tbuckley/cabot-search huggingface dataset:
Engineering fibronectin-templated multi-component fibrillar extracellular matrices to modulate tissue-specific cell response
Authors: Seungkuk Ahn, Akanksha Jain, Krishna Chaitanya Kasuba, Makiko Seimiya, Ryoko Okamoto, Barbara Treutlein, Daniel J. Müller
Journal: Biomaterials (2024)

Cells assemble fibronectin, the major extracellular matrix (ECM) protein, into fibrillar matrices, which serve as 3D architectural scaffolds to provide, together with other ECM proteins tissue-specific environments. Although recent approaches enable to bioengineer 3D fibrillar fibronectin matrices in vitro, it remains elusive how fibronectin can be co-assembled with other ECM proteins into complex 3D fibrillar matrices that recapitulate tissue-specific compositions and cellular responses. Here, we introduce the engineering of fibrillar fibronectin-templated 3D matrices that can be complemented with other ECM proteins, including vitronectin, collagen, and laminin to resemble ECM architectures observed in vivo. For the co-assembly of different ECM proteins, we employed their innate fibrillogenic mechanisms including shear forces, pH-dependent electrostatic interactions, or specific binding domains. Through recapitulating various tissue-specific ECM compositions and morphologies, the large scale multi-composite 3D fibrillar ECM matrices can guide fibroblast adhesion, 3D fibroblast tissue formation, or tissue morphogenesis of epithelial cells. In other examples, we customize multi-composite 3D fibrillar matrices to support the growth of signal propagating neuronal networks and of human brain organoids. We envision that these 3D fibrillar ECM matrices can be tailored in scale and composition to modulate tissue-specific responses across various biological length scales and systems, and thus to advance manyfold studies of cell biological systems.
Cancer Builds a Noxious Partnership with Psychologic Stress
Authors: Claire Magnon
Journal: Cancer Research (2024)

Abstract I was recently surprised to hear a medical doctor on a TV show refute the role of stress in cancer, assuming that “the whole population would have cancer if this was the case.” This statement illustrates a long and winding road since Hippocrates suggested the potential relationship between cancer and psychologic disturbances. The 20th and 21st centuries have finally witnessed the evidence of how physical or psychosocial stress situations contribute to the development and progression of cancer, and it is now assumed that psychologic stress does affect multiple aspects of cancer such as angiogenesis, immunologic escape, invasion, and metastasis. The 2010 publication by Sloan and colleagues in Cancer Research achieved a mechanistic step toward the understanding of how physical distress enhances metastasis through perturbation of the tumor immune system and paves the way for future cancer research in psychoneuroimmunology. This Landmark commentary places this publication in the historical context of science, discusses major advances in the field, and asks questions to be answered while drawing perspectives on the key role of the peripheral and central nervous systems in cancer. See related article by Sloan and colleagues, Cancer Res 2010;70:7042–52
Targeting Metabolic Dependencies Fueling the TCA Cycle to Circumvent Therapy Resistance in Acute Myeloid Leukemia
Authors: Emeline Boët, Jean-Emmanuel Sarry
Journal: Cancer Research (2024)

Abstract Acute myeloid leukemia (AML) is one of the most prevalent blood cancers, characterized by a dismal survival rate. This poor outcome is largely attributed to AML cells that persist despite treatment and eventually result in relapse. Relapse-initiating cells exhibit diverse resistance mechanisms, encompassing genetic factors and, more recently discovered, nongenetic factors such as metabolic adaptations. Leukemic stem cells (LSC) rely on mitochondrial metabolism for their survival, whereas hematopoietic stem cells primarily depend on glycolysis. Furthermore, following treatments such as cytarabine, a standard in AML treatment for over four decades, drug-persisting leukemic cells exhibit an enhanced reliance on mitochondrial metabolism. In this issue of Cancer Research, two studies investigated dependencies of AML cells on two respiratory substrates, α-ketoglutarate and lactate-derived pyruvate, that support mitochondrial oxidative phosphorylation (OXPHOS) following treatment with the imipridone ONC-213 and the BET inhibitor INCB054329, respectively. Targeting lactate utilization by interfering with monocarboxylate transporter 1 (MCT1 or SLC16A1) or lactate dehydrogenase effectively sensitized cells to BET inhibition in vitro and in vivo. In addition, ONC-213 affected αKGDH, a pivotal NADH-producing enzyme of the TCA cycle, to induce a mitochondrial stress response through ATF4 activation that diminished the expression of the antiapoptotic protein MCL1, consequently promoting apoptosis of AML cells. In summary, targeting these mitochondrial dependencies might be a promising strategy to kill therapy-naïve and treatment-resistant OXPHOS-reliant LSCs and to delay or prevent relapse. See related articles by Monteith et al., p. 1101 and Su et al., p. 1084
Personalized Cancer Vaccines Directed against Tumor Mutations: Building Evidence from Mice to Humans
Authors: Edward F. Fritsch, Patrick A. Ott
Journal: Cancer Research (2024)

Abstract Personalized vaccines directed to tumor mutations have recently gained significant momentum. On the basis of the concept of stimulating T-cell responses against neoantigens encoded by a tumor's host of personal mutations, these vaccines utilize genome or exome sequencing, mutation calling, and epitope prediction followed by manufacturing of a customized vaccine for each patient. In their 2012 Cancer Research publication, Castle and colleagues provided evidence that vaccinating with long peptide vaccines encompassing neoantigens can generate robust immune responses and induce antitumor activity in a mouse B16F10 melanoma. This approach, harnessing the exquisite specificity of mutations to the tumor and thus providing an effective target for cancer vaccines, was subsequently shown to be safe and immunogenic in a series of small first in man trials in patients with melanoma. The field has accelerated and expanded substantially over the last 5 years, propelled by increasing evidence for vaccine-mediated clinical efficacy, leading to ongoing registrational trials using personalized RNA neoantigen vaccines in patients with melanoma and several other malignancies. See related article by Castle and colleagues, Cancer Res 2012;72:1081–91
Exploring Ferroptosis-Inducing Therapies for Cancer Treatment: Challenges and Opportunities
Authors: Guang Lei, Boyi Gan
Journal: Cancer Research (2024)

Abstract Conventional cancer therapies typically aim to eliminate tumor cells by inducing cell death. The emergence of resistance to these standard treatments has spurred a shift in focus toward exploring alternative cell death pathways beyond apoptosis. Ferroptosis—an iron-dependent regulated cell death triggered by lipid peroxide accumulation—has gained prominence in cancer research in recent years. Ferroptosis-inducing therapies hold promise for overcoming resistance encountered with conventional treatments. However, challenges, including the lack of distinctive ferroptosis markers and the intricate role of ferroptosis within the tumor microenvironment, currently hinder the clinical translation of these therapies. This perspective article critically outlines these hurdles and highlights unexplored opportunities in ferroptosis research, aiming to refine its therapeutic utilization in combating cancer.
Effect of Secukinumab Versus Adalimumab Biosimilar on Radiographic Progression in Patients With Radiographic Axial Spondyloarthritis: Results From a <scp>Head‐to‐Head</scp> Randomized Phase <scp>IIIb</scp> Study
Authors: Xenofon Baraliakos, Mikkel Østergaard, Denis Poddubnyy, Désirée van der Heijde, Atul Deodhar, Pedro M. Machado, Victoria Navarro‐Compán, Kay Geert A. Hermann, Mitsumasa Kishimoto, Eun Young Lee, Lianne S. Gensler, Uta Kiltz, Marco F. Eigenmann, Patricia Pertel, Aimee Readie, Hanno B. Richards, Brian Porter, Juergen Braun
Journal: Arthritis & Rheumatology (2024)

Objective Spinal radiographic progression is an important outcome in radiographic axial spondyloarthritis (SpA). The objective of the phase IIIb SURPASS study was to compare spinal radiographic progression in patients with radiographic axial SpA treated with secukinumab (interleukin‐17A inhibitor) versus adalimumab biosimilar (Sandoz adalimumab [SDZ‐ADL]; tumor necrosis factor inhibitor). Methods Biologic‐naive patients with active radiographic axial SpA, at high risk of radiographic progression (high‐sensitivity C‐reactive protein [hsCRP] ≥5 mg/L and/or ≥1 syndesmophyte[s] on spinal radiographs), were randomized (1:1:1) to secukinumab (150/300 mg) or SDZ‐ADL (40 mg). The proportion of patients with no radiographic progression (change from baseline [CFB] in modified Stoke Ankylosing Spondylitis Spinal Score [mSASSS] ≤0.5) on secukinumab versus SDZ‐ADL at week 104 (primary endpoint), mean CFB‐mSASSS, proportion of patients with ≥1 syndesmophyte(s) at baseline with no new syndesmophyte(s), and safety were evaluated. Results Overall, 859 patients (78.5% male, mSASSS 16.6, Bath Ankylosing Spondylitis Disease Activity Index 7.1, hsCRP 20.4 mg/L, and 73.0% with ≥1 syndesmophyte[s]) received secukinumab 150 mg (n = 287), secukinumab 300 mg (n = 286), or SDZ‐ADL (n = 286). At week 104, the proportion of patients with no radiographic progression was 66.1%, 66.9%, and 65.6% ( P = not significant, both secukinumab doses) and mean CFB‐mSASSS was 0.54, 0.55, and 0.72 in secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL arms, respectively. Overall, 56.9%, 53.8%, and 53.3% of patients on secukinumab 150 mg, secukinumab 300 mg, and SDZ‐ADL, respectively, with ≥1 syndesmophyte(s) at baseline did not develop new syndesmophyte(s) by week 104. There were no unexpected safety findings. Conclusion Spinal radiographic progression over two years was low with no significant difference between secukinumab and SDZ‐ADL arms. The safety of both treatments was consistent with previous reports.
The Rigidity Connection: Matrix Stiffness and Its Impact on Cancer Progression
Authors: Anna Yui, Madeleine J. Oudin
Journal: Cancer Research (2024)

Abstract The extracellular matrix (ECM) has always been studied in the context of the structural support it provides tissues. However, more recently, it has become clear that ECM proteins do more to regulate biological processes relevant to cancer progression: from activating complex signaling pathways to presenting soluble growth factors. In 2009, Ulrich and colleagues provided evidence that the physical properties of the ECM could also contribute to glioblastoma tumor cell proliferation and invasion using tunable hydrogels, emphasizing a role for tumor rigidity in central nervous system cancer progression. Here, we will discuss the results of this landmark article, as well as highlight other work that has shown the importance of tissue stiffness in glioblastoma and other tumor types in the tumor microenvironment. Finally, we will discuss how this research has led to the development of novel treatments for cancer that target tumor rigidity. See related article by Ulrich and colleagues, Cancer Res 2009;69:4167–74
A serine-conjugated butyrate prodrug with high oral bioavailability suppresses autoimmune arthritis and neuroinflammation in mice
Authors: Shijie Cao, Erica Budina, Michal M. Raczy, Ani Solanki, Mindy Nguyen, Taryn N. Beckman, Joseph W. Reda, Kevin Hultgren, Phillip S. Ang, Anna J. Slezak, Lauren A. Hesser, Aaron T. Alpar, Kirsten C. Refvik, Lucas S. Shores, Ishita Pillai, Rachel P. Wallace, Arjun Dhar, Elyse A. Watkins, Jeffrey A. Hubbell
Journal: Nature Biomedical Engineering (2024)

Butyrate-a metabolite produced by commensal bacteria-has been extensively studied for its immunomodulatory effects on immune cells, including regulatory T cells, macrophages and dendritic cells. However, the development of butyrate as a drug has been hindered by butyrate's poor oral bioavailability, owing to its rapid metabolism in the gut, its low potency (hence, necessitating high dosing), and its foul smell and taste. Here we report that the oral bioavailability of butyrate can be increased by esterifying it to serine, an amino acid transporter that aids the escape of the resulting odourless and tasteless prodrug (O-butyryl-L-serine, which we named SerBut) from the gut, enhancing its systemic uptake. In mice with collagen-antibody-induced arthritis (a model of rheumatoid arthritis) and with experimental autoimmune encephalomyelitis (a model of multiple sclerosis), we show that SerBut substantially ameliorated disease severity, modulated key immune cell populations systemically and in disease-associated tissues, and reduced inflammatory responses without compromising the global immune response to vaccination. SerBut may become a promising therapeutic for autoimmune and inflammatory diseases.
Imaging Intratumoral Heterogeneity of Diffuse Pancreatic Neuroendocrine Tumor With Multitracer PET/CT
Authors: Bulin Du, Shu Wang, Yu Ma, Xuena Li, Yaming Li
Journal: Clinical Nuclear Medicine (2024)

Abstract Diffuse involvement of pancreatic neuroendocrine tumor (PNET) is a rare presentation. Here, we report a case of suspected autoimmune pancreatitis with 18 F-FDG and 18 F-FAPI-42 PET/CT showing increased tracer uptake in the entire pancreas, which was eventually confirmed by biopsy pathologic analysis as diffuse PNET. 18 F-AlF-NOTA-octreotide PET/CT imaging showed heterogeneous tracer uptake in the entire pancreas.
68Ga-DOTATATE and 68Ga-FAPI Imaging in Neuroendocrine Neoplasms of Different Grades
Authors: Yue Zhou, Lei Ou, Songke Yu, Hao Deng, Xiaoliang Chen
Journal: Clinical Nuclear Medicine (2024)

Abstract We report findings from 68 Ga-DOTATATE and 68 Ga-FAPI PET/CT in a 43-year-old woman with neuroendocrine neoplasms. DOTATATE and FAPI uptake differed in different lesions. These results suggest a potential value for dual-tracer imaging in the evaluation of neuroendocrine neoplasms that have different grades.
Outcomes of Patients With Diffuse Systemic Sclerosis Eligible for Autologous Stem Cell Transplantation Treated With Conventional Therapy
Authors: Kate Gregory, Dylan Hansen, Ross Penglase, Diane Apostolopoulos, Gene‐Siew Ngian, Wendy Stevens, Kathleen Morrisroe, Nava Ferdowsi, Laura Ross, Jennifer Walker, Helen Cooley, Peter Youssef, Kathleen Tymms, Lauren Host, Susanna Proudman, John Moore, Mandana Nikpour, Joanne Sahhar
Journal: Arthritis & Rheumatology (2024)

The study objective was to determine the event-free survival (EFS) of Australian patients with diffuse cutaneous systemic sclerosis (dcSSc) who met eligibility criteria for autologous stem cell transplant (ASCT) in previously published randomized controlled trials but were not treated with ASCT.
Distinct Plasma Extracellular Vesicle Transcriptomes in Acute Decompensated Heart Failure Subtypes: A Liquid Biopsy Approach
Authors: Priyanka Gokulnath, Michail Spanos, H. Immo Lehmann, Quanhu Sheng, Rodosthenis Rodosthenous, Mark Chaffin, Dimitrios Varrias, Emeli Chatterjee, Elizabeth Hutchins, Guoping Li, George Daaboul, Farhan Rana, Ashley Mingyi Wang, Kendall Van Keuren-Jensen, Patrick T. Ellinor, Ravi Shah, Saumya Das
Journal: Circulation (2024)
Unconventional human CD61 pairing with CD103 promotes TCR signaling and antigen-specific T cell cytotoxicity
Authors: Megat H. B. A. Hamid, Pablo F. Cespedes, Chen Jin, Ji-Li Chen, Uzi Gileadi, Elie Antoun, Zhu Liang, Fei Gao, Renuka Teague, Nikita Manoharan, David Maldonado-Perez, Nasullah Khalid-Alham, Lucia Cerundolo, Raul Ciaoca, Svenja S. Hester, Adán Pinto-Fernández, Simeon D. Draganov, Iolanda Vendrell, Guihai Liu, Xuan Yao, Audun Kvalvaag, Delaney C. C. Dominey-Foy, Charunya Nanayakkara, Nikolaos Kanellakis, Yi-Ling Chen, Craig Waugh, Sally-Ann Clark, Kevin Clark, Paul Sopp, Najib M. Rahman, Clare Verrill, Benedikt M. Kessler, Graham Ogg, Ricardo A. Fernandes, Roman Fisher, Yanchun Peng, Michael L. Dustin, Tao Dong
Journal: Nature Immunology (2024)

Abstract Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103 + T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61 + tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
Hybrid Hydrogels for Immunoregulation and Proangiogenesis through Mild Heat Stimulation to Accelerate Whole‐Process Diabetic Wound Healing
Authors: Qianru Guo, Tianyu Yin, Wei Huang, Rui Nan, Tao Xiang, Shaobing Zhou
Journal: Advanced Healthcare Materials (2024)

Intense and persistent oxidative stress, excessive inflammation, and impaired angiogenesis severely hinder diabetic wound healing. Bioactive hydrogel dressings with immunoregulatory and proangiogenic properties have great promise in treating diabetic wounds. However, the therapeutic effects of dressings always depend on drugs with side effects, expensive cytokines, and cell therapies. Herein, a novel dynamic borate-bonds crosslinked hybrid multifunctional hydrogel dressings with photothermal properties are developed to regulate the microenvironment of diabetic wound sites and accelerate the whole process of its healing without additional medication. The hydrogel is composed of phenylboronic acid-modified chitosan and hyaluronic acid (HA) crosslinked by tannic acid (TA) through borate bonds and Prussian blue nanoparticles (PBNPs) with photothermal response characteristics are embedded in the polymer networks. The results indicate hydrogels show inherent broad-spectrum antioxidative activities through the integrated interaction of borate bonds, TA, and PBNPs. Meanwhile, combined with the regulation of macrophage phenotype by HA, the inflammatory microenvironment of diabetic wounds is transformed. Moreover, the angiogenesis is then enhanced by the mild photothermal effect of PBNPs, followed by promoted epithelialization and collagen deposition. In summary, this hybrid hydrogel system accelerates all stages of wound repair through antioxidative stress, immunomodulation, and proangiogenesis, showing great potential applications in diabetic wound management.
The endotoxin hypothesis of Alzheimer’s disease
Authors: Guy C. Brown, Michael T. Heneka
Journal: Molecular Neurodegeneration (2024)

Abstract Lipopolysaccharide (LPS) constitutes much of the surface of Gram-negative bacteria, and if LPS enters the human body or brain can induce inflammation and act as an endotoxin. We outline the hypothesis here that LPS may contribute to the pathophysiology of Alzheimer’s disease (AD) via peripheral infections or gut dysfunction elevating LPS levels in blood and brain, which promotes: amyloid pathology, tau pathology and microglial activation, contributing to the neurodegeneration of AD. The evidence supporting this hypothesis includes: i) blood and brain levels of LPS are elevated in AD patients, ii) AD risk factors increase LPS levels or response, iii) LPS induces Aβ expression, aggregation, inflammation and neurotoxicity, iv) LPS induces TAU phosphorylation, aggregation and spreading, v) LPS induces microglial priming, activation and neurotoxicity, and vi) blood LPS induces loss of synapses, neurons and memory in AD mouse models, and cognitive dysfunction in humans. However, to test the hypothesis, it is necessary to test whether reducing blood LPS reduces AD risk or progression. If the LPS endotoxin hypothesis is correct, then treatments might include: reducing infections, changing gut microbiome, reducing leaky gut, decreasing blood LPS, or blocking LPS response.
Cardiovascular outcomes 50 years after antenatal exposure to betamethasone: Follow-up of a randomised double-blind, placebo-controlled trial
Authors: Anthony G. B. Walters, Greg D. Gamble, Caroline A. Crowther, Stuart R. Dalziel, Carl L. Eagleton, Christopher J. D. McKinlay, Barry J. Milne, Jane E. Harding
Journal: PLoS Medicine (2024)

Background Antenatal corticosteroids for women at risk of preterm birth reduce neonatal morbidity and mortality, but there is limited evidence regarding their effects on long-term health. This study assessed cardiovascular outcomes at 50 years after antenatal exposure to corticosteroids. Methods and findings We assessed the adult offspring of women who participated in the first randomised, double-blind, placebo-controlled trial of antenatal betamethasone for the prevention of neonatal respiratory distress syndrome (RDS) (1969 to 1974). The first 717 mothers received 2 intramuscular injections of 12 mg betamethasone or placebo 24 h apart and the subsequent 398 received 2 injections of 24 mg betamethasone or equivalent volume of placebo. Follow-up included a health questionnaire and consent to access administrative data sources. The co-primary outcomes were the prevalence of cardiovascular risk factors (any of hypertension, hyperlipidaemia, diabetes mellitus, gestational diabetes mellitus, or prediabetes) and age at first major adverse cardiovascular event (MACE) (cardiovascular death, myocardial infarction, coronary revascularisation, stroke, admission for peripheral vascular disease, and admission for heart failure). Analyses were adjusted for gestational age at entry, sex, and clustering. Of 1,218 infants born to 1,115 mothers, we followed up 424 (46% of survivors; 212 [50%] female) at mean (standard deviation) age 49.3 (1.0) years. There were no differences between those exposed to betamethasone or placebo for cardiovascular risk factors (159/229 [69.4%] versus 131/195 [67.2%]; adjusted relative risk 1.02, 95% confidence interval [CI] [0.89, 1.18;]; p = 0.735) or age at first MACE (adjusted hazard ratio 0.58, 95% CI [0.23, 1.49]; p = 0.261). There were also no differences in the components of these composite outcomes or in any of the other secondary outcomes. Key limitations were follow-up rate and lack of in-person assessments. Conclusions There is no evidence that antenatal corticosteroids increase the prevalence of cardiovascular risk factors or incidence of cardiovascular events up to 50 years of age. Established benefits of antenatal corticosteroids are not outweighed by an increase in adult cardiovascular disease.
In T2DM, periconceptional, noninsulin, second-line antidiabetes medications were not linked to major congenital malformations vs. insulin
Authors: Aoife M. Egan
Journal: Annals of Internal Medicine (2024)

Source CitationCesta CE, Rotem R, Bateman BT, et al. Safety of GLP-1 receptor agonists and other second-line antidiabetics in early pregnancy. JAMA Intern Med. 2024;184:144-152. https://pubmed.ncbi.nlm.nih.gov/38079178/