tbuckley/cabot-search huggingface dataset:
Dysbiosis, malnutrition and enhanced gut-lung axis contribute to age-related respiratory diseases
Authors: Vinciane Saint-Criq, Geanncarlo Lugo-Villarino, Muriel Thomas
Journal: Ageing Research Reviews (2020)

Older people are at an increased risk of developing respiratory diseases such as chronic obstructive pulmonary diseases, asthma, idiopathic pulmonary fibrosis or lung infections. Susceptibility to these diseases is partly due to the intrinsic ageing process, characterized by genomic, cellular and metabolic hallmarks and immunosenescence, and is associated with changes in the intestinal microbiota. Importantly, in the lungs, ageing is also associated with a dysbiosis and loss of resilience of the resident microbiota and alterations of the gut-lung axis. Notably, as malnutrition is often observed in the elderly, nutrition is one of the most accessible modifiable factors affecting both senescence and microbiota. This article reviews the changes affecting the lung and its resident microbiota during ageing, as well as the interconnections between malnutrition, senescence, microbiota, gut-lung axis and respiratory health. As the communication along the gut-lung axis becomes more permissive with ageing, this review also explores the evidence that the gut and lung microbiota are key players in the maintenance of healthy lungs, and as such, are potential targets for nutrition-based preventive strategies against lung disease in elderly populations.
DIPG-63. LOSS OF THE H4 LYSINE METHYLTRANSFERASE KMT5B DRIVES INVASION / MIGRATION BY DEPLETING H3K27me3 AT LOCI OTHERWISE RETAINED IN H3K27M MUTANT DIPG CELLS
Authors: Ketty Kessler, Alan Mackay, Valeria Molinari, Haider Tari, Anna Burford, Andrea Sottoriva, Maria Vinci, Chris Jones
Journal: Neuro-Oncology (2020)

Abstract Diffuse intrinsic pontine glioma (DIPG) and other diffuse midline glioma (DMG) are characterised by K27M mutations in histone H3 variants. The major functional consequence is a global loss of the repressive mark H3K27me3, causing a raft of transcriptional changes promoting tumorigenesis, although certain key loci retain trimethylation, such as CDKN2A/B. We recently identified subclonal loss-of-function mutations in the H4 lysine methyltransferase KMT5B to be associated with an enhanced invasion/migration, but the mechanism by which this occurred was unclear. Here we show by ChIP-seq using patient-derived subclonal DIPG models and CRISPR-Cas9 depletion that loss of KMT5B (or KMT5C) causes a paradoxical increase in global levels of H4K20me3 in promoters and regulatory regions, only ablated by knocking out both enzymes. Loss of KMT5B alone further causes loss of the majority of otherwise retained H3K27me3 loci in DIPG cells, although CDKN2A/B itself was spared. De-repression occurred at bivalent loci marked by H3K4me3 and had elevated gene expression by RNAseq; these were significantly enriched for genes involved in chromatin remodelling and invasion/migration, the latter including MMP9/MMP24. Phenotypic assessment of the models in vitro by high-throughput imaging demonstrated significantly increased invasion and migration in association with either KMT5B or KMT5C loss, but not both. Quantitative proteomic assessment of the secretome identified factors by which a minority of KMT5B-deficient cells may signal to promote motility of the neighbouring populations. These data suggest a previously unrecognised trans-histone (H4/H3) interaction in DIPG cells with a potentially profound effect on their diffusely infiltrating phenotype.
AB0038 IMMUNE PHENOTYPING OF ERDHEIM-CHESTER DISEASE THROUGH MASS CYTOMETRY
Authors: M. Papo, A. Corneau, F. Cohen, B. Robin, J.F. Emile, M. Miyara, C. Blanc, Z. Amoura, O. Hermine, J. Haroche, T. Trovati Maciel
Journal: Annals of the Rheumatic Diseases (2020)

<h3>Background:</h3> The understanding of Erdheim-Chester Disease (ECD) pathogenesis has been greatly improved these past few years with the discovery of activating MAPK pathway mutations in most of ECD patients. However, the inflammatory phenotype of ECD remains widely unknown. <h3>Objectives:</h3> We aimed to explore the inflammatory phenotype of Erdheim-Chester disease (ECD) using mass cytometry. <h3>Methods:</h3> We analyzed peripheral blood mononuclear cells from 13 ECD patients and 11 healthy donors (HD) using mass cytometry with 29 metal-conjugated antibodies. <h3>Results:</h3> Compared to HD, untreated ECD patients had increased proportion of classical monocytes (90.8 [87.1-96.5] vs 81.6 [76.2-87.5] %, p=0.02) and decreased proportion of non-classical monocytes (4.7 [3.4-9.7] vs 11.8 [6.6-17.2] %, p=0.047). Untreated ECD patients had more circulating Th17 cells compared to HD (3.3 [3-5.3] vs 1.3 [0.4-2.3] %, p=0.015) and ECD patients treated with BRAF or MEK inhibitors (3.3 (3-5.3] vs 1.9 [0.6-2.4] %, p=0.005). Moreover Treg cells were lower in ECD patients than HD, with an increased Th17/Treg ratio (1.37 [0.74-1.9] vs 0.34 [0.19-0.43], p=0.0004). There was no difference regarding Th1 cells, Th2 cells, B cells, NK cells and circulating dendritic cells. <h3>Conclusion:</h3> ECD monocyte profile seems similar to what have been described in CMML. Inflammation observed in ECD may be driven through Th17 cells, and might be targeted with specific treatment. <h3>Disclosure of Interests:</h3> None declared
SURG-42. SAFETY OF INTRA-ARTERIAL CHEMOTHERAPY WITH OR WITHOUT OSMOTIC BLOOD BRAIN BARRIER DISRUPTION IN TREATMENT OF BRAIN TUMORS
Authors: Kutluay Uluc, John Philip Tabb, Caleb S Nerison, Aclan Dogan, Ryan A Priest, Prakash Ambady, Edward Neuwelt
Journal: Neuro-Oncology (2020)

Abstract BACKGROUND Intra-arterial route of drug delivery (IA) without or with osmotic blood brain barrier disruption (IA/BBBD) is one of the available techniques to overcome the blood-brain barrier and enhance drug delivery to brain tumors. We present a large single institution safety data of IA or IA/BBBD. METHODS This is a retrospective review of the electronic records, imaging and complications in patients who underwent IA or IA/BBBD in OHSU between December, 1997 and November, 2018. Procedural complications were documented prospectively and reviewed in the electronic medical records. Toxicities, attributed to chemotherapy, were reported when grade is either II or higher by Common Terminology Criteria for Adverse Events (CTCAE). RESULTS Complications related to chemotherapy and procedure were reported separately. Total of 4940 procedures (1102 IAC and 3838 oBBBD) were performed on 436 patients (190 female and 246 male). Pathologies were primary central nervous system lymphoma (PCNSL) (n=115, 26%), secondary central nervous system involvement (SCNSL) (n=37, 8%), glioblastoma (n=79, 18%), astrocytoma (grade II/III) (n=34, 7%), oligodendroglioma (n=64, 14%), pilocytic astrocytoma (n=10, 2%), metastatic (n=38, 8%), embryologic (n=37, 8%), others (n=22, 5%). Procedural complications: groin related (n=16, 0.32%), transient neurological decline (n=57, 1.15%), subintimal arterial injury (n=13, 0.26%), asymptomatic imaging changes (T2 or DWI) (n=60, 1.21%), symptomatic stroke (n=21, 0.43%), myocardial infarction (n=3, 0.37%), cervical cord injury (n=6, 0.12%), death within 3 days (n=6, 0.12%). Minor complications are 2.86%, major complications are 1.12%. Eighty-four percent (n=369) of the patients experienced grade 2 or higher toxicities attributed to chemotherapy. CONCLUSION We present the largest safety data set to date from a single institution experience using IA and IA/BBBD for brain tumors. Our results suggest that IA and IA/BBBD is safe and can be performed multiple times in the same patients with acceptable procedure related complications. Efficacy of this approach is being evaluated in prospective clinical trials.
Hyperscanning Alone Cannot Prove Causality. Multibrain Stimulation Can
Authors: Giacomo Novembre, Gian Domenico Iannetti
Journal: Trends in Cognitive Sciences (2020)

Brains that work together, couple together through interbrain synchrony. Does interbrain synchrony causally facilitate social interaction? This question cannot be answered by simply recording from multiple brains (hyperscanning). It instead requires causal protocols entailing their simultaneous stimulation (multibrain stimulation). We highlight promising findings and future horizons of this nascent field.
CER-001 ameliorates lipid profile and kidney disease in a mouse model of familial LCAT deficiency
Authors: Alice Ossoli, Arianna Strazzella, Daniela Rottoli, Cristina Zanchi, Monica Locatelli, Carlamaria Zoja, Sara Simonelli, Fabrizio Veglia, Ronald Barbaras, Cyrille Tupin, Jean-Louis Dasseux, Laura Calabresi
Journal: Metabolism (2020)
Successful Use of BRAF/MEK Inhibitors as a Neoadjuvant Approach in the Definitive Treatment of Papillary Craniopharyngioma
Authors: Karam Khaddour, Michael R. Chicoine, Jiayi Huang, Sonika Dahiya, George Ansstas
Journal: Journal of the National Comprehensive Cancer Network (2020)

Craniopharyngiomas are rare tumors that arise in the suprasellar region of the brain and are known for their aggressive nature despite their WHO grade I. This is due to the complex neuroanatomy of the sellar/suprasellar region and their proximity to the optic nerve apparatus, hypothalamic-pituitary tract, and other critical neuroanatomical structures. Definitive treatment is based on a multidisciplinary approach and often involves a combination of surgical, radiation, and medical therapy. However, there is high morbidity associated with surgery and RT due to the complex neuroanatomy of this region. Recently, BRAFV600E somatic mutation has been identified in most papillary craniopharyngiomas. This discovery has led to the novel use of RAF pathway inhibitors to treat these tumors. We report the successful use of dabrafenib (BRAF inhibitor) and trametinib (mitogen-activated protein kinase kinase inhibitor) in the neoadjuvant setting followed by definitive stereotactic radiosurgery. We propose an algorithm based on available literature on the integration of targeted therapy in the management of papillary craniopharyngiomas. Our observations, together with prior case reports, advocate the incorporation of targeted therapy for unresectable craniopharyngiomas and reinforce that treatment with dual-targeted therapy is safe and effective.
Abstract P435: Associations of Endogenous Sex Hormone Levels With the Prevalence and Progression of Valvular and Thoracic Aortic Calcification in the Multi-Ethnic Study of Atherosclerosis (MESA)
Authors: Apurva Sharma, Oluseye Ogunmoroti, Oluwaseun Fashanu, Di Zhao, Pamela Ouyang, Matthew J Budoff, Isac C Thomas, Erin D Michos
Journal: Circulation (2020)

Background: Sex hormone (SH) levels may contribute to sex differences in cardiovascular disease (CVD) risk among women and men. We previously found that high free testosterone (T) and low sex hormone binding globulin (SHBG) were associated with progression of coronary artery calcification in women. Extra-coronary calcification (ECC) predicts incident clinical CVD independent of traditional risk factors. We examined whether SH were also associated with ECC prevalence and progression among MESA participants free of clinical CVD at baseline. Methods: We studied 2883 postmenopausal women and 3164 men who had endogenous SH levels measured at baseline. ECC was measured by non-contrast cardiac CT at baseline and at a follow-up visit up to 5 years later. ECC included ascending and descending thoracic aortic calcification (ATAC, DTAC), mitral annular calcification (MAC) and aortic valve calcification (AVC). We used multivariable Poisson regression to evaluate associations with ECC prevalence and risk of developing ECC (Agatston scores &gt;0) and linear mixed effects models for ECC progression, per 1 SD increment in log (SH) level in women and men separately. Results: The mean (SD) age was 64 (9) years for women and 62 (10) years for men. In women, greater free T and lower SHBG were associated with MAC incidence in a demographic-adjusted model but were no longer statistically significant after adjustment for CVD risk factors ( Table ). In men, lower free T was associated with MAC prevalence, DTAC incidence and progression while greater SHBG was associated with MAC prevalence and DTAC progression in fully adjusted models. We did not find associations of SH with AVC or ATAC in either men or women. Conclusion: In this diverse cohort free of CVD, we found certain associations of SH with measures of ECC. In particular, free T was inversely associated with prevalent MAC and DTAC progression in men independent of CVD risk factors. SH may influence vascular calcification but further work is needed to understand the clinical implications of these findings.
Regulation of Synovial Inflammation and Tissue Destruction by Guanylate Binding Protein 5 in Synovial Fibroblasts From Patients With Rheumatoid Arthritis and Rats With Adjuvant‐Induced Arthritis
Authors: Mahamudul Haque, Anil K. Singh, Madhu M. Ouseph, Salahuddin Ahmed
Journal: Arthritis & Rheumatology (2020)

Objective Rheumatoid arthritis synovial fibroblasts (RASFs) are crucial mediators of synovial inflammation and joint destruction. However, their intrinsic immunoregulatory mechanisms under chronic inflammation remain unclear. Thus, the present study was undertaken to understand the role of a newly identified GTPase, guanylate binding protein 5 (GBP‐5), in RA pathogenesis. Methods The expression of GBP1 – GBP7 transcripts was evaluated using quantitative reverse transcription–polymerase chain reaction in RA synovial tissue or synovial tissue unaffected by RA. Our investigation on transient small interfering RNA (siRNA) knockdown and lentiviral overexpression in human RASFs examined the regulatory role of GBP‐5 on proinflammatory cytokine signaling pathways. Unbiased whole transcriptome RNA sequencing analysis was used to assess the impact of GBP‐5 on RASF molecular functions. These findings were confirmed using a rat model of adjuvant‐induced arthritis (AIA) in vivo. Results Among different GBPs evaluated, GBP‐5 was selectively up‐regulated in RA synovial tissue ( P &lt; 0.05; n = 4) and in the joints of rats with AIA ( P &lt; 0.05; n = 6) and was significantly induced in human RASFs by interleukin‐1β (IL‐1β), tumor necrosis factor (TNF), and/or interferon‐γ (IFNγ) ( P &lt; 0.05; n = 3). Bioinformatics analysis of RNA sequencing data identified cytokine–cytokine receptor signaling as a major function altered by GBP‐5, with IL‐6 signaling as a primary target. Knockdown of GBP‐5 amplified IL‐1β–induced IL‐6, IL‐8, and epithelial neutrophil–activating peptide 78/CXCL5 production by 44%, 54%, 45%, respectively, and matrix metalloproteinase 1 (MMP‐1) production by several‐fold—effects that reversed with exogenously delivered GBP‐5. Lack of GBP‐5 increased IFNγ‐induced proliferation and migration of human RASFs. GBP‐5 knockdown in vivo using intraarticular siRNA exacerbated disease onset, severity, synovitis, and bone destruction in rat AIA. Conclusion Expressed by RASFs in response to cytokine stimulation, GBP‐5 has potential to restore cellular homeostasis and blunt inflammation and tissue destruction in RA.
Metabolic Gatekeepers of Pathological B Cell Activation
Authors: Teresa Sadras, Lai N. Chan, Gang Xiao, Markus Müschen
Journal: Annual Review of Pathology Mechanisms of Disease (2020)

Unlike other cell types, B cells undergo multiple rounds of V(D)J recombination and hypermutation to evolve high-affinity antibodies. Reflecting high frequencies of DNA double-strand breaks, adaptive immune protection by B cells comes with an increased risk of malignant transformation. In addition, the vast majority of newly generated B cells express an autoreactive B cell receptor (BCR). Thus, B cells are under intense selective pressure to remove autoreactive and premalignant clones. Despite stringent negative selection, B cells frequently give rise to autoimmune disease and B cell malignancies. In this review, we discuss mechanisms that we term metabolic gatekeepers to eliminate pathogenic B cell clones on the basis of energy depletion. Chronic activation signals from autoreactive BCRs or transforming oncogenes increase energy demands in autoreactive and premalignant B cells. Thus, metabolic gatekeepers limit energy supply to levels that are insufficient to fuel either a transforming oncogene or hyperactive signaling from an autoreactive BCR.
CBIO-13. EPIGENETIC DEREGULATION OF NUCLEAR TRANSLOCATION - A NOVEL MECHANISM FOR TREATMENT RESISTANCE IN GLIOBLASTOMA
Authors: Thi Tham Nguyen, Premnath Rajakannu, Minh Diêu Thanh Pham, Leo Weman, Alexander Jucht, Kristof Van Dommelen, Monika Hegi
Journal: Neuro-Oncology (2020)

Abstract In a genome-wide DNA methylation analysis of glioblastoma we identified aberrant methylation of the HIV-1 Tat interactive protein 2 (HTATIP2) gene promotor. This was strongly correlated with downregulation of HTATIP2 gene expression, suggesting a potential tumor suppressor function in glioblastoma. HTATIP2 has been shown to inhibit nuclear translocation through interaction with β-importins. We hypothesize that deregulation of HTATIP2 expression inhibits nuclear entry of cancer-relevant proteins, thereby disturbing their specific function in the nucleus. We identified N-Methylpurine-DNA Glycosylase (MPG) as a potential cancer relevant candidate with the observation of nuclear and/or cytoplasmic localization in glioblastoma. MPG is a DNA repair protein that recognizes DNA lesions (N7-meG, N3-meA) and initiates base excision repair. We have shown that nuclear MPG expression contributes to resistance of glioblastoma to treatment with the alkylating agent temozolomide. Here we investigated the effect of HTATIP2 on cellular localization of MPG using (i) an inducible system (TET-ON) to express HTATIP2 in non-expressing glioblastoma cells, and (ii) HTATIP2-targeting siRNAs to knock down HTATIP2 in cells with endogenous expression. Results from confocal microscopy or Imagestream analyses showed a significant cytoplasmic retention of MPG in presence of HTATIP2, while knock-down of HTATIP2 resulted in nuclear MPG localization. Cytoplasmic retention of MPG in the presence of HTATIP2 was associated with a significant increase in γ-H2Ax signal after treatment with the alkylating agent: methyl methanesulfonate (MMS), suggesting increase in DNA damage. Mechanistically, we found that HTATIP2 co-localizes with importin β1, and excludes MPG localization. Furthermore, HTATIP2 displayed a similar effect on cytoplasmic retention of MPG as pharmacologic inhibition of Importin β 1. Taken together, these results suggest that epigenetic silencing of HTATIP2 may increase nuclear localization of MPG, thereby increasing the capacity of the tumor cells to repair treatment related lesions and thereby contributing to treatment resistance.
Synergistic integration of metal nanoclusters and biomolecules as hybrid systems for therapeutic applications
Authors: Peng Gao, Xin Chang, Dagan Zhang, Yafei Cai, Gen Chen, Hao Wang, Tianfu Wang
Journal: Acta Pharmaceutica Sinica B (2020)

Therapeutic nanoparticles are designed to enhance efficacy, real-time monitoring, targeting accuracy, biocompatibility, biodegradability, safety, and the synergy of diagnosis and treatment of diseases by leveraging the unique physicochemical and biological properties of well-developed bio-nanomaterials. Recently, bio-inspired metal nanoclusters (NCs) consisting of several to roughly dozens of atoms (<2 nm) have attracted increasing research interest, owing to their ultrafine size, tunable fluorescent capability, good biocompatibility, variable metallic composition, and extensive surface bio-functionalization. Hybrid core-shell nanostructures that effectively incorporate unique fluorescent inorganic moieties with various biomolecules, such as proteins (enzymes, antigens, and antibodies), DNA, and specific cells, create fluorescently visualized molecular nanoparticle. The resultant nanoparticles possess combinatorial properties and synergistic efficacy, such as simplicity, active bio-responsiveness, improved applicability, and low cost, for combination therapy, such as accurate targeting, bioimaging, and enhanced therapeutic and biocatalytic effects. In contrast to larger nanoparticles, bio-inspired metal NCs allow rapid renal clearance and better pharmacokinetics in biological systems. Notably, advances in nanoscience, interfacial chemistry, and biotechnologies have further spurred researchers to explore bio-inspired metal NCs for therapeutic purposes. The current review presents a comprehensive and timely overview of various metal NCs for various therapeutic applications, with a special emphasis on the design rationale behind the use of biomolecules/cells as the main scaffolds. In the different hybrid platform, we summarize the current challenges and emerging perspectives, which are expected to offer in-depth insight into the rational design of bio-inspired metal NCs for personalized treatment and clinical translation.
Inducible Nitric Oxide Synthase in Severe Human Heart Failure⁎: Impact of Mechanical Unloading⁎Editorials published in the Journal of the American College of Cardiologyreflect the views of the authors and do not necessarily represent the views of JACCor the American College of Cardiology.
Authors: Randall C. Starling
Journal: Journal of the American College of Cardiology (2005)
Biomarker-Guided Treatment of Heart Failure: Still Waiting for a Definitive Answer⁎⁎Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
Authors: Richard W. Troughton, Chris M. Frampton, M. Gary Nicholls
Journal: Journal of the American College of Cardiology (2010)
Bioactive, Ion‐Releasing PMMA Bone Cement Filled with Functional Graphenic Materials
Authors: Zoe M. Wright, Avanti M. Pandit, Michelle M. Karpinsky, Brian D. Holt, Edward P. Zovinka, Stefanie A. Sydlik
Journal: Advanced Healthcare Materials (2020)

Abstract Graphene oxide and functionalized graphenic materials (FGMs) have promise as platforms for imparting programmable bioactivity to poly(methyl methacrylate) (PMMA)‐based bone cement. To date, however, graphenic fillers have only been feasible in PMMA cements at extremely low loadings, limiting the bioactive effects. At higher loadings, graphenic fillers decrease cement strength by aggregating and interfering with curing process. Here, these challenges are addressed by combining bioactive FGM fillers with a custom cement formulation. These cements contain an order of magnitude more graphenic filler than previous reports. Even at 1 wt% FGM, these cements have compressive strengths of 78– 88 MPa, flexural strengths of 74–81 MPa, and flexural stiffnesses of 1.8–1.9 GPa, surpassing the ASTM requirements for bone cement and competing with traditional PMMA cement. Further, by utilizing designer FGMs with programmed bioactivity, these cements demonstrate controlled release of osteogenic calcium ions (releasing a total of 5 ± 2 µmol of Ca2+ per gram of cement over 28 d) and stimulate a 290% increase in expression of alkaline phosphatase in human mesenchymal stem cells in vitro. Also, design criteria are described to guide creation of future generations of bone cements that utilize FGMs as platforms to achieve dynamic biological activity.
A chimeric hemagglutinin-based universal influenza virus vaccine approach induces broad and long-lasting immunity in a randomized, placebo-controlled phase I trial
Authors: Raffael Nachbagauer, Jodi Feser, Abdollah Naficy, David I. Bernstein, Jeffrey Guptill, Emmanuel B. Walter, Franceso Berlanda-Scorza, Daniel Stadlbauer, Patrick C. Wilson, Teresa Aydillo, Mohammad Amin Behzadi, Disha Bhavsar, Carly Bliss, Christina Capuano, Juan Manuel Carreño, Veronika Chromikova, Carine Claeys, Lynda Coughlan, Alec W. Freyn, Christopher Gast, Andres Javier, Kaijun Jiang, Chiara Mariottini, Meagan McMahon, Monica McNeal, Alicia Solórzano, Shirin Strohmeier, Weina Sun, Marie Van der Wielen, Bruce L. Innis, Adolfo García-Sastre, Peter Palese, Florian Krammer
Journal: Nature Medicine (2020)