tbuckley/cabot-search huggingface dataset:
PD-L1 Protein Expression on Both Tumor Cells and Macrophages are Associated with Response to Neoadjuvant Durvalumab with Chemotherapy in Triple-negative Breast Cancer
Authors: Fahad Shabbir Ahmed, Patricia Gaule, John McGuire, Katir Patel, Kim Blenman, Lajos Pusztai, David L. Rimm
Journal: Clinical Cancer Research (2020)

Abstract Purpose: In both the IMpassion 130 trial in the metastatic setting and in Keynote 522 in the neoadjuvant setting, patients with triple-negative breast cancer (TNBC) showed benefit from PD-1 axis immunotherapy. Here, we assess PD-L1 expression on both tumor and immune cells using quantitative immunofluorescence to assess association with benefit from neoadjuvant durvalumab concurrent with chemotherapy in TNBC. Experimental Design: Pretreatment core needle biopsies (n = 69) were obtained from patients who participated in a phase I/II clinical trial (NCT02489448). The final analysis included 45 patients [pathologic complete response (pCR) = 18, non-pCR = 27] due to technical issues and insufficient tissue. Slides were stained using a previously validated Ultivue DNA-based Ultimapper kit (CD8, CD68, PD-L1, Cytokeratin/Sox10, and Hoechst counterstain). The PD-L1 expression was analyzed by molecular compartmentalization without segmentation using AQUA software (version 3.2.2.1) in three tissue compartments including tumor (cytokeratin-positive cells), CD68+ cells, and overall stroma. Results: In patients with pCR, PD-L1 expression was significantly higher in tumor cells, in CD68+ cells and in the stroma compared with patients non-pCR. There was no difference in the amount of CD68+ cells in the tumor or stromal compartments between cases with pCR and non-pCR. Conclusions: Expression of PD-L1 in tumor cells, immune cells in stroma, and colocalized with CD68+ cells is associated with higher rates of pCR to durvalumab and chemotherapy in TNBC.
THU0146 Real-world experience with infliximab in the treatment of rheumatoid arthritis: a subgroup analysis of methotrexate receiving and non-receiving patients
Authors: D Erkan, Y Yazici, I Kulman, K Tai, J Markenson, MJ Harrison
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Infliximab is a chimeric monoclonal anti-TNF antibody developed to treat rheumatoid arthritis (RA) patients who have had a less than optimal response to previous therapy. It has been recommended that infliximab be given concomitantly with methotrexate (MTX) to prevent the development of autoantibodies. <h3>Objectives</h3> To identify clinical response and adverse events in RA patients treated with infliximab for a period of 6 months, with a subgroup analysis of MTX-receiving (MTX-R) and non-receiving (MTX-NR) patients. <h3>Methods</h3> RA patients receiving infliximab at our ambulatory infusion unit completed questionnaires regarding RA history, treatment, and measures of disease activity (HAQ) at baseline, and at 2 weeks, 8 weeks, and every 2 months thereafter. Patients were queried about side effects experienced between infusions. ANOVA statistics were used for comparison. <h3>Results</h3> 36 patients were started on infliximab between January–July 2000 (F/M: 33/3, mean age: 63 + 12.9 y, mean disease duration: 15.3+10.2 y) and 24 patients completed 6 months of treatment. Patients had failed an average of 3 DMARDs prior to infliximab. HAQ scores for 24/36 patients who completed 6 months of treatment significantly improved from 1.95+0.60 to 1.21+0.67 (p = 0.0002). In subgroup analysis, the baseline characteristics of MTX-R and MTX-NR groups were similar with respect to age and disease duration. Twenty (56%) patients were not receiving MTX due to history of adverse event, allergic reaction or patient refusal. For patients who completed 6 months of infliximab: in MTX-R group, HAQ scores for 14/24 patients improved from 1.99+0.58 to 1.34+0.54 (p = 0.005); and in MTX-NR group HAQ scores for 10/24 patients improved from 1.89+0.65 to 1.05+0.81 (p = 0.02). During 6 months of follow-up, 3/10 (30%) of MTX-NR and 9/14 (64%) of MTX-R patients had a total of 23 adverse events after 198 infusions. There was no difference between the 2 subgroups with respect to the type of adverse events. Ten MTX-NR patients discontinued treatment before 6 months (adverse events: 7, inadequate response to treatment: 2, and non-compliance:1. Only 2 MTX-R patients discontinued treatment prior to 6 months, due to inadequate response. <h3>Conclusion</h3> Following 6 months of infliximab treatment, RA patients with long-standing disease demonstrate a clinically important and statistically significant improvement in functional disability as measured by HAQ. However, our subgroup analysis suggests that infliximab administered without MTX carries a higher rate of discontinuation. These findings may be due to patient characteristics or our small sample size. Continuing follow-up of patients receiving infliximab in the absence of MTX will provide a better understanding of the true risk/benefit of infliximab used alone.
FRI0109 Survival and predictor variables for mortality in systemic lupus erythematosus
Authors: S Appenzeller, LT Costallat
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Survival of systemic lupus erythematosus (SLE) patients has improved significantly over time because of recognition of mild disease and better approaches to therapy. The identification of predictor variables for mortality is necessary to identify subgroups at greater risks to die and who need more aggressive therapy. <h3>Objectives</h3> To analyse survival and mortality risks of various clinical variables in a cohort of SLE patients, followed prospectively in a single centre. <h3>Methods</h3> The survival of a cohort of 509 SLE patients, SLE followed over a 20-year period according to a standard protocol was studied using the Kaplan Meier lifetable analysis methods. Univariate associations between clinical and laboratory informations and drugs used were calculated. The Cox proportional hazard regression model was used to estimate risk ratio of death and to examine the simultaneous effects of multiple prognostic factors. <h3>Results</h3> Over the duration of follow-up of 20 years, 58 (11.4%) died. The survival rate was 97% at 1 year, 90% at 5 years, 81% at 10 years and 75% at 20 years. Age &lt;16 years at diagnosis, hypertension, weight loss, nephritis, ocular involvement, the presence of anti DNA antibodies, the absence of artralgia/arthritis and frequent infections were significantly associated with reduced survival in univariate analysis. Using multivariate analysis, hypertension (OR 2.2, 95% CI 1.1–4.5), age &lt;16 years at diagnosis (OR 2.6, 95% CI 1.4–5.0), ocular involvement (OR 4.9, 95% CI 1.9–12.8), treatment without antimalarial drugs (OR 2.8, 95% CI 0.15–0.53)and frequent infections (OR 2.3, 95% CI 1.3–4.1) were independent risk factors associated with increased mortality. <h3>Conclusion</h3> Hypertension, age &lt;16 years at diagnosis , ocular involvement, treatment without antimalarial drugs and frequent infections were independent risk factors associated with increased mortality. <h3>References</h3> Uramoto, Kristine M, Michet CJJ, <i>et al</i>. Trends in the incidence of mortality of SLE. Arthritis Rheum 1999;42(1) Petri M. Hopkins Lupus Cohort. <i>Rheum Dis Clin N Am</i>. 2000;26(2)
pH-Responsive charge switchable PEGylated ε-poly-l-lysine polymeric nanoparticles-assisted combination therapy for improving breast cancer treatment
Authors: Zhihao Guo, Junhui Sui, Mengcheng Ma, Jianshe Hu, Yong Sun, Liqun Yang, Yujiang Fan, Xingdong Zhang
Journal: Journal of Controlled Release (2020)
The Respiratory Microbiome in Chronic Hypersensitivity Pneumonitis Is Distinct from That of Idiopathic Pulmonary Fibrosis
Authors: Rachele Invernizzi, Benjamin G. Wu, Joseph Barnett, Poonam Ghai, Shaun Kingston, Richard J. Hewitt, Johanna Feary, Yonghua Li, Felix Chua, Zhe Wu, Athol U. Wells, Peter M. George, Elisabetta A. Renzoni, Andrew G. Nicholson, Alexandra Rice, Anand Devaraj, Leopoldo N. Segal, Adam J. Byrne, Toby M. Maher, Clare M. Lloyd, Philip L. Molyneaux
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: Chronic hypersensitivity pneumonitis (CHP) is a condition that arises after repeated exposure and sensitization to inhaled antigens. The lung microbiome is increasingly implicated in respiratory disease, but, to date, no study has investigated the composition of microbial communities in the lower airways in CHP.Objectives: To characterize and compare the airway microbiome in subjects with CHP, subjects with idiopathic pulmonary fibrosis (IPF), and control subjects.Methods: We prospectively recruited individuals with a CHP diagnosis (n = 110), individuals with an IPF diagnosis (n = 45), and control subjects (n = 28). Subjects underwent BAL and bacterial DNA was isolated, quantified by quantitative PCR and the 16S ribosomal RNA gene was sequenced to characterize the bacterial communities in the lower airways.Measurements and Main Results: Distinct differences in the microbial profiles were evident in the lower airways of subjects with CHP and IPF. At the phylum level, the prevailing microbiota of both subjects with IPF and subjects with CHP included Firmicutes, Bacteroidetes, Proteobacteria, and Actinobacteria. However, in IPF, Firmicutes dominated, whereas the percentage of reads assigned to Proteobacteria in the same group was significantly lower than the percentage found in subjects with CHP. At the genus level, the Staphylococcus burden was increased in CHP, and Actinomyces and Veillonella burdens were increased in IPF. The lower airway bacterial burden in subjects with CHP was higher than that in control subjects but lower than that of those with IPF. In contrast to IPF, there was no association between bacterial burden and survival in CHP.Conclusions: The microbial profile of the lower airways in subjects with CHP is distinct from that of IPF, and, notably, the bacterial burden in individuals with CHP fails to predict survival.
Novel Documentation of Onset and Rapid Advancement of Pulmonary Arterial Hypertension without Symptoms in BMPR2 Mutation Carriers: Cautionary Tales?
Authors: Elena K. Amin, Eric D. Austin, Claire Parker, Elizabeth Colglazier, Hythem Nawaytou, Peter J. Leary, Anna R. Hemnes, David Teitel, Jeffrey R. Fineman
Journal: American Journal of Respiratory and Critical Care Medicine (2020)
In older adults, new use of allopurinol or febuxostat was linked to hypersensitivity reactions versus colchicine
Authors: Ami Schattner
Journal: Annals of Internal Medicine (2020)

Singh JA, Cleveland JD. Hypersensitivity reactions with allopurinol and febuxostat: a study using the Medicare claims data. Ann Rheum Dis. 2020;79:529-35. 32024648.
USP7 targeting modulates anti-tumor immune response by reprogramming Tumor-associated Macrophages in Lung Cancer
Authors: Xiaomeng Dai, Lisen Lu, Suke Deng, Jingshu Meng, Chao Wan, Jing Huang, Yajie Sun, Yan Hu, Bian Wu, Gang Wu, Jonathan F. Lovell, Honglin Jin, Kunyu Yang
Journal: Theranostics (2020)

Background: Tumor associated macrophages (TAMs) have strong plasticity and if reprogrammed, can clear tumor cells and regulate the adaptive immune system for cancer immunotherapy. Deubiquitinating enzymes (DUBs), which can remove ubiquitin (Ub) from Ub-modified substrates, have been associated with oncogenic metabolism but are not well-known for regulating TAMs repolarization. Methods: The expression of DUB related genes in macrophages (MΦs) was detected by reverse transcription-PCR. Flow cytometry and immunofluorescence were used to detect the changes of immune cells in the tumor microenvironment and spleen, including M1 (CD11b+F4/80+CD86+CD206-), and M2 (CD11b+F4/80+CD86-CD206+) MΦs, and IFN-γ+CD8+T cells. A proliferation assay was used to determine the effect of M2 MΦs treated with a USP7 inhibitor on T cell proliferation. Western blotting was used to detect the expression of USP7 and the activation of the MAPK pathway. The TGCA database was used to assess the role of USP7 in the immune microenvironment of human lung adenocarcinoma (LUAD). Results: 51 DUB genes were screened and USP7 was identified as a highly expressed gene in M2 but not M1 MΦs. Specific silencing of USP7 using siRNA or USP7 inhibitors led to phenotypical and functional changes in M2 MΦs, favoring CD8+T cells proliferation in vitro. USP7 inhibitors delayed tumor growth in mice with Lewis lung carcinoma, and promoted tumor infiltration of M1 MΦs and IFN-γ+CD8+T cells. Depletion of TAMs attenuated these therapeutic effects. USP7 inhibition was shown to mediate MΦs reprogramming by activating the p38 MAPK pathway. Administration of USP7 inhibitors increased the expression of programmed cell death ligand 1 (PD-L1) in tumors, while blocking programmed cell death protein 1 (PD-1) provided an effective anti-tumor response. Clinical databases suggest that high expression of USP7 in LUAD was negatively correlated with innate and adaptive immunity. Conclusions: Taken together, these results provide evidence to suggest that therapeutic approaches targeting USP7, in combination with immunotherapy, should be considered for lung cancer treatment.
Use of Hydrocortisone, Ascorbic Acid, and Thiamine in Adults with Septic Shock
Authors: Emily A. Vail, Hannah Wunsch, Ruxandra Pinto, Nicholas A. Bosch, Allan J. Walkey, Peter K. Lindenauer, Hayley B. Gershengorn
Journal: American Journal of Respiratory and Critical Care Medicine (2020)

Rationale: In December 2016, a single-center study describing significant improvements in mortality among a small group of patients with severe sepsis and septic shock treated with hydrocortisone, high-dose ascorbic acid, and thiamine (HAT therapy) was published online.Objectives: This study aims to describe the administration of HAT therapy among U.S. adults with septic shock before and after study publication and to compare outcomes between patients who received and did not receive HAT therapy.Methods: We performed a retrospective cohort study of 379 acute care hospitals in the Premier Healthcare Database including patients discharged from October 1, 2015, to September 30, 2018. Exposure was quarter year of hospital discharge; postpublication was defined as January 2017 onward (July 2017 for effectiveness analyses). The primary outcome was receipt of HAT at least once during hospitalization. We conducted unadjusted segmented regression analyses to examine temporal trends in HAT administration. In patients with early septic shock, we compared the association of early HAT therapy (within 2 d of hospitalization) with hospital mortality using multivariable modeling and propensity score matching.Measurements and Main Results: Among 338,597 patients, 3,574 (1.1%) received HAT therapy, 98.7% in the postpublication period. HAT administration increased from 0.03% of patients (95% confidence interval [CI], 0.02–0.04) before publication to 2.65% (95% CI, 2.46–2.83) in the last quarter, with a significant step up in use after December 2016 (P < 0.001). Receipt of early HAT was associated with higher hospital mortality (28.2% vs. 19.7%; P < 0.001; adjusted odds ratio, 1.17 [95% CI, 1.02–1.33]; primary propensity-matched model adjusted odds ratio, 1.19 [95% CI, 1.02–1.40]).Conclusions: Publication of a single-center retrospective study was associated with significantly increased administration of HAT. Among patients with early septic shock, receipt of HAT was not associated with mortality benefit.
Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study
Authors: Emily Heer, Andrew Harper, Noah Escandor, Hyuna Sung, Valerie McCormack, Miranda M Fidler-Benaoudia
Journal: The Lancet Global Health (2020)

Breast cancer has distinct causes, prognoses, and outcomes and effects in patients at premenopausal and postmenopausal ages. We sought to assess the global burden and trends in breast cancer by menopausal status.
Abstract 11526: A Case of Cardiac Myeloid Sarcoma as an Uncertain Etiology of Heart Failure With Preserved Ejection Fraction
Authors: Yogamaya Mantha, Andrew Assaf, Rakushumimarika Harada, Benjamin Jones, Jasmeet Gill, Rahul Gill, Brian Le, Michinari Hieda, Mark Feldman
Journal: Circulation (2019)

Background: The most common extramedullary sites of acute myeloid leukemia (AML) are skin, lymph nodes, the gastrointestinal tract, bones, and soft tissue, with a cardiac site being extremely rare....
A Distinct Transcriptional Program in Human CAR T Cells Bearing the 4-1BB Signaling Domain Revealed by scRNA-Seq
Authors: Angela C. Boroughs, Rebecca C. Larson, Nemanja D. Marjanovic, Kirk Gosik, Ana P. Castano, Caroline B.M. Porter, Selena J. Lorrey, Orr Ashenberg, Livnat Jerby, Matan Hofree, Gabriela Smith-Rosario, Robert Morris, Joshua Gould, Lauren S. Riley, Trisha R. Berger, Samantha J. Riesenfeld, Orit Rozenblatt-Rosen, Bryan D. Choi, Aviv Regev, Marcela V. Maus
Journal: Molecular Therapy (2020)

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have produced impressive outcomes for the treatment of B cell malignancies, but different products vary in kinetics, persistence, and toxicity profiles based on the co-stimulatory domains included in the CAR. In this study, we performed transcriptional profiling of bulk CAR T cell populations and single cells to characterize the transcriptional states of human T cells transduced with CD3ζ, 4-1BB-CD3ζ (BBζ), or CD28-CD3ζ (28ζ) co-stimulatory domains at rest and after activation by triggering their CAR or their endogenous T cell receptor (TCR). We identified a transcriptional signature common across CARs with the CD3ζ signaling domain, as well as a distinct program associated with the 4-1BB co-stimulatory domain at rest and after activation. CAR T cells bearing BBζ had increased expression of human leukocyte antigen (HLA) class II genes, ENPP2, and interleukin (IL)-21 axis genes, and decreased PD1 compared to 28ζ CAR T cells. Similar to previous studies, we also found BBζ CAR CD8 T cells to be enriched in a central memory cell phenotype and fatty acid metabolism genes. Our data uncovered transcriptional signatures related to costimulatory domains and demonstrated that signaling domains included in CARs uniquely shape the transcriptional programs of T cells.
The Chief Scientist Office Cardiovascular and Pulmonary Imaging in SARS Coronavirus disease-19 (CISCO-19) study
Authors: Kenneth Mangion, Andrew Morrow, Catherine Bagot, Hannah Bayes, Kevin G Blyth, Colin Church, David Corcoran, Christian Delles, Lynsey Gillespie, Douglas Grieve, Antonia Ho, Sharon Kean, Ninian N Lang, Vera Lennie, David J Lowe, Peter Kellman, Peter W Macfarlane, Alex McConnachie, Giles Roditi, Robert Sykes, Rhian M Touyz, Naveed Sattar, Ryan Wereski, Sylvia Wright, Colin Berry
Journal: Cardiovascular Research (2020)

COVID-19 is typically a primary respiratory illness with multisystem involvement. The prevalence and clinical significance of cardiovascular and multisystem involvement in COVID-19 remain unclear.This is a prospective, observational, multicentre, longitudinal, cohort study with minimal selection criteria and a near-consecutive approach to screening. Patients who have received hospital care for COVID-19 will be enrolled within 28 days of discharge. Myocardial injury will be diagnosed according to the peak troponin I in relation to the upper reference limit (URL, 99th centile) (Abbott Architect troponin I assay; sex-specific URL, male: >34 ng/L; female: >16 ng/L). Multisystem, multimodality imaging will be undertaken during the convalescent phase at 28 days post-discharge (Visit 2). Imaging of the heart, lung, and kidneys will include multiparametric, stress perfusion, cardiovascular magnetic resonance imaging, and computed tomography coronary angiography. Health and well-being will be assessed in the longer term. The primary outcome is the proportion of patients with a diagnosis of myocardial inflammation.CISCO-19 will provide detailed insights into cardiovascular and multisystem involvement of COVID-19. Our study will inform the rationale and design of novel therapeutic and management strategies for affected patients.ClinicalTrials.gov identifier NCT04403607.
Trends in US Suicide Deaths—Reply
Authors: Brian L. Mishara, Stefan Stijelja
Journal: JAMA Pediatrics (2020)

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The perceived barriers and facilitators to implementation of ECMO services in acute hospitals
Authors: Bentley J. Fulcher, Angus J. Nicholson, Natalie J. Linke, Danielle Berkovic, Carol L. Hodgson, Shannah Anderson, Michael J. Bailey, Stephen Bernard, Jasmin V. Board, Daniel Brodie, Heidi Buhr, Aidan J. C. Burrell, David J. Cooper, Eddy Fan, John F. Fraser, David J. Gattas, Alisa M. Higgins, Ingrid K. Hopper, Sue Huckson, Edward Litton, Shay P. McGuinness, Priya Nair, Neil Orford, Rachael L. Parke, Vincent A Pellegrino, David V. Pilcher, Benjamin A. J. Reddi, Dion Stub, Tony Trapani, Andrew A. Udy
Journal: Intensive Care Medicine (2020)