tbuckley/cabot-search huggingface dataset:
MicroRNAs and immunity in periodontal health and disease
Authors: Xianghong Luan, Xiaofeng Zhou, Afsar Naqvi, Marybeth Francis, Deborah Foyle, Salvador Nares, Thomas G. H. Diekwisch
Journal: International Journal of Oral Science (2018)

MicroRNAs (miRNAs) are critical regulators of the host immune and inflammatory response against bacterial pathogens. In the present review, we discuss target genes, target gene functions, the potential regulatory role of miRNAs in periodontal tissues, and the potential role of miRNAs as biomarkers and therapeutics. In periodontal disease, miRNAs exert control over all aspects of innate and adaptive immunity, including the functions of neutrophils, macrophages, dendritic cells and T and B cells. Previous human studies have highlighted some key miRNAs that are dysregulated in periodontitis patients. In the present study, we mapped the major miRNAs that were altered in our reproducible periodontitis mouse model relative to control animals. The miRNAs that were upregulated as a result of periodontal disease in both human and mouse studies included miR-15a, miR-29b, miR-125a, miR-146a, miR-148/148a and miR-223, whereas miR-92 was downregulated. The association of individual miRNAs with unique aspects of periodontal disease and their stability in gingival crevicular fluid underscores their potential as markers for periodontal disease progression or healthy restitution. Moreover, miRNA therapeutics hold great promise for the future of periodontal therapy because of their ability to modulate the immune response to infection when applied in conjunction with synthetic antagomirs and/or relatively straightforward delivery strategies.
Plasma sRAGE is independently associated with increased mortality in ARDS: a meta-analysis of individual patient data
Authors: Matthieu Jabaudon, Raiko Blondonnet, Bruno Pereira, Rodrigo Cartin-Ceba, Christoph Lichtenstern, Tommaso Mauri, Rogier M. Determann, Tomas Drabek, Rolf D. Hubmayr, Ognjen Gajic, Florian Uhle, Andrea Coppadoro, Antonio Pesenti, Marcus J. Schultz, Marco V. Ranieri, Helena Brodska, Ségolène Mrozek, Vincent Sapin, Michael A. Matthay, Jean-Michel Constantin, Carolyn S. Calfee
Journal: Intensive Care Medicine (2018)

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of lung epithelial injury and alveolar fluid clearance (AFC), with promising values for assessing prognosis and lung injury severity in acute respiratory distress syndrome (ARDS). Because AFC is impaired in most patients with ARDS and is associated with higher mortality, we hypothesized that baseline plasma sRAGE would predict mortality, independently of two key mediators of ventilator-induced lung injury.
Tackling benzodiazepine misuse
Authors: Benedict Hayhoe, James Lee-Davey
Journal: BMJ (2018)

Discovered in the 1950s by Leo Sternbach, 1 benzodiazepines were enthusiastically adopted as a safer alternative to barbiturates for management of insomnia and anxiety.Evidence quickly accrued, however, of substantial risk of dependence.Despite recommendation that they be prescribed for no more than four weeks, long term use remains common, with 300 000 long term users in the UK. 2 Benzodiazepines, and the related z drugs (zopidem, zopiclone, and zalepon), potentiate the rapid neuroinhibitory effect of the neurotransmitter γ aminobutyric acid (GABA) in the brain and spinal cord.This results in reduction of anxiety, induction of sleep, and muscle relaxation.Consequently, benzodiazepines are commonly prescribed for anxiety and sleep disorders, but are also highly effective as muscle relaxants; for treating epilepsy, alcohol withdrawal syndrome, and acute behavioural disturbance; and as a premedicant in anaesthesia.
A thioredoxin-mimetic peptide exerts potent anti-inflammatory, antioxidant, and atheroprotective effects in ApoE2.Ki mice fed high fat diet
Authors: Fanny Canesi, Véronique Mateo, Dominique Couchie, Sonia Karabina, Anne Nègre-Salvayre, Mustapha Rouis, Khadija El Hadri
Journal: Cardiovascular Research (2018)

Oxidative stress and inflammation play a pathogenic role in atherosclerosis. Thioredoxin-1 (Trx-1) is an anti-oxidative, anti-inflammatory protein with atheroprotective effects. However, in vivo cleavage of Trx-1 generates a truncated pro-inflammatory protein, Trx-80, which compromises the therapeutic use of Trx-1. Here we analysed whether the thioredoxin-mimetic peptide (TxMP), CB3 might exert anti-oxidative, anti-inflammatory, and atheroprotective effects in ApoE2.Ki mice. We synthesized a small TxMP, Ac-Cys-Pro-Cys-amide, CB3 and characterized its antioxidant and anti-inflammatory effects on cultured peritoneal murine macrophages. CB3 significantly and dose-dependently reduced the level of reactive oxygen species in lipopolysaccharides (LPS)-activated macrophages. In addition, it efficiently lowered LPS-induced inflammatory process through NF-κB inhibition, as evidenced by the reduced secretion of monocyte chemoattractant protein-1, interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α by macrophages. Nevertheless, CB3 did not affect cholesterol accumulation in macrophages. A daily-administered dose of 10 µg/g body weight CB3 to ApoE2.Ki mice on high fat diet did not affect plasma of total cholesterol and triglycerides levels but significantly reduced the plasma levels of pro-inflammatory cytokines (IL-33 and TNF-α) and oxidative markers. In contrast, it significantly induced the plasma levels of anti-inflammatory proteins (adiponectin, IL-10). In addition, CB3 reduced the number of pro-inflammatory M1 macrophages in spleen and decreased the ratio of M1/M2 macrophages in atherosclerotic lesion areas. Finally, CB3 significantly reduced the surface area of aortic lesions. Our results clearly showed that similar to the full length Trx-1, CB3 exerts protective effects, by reducing inflammation and oxidative stress in macrophages and in ApoE2.Ki mice. The atheroprotective effect of CB3 opens promising therapeutic approaches for treatment of atherosclerosis.
Radiofrequency Catheter Ablation of Sustained Ventricular Tachycardia in Idiopathic Dilated Cardiomyopathy
Authors: HansKottkamp, GerhardHindricks, XuChen, JürgenBrunn, StephanWillems, WilhelmHaverkamp, MichaelBlock, GünterBreithardt, MartinBorggrefe
Journal: Circulation (1995)

Background The feasibility of radiofrequency (RF) catheter ablation for the treatment of sustained ventricular tachycardia (VT) in patients with coronary artery disease and remote myocardial infarction has recently been demonstrated. At present, therapeutic options for VT in patients with idiopathic dilated cardiomyopathy (DCM) include antiarrhythmic drugs and implantable cardioverter/defibrillators (ICD). The purpose of the present study was to investigate the feasibility of RF catheter ablation in patients with idiopathic DCM who could not be adequately treated by conventional treatment modalities because of incessant or frequent, recurrent VT. Methods and Results RF current application for ablation of 9 VTs (mean cycle length, 402±78 ms) was attempted in 8 patients with idiopathic DCM (4 men, 4 women; mean age, 54±6 years; mean left ventricular ejection fraction, 30±9%). Inclusion criteria for ablation were incessant VT (n=4) or frequent, recurrent VT reproducibly inducible with programmed electrical s...
Impact of Weight Reduction During Adolescence on Parameters of Cardiac Geometry and Function in Obese Children
Authors: Sandra Erbs, Henriette Broniecki, Kathrin Scheuermann, Ephraim Winzer, Jennifer Adam, Ulrike Spielau, Felix Woitek, Marcus Sandri, Marion Zimmer, Christian Besler, Wieland Kiess, Axel Linke, Antje Körner, Norman Mangner
Journal: JACC. Cardiovascular imaging (2018)
The VEGF receptor tyrosine kinase inhibitor AZD2171 inhibits VEGF signaling, angiogenesis, and tumor growth in vivo
Authors: Stephen R. Wedge, Jane Kendrew, Paula J. Valentine, Lyndsey L. Kilburn, Jon O. Curwen, Helen L. Musgrove, Martine J. Mellor, Sharon Barnett, Peter F. Wadsworth, Graham H. Richmond, Alison L. Bigley, Laurent F. Hennequin, Patrick Ple, Elaine S. Stokes, Donald J. Ogilvie
Journal: Cancer Research (2004)

4555   AZD2171 is a sub-nanomolar inhibitor of vascular endothelial growth factor (VEGF)-induced KDR (VEGFR-2) signaling in human endothelial cells  in vitro . Signaling from this receptor is considered to be the major stimulus of physiological and pathological angiogenesis. AZD2171 may therefore have potential as an inhibitor of tumor neovascularization in a range of malignancies. To demonstrate inhibition of VEGF signaling by AZD2171  in vivo  and to examine the consequences of chronic administration, a range of endpoints were studied. Direct inhibition of VEGF signaling  in vivo  was shown using an acute growth factor hypotension model in anesthetized rats. AZD2171 (250 μg/kg i.v.) completely reversed a hypotensive change induced by intravenous bolus injection of VEGF (32 μg/kg). Chronic inhibition of VEGF signaling has been shown to prevent ossification during long bone growth, by inhibiting vascular invasion of the growth plate. AZD2171 (1.25–5 mg/kg/day) inhibited endochondral ossification significantly, producing a dose-dependent increase in the hypertrophic chondrocyte zone. Morphometric image analysis of femoral and tibial growth plates indicated that AZD2171 (5 mg/kg/day for 28 days) increased the combined growth plate area by more than 400%. This phenotype was fully reversed when followed by an additional period of 28 days without drug treatment. In female rats, significant inhibition of corpora lutea formation was observed in the ovary following AZD2171 treatment (5 mg/kg/day for 28 days): an additional physiological process that is dependent upon angiogenesis. To evaluate antitumor activity in the rat, athymic animals bearing established Calu-6 human lung cancer xenografts (0.23–0.5 cm 3  volume) were treated once daily with AZD2171 (0.1–3 mg/kg p.o.) for 28 days. A dose-dependent inhibition of tumor growth was observed, with statistically significant activity at all doses ( P  90% growth inhibition at 3 mg/kg/day. Calu-6 tumors retrieved from athymic mice following chronic AZD2171 treatment were examined by immunohistochemistry. Tumors from mice treated with 6 mg/kg/day AZD2171 (for 28 days), were found to have significantly reduced CD31 vessel staining and a six-fold increase in tumor cell necrosis, when compared with control tumors. These observations are compatible with inhibiting VEGF-dependent neovascularization and vascular permeability in tumors. Collectively, the preclinical data obtained with AZD2171 are consistent with potent inhibition of VEGF signaling and angiogenesis  in vivo . AZD2171 is currently in clinical development as a once daily oral therapy for the treatment of cancer.
알코올 간질환의 예후 모델
Authors: 은종렬 ( Jong Ryul Eun )
Journal: Clinical and Molecular Hepatology (2011)

The prognosis of patients with severe alcoholic hepatitis (AH) remains poor, with a 40% in-hospital mortality rate. Corticosteroids improve the short-term survival of the patients with severe AH. Therefore, it is important to select the subjects who should be treated with corticosteroids. Traditionally, the severity of patients with AH has been assessed using Maddrey`s discriminant function (DF). However, the model for end-stage liver disease, the Glasgow alcoholic hepatitis score and ABIC score have been reported to be superior to predict survival than Maddrey`s DF in patients with AH. More recently, the Lille model has shown to have a high sensitivity and specificity in predicting survival at 6 months in patients with AH treated with corticosteroids who do not improve after 7 days of treatment. This review will cover the characteristics of various prognostic models, and the best approach to evaluate the prognosis of patients with AH.
CART cells are prone to Fas- and DR5-mediated cell death
Authors: Benjamin O. Tschumi, Nina Dumauthioz, Bastien Marti, Lianjun Zhang, Pascal Schneider, Jean-Pierre Mach, Pedro Romero, Alena Donda
Journal: Journal for ImmunoTherapy of Cancer (2018)

Adoptive transfer of T cells transduced with Chimeric Antigen Receptors (CAR) are now FDA-approved for the treatment of B-cell malignancies. Yet, the functionality of the endogenous TCR in CART cells has not been fully assessed. Here, we demonstrate that CART cells progressively upregulate Fas, FasL, DR5 and TRAIL, which result in their programmed cell death, independently of antigen-mediated TCR or CAR activation. CART cell apoptosis occurs even when the CAR contains a single (co-)activatory domain such as CD3ζ, CD28 or 4-1BB. Importantly, the dominant role of the Fas and DR5 pathways in CART cell apoptosis is demonstrated by the significant rescue of CART cells upon in vivo blockade by combined Fas-Fc and DR5-Fc recombinant proteins. These observations are of crucial importance for the long-term persistence of CART cells and for the development of new applications including the combined TCR and CAR activation against solid tumors.
Quantitative CT texture assessment of tumour heterogeneity to predict those patients with non-small cell lung cancer most likely to benefit from immune checkpoint inhibitors.
Authors: Rahul Ladwa, Kate Elizabeth Roberts, Kenneth John O'Byrne, Ken Miles
Journal: Journal of Clinical Oncology (2018)

e21027 Background: Attempts to isolate reliable predictive biomarkers have been unsuccessful for the use of immunotherapy agents targeting PD-1 and PD-L1 immune checkpoint proteins in the treatment of non-small cell lung cancer (NSCLC). This study assessed whether CT texture analysis as a potential correlate for genomic heterogeneity could predict those patients most likely to benefit from Nivolumab. Methods: A single centre retrospective analysis was undertaken of patients with NSCLC previously treated with platinum doublet chemotherapy who underwent nivolumab immunotherapy. Texture analysis was used to quantify heterogeneity within the single largest tumour site identified on contrast enhanced CT of the thorax prior to commencement of immunotherapy. Based on histogram analysis of tumour regions processed to highlight image features of 4mm radius, tumours were classified as hyperdense (positive skewness) or hypodense (negative skewness) and then sub-classified based on their median standard deviation value (SD). Progression-free survival (PFS) was assessed for each group using Kaplan-Meier analysis. Results: A total of 47 patients were included in the study, median age 64 (47-84) years. Squamous (N = 21) and non-squamous (N = 26) histology were included. All patients had progressed on prior platinum doublet chemotherapy except one who developed toxicity. Nivolumab was discontinued (N = 37) due to progression (N = 34) and toxicity (N = 3), with treatment ongoing in the remaining patients (N = 10). With a median follow up of 18 months, hyperdense tumours with low SD (n = 14), findings consistent with tumour heterogeneity, showed significantly longer PFS compared to the hypodense group (median NR versus 1.5 months, Hazard Ratio: 2.05, p = 0.018). At 12 months more patients had not progressed in the hyperdense group (53%) versus the hypodense group (12%). Conclusions: This to date is the first preliminary study of quantitative CT texture assessment for tumour heterogeneity in NSCLC allowing us to identify patients who will benefit from immunotherapy in metastatic NSCLC. Further prospective trials will be required to assess its efficacy.
Activation of NKT Cells in an Anti-PD-1–Resistant Tumor Model Enhances Antitumor Immunity by Reinvigorating Exhausted CD8 T Cells
Authors: Eun-Ah Bae, Hyungseok Seo, Byung-Seok Kim, Jeongwon Choi, Insu Jeon, Kwang-Soo Shin, Choong-Hyun Koh, Boyeong Song, Il-Kyu Kim, Byung Soh Min, Yoon Dae Han, Sang Joon Shin, Chang-Yuil Kang
Journal: Cancer Research (2018)

Abstract PD-1–based cancer immunotherapy is a successful example of immune checkpoint blockade that provides long-term durable therapeutic effects in patients with cancer across a wide spectrum of cancer types. Accumulating evidence suggests that anti-PD-1 therapy enhances antitumor immunity by reversing the function of exhausted T cells in the tumor environment. However, the responsiveness rate of patients with cancer to anti-PD-1 therapy remains low, providing an urgent need for optimization and improvement. In this study, we designed an anti-PD-1–resistant mouse tumor model and showed that unresponsiveness to anti-PD-1 is associated with a gradual increase in CD8 T-cell exhaustion. We also found that invariant natural killer T cell stimulation by the synthetic ligand α-galactosylceramide (αGC) can enhance the antitumor effect in anti-PD-1–resistant tumors by restoring the effector function of tumor antigen–specific exhausted CD8 T cells. IL2 and IL12 were among the cytokines produced by αGC stimulation critical for reinvigorating exhausted CD8 T cells in tumor-bearing mice and patients with cancer. Furthermore, we observed a synergistic increase in the antitumor effect between αGC-loaded antigen-presenting cells and PD-1 blockade in a therapeutic murine tumor model. Our study suggests NKT cell stimulation as a promising therapeutic strategy for the treatment of patients with anti-PD-1–resistant cancer. Significance: These findings provide mechanistic insights into the application of NKT cell stimulation as a potent adjuvant for immunotherapy against advanced cancer. Cancer Res; 78(18); 5315–26. ©2018 AACR.
Abstract 19839: Annexin-a1 Tripeptide is Cardioprotective in Several Preclinical Models of Ischemia-Reperfusion Through Resolution of Myocardial Inflammation
Authors: Zhiquan Zhang, Qing Ma, James Frederiksen, George Quick, Kevin Collins, Burkhard Mckensen, Mihai Podgoreanu
Journal: Circulation (2010)

Background:  Annexin A1 is a glucocorticoid-regulated protein that plays a pivotal role as an endogenous regulator of the inflammatory response, with many of its anti-inflammatory properties retained by the N-terminal peptides. Using in vitro and in vivo models of myocardial ischemia-reperfusion (I/R) under both normo- and hyperglycemic conditions, we tested the hypothesis that a novel annexin A1 tripeptide (ANXA1sp) exerts cardioprotective effects through resolution of myocardial inflammation.   Methods:  In vitro simulated I/R:  Adult rat ventricular cardiomyocytes were incubated in normal or high glucose (25mM), with and without ANXA1sp (30 μM) for 24h, subjected to 2h oxygen-glucose deprivation, followed by 24h reoxygenation in either normo- or hyperglycemic medium.  Rat I/R:  SD rats underwent 75 min of mild hypothermic cardiopulmonary bypass (CPB) with 45 min of cardioplegic arrest (CA) in 4 groups: normo- and hyperglycemic (20mM) CA, each treated with ANXA1sp (3mg/kg) or vehicle.  Pig I/R:  Yorkshire pigs subjected to 180 min of mild hypothermic CPB with 60 min of CA received ANXA1sp (4mg/kg) or vehicle.  Efficacy endpoints  assessed at 24h post-reoxygenation (ARVC), 24h (rat) and 6h (pig) post-reperfusion include markers of myonecrosis, apoptosis, myocardial inflammation, leukocyte extravasation, and pump function.   Results:  ANXA1sp consistently attenuated myocardial I/R injury under both glycemic conditions, which correlated with reduced activation of NF-κB pathway (Figure). Peptide treated pigs further demonstrated improved myocardial energetics and hemodynamics, none requiring inotropic or vasopressor support, which was substantial in all control animals.   Conclusions:  Using a translational approach and robust efficacy endpoints, we report that ANXA1sp elicits cardioprotection  in vitro  and in small and large animal models of surgical I/R. The effects are not blunted by hyperglycemia and involve attenuation of myocardial inflammation.
Germline-activating mutations in <i>PIK3CD</i> compromise B cell development and function
Authors: Danielle T. Avery, Alisa Kane, Tina Nguyen, Anthony Lau, Akira Nguyen, Helen Lenthall, Kathryn Payne, Wei Shi, Henry Brigden, Elise French, Julia Bier, Jana R. Hermes, David Zahra, William A. Sewell, Danyal Butt, Michael Elliott, Kaan Boztug, Isabelle Meyts, Sharon Choo, Peter Hsu, Melanie Wong, Lucinda J. Berglund, Paul Gray, Michael O’Sullivan, Theresa Cole, Steven M. Holland, Cindy S. Ma, Christoph Burkhart, Lynn M. Corcoran, Tri Giang Phan, Robert Brink, Gulbu Uzel, Elissa K. Deenick, Stuart G. Tangye
Journal: The Journal of Experimental Medicine (2018)

Gain-of-function (GOF) mutations in PIK3CD, encoding the p110δ subunit of phosphatidylinositide 3-kinase (PI3K), cause a primary immunodeficiency. Affected individuals display impaired humoral immune responses following infection or immunization. To establish mechanisms underlying these immune defects, we studied a large cohort of patients with PIK3CD GOF mutations and established a novel mouse model using CRISPR/Cas9-mediated gene editing to introduce a common pathogenic mutation in Pik3cd. In both species, hyperactive PI3K severely affected B cell development and differentiation in the bone marrow and the periphery. Furthermore, PI3K GOF B cells exhibited intrinsic defects in class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature and phenotype. Importantly, defects in CSR, AID expression, and Ig secretion were restored by leniolisib, a specific p110δ inhibitor. Our findings reveal key roles for balanced PI3K signaling in B cell development and long-lived humoral immunity and memory and establish the validity of treating affected individuals with p110δ inhibitors.
Physiological responses to leptin levels in lipodystrophy: a model for other hypoleptinemias?
Authors: Michael Rosenbaum, Rudolph L. Leibel
Journal: Journal of Clinical Investigation (2018)

Brown et al. report that two weeks of exogenous leptin administration to leptin-naive individuals with lipodystrophy resulted in increased energy expenditure and lipolysis, decreased ectopic liver fat, improved hepatic and peripheral insulin sensitivity, and attenuated dyslipidemia. Leptin withdrawal in individuals with lipodystrophy did not produce reciprocal effects on these phenotypes and resulted in significant improvements only in hepatic insulin sensitivity. This asymmetry in responses to leptin initiation and cessation is consistent with the other aspects of leptin biology that are dependent on the metabolic context in which this adipocyte-derived hormone functions.
Persistence of Ebola virus after the end of widespread transmission in Liberia: an outbreak report
Authors: Emily Kainne Dokubo, Annika Wendland, Suzanne E Mate, Jason T Ladner, Esther L Hamblion, Philomena Raftery, David J Blackley, A Scott Laney, Nuha Mahmoud, Gloria Wayne-Davies, Lisa Hensley, Eric Stavale, Lawrence Fakoli, Christopher Gregory, Tai-Ho Chen, Augustine Koryon, Denise Roth Allen, Jennifer Mann, Andrew Hickey, John Saindon, Mehboob Badini, April Baller, Peter Clement, Fatorma Bolay, Yatta Wapoe, Michael R Wiley, James Logue, Bonnie Dighero-Kemp, Elizabeth Higgs, Alex Gasasira, Desmond E Williams, Bernice Dahn, Francis Kateh, Tolbert Nyenswah, Gustavo Palacios, Mosoka P Fallah
Journal: The Lancet Infectious Diseases (2018)