tbuckley/cabot-search huggingface dataset:
The Commensal Microbe V eillonella as a Marker for Response to an FGF19 Analog in NASH
Authors: Rohit Loomba, Lei Ling, Duy M. Dinh, Alex M. DePaoli, Hsiao D. Lieu, Stephen A. Harrison, Arun J. Sanyal
Journal: Hepatology (2020)

Background and Aims The composition of the human gut microbiota is linked to health and disease, and knowledge of the impact of therapeutics on the microbiota is essential to decipher their biological roles and to gain new mechanistic insights. Here we report the effect of aldafermin, an analog of the gut hormone FGF19, versus placebo on the gut microbiota in a prospective, phase 2 study in patients with NASH. Approach and Results A total of 176 patients with biopsy‐confirmed nonalcoholic steatohepatitis (NASH) (nonalcoholic fatty liver disease activity score ≥ 4), fibrosis (F1‐F3 by NASH Clinical Research Network criteria), and elevated liver fat content (≥ 8% by magnetic resonance imaging–proton density fat fraction) received 0.3 mg (n = 23), 1 mg (n = 49), 3 mg (n = 49), and 6 mg (n = 28) aldafermin or placebo (n = 27) for 12 weeks. Stool samples were collected on day 1 and week 12 and profiled using 16S ribosomal RNA gene sequencing; 122 patients had paired stool microbiome profiles at both day 1 and week 12. Overall, the state of the gut microbial community was distinctly stable in patients treated with aldafermin, with all major phyla and genera unaltered during therapy. Patients treated with aldafermin showed a significant, dose‐dependent enrichment in the rare genus Veillonella , a commensal microbe known to have lactate‐degrading and performance‐enhancing properties, which correlated with changes in serum bile acid profile. Conclusions Veillonella may be a bile acid–sensitive bacteria whose enrichment is enabled by aldafermin‐mediated suppression of bile acid synthesis and, in particular, decreases in toxic bile acids. This study provides an integrated analysis of gut microbiome, serum bile acid metabolome, imaging, and histological measurements in clinical trials testing aldafermin for NASH. Our results provide a better understanding of the intricacies of microbiome–host interactions (clinicaltrials.gov trial No. NCT02443116).
Subclonal reconstruction of tumors by using machine learning and population genetics
Authors: Giulio Caravagna, Timon Heide, Marc J. Williams, Luis Zapata, Daniel Nichol, Ketevan Chkhaidze, William Cross, George D. Cresswell, Benjamin Werner, Ahmet Acar, Louis Chesler, Chris P. Barnes, Guido Sanguinetti, Trevor A. Graham, Andrea Sottoriva
Journal: Nature Genetics (2020)
Abstract #2772: Enhanced sensitivity of tumor cells to the EGFR/VEGFR inhibitor ZD6474 by FUS1 and FHIT-nanoparticle-mediated gene therapy in human lung cancer
Authors: Ryo Sakai, Gitanjali Jayachandran, Bingliang Fang, Jack Roth, Lin Ji
Journal: Cancer Research (2009)

Dysregulation of the epidermal growth factor receptor (EGFR) and vascular endothelial growth factor/receptor (VEGF/VEGFR) signaling and the apoptotic pathways is the hallmark of human lung cancer and plays an important role in tumor cell proliferation, survival, angiogenesis, and metastasis. Inhibition of these oncogenic EGFR, VEGF, VEGFR activities and restoration or activation of the pro-apoptotic factors and tumor suppressor genes in tumor cells are proving to be effective therapeutic strategies for lung cancer. ZD6474 is an orally available small-molecule that inhibits both EGFR and VEGFR2 tyrosine kinases. The FUS1 and FHIT are novel tumor suppressor genes identified in the humanchromosome 3p21.3 and 3p14.2 regions, respectively and have been shown to suppress tumor cell growth by the induction of apoptosis and the down-regulation ofmultiple oncogenic tyrosine kinase activities in human non-small-celllung cancer (NSCLC) cells in vitro and in vivo. In this study we evaluated the combined antitumor effects of molecular therapeutic agents ZD6474 and FUS1 or FHIT-nanoparticles targeting the EGFR/VEGFR and apoptosis pathways in NSCLC cells. We found that expression of wild type FUS1or FHIT by DOTAP-Cholesterol nanoparticle-mediated gene transfer sensitized NSCLC cells to ZD6474 treatment, as shown by significantly enhanced inhibitionof tumor cell growth by XTT cell proliferation assay. FUS1-nanoparticles combined with ZD6474 inhibited tumor cell-induced colony formation in H1299 cells. The co-treatment with ZD6474 and FUS1 or FHIT-nanoparticles showed the down-regulation of EGFR signaling pathway as indicated by the reduced expression of the phosphorylated EGFR and AKT on the Western blots. We also evaluated the antitumor effects of combination therapy using three-dimensional lung cancer organotypic culture and found an increased level of apoptosis by in situ TUNEL staining and decreased activities of p-EGFR by fluorescence imaging analysis in NSCLC cells co-treated with ZD6474 and FUS1 or FHIT-nanoparticles compared with untreated and non-specific vector-treated controls. Our findings imply that a combination treatmentwith FUS1 or FHIT-nanoparticles and ZD6474 may be a useful strategyfor enhancing lung cancer therapy. This abstract is supported by grants of NIH NCI (SPORE P50CA70907 and RO1CA116322).  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2772.
Final Analysis of the Ipilimumab Versus Placebo Following Radiotherapy Phase III Trial in Postdocetaxel Metastatic Castration-resistant Prostate Cancer Identifies an Excess of Long-term Survivors
Authors: Karim Fizazi, Charles G. Drake, Tomasz M. Beer, Eugene D. Kwon, Howard I. Scher, Winald R. Gerritsen, Alberto Bossi, Alfons J.M. van den Eertwegh, Michael Krainer, Nadine Houede, Ricardo Santos, Hakim Mahammedi, Siobhan Ng, Riccardo Danielli, Fabio A. Franke, Santhanam Sundar, Neeraj Agarwal, André M. Bergman, Tudor E. Ciuleanu, Ernesto Korbenfeld, Lisa Sengeløv, Steinbjorn Hansen, M. Brent McHenry, Allen Chen, Christopher Logothetis
Journal: European Urology (2020)
Trends in Number and Distribution of COVID-19 Hotspot Counties — United States, March 8–July 15, 2020
Authors: Alexandra M. Oster, Gloria J. Kang, Amy E. Cha, Vladislav Beresovsky, Charles E. Rose, Gabriel Rainisch, Laura Porter, Eduardo E. Valverde, Elisha B. Peterson, Anne K. Driscoll, Tina Norris, Nana Wilson, Matthew Ritchey, Henry T. Walke, Dale A. Rose, Nadia L. Oussayef, Monica E. Parise, Zack S. Moore, Aaron T. Fleischauer, Margaret A. Honein, Emilio Dirlikov, Julie Villanueva
Journal: MMWR Morbidity and Mortality Weekly Report (2020)

The geographic areas in the United States most affected by the coronavirus disease 2019 (COVID-19) pandemic have changed over time. On May 7, 2020, CDC, with other federal agencies, began identifying counties with increasing COVID-19 incidence (hotspots) to better understand transmission dynamics and offer targeted support to health departments in affected communities. Data for January 22-July 15, 2020, were analyzed retrospectively (January 22-May 6) and prospectively (May 7-July 15) to detect hotspot counties. No counties met hotspot criteria during January 22-March 7, 2020. During March 8-July 15, 2020, 818 counties met hotspot criteria for ≥1 day; these counties included 80% of the U.S. population. The daily number of counties meeting hotspot criteria peaked in early April, decreased and stabilized during mid-April-early June, then increased again during late June-early July. The percentage of counties in the South and West Census regions* meeting hotspot criteria increased from 10% and 13%, respectively, during March-April to 28% and 22%, respectively, during June-July. Identification of community transmission as a contributing factor increased over time, whereas identification of outbreaks in long-term care facilities, food processing facilities, correctional facilities, or other workplaces as contributing factors decreased. Identification of hotspot counties and understanding how they change over time can help prioritize and target implementation of U.S. public health response activities.
Abstract 6512: Tissue engineered metastases to improve cancer immunotherapy
Authors: Nikhila Reddy Sultanpuram
Journal: Cancer Research (2020)

Abstract Background: Radiotherapy can induce the abscopal effect when combined with immune checkpoint inhibition. The main limitations to this treatment are the lack of control over the tumor microenvironment and the tumor is not amendable for radiosurgery. To overcome this, we hypothesize that using ex-vivo engineered cancer metastases treated with radiotherapy can improve the impact of the abscopal effect, as the immune cascade reaction is radiotherapy dose dependent and tumors can be exposed to higher amounts of radiation ex-vivo without the risk of radiation toxicity using our tissue engineered metastases model to boost immune response. Methods: Using B16F10 as a model, we first engineered B16F10 lung metastasis ex-vivo using decellularized rat lung biomatrix scaffolds. The engineered lung metastases were then lethally irradiated with 100 Gy of radiotherapy. The cells were then injected subcutaneously into tumor bearing C57BL6 mice in combination with anti PD-1 checkpoint inhibitor. Experimental groups included: no treatment, anti PD-1 only, cell lysate with and without anti PD-1, and irradiated engineered metastases with and without anti PD-1. All the mice were inoculated with 50,000 plastic grown B16F10 cells. On days 3, 6, and 9 the mice received immunotherapy and radiotherapy combinations based on their respective groups. The tumors were then analyzed by flow cytometry and IHC staining for different T cell populations. Results: We successfully engineered B16F10 lung metastasis ex vivo. We then demonstrated that mice treated irradiated engineered lung metastasis had significantly better survival than any other treatment arms with median survival twice that of irradiated cells (P &amp;lt;0.01). Correlative studies showed that mice that received irradiated engineered metastasis had increased CD8+ cells and lower Treg cells when compared to other experimental groups. This indicates that engineered metastasis increased immune activation and response to tumor. Conclusions: Our data demonstrates that engineered metastases can indeed improve cancer immunotherapy and induce a robust abscopal/vaccine effect. Citation Format: Nikhila Reddy Sultanpuram. Tissue engineered metastases to improve cancer immunotherapy [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 6512.
Evolution of Genomic and T-cell Repertoire Heterogeneity of Malignant Pleural Mesothelioma Under Dasatinib Treatment
Authors: Runzhe Chen, Won-Chul Lee, Junya Fujimoto, Jun Li, Xin Hu, Reza Mehran, David Rice, Stephen G. Swisher, Boris Sepesi, Hai T. Tran, Chi-Wan Chow, Latasha D. Little, Curtis Gumbs, Cara Haymaker, John V. Heymach, Ignacio I. Wistuba, J. Jack Lee, P. Andrew Futreal, Jianhua Zhang, Alexandre Reuben, Anne S. Tsao, Jianjun Zhang
Journal: Clinical Cancer Research (2020)

Malignant pleural mesothelioma (MPM) is considered an orphan disease with few treatment options. Despite multimodality therapy, the majority of MPMs recur and eventually become refractory to any systemic treatment. One potential mechanism underlying therapeutic resistance may be intratumor heterogeneity (ITH), making MPM challenging to eradicate. However, the ITH architecture of MPM and its clinical impact have not been well studied.We delineated the immunogenomic ITH by multiregion whole-exome sequencing and T-cell receptor (TCR) sequencing of 69 longitudinal MPM specimens from nine patients with resectable MPM, who were treated with dasatinib.The median total mutation burden before dasatinib treatment was 0.65/Mb, similar with that of post-dasatinib treatment (0.62/Mb). The median proportion of mutations shared by any given pair of two tumor regions within the same tumors was 80% prior to and 83% post-dasatinib treatment indicating a relatively homogenous genomic landscape. T-cell clonality, a parameter indicating T-cell expansion and reactivity, was significantly increased in tumors after dasatinib treatment. Furthermore, on average, 82% of T-cell clones were restricted to individual tumor regions, with merely 6% of T-cell clones shared by all regions from the same tumors indicating profound TCR heterogeneity. Interestingly, patients with higher T-cell clonality and higher portion of T cells present across all tumor regions in post-dasatinib-treated tumors had significantly longer survival.Despite the homogeneous genomic landscape, the TCR repertoire is extremely heterogeneous in MPM. Dasatinib may potentially induce T-cell response leading to improved survival.
HVEM signaling promotes protective antibody-dependent cellular cytotoxicity (ADCC) vaccine responses to herpes simplex viruses
Authors: Clare Burn Aschner, Lip Nam Loh, Benjamin Galen, Isabel Delwel, Rohit K. Jangra, Scott J. Garforth, Kartik Chandran, Steven Almo, William R. Jacobs, Carl F. Ware, Betsy C. Herold
Journal: Science Immunology (2020)

Herpes simplex virus glycoprotein D allows viral evasion of protective host ADCC responses by interfering with LIGHT-HVEM signaling.
Respiratory Diseases as Risk Factors for Seropositive and Seronegative Rheumatoid Arthritis and in Relation to Smoking
Authors: Vanessa L. Kronzer, Helga Westerlind, Lars Alfredsson, Cynthia S. Crowson, Fredrik Nyberg, Göran Tornling, Lars Klareskog, Marie Holmqvist, Johan Askling
Journal: Arthritis & Rheumatology (2020)

The link and interplay between different airway exposures and rheumatoid arthritis (RA) risk are unclear. This study was undertaken to determine whether respiratory disease is associated with development of RA, and specifically to examine this relationship by RA serostatus and smoking exposure.Using data from the Epidemiological Investigation of Rheumatoid Arthritis study, this analysis included 1,631 incident RA cases and 3,283 matched controls recruited from 2006 to 2016. Linking these individuals to the National Patient Register provided information on past acute or chronic, upper or lower respiratory disease diagnoses. For each disease group, we estimated adjusted odds ratios (ORadj ) with 95% confidence intervals (95% CI) for RA, using logistic regression models adjusted for age, sex, residential area, body mass index, and education both overall and stratified by anti-citrullinated protein antibody (ACPA)/rheumatoid factor (RF) status and by smoking status.Respiratory disease diagnoses were associated with risk of RA, with an ORadj of 1.2 for acute upper respiratory disease (95% CI 0.8-1.7), 1.4 for chronic upper respiratory disease (95% CI 1.1-1.9), 2.4 for acute lower respiratory disease (95% CI 1.5-3.6), and 1.6 for chronic lower respiratory disease (95% CI 1.5-3.6). These associations were present irrespective of RF or ACPA status, though the association was somewhat stronger for ACPA/RF-positive than ACPA/RF-negative RA. The association between any respiratory disease and RA was stronger for nonsmokers (ORadj 2.1 [95% CI 1.5-2.9]) than for smokers (ORadj 1.2 [95% CI 0.9-1.5]).Respiratory diseases increase the risk for both seropositive and seronegative RA, but only among nonsmokers. These findings raise the hypothesis that smoking and airway disease are associated with RA development through partly different mechanisms.
Abstract 16949: Conventional Bystander CPR is Associated With Higher Neurologically Favorable Survival in Children Compared to Compression Only CPR Following Pediatric Out of Hospital Cardiac Arrest
Authors: Maryam Y Naim, Heather Griffis, Robert A Berg, Richard N Bradley, Rita V Burke, David Markenson, Bryan F McNally, Vinay M Nadkarni, Lihai Song, Kimberly Vellano, Joseph W Rossano
Journal: Circulation (2018)

Introduction: There are conflicting data regarding the benefit of conventional bystander CPR (BCPR) compared to compression only BCPR (CO-BCPR) for children following out of hospital cardiac arrest (OHCA). Hypothesis: Conventional BCPR is associated with improved outcome compared to CO-BCPR in infants, children and adolescents following OHCA. Methods: An analysis of the Cardiac Arrest Registry to Enhance Survival was conducted. Inclusion criteria were age ≤ 18 years and non-traumatic OHCA from 2013 through 2017. The primary outcome was neurologically favorable survival (cerebral performance category score of 1 or 2). Age groups included infants (≤1 year), children (2-11 years), and adolescents (≥12 years). Results: Of 6249 cardiac arrests, 1191 received conventional BCPR, 1386 received CO-BCPR, and 3672 received no BCPR. The highest neurologically favorable survival was associated with conventional BCPR (adjusted proportion12.5%, OR 2.5, 95% CI 1.9, 3.2) for the overall cohort compared to CO-BCPR (9%, OR 1.6, 95% CI 1.2, 2.0) and no BCPR (6.4%). Conventional BCPR was significantly associated with improved neurologically favorable survival vs. no BCPR in the overall cohort and in all age groups (infants 9.4% vs. 5.4%, children 17.9% vs. 6.2%, adolescents 14% vs. 8,1%, p-value (for all) &lt;0.001). Conventional BCPR was also significantly associated with improved neurologically favorable survival vs. CO-BCPR in the overall cohort and for infants (9.4% vs. 6.1%, p=0.02). CO-BCPR was significantly associated with improved neurologically favorable survival compared to no BCPR in the overall cohort and in children (13.5% vs. 6.2%, p&lt;0.001), but not in infants or adolescents. Conclusion: Conventional BCPR was associated with higher neurologically favorable survival compared to no BCPR in all children and compared to CO-BCPR in most age groups. These results support current AHA/ILCOR recommendations for the provision of conventional BCPR in pediatric OHCA.
THU0249 Family history of autoimmune diseases as a risk factor for sjÖgren’s syndrome: a case-control study
Authors: R Priori, F Conti, E Cassarà, E Medda, MA Stazi, M Cesarotti, P Rovere, C Antonioli, MG Danieli, M Pietrogrande, G Valesini
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> As far as we know, no epidemiological study is available regarding risk factors for Sjögren's syndrome (SS). <h3>Objectives</h3> A multicentre case-control study was carried out in Italy to evaluate the relationship between SS and a history of autoimmune diseases (AD) in first degree relatives (FDR). <h3>Methods</h3> Cases and controls were randomly selected and interviewed by trained medical doctors using a detailed questionnaire. The strenght of the association between family history of AD and SS was measured as an odds ratio (OR). The adjusted OR was obtained by unconditional logistic regression model and the potentially confounding covariates were family size, age and sex of proband. <h3>Results</h3> A total of 143 eligible SS cases (EEC criteria,1994) and 140 healthy controls were identified. 27/143 (18.8%) SS and 7/140 (5%) controls had one FDR with AD, 7/143 (4.9%) and 1/140 (0.7%) had two or more FDR with AD. Considering the proband with one FDR with AD (therefore belonging to a multiplex family) in comparison to probands without any FDR affected (belonging to a simplex family), the adjusted OR was 6.19 (95% CI 2.3–16.7); the risk is higher if the relatives are two or more: OR 19.2 (95% CI 1.69–216). <h3>Conclusion</h3> This study indicates that a family history of autoimmune disorders is a risk factor for SS. Probands from multiplex families have an higher risk to have SS compared to simplex families. The risk increases with the number of FDR with AD.
Management of Thrombotic Complications in COVID-19: An Update
Authors: Adrija Hajra, Sheetal Vasundara Mathai, Somedeb Ball, Dhrubajyoti Bandyopadhyay, Maedeh Veyseh, Sandipan Chakraborty, Carl J. Lavie, Wilbert S. Aronow
Journal: Drugs (2020)

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV‑2), is now a global pandemic. This virus primarily affects the respiratory tract and causes lung injury characterized by acute respiratory distress syndrome. Although the pathophysiology of COVID-19 is not yet clear, the most widely accepted mechanism is systemic inflammation. A clinically significant effect of the inflammation is coagulopathy. As a result of this effect, patients are found to have a high risk of venous thromboembolism. Studies have reported a high incidence of thrombotic complications in critically ill patients with COVID-19. In this review, we discuss the most updated evidence on the pathophysiology, diagnosis, and treatment of the coagulopathy of COVID-19. Prophylactic anticoagulation is recommended for all in-patients with COVID-19. Those with a higher risk of developing thromboembolic events or who have already developed venous thromboembolism should be treated with therapeutic anticoagulation. We also discuss post-discharge prophylaxis for high-risk patients and some newly proposed treatments for the hypercoagulability that could improve the outcomes of the affected patients.
Opposing Associations of NT-proBNP With Risks of Diabetes and Diabetes-Related Complications
Authors: Anna Birukov, Fabian Eichelmann, Olga Kuxhaus, Elli Polemiti, Andreas Fritsche, Janine Wirth, Heiner Boeing, Cornelia Weikert, Matthias B. Schulze
Journal: Diabetes Care (2020)

Circulating N-terminal pro B-type natriuretic peptide (NT-proBNP) is a classic diagnostic and prognostic marker for heart failure. However, it is inversely associated with diabetes risk. We aimed to investigate relationships of NT-proBNP with risk of diabetes-related complications in initially healthy individuals.We performed a case-cohort study within the European Prospective Investigation Into Cancer and Nutrition (EPIC)-Potsdam cohort including a random subcohort (n = 1,294) and incident cases of type 2 diabetes (n = 649) and cardiovascular diseases (n = 478). Incident cases of type 2 diabetes (n = 545) were followed up for microvascular (n = 133) and macrovascular (n = 50) complications. Plasma NT-proBNP was measured at baseline in initially healthy participants.In multivariable models, NT-proBNP was linearly inversely associated with incident type 2 diabetes with a hazard ratio (HR) (95% CI) per doubling in NT-proBNP of 0.91 (0.86, 0.98). The association was only observable in women (0.80 [0.72, 0.90]) compared with men (0.98 [0.91, 1.07]). Among people with incident diabetes, NT-proBNP was positively associated with diabetes complications: overall, 1.31 (1.13, 1.53); microvascular complications, 1.20 (1.01, 1.43); and macrovascular complications, 1.37 (1.03, 1.83).Although higher NT-proBNP levels are associated with lower diabetes risk, NT-proBNP is a biomarker for vascular complications in people who develop diabetes independent of potential confounders. Thus, NT-proBNP might be informative to monitor risk for diabetes-related microvascular and macrovascular complications, which should be further explored in future prospective studies.