tbuckley/cabot-search huggingface dataset:
Covid-19: Charity to challenge rules on visits to care homes
Authors: Abi Rimmer
Journal: BMJ (2020)

<h3>Abstract</h3> Retrospective analyses of interventions to epidemics, in which the effectiveness of strategies implemented are compared to hypothetical alternatives, are valuable for performing the cost-benefit calculations necessary to optimize infection countermeasures. SIR (susceptible-infected-removed) models are useful in this regard but are limited by the challenge of deciding how and when to update the numerous parameters as the epidemic changes in response to population behaviors. Behaviors of particular interest include facemasks adoption (at various levels) and social distancing. We present a method that uses a “dynamic spread function” to systematically capture the continuous variation in the population behavior, and the gradual change in infection evolution, resulting from interventions. No parameter updates are made by the user. We use the tool to quantify the reduction in infection rate realizable from the population of New York City adopting different facemask strategies during COVID-19. Assuming a baseline facemask of 67% filtration efficiency, calculations show that increasing the efficiency to 80% could have reduced the roughly 5000 new infections per day occurring at the peak of the epidemic to around 4000. Population behavior that may not be varied as part of the retrospective analysis, such as social distancing in a facemask analysis, are automatically captured as part of the calibration of the dynamic spread function.
Infographic. Clinical recommendations for return to play during the COVID-19 pandemic
Authors: Herbert Löllgen, Norbert Bachl, Theodora Papadopoulou, Andrew Shafik, Graham Holloway, Karin Vonbank, Nigel Edward Jones, Xavier Bigard, David Niederseer, Joachim Meyer, Borja Muniz-Pardos, Andre Debruyne, Petra Zupet, Jürgen M Steinacker, Bernd Wolfarth, James Lee John Bilzon, Anca Ionescu, Michiko Dohi, Jeroen Swart, Victoriya Badtieva, Irina Zelenkova, Maurizio Casasco, Michael Geistlinger, Luigi Di Luigi, Nick Webborn, Patrick Singleton, Mike Miller, Fabio Pigozzi, Yannis P Pitsiladis
Journal: British Journal of Sports Medicine (2020)

BACKGROUND: A non-invasive marker is needed to identify patients with significant gastrointestinal injury due to non-steroidal anti-inflammatory drugs. Gastrointestinal permeability to sucrose has been suggested as such a test. AIMS: To assess the utility of sucrose permeability as a marker of gastroduodenal mucosal injury after single and multiple doses of aspirin, to identify the site of increased sucrose permeability, to explore the relation between sucrose permeability and endoscopic findings, and to evaluate whether Helicobacter pylori infection influenced gastroduodenal sucrose permeability. METHODS: After a fasting urine was obtained, 500 ml of a solution containing 100 g of sucrose was ingested. Urine was collected for five hours and assayed for sucrose by high performance liquid chromatography. Sucrose permeability was also assessed 20 minutes after ingestion of 650 mg of aspirin and eight to 12 hours after a 72 hour course of 650 mg aspirin four times a day. The site of increased permeability was identified after pyloric occlusion with a double balloon tube. RESULTS: Thirty seven healthy volunteers participated. Sucrose permeability (mean (SEM)) increased after both single (195.2 (27) mg and multiple (196.4 (31) mg) doses of aspirin compared with baseline (53.7 (10) mg; p &lt; 0.0005). Balloon pyloric occlusion confirmed that the site of increased sucrose permeability was the stomach. The effect of aspirin on sucrose permeability was similar in those with and without H pylori infection. CONCLUSION: These results confirm the use of sucrose permeability as a marker of aspirin induced gastroduodenal mucosal injury and identify the stomach as the major site of increased permeability. H pylori infection does not seem to change gastric mucosal sucrose permeability either at baseline or after ingestion of aspirin.
Abstract 15274: Next Generation Sequencing in Kawasaki Disease: A Pilot Study
Authors: Dongngan Truong, Luann Minich, Edwin Lin, Richard V Williams, Robert Schlaberg, Linda M Lambert, Yueqin Yang, Igor Areinamo, Krow Ampofo, Martin Tristani-Firouzi
Journal: Circulation (2019)

Introduction: The etiology and inflammatory cascade leading to Kawasaki disease (KD) remain poorly understood using traditional methods. Diagnosis of KD is made by clinical and laboratory findings,...
A Novel Blood-Based Panel of Methylated DNA and Protein Markers for Detection of Early-Stage Hepatocellular Carcinoma
Authors: Naga P. Chalasani, Tiruvidaimarudur S. Ramasubramanian, Abhik Bhattacharya, Marilyn C. Olson, David K. Edwards V, Lewis R. Roberts, John B. Kisiel, K. Rajender Reddy, Graham P. Lidgard, Scott C. Johnson, Janelle J. Bruinsma
Journal: Clinical Gastroenterology and Hepatology (2020)

Hepatocellular carcinoma (HCC) can be treated effectively if detected at an early stage. Recommended surveillance strategies for at-risk patients include ultrasound with or without α-fetoprotein (AFP), but their sensitivity is suboptimal. We sought to develop a novel, blood-based biomarker panel with improved sensitivity for early-stage HCC detection.In a multicenter, case-control study, we collected blood specimens from patients with HCC and age-matched controls with underlying liver disease but without HCC. Ten previously reported methylated DNA markers (MDMs) associated with HCC, methylated B3GALT6 (reference DNA marker), and 3 candidate proteins, including AFP, were assayed and analyzed by a logistic regression algorithm to predict HCC cases. The accuracy of the multi-target HCC panel was compared with that of other blood-based biomarkers for HCC detection.The study included 135 HCC cases and 302 controls. We identified a multi-target HCC panel of 3 MDMs (HOXA1, EMX1, and TSPYL5), B3GALT6 and 2 protein markers (AFP and AFP-L3) with a higher sensitivity (71%, 95% CI: 60-81%) at 90% specificity for early-stage HCC than the GALAD score (41%, 95% CI: 30-53%) or AFP ≥7.32 ng/mL (45%, 95% CI: 33-57%). The AUC for the multi-target HCC panel for detecting any stage HCC was 0.92 compared with 0.87 for the GALAD score and 0.81 for AFP alone. The panel performed equally well in important subgroups based on liver disease etiology, presence of cirrhosis, or sex.We developed a novel, blood-based biomarker panel that demonstrates high sensitivity for early-stage HCC. These data support the potential for liquid biopsy detection of early-stage HCC to clinically benefit at-risk patients. This study was registered on ClinicalTrials.gov (NCT03628651).
Abstract 9852: The Coefficient of Variation of Fourth Harmonic Amplitude of Radial Pulse Wave Predicts Major Adverse Cardiovascular Events in Asymptomatic Patients With Type 2 Diabetes
Authors: kuomeng Liao, Chi-Wei Chang, Yi-Ting Chang, Sheng-Hung Wang, Ying jin Chen, gin-chung wang
Journal: Circulation (2019)

The coefficient of variation of the fourth harmonic amplitude of the radial pulse (C4CV) is associated with myocardial ischemia and left ventricular dysfunction. We sought to further clarify whethe...
Abstract 13303: 3D Light Sheet Imaging of Left Anterior Descending Artery Ligation-Induced Myocardial Infarction in Mice
Authors: Urmas Roostalu, Nora Elisabeth Zois, Philip G Pedersen, Tanja X Pedersen, Niels Vrang, Jacob Hecksher Sorensen
Journal: Circulation (2019)

Introduction: The discovery of new therapeutics for myocardial infarction has been hampered by difficulties in visualizing the full spectrum of the disease in mouse models. Especially, branching pa...
Altered HSC Programming Drives Aberrant Blood Output Underlying RA Pathogenesis
Authors: Taylor Mills, Giovany Hernandez, Susan Kuldanek, Jennifer L Rabe, Greg Kirkpatrick, Leila Noetzli, Erin Severs, Diana Ir, Sumitra Acharya, Biniam Adane, Craig T. Jordan, Jorge Di Paola, Daniel Frank, Kristine Kuhn, Michael Holers, Nirmal Banda, Eric Martin Pietras
Journal: Blood (2017)
Agrin induces long-term osteochondral regeneration by supporting repair morphogenesis
Authors: Suzanne E. Eldridge, Aida Barawi, Hui Wang, Anke J. Roelofs, Magdalena Kaneva, Zeyu Guan, Helen Lydon, Bethan L. Thomas, Anne-Sophie Thorup, Beatriz F. Fernandez, Sara Caxaria, Danielle Strachan, Ahmed Ali, Kanatheepan Shanmuganathan, Costantino Pitzalis, James R. Whiteford, Frances Henson, Andrew W. McCaskie, Cosimo De Bari, Francesco Dell’Accio
Journal: Science Translational Medicine (2020)

Cartilage loss leads to osteoarthritis, the most common cause of disability for which there is no cure. Cartilage regeneration, therefore, is a priority in medicine. We report that agrin is a potent chondrogenic factor and that a single intraarticular administration of agrin induced long-lasting regeneration of critical-size osteochondral defects in mice, with restoration of tissue architecture and bone-cartilage interface. Agrin attracted joint resident progenitor cells to the site of injury and, through simultaneous activation of CREB and suppression of canonical WNT signaling downstream of β-catenin, induced expression of the chondrogenic stem cell marker GDF5 and differentiation into stable articular chondrocytes, forming stable articular cartilage. In sheep, an agrin-containing collagen gel resulted in long-lasting regeneration of bone and cartilage, which promoted increased ambulatory activity. Our findings support the therapeutic use of agrin for joint surface regeneration.
Abstract B49: Effects of exercise on ovarian cancer initiation and progression
Authors: Fangfang Bi, Madeline Morrisson, Sarah Cady, Alexandra Cerchia, Kevin Yang, Ivy Ling, Yang Yang-Hartwich
Journal: Clinical Cancer Research (2020)

Abstract Epidemiology studies support a strong association between physical activity and lower risk of cancer. Exercise is a promising nonpharmacologic strategy in preventing cancer and mitigating adverse effects of cancer and anticancer therapies. However, we have not been able to optimize the efficacy of exercise training as an anticancer intervention due to the lack of knowledge regarding the biologic mechanisms of action, the effective doses, and the biomarkers for predicting and monitoring responses of exercise-based intervention. Our objective is to utilize mouse models to determine the effects and underlying mechanisms of exercise on ovarian cancer initiation and progression. C57BL/6 mice ran on a treadmill for 45min daily to mimic human exercise activity. The control groups were placed on treadmill for 45min daily. After a month of this exercise regiment, both groups were injected with cancer cells derived from ovarian tumors of Dicer-/-; Pten-/-; Tp53R172H mice. Tumor progression was monitored through IVIS imaging system. Blood and peritoneal fluid samples were tested for cytokine levels. Tissue samples were collected and gene expression levels were quantified via qPCR. Peritoneal macrophages were isolated after acute exercise and were used in flow cytometry analysis or cocultured with cancer cells. Our model resembled the biologic changes of exercise in human. Eight-week treadmill-running exercise suppressed early tumor formation and tumor spreading. Exercise altered visceral fat tissue gene expression profile, which may inhibit cancer-induced cachexia and metabolic imbalance. In addition, one-hour exercise induced the acute proinflammatory activation of peritoneal macrophages. Coculture of peritoneal macrophages and PBMC (peripheral blood mononuclear cells) or NK (natural killer) cells from the exercise group and cancer cells reduced survival of cancer cells. Chronic and acute exercise can both suppress ovarian cancer tumorigenesis in mouse models. The underlying mechanisms involve enhancing anticancer immune system responses and adjusting metabolic balance. More research is needed to determine the specific mechanisms by which chronic and acute exercise affects ovarian cancer. Citation Format: Fangfang Bi, Madeline Morrisson, Sarah Cady, Alexandra Cerchia, Kevin Yang, Ivy Ling, Yang Yang-Hartwich. Effects of exercise on ovarian cancer initiation and progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr B49.
Abstract 5260: Preclinical studies with ONC201 in combination with clinically approved chemotherapy as a novel treatment strategy against Small Cell Lung Cancer (SCLC)
Authors: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry
Journal: Cancer Research (2020)

Abstract According to the American Cancer Society, about 10-15 percent of all lung cancer diagnoses are small cell lung cancer (SCLC). The median survival rate of limited-stage small cell lung cancer is about 12 to 16 months. Several clinically approved chemotherapy drugs have been used to treat SCLC, with several more currently under clinical trials. However, a novel combination is still needed to increase patient life expectancy. ONC201 is an impridone, currently in clinical trials, that has proven to have proapoptotic effects in multiple tumor types. We hypothesized that treating SCLC cell lines with ONC201 in conjunction with clinically approved chemotherapy drugs, such as etoposide and carboplatin, will have a synergistic effect and serve as a potential novel combination treatment plan. SCLC cell lines H1048 and H1105 were treated for 72 hours with ONC201 and etoposide, or ONC201 and carboplatin. CellTiter-Glo cell viability assay and Western blotting of PARP cleavage and ATF4 were used to check synergy in the combination treatments. The combination of ONC201 and clinically approved chemotherapy drugs, etoposide and carboplatin, revealed that there was an upregulation in cleaved PARP and a synergistic effect on the overall cell samples. When looking at the combination index of the cell proliferation assays, the best index for each combination was 0.867 with an ONC201 dosage of 4 μM and an etoposide dosage of 0.05 μg/mL in H1048, 0.43191 at ONC201 dosage 0.3125 μM and etoposide dosage 2.5 μg/mL in H1105, and 0.20278 at ONC201 dosage 2.5 μM and carboplatin dosage 3.125 μg/mL in H1105. We are currently testing drug combinations including a triple drug combination of ONC201 and two clinically approved drugs and studying the mechanism underlying the synergies, with the potential to translate this novel combination treatment plan of ONC201 and clinically approved drugs into a clinical regimen to improve the outcome of SCLC patients. Citation Format: Young S. Lee, Lanlan Zhou, Christopher Azzoli, Wafik S. El-Deiry. Preclinical studies with ONC201 in combination with clinically approved chemotherapy as a novel treatment strategy against Small Cell Lung Cancer (SCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5260.
Abstract 3232: <i>In vitro</i> cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies
Authors: Sanne Holt, Sophie Vermond, Monique Hazenoot Hazenoot, Jeroen Overman, Jamil Aarbiou Aarbiou, Jeroen DeGroot DeGroot
Journal: Cancer Research (2020)

Abstract Chimeric antigen receptor (CAR) and T cell receptor (TCR) engineered T cells are part of a big wave of immunotherapies showing great promise in cancer clinical trials. With the first T cell based therapies targeting hematological malignances now approved, their next challenge is solid tumors. Solid tumors create an additional challenge due to the lack of tumor specific target antigens, posing significant safety risks, i.e. on-target on-tumor, on-target off-tumor and off-target toxicities. Toxic effects previously reported vary from mild-severe cytokine release syndrome (CRS) to neurotoxicity and death. We have developed in vitro assays utilizing primary human cells from healthy tissue and/or differentiated iPCS-derived cells to assess on-target off-tumor and/or off-target cytotoxicity for engineered T cell therapies. The presence of CAR-T cell mediated cytotoxicity was measured through co-culture with healthy human primary cells to assess unwanted CAR-T reactivity as well as a high target antigen expressing control cancer cell line to confirm CAR-T functionality. The human primary cell type was selected based on its potential safety risk by establishing low level protein expression of the target antigen. Readouts included IFNγ production determined by MesoScale Discovery platform as a measure of T cell activation and Hoechst/PI staining of target cells by flow cytometry. Our study generated high quality data of the CAR-T cell, confirming functionality by showing consistent T cell activation and killing against a positive control cell line. Moreover, we were able establish a clear absence of activity against the primary human cells thus providing insight into the safety of the CAR-T therapy. The developed safety assays provide a robust and rapid platform to assess on-target off-tumor and off-target effects within immuno-oncology therapies, either TCR or CAR-T cells, in both early stage development or late stage testing of the therapeutic product. Through inclusion of a wide range of human primary cells, both high risk tissues and major organs at risk of off-target toxicity, a clear safety profile can be generate in vitro for these novel T cell therapies. Safety risks associated with cell based IO-therapies is the biggest challenge for the success of these therapies, performing a thorough safety screen on healthy primary human tissues is therefore crucial. Citation Format: Sanne Holt, Sophie Vermond, Monique Hazenoot Hazenoot, Jeroen Overman, Jamil Aarbiou Aarbiou, Jeroen DeGroot DeGroot. In vitro cell based cytotoxicity and T cell activation assays to assess safety and efficacy of engineered T cell therapies [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3232.
A pH-responsive Pickering Nanoemulsion for specified spatial delivery of Immune Checkpoint Inhibitor and Chemotherapy agent to Tumors
Authors: Le Jia, Minghui Pang, Man Fan, Xuan Tan, Yiqian Wang, Menglin Huang, Yijing Liu, Qin Wang, Yanhong Zhu, Xiangliang Yang
Journal: Theranostics (2020)

Rationale: Immune checkpoint (ICP) blockade therapy combined with chemotherapy is a promising treatment strategy for tumors. Chemotherapeutic agents usually function inside the tumor cells, while ICP inhibitors are efficacious out of the tumor cells. It is desirable to effectively co-deliver an ICP inhibitor and a chemotherapy agent to different sites of a tumor. We have designed an effective drug delivery system to accomplish both objectives. Methods: We designed a Pickering nanoemulsion (PNE) using multi-sensitive nanogels with pH-responsive, hydrophilicity-hydrophobicity switch, and redox-responding properties as an oil/water interfacial stabilizer. The D/HY@PNE was employed for specified spatial delivery of the chemotherapy agent doxorubicin (DOX) and ICP inhibitor HY19991 (HY). We systematically investigated the pH-responsive disassembly of PNE, the release of DOX and HY from D/HY@PNE in the tumor microenvironment, enhanced tumor penetration of DOX, immunogenic cell death (ICD), antitumor efficacy, and the immune response induced by D/HY@PNE in vitro and in vivo. Results: D/HY@PNE disassembled to release the ICP inhibitor HY and DOX-loaded nanogels due to the hydrophilicity-hydrophobicity reversal of nanogels in the acidic tumor microenvironment. Quantitative analysis indicates that D/HY@PNE presents enhanced tumor penetration behavior and effectively induces ICD. The strong immune response induced by D/HY@PNE was due to the efficient synergetic combination of chemotherapy and immunotherapy and resulted in enhanced antitumor efficacy in 4T1 tumor-bearing mice. Conclusion: This novel strategy highlights the promising potential of a universal platform to co-deliver different therapeutic or diagnostic reagents with spatial regulation to improve the anti-tumor effect.
rs641738C&gt;T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis
Authors: Kevin Teo, Kushala W.M. Abeysekera, Leon Adams, Elmar Aigner, Quentin M. Anstee, Jesus M. Banales, Rajarshi Banerjee, Priyadarshi Basu, Thomas Berg, Pallav Bhatnagar, Stephan Buch, Ali Canbay, Sonia Caprio, Ankita Chatterjee, Yii-Der Ida Chen, Abhijit Chowdhury, Ann K. Daly, Christian Datz, Dana de Gracia Hahn, Johanna K. DiStefano, Jiawen Dong, Amedine Duret, Connor Emdin, Madison Fairey, Glenn S. Gerhard, Xiuqing Guo, Jochen Hampe, Matthew Hickman, Lena Heintz, Christian Hudert, Harriet Hunter, Matt Kelly, Julia Kozlitina, Marcin Krawczyk, Frank Lammert, Claudia Langenberg, Joel Lavine, Lin Li, Hong Kai Lim, Rohit Loomba, Panu K. Luukkonen, Phillip E. Melton, Trevor A. Mori, Nicholette D. Palmer, Constantinos A. Parisinos, Sreekumar G. Pillai, Faiza Qayyum, Matthias C. Reichert, Stefano Romeo, Jerome I. Rotter, Yu Ri Im, Nicola Santoro, Clemens Schafmayer, Elizabeth K. Speliotes, Stefan Stender, Felix Stickel, Christopher D. Still, Pavel Strnad, Kent D. Taylor, Anne Tybjærg-Hansen, Giuseppina Rosaria Umano, Mrudula Utukuri, Luca Valenti, Lynne E. Wagenknecht, Nicholas J. Wareham, Richard M. Watanabe, Julia Wattacheril, Hanieh Yaghootkar, Hannele Yki-Järvinen, Kendra A. Young, Jake P. Mann, Anita Vreugdenhil, Anna Alisi, Piotr Socha, Wojciech Jańczyk, Ulrich Baumann, Sanjay Rajwal, Indra van Mourik, Florence Lacaille, Myriam Dabbas, Deirdre A. Kelly, Valerio Nobili, Gudny Eiriksdottir, Melissa E. Garcia, Vilmundur Gudnason, Tamara B. Harris, Lauren J. Kim, Lenore J. Launer, Michael A. Nalls, Albert V. Smith, Jeanne M. Clark, Ruben Hernaez, W.H. Linda Kao, Braxton D. Mitchell, Alan R. Shuldiner, Laura M. Yerges-Armstrong, Ingrid B. Borecki, J. Jeffrey Carr, Mary F. Feitosa, Jun Wu, Johannah L. Butler, Caroline S. Fox, Joel N. Hirschhorn, Udo Hoffmann, Shih-Jen Hwang, Joseph M. Massaro, Christopher J. O'Donnell, Cameron D. Palmer, Dushyant V. Sahani, Elizabeth K. Speliotes
Journal: Journal of Hepatology (2020)

A common genetic variant near MBOAT7 (rs641738C>T) has been previously associated with hepatic fat and advanced histology in NAFLD; however, these findings have not been consistently replicated in the literature. We aimed to establish whether rs641738C>T is a risk factor across the spectrum of NAFLD and to characterise its role in the regulation of related metabolic phenotypes through a meta-analysis.
Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death
Authors: Lucia Cottone, Adam P. Cribbs, Garima Khandelwal, Graham Wells, Lorena Ligammari, Martin Philpott, Anthony Tumber, Patrick Lombard, Edward S. Hookway, Tamas Szommer, Catrine Johansson, Paul E. Brennan, Nischalan Pillay, Richard G. Jenner, Udo Oppermann, Adrienne M. Flanagan
Journal: Cancer Research (2020)

Expression of the transcription factor brachyury (TBXT) is normally restricted to the embryo, and its silencing is epigenetically regulated. TBXT promotes mesenchymal transition in a subset of common carcinomas, and in chordoma, a rare cancer showing notochordal differentiation, TBXT acts as a putative oncogene. We hypothesized that TBXT expression is controlled through epigenetic inhibition to promote chordoma cell death. Screening of five human chordoma cell lines revealed that pharmacologic inhibition of the histone 3 lysine 27 demethylases KDM6A (UTX) and KDM6B (JMJD3) leads to cell death. This effect was phenocopied by dual genetic inactivation of KDM6A/B using CRISPR/Cas9. Inhibition of KDM6A/B with a novel compound KDOBA67 led to a genome-wide increase in repressive H3K27me3 marks with concomitant reduction in active H3K27ac, H3K9ac, and H3K4me3 marks.