tbuckley/cabot-search huggingface dataset:
Antibody‐Conjugated Nanogel with Two Immune Checkpoint Inhibitors for Enhanced Cancer Immunotherapy
Authors: Yun Jin Chae, Kang‐Gon Lee, Doogie Oh, Su‐Kyoung Lee, Yongdoo Park, Jongseong Kim
Journal: Advanced Healthcare Materials (2024)

Abstract Cancer immunotherapy by immune checkpoint inhibitors (ICIs) acts on antitumor responses by stimulating the immune system to attack cancer cells. However, this powerful therapy is hampered by its high treatment cost and limited efficacy. Here, it is shown that the development of an antibody‐conjugated nanogel (ANGel), consisting of N ‐isopropylacrylamide‐ co ‐acrylic acid and antibody‐binding protein (protein A), potentiates the efficacy of two ICI monoclonal antibodies (mAbs) (cytotoxic‐T‐lymphocyte‐associated antigen 4 and programmed death ligand‐1 mAbs). Compared with mAb treatment alone, treatment with a bispecific ANGel surface‐conjugated with the mAbs significantly decreases both the survival of Michigan Cancer Foundation‐7 (MCF‐7) and M D Anderson‐Metastatic Breast‐231 (MDA‐MB‐231) breast cancer cells in vitro and the burden of 4T1‐luciferase‐2‐derived orthotopic syngeneic tumors in vivo. The bispecific ANGel is also more potent than the conventional treatment at prolonging survival in animals with triple‐negative breast cancer. The advantage of the bispecific ANGel over other engineered bispecific antibodies arises not only from the adaptability to link multiple antibodies quickly and easily, but also from the capability to maintain the anticancer effect steadily at subcutaneously delivered tumor site. This finding has an important implication for cancer immunotherapy, opening a new paradigm to treat solid tumors.
Emerging methods for genome-scale metabolic modeling of microbial communities
Authors: Chaimaa Tarzi, Guido Zampieri, Neil Sullivan, Claudio Angione
Journal: Trends in Endocrinology and Metabolism (2024)

Genome-scale metabolic models (GEMs) are consolidating as platforms for studying mixed microbial populations, by combining biological data and knowledge with mathematical rigor. However, deploying these models to answer research questions can be challenging due to the increasing number of available computational tools, the lack of universal standards, and their inherent limitations. Here, we present a comprehensive overview of foundational concepts for building and evaluating genome-scale models of microbial communities. We then compare tools in terms of requirements, capabilities, and applications. Next, we highlight the current pitfalls and open challenges to consider when adopting existing tools and developing new ones. Our compendium can be relevant for the expanding community of modelers, both at the entry and experienced levels.
The EAT-Lancet Diet Index, Plasma Proteins, and Risk of Heart Failure in a Population-Based Cohort
Authors: Shunming Zhang, Ida Marken, Anna Stubbendorff, Ulrika Ericson, Lu Qi, Emily Sonestedt, Yan Borné
Journal: JACC Heart Failure (2024)

The landmark EAT-Lancet Commission proposed that a planetary health diet is comprised mainly of plant-based foods. However, studies examining whether this diet is associated with heart failure (HF) are currently lacking. In addition, the potential proteomics mechanism on the association between diet and HF warrants further elucidation. This study aims to both examine the association between the EAT-Lancet diet index and risk of HF and identify plasma proteins underlying such an association. This prospective cohort study included 23,260 participants. HF cases during the follow-up were identified through the Swedish national register. An EAT-Lancet diet index (score range: 0-42) was created to assess adherence to the EAT-Lancet reference diet. In a subcohort (n = 4,742), fasting plasma proteins were quantified. During a median follow-up of 25.0 years, 1,768 incident HF cases were documented. After adjusting for sociodemographic, lifestyle, diabetes, hypertension, use of lipid-lowering drugs, and body mass index, the HR per 3-point increase of the EAT-Lancet diet index was 0.93 (95% CI: 0.88-0.97). This association was robust in several sensitivity analyses. Among the included 136 plasma proteins, a total of 8 proteins (AM, GDF15, IL6, TIM, CTSD, CCL20, FS, and FUR) were both inversely associated with the EAT-Lancet diet index and positively associated with risk of HF; the overall proteomic score mediated 9.4% (95% CI: 2.2%-32.1%) of the association. Higher adherence to the EAT-Lancet diet was associated with a lower risk of HF. The identified eight plasma proteins provide information on potential pathways mediating such an association.
Prevalence of Pathogenic Variants in Cardiomyopathy-Associated Genes in Acute Myocarditis
Authors: Emanuele Monda, Athanasios Bakalakos, Douglas Cannie, Constantinos O’Mahony, Petros Syrris, Juan Pablo Kaski, Giuseppe Limongelli, Perry Mark Elliott
Journal: JACC Heart Failure (2024)
Inhibition of MERTK reduces organ fibrosis in mouse models of fibrotic disease
Authors: Ziyan Pan, Rasha El Sharkway, Ali Bayoumi, Mayada Metwally, Brian S. Gloss, Robert Brink, David Bo Lu, Christopher Liddle, Saleh A. Alqahtani, Jun Yu, Philip J. O’Connell, Jacob George, Mohammed Eslam
Journal: Science Translational Medicine (2024)

Transforming growth factor–β (TGFβ) drives fibrosis and disease progression in a number of chronic disorders, but targeting this ubiquitously expressed cytokine may not yield a viable and safe antifibrotic therapy. Here, we sought to identify alternative ways to inhibit TGFβ signaling using human hepatic stellate cells and macrophages from humans and mice in vitro, as well as mouse models of liver, kidney, and lung fibrosis. We identified Mer tyrosine kinase (MERTK) as a TGFβ-inducible effector of fibrosis that was up-regulated during fibrosis in multiple organs in three mouse models. We confirmed these findings in liver biopsy samples from patients with metabolic dysfunction-associated fatty liver disease (MAFLD). MERTK also induced TGFβ expression and drove TGFβ signaling resulting in a positive feedback loop that promoted fibrosis in cultured cells. MERTK regulated both canonical and noncanonical TGFβ signaling in both mouse and human cells in vitro. MERTK increased transcription of genes regulating fibrosis by modulating chromatin accessibility and RNA polymerase II activity. In each of the three mouse models, disrupting the fibrosis-promoting signaling loop by reducing MERTK expression reduced organ fibrosis. Pharmacological inhibition of MERTK reduced fibrosis in these mouse models either when initiated immediately after injury or when initiated after fibrosis was established. Together, these data suggest that MERTK plays a role in modulating organ fibrosis and may be a potential target for treating fibrotic diseases.
Antibody-mediated targeting of human microglial leukocyte Ig-like receptor B4 attenuates amyloid pathology in a mouse model
Authors: Jinchao Hou, Yun Chen, Zhangying Cai, Gyu Seong Heo, Carla M. Yuede, Zuoxu Wang, Kent Lin, Fareeha Saadi, Tihana Trsan, Aivi T. Nguyen, Eleni Constantopoulos, Rachel A. Larsen, Yiyang Zhu, Nicole D. Wagner, Nolan McLaughlin, Xinyi Cynthia Kuang, Alexander D. Barrow, Dian Li, Yingyue Zhou, Shoutang Wang, Susan Gilfillan, Michael L. Gross, Simone Brioschi, Yongjian Liu, David M. Holtzman, Marco Colonna
Journal: Science Translational Medicine (2024)

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in the microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4 , we corroborated abundant LILRB4 expression in microglia wrapping around Aβ plaques. Systemic treatment of these mice with an anti-human LILRB4 monoclonal antibody (mAb) reduced Aβ load, mitigated some Aβ-related behavioral abnormalities, enhanced microglia activity, and attenuated expression of interferon-induced genes. In vitro binding experiments established that human LILRB4 binds both human and mouse ApoE and that anti-human LILRB4 mAb blocks such interaction. In silico modeling, biochemical, and mutagenesis analyses identified a loop between the two extracellular Ig domains of LILRB4 required for interaction with mouse ApoE and further indicated that anti-LILRB4 mAb may block LILRB4-mApoE by directly binding this loop. Thus, targeting LILRB4 may be a potential therapeutic avenue for AD.
Pathogenic <i>TNNI1</i> variants disrupt sarcomere contractility resulting in hypo- and hypercontractile muscle disease
Authors: Sandra Donkervoort, Martijn van de Locht, Dario Ronchi, Janine Reunert, Catriona A. McLean, Maha Zaki, Rotem Orbach, Josine M. de Winter, Stefan Conijn, Daan Hoomoedt, Osorio Lopes Abath Neto, Francesca Magri, Angela N. Viaene, A. Reghan Foley, Svetlana Gorokhova, Véronique Bolduc, Ying Hu, Nicole Acquaye, Laura Napoli, Julien H. Park, Kalyan Immadisetty, Lee B. Miles, Mona Essawi, Salar McModie, Leonardo F. Ferreira, Simona Zanotti, Sarah B. Neuhaus, Livija Medne, Nagham ElBagoury, Kory R. Johnson, Yong Zhang, Nigel G. Laing, Mark R. Davis, Robert J. Bryson-Richardson, Darren T. Hwee, James J. Hartman, Fady I. Malik, Peter M. Kekenes-Huskey, Giacomo Pietro Comi, Wessam Sharaf-Eldin, Thorsten Marquardt, Gianina Ravenscroft, Carsten G. Bönnemann, Coen A. C. Ottenheijm
Journal: Science Translational Medicine (2024)

Troponin I (TnI) regulates thin filament activation and muscle contraction. Two isoforms, TnI-fast ( TNNI2 ) and TnI-slow ( TNNI1 ), are predominantly expressed in fast- and slow-twitch myofibers, respectively. TNNI2 variants are a rare cause of arthrogryposis, whereas TNNI1 variants have not been conclusively established to cause skeletal myopathy. We identified recessive loss-of-function TNNI1 variants as well as dominant gain-of-function TNNI1 variants as a cause of muscle disease, each with distinct physiological consequences and disease mechanisms. We identified three families with biallelic TNNI1 variants (F1: p.R14H/c.190-9G&gt;A, F2 and F3: homozygous p.R14C), resulting in loss of function, manifesting with early-onset progressive muscle weakness and rod formation on histology. We also identified two families with a dominantly acting heterozygous TNNI1 variant (F4: p.R174Q and F5: p.K176del), resulting in gain of function, manifesting with muscle cramping, myalgias, and rod formation in F5. In zebrafish, TnI proteins with either of the missense variants (p.R14H; p.R174Q) incorporated into thin filaments. Molecular dynamics simulations suggested that the loss-of-function p.R14H variant decouples TnI from TnC, which was supported by functional studies showing a reduced force response of sarcomeres to submaximal [Ca 2+ ] in patient myofibers. This contractile deficit could be reversed by a slow skeletal muscle troponin activator. In contrast, patient myofibers with the gain-of-function p.R174Q variant showed an increased force to submaximal [Ca 2+ ], which was reversed by the small-molecule drug mavacamten. Our findings demonstrated that TNNI1 variants can cause muscle disease with variant-specific pathomechanisms, manifesting as either a hypo- or a hypercontractile phenotype, suggesting rational therapeutic strategies for each mechanism.
TSPAN8 <sup>+</sup> myofibroblastic cancer–associated fibroblasts promote chemoresistance in patients with breast cancer
Authors: Guangjian Fan, Bo Yu, Lei Tang, Rongxuan Zhu, Jianhua Chen, Ying Zhu, He Huang, Liying Zhou, Jun Liu, Wei Wang, Zhonghua Tao, Fengchun Zhang, Siwei Yu, Xiaoqing Lu, Yuan Cao, Shaoqian Du, Huihui Li, Junjian Li, Jian Zhang, He Ren, Olivier Gires, Haikun Liu, Xin Wang, Jun Qin, Hongxia Wang
Journal: Science Translational Medicine (2024)

Cancer-associated fibroblasts (CAFs) are abundant stromal cells in the tumor microenvironment that promote cancer progression and relapse. However, the heterogeneity and regulatory roles of CAFs underlying chemoresistance remain largely unclear. Here, we performed a single-cell analysis using high-dimensional flow cytometry analysis and identified a distinct senescence-like tetraspanin-8 (TSPAN8)
Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates
Authors: Larry Zeitlin, Robert W. Cross, Courtney Woolsey, Brandyn R. West, Viktoriya Borisevich, Krystle N. Agans, Abhishek N. Prasad, Daniel J. Deer, Lauren Stuart, Maria McCavitt-Malvido, Do H. Kim, James Pettitt, James E. Crowe, Kevin J. Whaley, David Veesler, Antony Dimitrov, Dafna M. Abelson, Thomas W. Geisbert, Christopher C. Broder
Journal: Science Translational Medicine (2024)

No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra virus (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial and has been provided under compassionate use for both HeV and NiV exposures. NiV is a highly pathogenic zoonotic paramyxovirus causing regular outbreaks in humans and animals in South and Southeast Asia. The mortality rate of NiV infection in humans ranges from 40% to more than 90%, making it a substantial public health concern. The NiV G glycoprotein mediates host cell attachment, and the F glycoprotein facilitates membrane fusion and infection. We hypothesized that a mAb against the prefusion conformation of the F glycoprotein may confer better protection than m102.4. To test this, two potent neutralizing mAbs against NiV F protein, hu1F5 and hu12B2, were compared in a hamster model. Hu1F5 provided superior protection to hu12B2 and was selected for comparison with m102.4 for the ability to protect African green monkeys (AGMs) from a stringent NiV challenge. AGMs were exposed intranasally to the Bangladesh strain of NiV and treated 5 days after exposure with either mAb (25 milligrams per kilogram). Whereas only one of six AGMs treated with m102.4 survived until the study end point, all six AGMs treated with hu1F5 were protected. Furthermore, a reduced 10 milligrams per kilogram dose of hu1F5 also provided complete protection against NiV challenge, supporting the upcoming clinical advancement of this mAb for postexposure prophylaxis and therapy.
Role of the gut microbiota in tumorigenesis and treatment
Authors: Qingya Liu, Yun Yang, Meng Pan, Fan Yang, Yan Yu, Zhiyong Qian
Journal: Theranostics (2024)

The gut microbiota is a crucial component of the intricate microecosystem within the human body that engages in interactions with the host and influences various physiological processes and pathological conditions.In recent years, the association between dysbiosis of the gut microbiota and tumorigenesis has garnered increasing attention, as it is recognized as a hallmark of cancer within the scientific community.However, only a few microorganisms have been identified as potential drivers of tumorigenesis, and enhancing the molecular understanding of this process has substantial scientific importance and clinical relevance for cancer treatment.In this review, we delineate the impact of the gut microbiota on tumorigenesis and treatment in multiple types of cancer while also analyzing the associated molecular mechanisms.Moreover, we discuss the utility of gut microbiota data in cancer diagnosis and patient stratification.We further outline current research on harnessing microorganisms for cancer treatment while also analyzing the prospects and challenges associated with this approach.
From molecules to medicine: thiol selective bioconjugation in synthesis of diagnostic and therapeutic radiopharmaceuticals
Authors: Iqra Bibi, Sajid Mushtaq, Kyo Chul Lee, Ji Ae Park, Jung Young Kim
Journal: Theranostics (2024)

Radiolabeling of biomolecules and cells with radiolabeled prosthetic groups has significant implications for nuclear medicine, imaging, and radiotherapy.Achieving site-specific and controlled incorporation of radiolabeled prostheses under mild reaction conditions is crucial for minimizing the impact on the bioactivity of the radiolabeled compounds.The targeting of natural and abundant amino acids during radiolabeling of biomolecules often results in nonspecific and uncontrolled modifications.Cysteine is distinguished by its low natural abundance and unique nucleophilicity.It is therefore an optimal target for site-selective and site-specific radiolabeling of biomolecules under controlled parameters.This review extensively discusses thiol-specific radiolabeled prosthetic groups and provides a critical analysis and comprehensive study of the synthesis of these groups, their in vitro and in vivo stability profiles, reaction kinetics, stability of resulting adducts, and overall impact on the targeting ability of radiolabeled biomolecules.The insights presented here aim to facilitate the development of highly efficient radiopharmaceuticals, initially in preclinical settings and ultimately in clinical applications.
Theranostics - a sure cure for cancer after 100 years?
Authors: Yangmeihui Song, Jianhua Zou, E. Alejandro Castellanos, Naomi Matsuura, John A. Ronald, Adam Shuhendler, Wolfgang A Weber, Assaf A. Gilad, Cristina Müller, Timothy H. Witney, Xiaoyuan Chen
Journal: Theranostics (2024)

Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide.Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer.This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects.We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade.From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine.Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine.Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.
The HSP90 inhibitor HVH-2930 exhibits potent efficacy against trastuzumab-resistant HER2-positive breast cancer
Authors: Minsu Park, Eunsun Jung, Jung Min Park, Soeun Park, Dongmi Ko, Juyeon Seo, Seongjae Kim, Kee Dal Nam, Yong Koo Kang, Lee Farrand, Van-Hai Hoang, Cong-Truong Nguyen, Minh Thanh La, Gibeom Nam, Hyun-Ju Park, Jihyae Ann, Jeewoo Lee, Yoon-Jae Kim, Ji Young Kim, Jae Hong Seo
Journal: Theranostics (2024)

Rationale: Resistance to targeted therapies like trastuzumab remains a critical challenge for HER2-positive breast cancer patients.Despite the progress of several N-terminal HSP90 inhibitors in clinical trials, none have achieved approval for clinical use, primarily due to issues such as induction of the heat shock response (HSR), off-target effects, and unfavorable toxicity profiles.We sought to examine the effects of HVH-2930, a novel C-terminal HSP90 inhibitor, in overcoming trastuzumab resistance.Methods: The effect of HVH-2930 on trastuzumab-sensitive and -resistant cell lines in vitro was evaluated in terms of cell viability, expression of HSP90 client proteins, and impact on cancer stem cells.An in vivo model with trastuzumab-resistant JIMT-1 cells was used to examine the efficacy and toxicity of HVH-2930.Results: HVH-2930 was rationally designed to fit into the ATP-binding pocket interface cavity of the hHSP90 homodimer in the C-terminal domain of HSP90, stabilizing its open conformation and hindering ATP binding.HVH-2930 induces apoptosis without inducing the HSR but by specifically suppressing the HER2 signaling pathway.This occurs with the downregulation of HER2/p95HER2 and disruption of HER2 family member heterodimerization.Attenuation of cancer stem cell (CSC)-like properties was associated with the downregulation of stemness factors such as ALDH1, CD44, Nanog and Oct4.Furthermore, HVH-2930 administration inhibited angiogenesis and tumor growth in trastuzumab-resistant xenograft mice.A synergistic effect was observed when combining HVH-2930 and paclitaxel in JIMT-1 xenografts.Conclusion: Our findings highlight the potent efficacy of HVH-2930 in overcoming trastuzumab resistance in HER2-positive breast cancer.Further investigation is warranted to fully establish its therapeutic potential.
Dysregulated <scp><i>NUB1</i></scp> and Neddylation Enhances Rheumatoid Arthritis <scp>Fibroblast‐Like</scp> Synoviocyte Inflammatory Responses
Authors: Sho Sendo, Camilla R. L. Machado, David L. Boyle, Robert J. Benschop, Narayanan B. Perumal, Eunice Choi, Wei Wang, Gary S. Firestein
Journal: Arthritis & Rheumatology (2024)

Fibroblast-like synoviocytes (FLS) contribute to the pathogenesis of rheumatoid arthritis (RA), in part due to activation of the proinflammatory transcription factor NF-κB. Neddylation is modulated by the negative regulator of ubiquitin-like protein (NUB) 1. We determined whether NUB1 and neddylation are aberrant in the models with RA FLS, thereby contributing to their aggressive phenotype.
Evaluating large language models as agents in the clinic
Authors: Nikita Mehandru, Brenda Y. Miao, Eduardo Rodriguez Almaraz, Madhumita Sushil, Atul J. Butte, Ahmed Alaa
Journal: npj Digital Medicine (2024)

Recent developments in large language models (LLMs) have unlocked opportunities for healthcare, from information synthesis to clinical decision support. These LLMs are not just capable of modeling language, but can also act as intelligent "agents" that interact with stakeholders in open-ended conversations and even influence clinical decision-making. Rather than relying on benchmarks that measure a model's ability to process clinical data or answer standardized test questions, LLM agents can be modeled in high-fidelity simulations of clinical settings and should be assessed for their impact on clinical workflows. These evaluation frameworks, which we refer to as "Artificial Intelligence Structured Clinical Examinations" ("AI-SCE"), can draw from comparable technologies where machines operate with varying degrees of self-governance, such as self-driving cars, in dynamic environments with multiple stakeholders. Developing these robust, real-world clinical evaluations will be crucial towards deploying LLM agents in medical settings.