tbuckley/cabot-search huggingface dataset:
Rhein modulates host purine metabolism in intestine through gut microbiota and ameliorates experimental colitis
Authors: Jiawei Wu, Zhonghong Wei, Peng Cheng, Cheng Qian, Fangming Xu, Yu Yang, Aiyun Wang, Wenxing Chen, Zhiguang Sun, Yin Lu
Journal: Theranostics (2020)

Background: Gut microbiota, which plays a crucial role in inflammatory bowel diseases (IBD), might have therapeutic benefits for ulcerative colitis or Crohn's disease. Targeting gut microbiota represents a new treatment strategy for IBD patients. Rhein is one of the main components of rhubarb and exhibits poor oral bioavailability but still exerts anti-inflammatory effects in some diseases. Therefore, we investigated the effect of rhein on colitis and studied its possible mechanisms. Methods: The chronic mouse colitis model was induced by four rounds of 2% dextran sulfate sodium (DSS) treatment. The mice were treated with 50 mg/kg and 100 mg/kg rhein daily, body weight, colon length, histological score, inflammatory cytokines in serum or intestine, and fecal lipocalin 2 concentration were determined. Th17 cell, Th1 cell and Th2 cell infiltration in the mesenteric lymph node were analyzed by flow cytometry. Metabolic profiles were collected by non-targeted metabolomics and key metabolic pathways were identified using MetaboAnalyst 4.0. We also assessed intestinal barrier permeability and performed 16s rDNA sequencing. Lactobacillus sp. was cultured, and fecal microbiota transplantation (FMT) was employed to evaluate the contribution of gut microbiota. Results: Rhein could significantly alleviate DSS-induced chronic colitis. Uric acid was identified as a crucial modulator of colitis and rhein treatment led to decreased uric acid levels. We determined that rhein changed purine metabolism indirectly, while the probiotic Lactobacillus was involved in the regulation of host metabolism. Uric acid resulted in a worsened intestinal barrier, which could be rescued by rhein. We further confirmed that rhein-treated gut microbiota was sufficient to relieve DSS-induced colitis by FMT. Conclusion: We showed that rhein could modulate gut microbiota, which indirectly changed purine metabolism in the intestine and subsequently alleviated colitis. Our study has identified a new approach to the clinical treatment of colitis.
Inhibition of the Adenosine Pathway to Potentiate Cancer Immunotherapy: Potential for Combinatorial Approaches
Authors: Elizabeth A. Thompson, Jonathan D. Powell
Journal: Annual Review of Medicine (2020)

Cancer immunotherapy has revolutionized the way that we think about treating cancer. Although checkpoint blockade therapy, including anti-PD-1/PD-L1 and anti-CTLA-4, has shown remarkable success, the responses are limited to only a subset of patients. This discrepancy highlights the many overlapping avenues for immune evasion or suppression that can be employed by a tumor. One such mechanism of immunosuppression is adenosinergic signaling within the tumor microenvironment. We provide an overview of the current status of clinical trials targeting the adenosine pathway, including CD73, CD39, and adenosine receptors. Additionally, we highlight several avenues that may be explored to further potentiate responses in the clinic by combining adenosine-targeting agents to target multiple arms of the pathway or by using conventional immunotherapy agents.
IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcus aureus
Authors: Philipp Starkl, Martin L. Watzenboeck, Lauren M. Popov, Sophie Zahalka, Anastasiya Hladik, Karin Lakovits, Mariem Radhouani, Arvand Haschemi, Thomas Marichal, Laurent L. Reber, Nicolas Gaudenzio, Riccardo Sibilano, Lukas Stulik, Frédéric Fontaine, André C. Mueller, Manuel R. Amieva, Stephen J. Galli, Sylvia Knapp
Journal: Immunity (2020)
SB 9200 Shows Antiviral Activity Against HCV-RNA by Targeting Host Cytosolic Sensor Proteins RIG-I and NOD-2 to activate IFN signaling pathways
Authors: Kumar Visvanathan, Rosemary M Millen, Stuart K Roberts, Peter W Angus, Wendy Cheng, Nada Farhat, My My Trinh, Radhakrishnan P Iyer, Murray L Barclay, Alex J Thompson
Journal: Hepatology (2015)
Ultrasensitive molecular imaging of intestinal mucosal inflammation using leukocyte-mimicking particles targeted to MAdCAM-1 in mice
Authors: Antoine P. Fournier, Sara Martinez de Lizarrondo, Adrien Rateau, Axel Gerard-Brisou, Maximilian J. Waldner, Markus F. Neurath, Denis Vivien, Fabian Docagne, Maxime Gauberti
Journal: Science Translational Medicine (2020)

Molecular magnetic resonance imaging allows noninvasive evaluation of intestinal mucosal inflammation in clinically relevant mouse models.
Impact of admixture and ancestry on eQTL analysis and GWAS colocalization in GTEx
Authors: Nicole R. Gay, Michael Gloudemans, Margaret L. Antonio, Nathan S. Abell, Brunilda Balliu, YoSon Park, Alicia R. Martin, Shaila Musharoff, Abhiram S. Rao, François Aguet, Alvaro N. Barbeira, Rodrigo Bonazzola, Farhad Hormozdiari, Kristin G. Ardlie, Christopher D. Brown, Hae Kyung Im, Tuuli Lappalainen, Xiaoquan Wen, Stephen B. Montgomery
Journal: Genome biology (2020)

Abstract Background Population structure among study subjects may confound genetic association studies, and lack of proper correction can lead to spurious findings. The Genotype-Tissue Expression (GTEx) project largely contains individuals of European ancestry, but the v8 release also includes up to 15% of individuals of non-European ancestry. Assessing ancestry-based adjustments in GTEx improves portability of this research across populations and further characterizes the impact of population structure on GWAS colocalization. Results Here, we identify a subset of 117 individuals in GTEx (v8) with a high degree of population admixture and estimate genome-wide local ancestry. We perform genome-wide cis -eQTL mapping using admixed samples in seven tissues, adjusted by either global or local ancestry. Consistent with previous work, we observe improved power with local ancestry adjustment. At loci where the two adjustments produce different lead variants, we observe 31 loci (0.02%) where a significant colocalization is called only with one eQTL ancestry adjustment method. Notably, both adjustments produce similar numbers of significant colocalizations within each of two different colocalization methods, COLOC and FINEMAP. Finally, we identify a small subset of eQTL-associated variants highly correlated with local ancestry, providing a resource to enhance functional follow-up. Conclusions We provide a local ancestry map for admixed individuals in the GTEx v8 release and describe the impact of ancestry and admixture on gene expression, eQTLs, and GWAS colocalization. While the majority of the results are concordant between local and global ancestry-based adjustments, we identify distinct advantages and disadvantages to each approach.
Using charge-reversal and size oscillation of polyelectrolytes through pH-dependence medium for localized recombinant adeno-associated virus serotype 2 delivery
Authors: S.-Ja Tseng, Ivan M. Kempson, Shu-Fen Peng, Bai-Hung Ke, Hsiang-Hisn Chen, Pei-Feng Chen, Y. Hwu
Journal: Journal of Controlled Release (2013)
Trends in Utilization and Cost of Low-Density Lipoprotein Cholesterol–Lowering Therapies Among Medicare Beneficiaries
Authors: Andrew Sumarsono, Hussain S. Lalani, Muthiah Vaduganathan, Ann Marie Navar, Gregg C. Fonarow, Sandeep R. Das, Ambarish Pandey
Journal: JAMA Cardiology (2020)

Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are a cornerstone of prevention in atherosclerotic cardiovascular disease. With the introduction of generic formulations and the release of new therapies, including proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, contemporary Medicare utilization of these therapies remains unknown.To determine trends in utilization and spending on brand-name and generic LDL-C-lowering therapies and to estimate potential savings if all Medicare beneficiaries were switched to available therapeutically equivalent generic formulations.This cross-sectional study analyzed prescription drug utilization and cost trend data from the Medicare Part D Prescription Drug Event data set from 2014 to 2018 for LDL-C-lowering therapies. A total of 11 LDL-C-lowering drugs with 25 formulations, including 16 brand-name and 9 generic formulations, were included. Data were collected and analyzed from October 2019 to June 2020.Number of Medicare Part D beneficiaries, annual spending, and spending per beneficiary for all formulations.The total number of Medicare Part D beneficiaries ranged from 37 720 840 in 2014 to 44 249 461 in 2018. The number of Medicare beneficiaries taking LDL-C-lowering therapies increased by 23% (from 20.5 million in 2014 to 25.2 million in 2018), while the associated Medicare expenditure decreased by 46% (from $6.3 billion in 2014 to $3.3 billion in 2018). Lower expenditure was driven by greater uptake of generic statin and ezetimibe and a concurrent rapid decline in the use of their brand-name formulations. Medicare spent $9.6 billion on brand-name statins and ezetimibe and could have saved $2.1 billion and $0.4 billion, respectively, if brand-name formulations were switched to equivalent generic versions when available. The number of beneficiaries using PCSK9 inhibitors since their introduction in 2015 has been modest, although use has increased by 144% (from 25 569 in 2016 to 62 476 in 2018) and total spending has increased by 199% (from $164 million in 2016 to $491 million in 2018).Between 2014 and 2018, LDL-C-lowering therapies were used by 4.8 million more Medicare beneficiaries annually, with an associated $3.0 billion decline in Medicare spending. This cost reduction was driven by the rapid transition from brand-name formulations to lower-cost generic formulations of statins and ezetimibe. Use of PCSK9 inhibitions, although low, increased over time and could have broad implications on future Medicare spending.
Evaluating the Performance of Malaria Genetics for Inferring Changes in Transmission Intensity Using Transmission Modeling
Authors: Oliver J Watson, Lucy C Okell, Joel Hellewell, Hannah C Slater, H Juliette T Unwin, Irene Omedo, Philip Bejon, Robert W Snow, Abdisalan M Noor, Kirk Rockett, Christina Hubbart, Joaniter I Nankabirwa, Bryan Greenhouse, Hsiao-Han Chang, Azra C Ghani, Robert Verity
Journal: Molecular Biology and Evolution (2020)

Substantial progress has been made globally to control malaria, however there is a growing need for innovative new tools to ensure continued progress. One approach is to harness genetic sequencing and accompanying methodological approaches as have been used in the control of other infectious diseases. However, to utilize these methodologies for malaria, we first need to extend the methods to capture the complex interactions between parasites, human and vector hosts, and environment, which all impact the level of genetic diversity and relatedness of malaria parasites. We develop an individual-based transmission model to simulate malaria parasite genetics parameterized using estimated relationships between complexity of infection and age from five regions in Uganda and Kenya. We predict that cotransmission and superinfection contribute equally to within-host parasite genetic diversity at 11.5% PCR prevalence, above which superinfections dominate. Finally, we characterize the predictive power of six metrics of parasite genetics for detecting changes in transmission intensity, before grouping them in an ensemble statistical model. The model predicted malaria prevalence with a mean absolute error of 0.055. Different assumptions about the availability of sample metadata were considered, with the most accurate predictions of malaria prevalence made when the clinical status and age of sampled individuals is known. Parasite genetics may provide a novel surveillance tool for estimating the prevalence of malaria in areas in which prevalence surveys are not feasible. However, the findings presented here reinforce the need for patient metadata to be recorded and made available within all future attempts to use parasite genetics for surveillance.
Insufficient evidence exists to use histopathologic subtype to guide treatment of idiopathic multicentric Castleman disease
Authors: David C. Fajgenbaum, David Wu, Aaron Goodman, Raymond Wong, Amy Chadburn, Sunita Nasta, Gordan Srkalovic, Sudipto Mukherjee, Heather Leitch, Raj Jayanthan, Simone Ferrero, Yasuharu Sato, Steve Schey, Angela Dispenzieri, Eric Oksenhendler, Pier Luigi Zinzani, Mary Jo Lechowicz, Christian Hoffmann, Naveen Pemmaraju, Adam Bagg, Alexander Fossa, Megan S. Lim, Frits van Rhee
Journal: American Journal of Hematology (2020)

Idiopathic multicentric Castleman disease (iMCD) is a rare immunologic disorder characterized by systemic inflammation, multicentric lymphadenopathy, and organ dysfunction. Enlarged lymph nodes demonstrate a spectrum of characteristic but variable histopathologic features historically categorized into hyaline vascular (HV) (or hypervascular [HyperV] more recently), plasmacytic, or "mixed." Though the etiology is unknown, a pro-inflammatory cytokine storm, often involving interleukin-6 (IL-6), contributes to pathogenesis. Anti-IL-6 therapy with siltuximab is the only FDA- or EMA-approved treatment based on efficacy and safety in multiple studies. Importantly, no patients considered to have HV histopathology achieved the primary endpoint in the Phase II study. NCCN currently recommends siltuximab first-line for iMCD, except for patients considered to have HV histopathology. We investigated whether histopathologic subtype should guide siltuximab treatment decisions. Secondary analyses of clinical trial and real-world data revealed similar clinical benefit across histopathologic subtypes. Notably, only 18 of 79 patients in the Phase II study were consistently classified into histopathologic subtype by three independent review panels, demonstrating limited reliability to guide treatment decisions. Real-world data further demonstrate siltuximab's effectiveness in patients considered to have HV (or HyperV). Though histopathology is a critical component for diagnosis, there is insufficient evidence to guide treatment based solely on lymph node histopathologic subtype.
Locations of Mass Shootings Relative to Schools and Places Frequented by Children
Authors: Michael L. Nance, Joseph D. DeSimone, Scott A. Lorch, Molly Passarella, Keri M. Cronin, Jason Kreinces, Sage R. Myers
Journal: JAMA Pediatrics (2020)

Jessica H. Beard, MD, MPH; Sara F. Jacoby, PhD, MPH; Zoë Maher, MD; Beidi Dong, PhD; Elinore J. Kaufman, MD; Amy J. Goldberg, MD; Christopher N. Morrison, PhD
Extracellular Matrix Injury of Kidney Allografts in Antibody-Mediated Rejection: A Proteomics Study
Authors: Sergi Clotet-Freixas, Caitriona M. McEvoy, Ihor Batruch, Chiara Pastrello, Max Kotlyar, Julie Anh Dung Van, Madhurangi Arambewela, Alex Boshart, Sofia Farkona, Yun Niu, Yanhong Li, Olusegun Famure, Andrea Bozovic, Vathany Kulasingam, Peixuen Chen, S. Joseph Kim, Emilie Chan, Sajad Moshkelgosha, Syed Ashiqur Rahman, Jishnu Das, Tereza Martinu, Stephen Juvet, Igor Jurisica, Andrzej Chruscinski, Rohan John, Ana Konvalinka
Journal: Journal of the American Society of Nephrology (2020)

Antibody-mediated rejection (AMR) accounts for >50% of kidney allograft loss. Donor-specific antibodies (DSA) against HLA and non-HLA antigens in the glomeruli and the tubulointerstitium cause AMR while inflammatory cytokines such as TNFα trigger graft injury. The mechanisms governing cell-specific injury in AMR remain unclear.Unbiased proteomic analysis of laser-captured and microdissected glomeruli and tubulointerstitium was performed on 30 for-cause kidney biopsy specimens with early AMR, acute cellular rejection (ACR), or acute tubular necrosis (ATN).A total of 107 of 2026 glomerular and 112 of 2399 tubulointerstitial proteins was significantly differentially expressed in AMR versus ACR; 112 of 2026 glomerular and 181 of 2399 tubulointerstitial proteins were significantly dysregulated in AMR versus ATN (P<0.05). Basement membrane and extracellular matrix (ECM) proteins were significantly decreased in both AMR compartments. Glomerular and tubulointerstitial laminin subunit γ-1 (LAMC1) expression decreased in AMR, as did glomerular nephrin (NPHS1) and receptor-type tyrosine-phosphatase O (PTPRO). The proteomic analysis revealed upregulated galectin-1, which is an immunomodulatory protein linked to the ECM, in AMR glomeruli. Anti-HLA class I antibodies significantly increased cathepsin-V (CTSV) expression and galectin-1 expression and secretion in human glomerular endothelial cells. CTSV had been predicted to cleave ECM proteins in the AMR glomeruli. Glutathione S-transferase ω-1, an ECM-modifying enzyme, was significantly increased in the AMR tubulointerstitium and in TNFα-treated proximal tubular epithelial cells.Basement membranes are often remodeled in chronic AMR. Proteomic analysis performed on laser-captured and microdissected glomeruli and tubulointerstitium identified early ECM remodeling, which may represent a new therapeutic opportunity.
The Neuroanatomical Ultrastructure and Function of a Biological Ring Attractor
Authors: Daniel B. Turner-Evans, Kristopher T. Jensen, Saba Ali, Tyler Paterson, Arlo Sheridan, Robert P. Ray, Tanya Wolff, J. Scott Lauritzen, Gerald M. Rubin, Davi D. Bock, Vivek Jayaraman
Journal: Neuron (2020)
Prevalence of Underlying Medical Conditions Among Selected Essential Critical Infrastructure Workers — Behavioral Risk Factor Surveillance System, 31 States, 2017–2018
Authors: Sharon R. Silver, Jia Li, Winifred L. Boal, Taylor L. Shockey, Matthew R. Groenewold
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

Certain underlying medical conditions are associated with higher risks for severe morbidity and mortality from coronavirus disease 2019 (COVID-19) (1).Prevalence of these underlying conditions among workers differs by industry and occupation.Many essential workers, who hold jobs critical to the continued function of infrastructure operations (2), have high potential for exposure to SARS-CoV-2, the virus that causes COVID-19, because their jobs require close contact with patients, the general public, or coworkers.To assess the baseline prevalence of underlying conditions among workers in six essential occupations and seven essential industries, CDC analyzed data from the 2017 and 2018 Behavioral Risk Factor Surveillance System (BRFSS) surveys, the most recent data available.*This report presents unadjusted prevalences and adjusted prevalence ratios (aPRs) for selected underlying conditions.Among workers in the home health aide occupation and the nursing home/rehabilitation industry, aPRs were significantly elevated for the largest number of conditions.Extra efforts to minimize exposure risk and prevent and treat underlying conditions are warranted to protect workers whose jobs increase their risk for exposure to SARS-CoV-2.BRFSS is an annual, state-based, random-digit-dialed landline and cellular telephone survey collecting demographic and health-related information among noninstitutionalized U.S residents aged ≥18 years.BRFSS includes standard core questions and optional modules, including an industry and occupation module.All participants are asked to report their height and weight and also asked "Has a doctor, nurse, or other health practitioner ever told you that you have…" followed by a list of underlying conditions.† In 2017 and 2018, 31 states § administered the industry and occupation module for at least 1 year to currently or recently employed participants; the study sample comprised currently employed module respondents.¶ Open-ended responses to questions eliciting respondent industry and occupation** were coded to the U.S. Census Bureau's 2010 industry and occupation codes.† † Among states using the industry and occupation questions, the median overall survey response rate was 42.5% in 2017 § § and 49.1% in 2018.
Reply to Zhang and Hei: Mesenchymal Stem Cell–derived Exosomes: Are They Another Therapeutic Method for Extracorporeal Membrane Oxygenation–supported Acute Respiratory Distress Syndrome?
Authors: Jonathan E. Millar, Jacky Y. Suen, Daniel F. McAuley, John F. Fraser
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

We thank Zhang and Hei for their insightful comments on our study of mesenchymal stromal cells (MSCs) in a sheep model of extracorporeal membrane oxygenation and acute respiratory distress syndrome (ARDS) (1). Their principal thesis is that the adverse interaction that we observed, between MSCs and the membrane oxygenator, may be overcome by substituting MSCs with MSCderived exosomes. This proposal has merit. The MSC secretome has been of interest as a therapeutic for some time, particularly MSCderived extracellular vesicles (2), MSC-derived exosomes (3), and MSC-conditioned media (4). These each offer several theoretical advantages over conventional MSC therapy. First, contents of the secretome do not express major histocompatibility complex antigens, removing concerns about immunogenicity. Second, components of the secretome are, in general, easier to store and less susceptible to the adverse effects of storage on efficacy. Third, components of the MSC secretome are much smaller than the cells from which they are derived and thus less likely to be subject to “trapping” in the pulmonary circulation (5). Recently, an early phase trial of an MSCderived exosome treatment for severe coronavirus disease (COVID19) has been reported with no apparent safety issues (6). However, there are some unresolved issues that should be borne in mind.