferroptosis. Following this, the discussion delves into biological functions and diseases associated dysregulated programmed cell death. Finally, we highlight existing and potential therapeutic targets and strategies focused on cancers and neurodegenerative diseases. This review aims to summarize the latest insights on programmed cell death from mechanisms to diseases and provides a more reliable approach for clinical transformation.