tbuckley/cabot-search huggingface dataset:
SURF: integrative analysis of a compendium of RNA-seq and CLIP-seq datasets highlights complex governing of alternative transcriptional regulation by RNA-binding proteins
Authors: Fan Chen, Sündüz Keleş
Journal: Genome biology (2020)

Advances in high-throughput profiling of RNA-binding proteins (RBPs) have resulted inCLIP-seq datasets coupled with transcriptome profiling by RNA-seq. However, analysis methods that integrate both types of data are lacking. We describe SURF, Statistical Utility for RBP Functions, for integrative analysis of large collections of CLIP-seq and RNA-seq data. We demonstrate SURF's ability to accurately detect differential alternative transcriptional regulation events and associate them to local protein-RNA interactions. We apply SURF to ENCODE RBP compendium and carry out downstream analysis with additional reference datasets. The results of this application are browsable at http://www.statlab.wisc.edu/shiny/surf/.
Standardisation of PR3-ANCA and MPO-ANCA: evaluation of certified reference materials
Authors: Xavier Bossuyt, Doreen Dillaerts, Michael Mahler, Dirk Roggenbuch, Ulrich Leinfelder, Friederike Hammar, Wolfgang Schlumberger, Nina Olschowka, Jan Damoiseaux
Journal: Annals of the Rheumatic Diseases (2020)

Antineutrophil cytoplasmic antibodies (ANCAs) are important laboratory markers to support the diagnosis of ANCA-associated vasculitis. A 2017 international consensus states that high-quality immunoassays for proteinase-3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA can be used as the primary screening method for patients suspected of having granulomatosis with polyangiitis or microscopic polyangiitis.1

Efforts have been undertaken to standardise PR3-ANCA and MPO-ANCA measurements. More than 10 years ago, PR3-ANCA and MPO-ANCA reference standards have been prepared (from single patients) under the umbrella of the International Union of Immunological Societies (IUIS) and are available through the Autoantibody Standardization Committee (www.AutoAb.org). Several companies are using these reference standards (assigned value: 100 IU/mL) to calibrate their assays, such as Svar Life Science (ELISA), Thermo Fisher Scientific (fluoroenzyme immunoassay (FEIA)), Medipan (CytoBead assay) and Inova Diagnostics (chemiluminescence assay (CLIA)).

The Institute for Reference Materials and Measurements (IRMM) recently released certified reference materials for MPO-ANCA (ERM-DA476/IFCC) and for PR3-ANCA (ERM-DA483/IFCC).2 3 Both reference materials are based on plasmapheresis samples from single patients. We evaluated whether using the IRMM-certified reference materials aligns results for PR3-ANCA and MPO-ANCA across assays.

A random selection of 98 serum samples covering low, medium and high PR3-ANCA or MPO-ANCA levels from the Leuven and the Maastricht cohort included in the international EUVAS study4 were distributed to five manufacturers, together with the PR3-ANCA and …
The receptor-binding domain of the viral spike protein is an immunodominant and highly specific target of antibodies in SARS-CoV-2 patients
Authors: Lakshmanane Premkumar, Bruno Segovia-Chumbez, Ramesh Jadi, David R. Martinez, Rajendra Raut, Alena J. Markmann, Caleb Cornaby, Luther Bartelt, Susan Weiss, Yara Park, Caitlin E. Edwards, Eric Weimer, Erin M. Scherer, Nadine Rouphael, Srilatha Edupuganti, Daniela Weiskopf, Longping V. Tse, Yixuan J. Hou, David Margolis, Alessandro Sette, Matthew H. Collins, John Schmitz, Ralph S. Baric, Aravinda M. de Silva
Journal: Science Immunology (2020)

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that first emerged in late 2019 is responsible for a pandemic of severe respiratory illness. People infected with this highly contagious virus can present with clinically inapparent, mild, or severe disease. Currently, the virus infection in individuals and at the population level is being monitored by PCR testing of symptomatic patients for the presence of viral RNA. There is an urgent need for SARS-CoV-2 serologic tests to identify all infected individuals, irrespective of clinical symptoms, to conduct surveillance and implement strategies to contain spread. As the receptor binding domain (RBD) of the spike protein is poorly conserved between SARS-CoVs and other pathogenic human coronaviruses, the RBD represents a promising antigen for detecting CoV-specific antibodies in people. Here we use a large panel of human sera (63 SARS-CoV-2 patients and 71 control subjects) and hyperimmune sera from animals exposed to zoonotic CoVs to evaluate RBD's performance as an antigen for reliable detection of SARS-CoV-2-specific antibodies. By day 9 after the onset of symptoms, the recombinant SARS-CoV-2 RBD antigen was highly sensitive (98%) and specific (100%) for antibodies induced by SARS-CoVs. We observed a strong correlation between levels of RBD binding antibodies and SARS-CoV-2 neutralizing antibodies in patients. Our results, which reveal the early kinetics of SARS-CoV-2 antibody responses, support using the RBD antigen in serological diagnostic assays and RBD-specific antibody levels as a correlate of SARS-CoV-2 neutralizing antibodies in people.
AB1098 STRUCTURAL ELEMENTS OF THE KNEE ENTHESES ASSESSED IN HEALTHY SUBJECTS WITH ULTRA HIGH FIELD MRI (150 MICRONS).
Authors: D. Roche, C. Michel, P. Daudé, A. Le Troter, C. Chagnaud, J. P. Mattei, L. Pini, M. Guye, D. Bendahan, S. Guis
Journal: Annals of the Rheumatic Diseases (2020)

Background: Fibrocartilaginous enthesis is composed of different histological zones which are commonly referred to the tendon distal extremity (a lamellar tissue with a low cell density, collagen and connective tissue), the fibrocartilaginous zone (with chondrocytes), a progressively mineralized zone and the bone. The MRI visualization of the water content of entheses is challenging given the very short relation time so that entheses has been very poorly assessed using MRI (1). Objectives: The main objective of the study was to assess the structural elements of the knee enthesis based on the quantitative T2* measurements using Ultra High Field (UHF) MRI. Methods: Twelve healthy subjects without any osteoarticular pathology were included in the study after they provided their informed consent. 3D gradient echo sequence with a 4.3 ms echo time and T2* mapping were performed. The lateral internal, external and crossed ligaments, patellar and quadricipital tendons were assessed. T2* measurements were performed specifically on the quadricipital tendon. Results: The quadricipital tendon and the bone trabeculation could be visualized on the UHF MR image. The T2* mapping analysis illustrated a large value (16.4 ± 4 ms) for the subchondral bone and much lower values for the trabecular bone (11 ± 4.5 ms) and the different zones of the keen entheses (7.7 ± 1.9 ms). Conclusion: Based on T2* measurements performed using UHF MRI, the different structural elements of the knee entheses were distinguished. This quantitative stratification could be used to assess changes in pathological conditions such as SpA and trauma. References: [1]Benjamin M, Bydder GM. Magnetic resonance imaging of entheses using ultrashort TE (UTE) pulse sequences. Journal of magnetic resonance imaging: JMRI. 2007;25(2):381-9. Disclosure of Interests: None declared
Health System Costs of Treating Latent Tuberculosis Infection With Four Months of Rifampin Versus Nine Months of Isoniazid in Different Settings
Authors: Mayara Lisboa Bastos, Jonathon R. Campbell, Olivia Oxlade, Menonli Adjobimey, Anete Trajman, Rovina Ruslami, Hee Jin Kim, Joseph Obeng Baah, Brett G. Toelle, Richard Long, Vernon Hoeppner, Kevin Elwood, Hamdan Al-Jahdali, Lika Apriani, Andrea Benedetti, Kevin Schwartzman, Dick Menzies
Journal: Annals of Internal Medicine (2020)

Background: Four months of rifampin treatment for latent tuberculosis infection is safer, has superior treatment completion rates, and is as effective as 9 months of isoniazid. However, daily medication costs are higher for a 4-month rifampin regimen than a 9-month isoniazid regimen. Objective: To compare health care use and associated costs of 4 months of rifampin and 9 months of isoniazid. Design: Health system cost comparison using all health care activities recorded during 2 randomized clinical trials. (ClinicalTrials.gov: NCT00931736 and NCT00170209) Setting: High-income countries (Australia, Canada, Saudi Arabia, and South Korea), middle-income countries (Brazil and Indonesia), and African countries (Benin, Ghana, and Guinea). Participants: Adults and children with clinical or epidemiologic factors associated with increased risk for developing tuberculosis that warranted treatment for latent tuberculosis infection. Measurements: Health system costs per participant. Results: A total of 6012 adults and 829 children were included. In both adults and children, greater health system use and higher costs were observed with 9 months of isoniazid than with 4 months of rifampin. In adults, the ratios of costs of 4 months of rifampin versus 9 months of isoniazid were 0.76 (95% CI, 0.70 to 0.82) in high-income countries, 0.90 (CI, 0.85 to 0.96) in middle-income countries, and 0.80 (CI, 0.78 to 0.81) in African countries. Similar findings were observed in the pediatric population. Limitation: Costs may have been overestimated because the trial protocol required a minimum number of follow-up visits, although fewer than recommended by many authoritative guidelines. Conclusion: A 4-month rifampin regimen was safer and less expensive than 9 months of isoniazid in all settings. This regimen could be adopted by tuberculosis programs in many countries as first-line therapy for latent tuberculosis infection. Primary Funding Source: Canadian Institutes of Health Research.
Identification of PD1-mediated regulation of antitumor antigen response in patients with NSCLC using the trans vivo DTH assay
Authors: Diego A Lema, Ewa Jankowska-Gan, Nan Sethakorn, William Burlingham, Ticiana Leal
Journal: Journal for ImmunoTherapy of Cancer (2020)

Objectives Emerging evidence has shown a role for tumor antigen-specific regulation in cancer. Identifying individuals with pre-existing regulatory responses may be key to understand those who are more likely to respond to Programmed Death-1 (PD-1) or PD-1 Ligand 1 (PD-L1) checkpoint blockade. We hypothesized that a functional assay could identify the role of PD-1/PD-L1 interactions on tumor-specific immune cells in the peripheral blood in patients with advanced non-small-cell lung cancer (NSCLC). Methods We performed the trans vivo delayed-type hypersensitivity assay to identify the role of PD-1/PD-L1-mediated tumor-specific immune regulation in ten patients with advanced NSCLC. Results The majority of patients had PD-1-mediated anergic immune responses towards their tumor antigens. Eight out of nine of these patients did not respond to their own tumor antigens but responded in the presence of anti-PD-1 antibody (‘PD-1 anergy’ phenotype). A minority (3/9) also had ‘active’ PD-1-mediated immune suppressive regulatory responses. Our results suggest that PD-1-anergy is a common feature of NSCLC immune responses, whereas PD-1-mediated immune suppression is present only in a minority of patients. The latter was associated with poor clinical outcomes in our sample. Conclusions Overall, our results indicate that bystander suppression or the ‘anergy-only’ phenomenon may be novel biomarkers in NSCLC and suggest prediction value based on these phenotypes.
Abstract A25: Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma
Authors: Theresa Guo, Kristina D. A. Zambo, Fernando T. Zamuner, Tingting Ou, Christopher Hopkins, Dylan Z. Kelley, Hildegard A. Wulf, Ludmila V. Danilova, Michael Considine, David Sidransky, Alexander V. Favorov, Liliana Florea, Elana J. Fertig, Daria A. Gaykalova
Journal: Clinical Cancer Research (2020)

Abstract Human papillomavirus-related oropharyngeal squamous cell carcinoma (HPV+ OPSCC) represents a unique disease entity within head and neck cancer with rising incidence. Previous work has shown that alternative splicing events (ASEs) are prevalent in HPV+ OPSCC, but further validation is needed to understand the regulation of this process and its role in these tumors. In this study, eleven ASEs (GIT2, CTNNB1, MKNK2, MRPL33, SIPA1L3, SNHG6, SYCP2, TPRG1, ZHX2, ZNF331, and ELOVL1) were selected for validation from 109 previously published candidate ASEs to elucidate the post-transcriptional mechanisms of oncogenesis in HPV+ disease. In vitro qRT-PCR confirmed differential expression of 9 of 11 ASE candidates, and in silico analysis within the TCGA cohort confirmed 8 of 11 candidates. Six ASEs (MRPL33, SIPA1L3, SNHG6, TPRG1, ZHX2, and ELOVL1) showed significant differential expression across both methods. Further evaluation of chromatin structure revealed that ASEs strongly correlated with the cancer-specific distribution of acetylated lysine 27 of histone 3 (H3K27ac). Subsequent epigenetic treatment of HPV+ HNSCC cell lines (UM-SCC-047 and UPCI-SCC-090) with JQ1 not only induced downregulation of cancer-specific ASE isoforms but also growth inhibition in both cell lines. The UPCI-SCC-090 cell line, with greater ASE expression, also showed more significant growth inhibition after JQ1 treatment. This study confirms several novel cancer-specific ASEs in HPV+OPSCC and provides evidence for the role of chromatin structure in regulation of alternative splicing in HPV+OPSCC. Our findings highlight the role of epigenetic changes in the oncogenesis of HPV+OPSCC, which represents a unique, unexplored target for biomarkers, neoantigens, and therapeutics. Citation Format: Theresa Guo, Kristina D. A. Zambo, Fernando T. Zamuner, Tingting Ou, Christopher Hopkins, Dylan Z. Kelley, Hildegard A. Wulf, Ludmila V. Danilova, Michael Considine, David Sidransky, Alexander V. Favorov, Liliana Florea, Elana J. Fertig, Daria A. Gaykalova. Chromatin structure regulates cancer-specific alternative splicing events in primary HPV-related oropharyngeal squamous cell carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; 2019 Apr 29-30; Austin, TX. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(12_Suppl_2):Abstract nr A25.
Heart failure and nephropathy: Catastrophic and interrelated complications of diabetes
Authors: Richard E Gilbert, Kim Connelly, Darren J Kelly, Carol A Pollock, Henry Krum
Journal: Journal of the American Society of Nephrology (2006)

Heart failure (HF) is a major contributor to poor quality of life, a leading cause of hospitalization, and cause of premature death. Both kidney disease and diabetes are major and independent risk factors for the development of heart failure, such that individuals with diabetic nephropathy are at especially high risk. Such patients not only are likely to have coronary artery disease and hypertension but also are likely to have diabetic cardiomyopathy, a distinct pathologic entity that is more closely associated with the microvascular than the macrovascular complications of diabetes. In addition to a better understanding of the epidemiology of HF, advances in noninvasive imaging have highlighted the importance of early cardiac dysfunction in diabetes and the high prevalence of HF with preserved left ventricular systolic function. Although significant renal dysfunction is usually an exclusion criterion in HF trials, diabetes is often a prespecified subgroup so that subanalyses of large multicenter clinical trials do provide some guidance in therapeutic decision-making. However, further therapies for both HF and nephropathy in diabetes clearly are needed, and a number of new therapeutic strategies that target both disorders have already entered the clinical arena.
Molecular Landscape of BRAF-Mutant NSCLC Reveals an Association Between Clonality and Driver Mutations and Identifies Targetable Non-V600 Driver Mutations
Authors: Marcelo V. Negrao, Victoria M. Raymond, Richard B. Lanman, Jacqulyne P. Robichaux, Junqin He, Monique B. Nilsson, Patrick K.S. Ng, Bianca E. Amador, Emily B. Roarty, Rebecca J. Nagy, Kimberly C. Banks, Viola W. Zhu, Chun Ng, Young Kwang Chae, Jeffrey M. Clarke, Jeffrey A. Crawford, Funda Meric-Bernstam, Sai-Hong Ignatius Ou, David R. Gandara, John V. Heymach, Trever G. Bivona, Caroline E. McCoach
Journal: Journal of Thoracic Oncology (2020)

Approximately 4% of NSCLC harbor BRAF mutations, and approximately 50% of these are non-V600 mutations. Treatment of tumors harboring non-V600 mutations is challenging because of functional heterogeneity and lack of knowledge regarding their clinical significance and response to targeted agents.We conducted an integrative analysis of BRAF non-V600 mutations using genomic profiles of BRAF-mutant NSCLC from the Guardant360 database. BRAF mutations were categorized by clonality and class (1 and 2: RAS-independent; 3: RAS-dependent). Cell viability assays were performed in Ba/F3 models. Drug screens were performed in NSCLC cell lines.A total of 305 unique BRAF mutations were identified. Missense mutations were most common (276, 90%), and 45% were variants of unknown significance. F468S and N581Y were identified as novel activating mutations. Class 1 to 3 mutations had higher clonality than mutations of unknown class (p < 0.01). Three patients were treated with MEK with or without BRAF inhibitors. Patients harboring G469V and D594G mutations did not respond, whereas a patient with the L597R mutation had a durable response. Trametinib with or without dabrafenib, LXH254, and lifirafenib had more potent inhibition of BRAF non-V600-mutant NSCLC cell lines than other MEK, BRAF, and ERK inhibitors, comparable with the inhibition of BRAF V600E cell line.In BRAF-mutant NSCLC, clonality is higher in known functional mutations and may allow identification of variants of unknown significance that are more likely to be oncogenic drivers. Our data indicate that certain non-V600 mutations are responsive to MEK and BRAF inhibitors. This integration of genomic profiling and drug sensitivity may guide the treatment for BRAF-mutant NSCLC.
Low risk for SARS-CoV2 symptomatic infection and early complications in paediatric patients during the ongoing CoVID19 epidemics in Lombardy
Authors: F. Rovida, D. Cereda, S. Novati, A. Licari, A. Triarico, G.L. Marseglia, R. Bruno, F. Baldanti, R. Bruno, M. Mondelli, E. Brunetti, A. Di Matteo, E. Seminari, L. Maiocchi, V. Zuccaro, L. Pagnucco, B. Mariani, S. Ludovisi, R. Lissandrin, A. Parisi, P. Sacchi, S.F.A. Patruno, G. Michelone, R. Gulminetti, D. Zanaboni, S. Novati, R. Maserati, P. Orsolini, M. Vecchia, M. Sciarra, E. Asperges, M. Colaneri, A. Di Filippo, M. Sambo, S. Biscarini, M. Lupi, S. Roda, T.C. Pieri, I. Gallazzi, M. Sachs, P. Valsecchi, S. Perlini, C. Alfano, M. Bonzano, F. Briganti, G. Crescenzi, A.G. Falchi, R. Guarnone, B. Guglielmana, E. Maggi, I. Martino, P. Pettenazza, S. Pioli di Marco, F. Quaglia, A. Sabena, F. Salinaro, F. Speciale, I. Zunino, M. De Lorenzo, G. Secco, L. Dimitry, G. Cappa, I. Maisak, B. Chiodi, M. Sciarrini, B. Barcella, F. Resta, L. Moroni, G. Vezzoni, L. Scattaglia, E. Boscolo, C. Zattera, M.F. Tassi, V. Capozza, D. Vignaroli, M. Bazzini, G. Iotti, F. Mojoli, M. Belliato, L. Perotti, S. Mongodi, G. Tavazzi, G. Marseglia, A. Licari, I. Brambilla, D. Barbarini, A. Bruno, P. Cambieri, G. Campanini, G. Comolli, M. Corbella, R. Daturi, M. Furione, B. Mariani, R. Maserati, E. Monzillo, S. Paolucci, M. Parea, E. Percivalle, A. Piralla, F. Rovida, A. Sarasini, M. Zavattoni, G. Adzasehoun, L. Bellotti, E. Cabano, G. Casali, L. Dossena, G. Frisco, G. Garbagnoli, A. Girello, V. Landini, C. Lucchelli, V. Maliardi, S. Pezzaia, M. Premoli, A. Bonetti, G. Caneva, I. Cassaniti, A. Corcione, R. Di Martino, A. Di Napoli, A. Ferrari, G. Ferrari, L. Fiorina, F. Giardina, A. Mercato, F. Novazzi, G. Ratano, B. Rossi, I.M. Sciabica, M. Tallarita, E. Vecchio Nepita, M. Calvi, M. Tizzoni, C. Nicora, A. Triarico, V. Petronella, C. Marena, A. Muzzi, P. Lago
Journal: Clinical Microbiology and Infection (2020)
AB0224 ASSOCIATIONS BETWEEN JOINT REPLACEMENT HISTORY AND CYCLIC CITRULLINATED PEPTIDE ANTIBODY TITERS IN RHEUMATOID ARTHRITIS PATIENTS
Authors: M. Sato, M. Takemura
Journal: Annals of the Rheumatic Diseases (2020)

Background: High titers of cyclic citrullinated peptide antibodies (anti-CCP) are predictive of poor prognosis in the treatment of rheumatoid arthritis (RA). The 2010 ACR/EULAR classification criteria for early RA assign a high point value to cases having highly positive anti-CCP titers. Previous reports have claimed that osteoarthritic damage is more severe and advanced in RA patients who test positive for anti-CCP than in their negative counterparts. Objectives: To retrospectively investigate whether anti-CCP titers were associated with the extent of osteoarthritic damage in RA patients treated at our institution. Methods: Data were analyzed for 422 RA patients who received biologic agents due to resistance to methotrexate or other conventional antirheumatic drugs. Associations were explored between joint replacement history-i.e. total knee replacement (TKR), total hip replacement (THR), or lack thereof—and anti-CCP positivity rates and titers. Results: The sample consisted of 90 men and 332 women. On average, patients were put on biologics at 58.6 years of age (range: 22–85), and had a disease duration of 9.3 years. The first biologic agent chosen was infliximab (IFX) in 154 cases, etanercept (ETN) in 76, adalimumab (ADA) in 61, tocilizumab (TCZ) in 70, abatacept (ABT) in 41, golimumab (GLM) in 18, and certolizumab pegol (CZP) in 2. In total, 331/422 patients (78.4%) tested positive for anti-CCP. TKR was performed in 46 cases (M:F ratio: 7:39, mean age: 64.7 y, mean disease duration: 15.1 y), of which 46 were positive for anti-CCP (100%). THR was performed in 18 cases (M:F ratio: 2:16, mean age: 62.3 y, mean disease duration: 18.5 y), of which 17 were positive for anti-CCP (94.4%). The mean anti-CCP titer among all positive patients (n=331) was 152.9 IU/ml. This value was significantly higher in patients who underwent either joint replacement procedure than those who did not (215.4 v. 142.8 IU/ml, p&lt;0.0005). Conclusion: With one exception, all RA patients who underwent joint replacement were positive for anti-CCP, and their titers were higher than non-surgical cases. Practitioners should be aware of this trend, and pay attention to the progression of damage in the knee and hip joints when treating RA patients with high anti-CCP titers. Disclosure of Interests: None declared