tbuckley/cabot-search huggingface dataset:
Inhibiting Wee1 and ATR kinases produces tumor-selective synthetic lethality and suppresses metastasis
Authors: Amirali B. Bukhari, Cody W. Lewis, Joanna J. Pearce, Deandra Luong, Gordon K. Chan, Armin M. Gamper
Journal: Journal of Clinical Investigation (2019)

We used the cancer-intrinsic property of oncogene-induced DNA damage as the base for a conditional synthetic lethality approach. To target mechanisms important for cancer cell adaptation to genotoxic stress and thereby to achieve cancer cell-specific killing, we combined inhibition of the kinases ATR and Wee1. Wee1 regulates cell cycle progression, whereas ATR is an apical kinase in the DNA-damage response. In an orthotopic breast cancer model, tumor-selective synthetic lethality of the combination of bioavailable ATR and Wee1 inhibitors led to tumor remission and inhibited metastasis with minimal side effects. ATR and Wee1 inhibition had a higher synergistic effect in cancer stem cells than in bulk cancer cells, compensating for the lower sensitivity of cancer stem cells to the individual drugs. Mechanistically, the combination treatment caused cells with unrepaired or under-replicated DNA to enter mitosis leading to mitotic catastrophe. As these inhibitors of ATR and Wee1 are already in phase I/II clinical trials, this knowledge could soon be translated into the clinic, especially as we showed that the combination treatment targets a wide range of tumor cells. Particularly, the antimetastatic effect of combined Wee1/ATR inhibition and the low toxicity of ATR inhibitors compared with Chk1 inhibitors have great clinical potential.
FRI0428 Mean number of capillaries is associated with disease activity at 6 months follow-up in systemic sclerosis patients
Authors: A.M. Gheorghiu, R. Oneata, A. Radu, A. Briceag, C. Draganescu, C. Vranceanu, S. Magda, T. Constantinescu, A. Soare, R. Dobrota, I. Ancuta, C. Ciofu, L. Macovei, M. Milicescu, M. Sasu, A. Enuica, O. Linte, G. Stan, B. Comanescu, T. Necsoiu, M. Bojinca, V. Stoica, C. Mihai
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Nailfold capillaroscopy (NFC) is essential in the evaluation and classification of systemic sclerosis (SSc). The mean number of capillaries is considered a promising tool for assessing vascular involvement in SSc, however there is no consensus yet over how many digits should be analysed and how. <h3>Objectives</h3> Investigation of the associations of the mean number of capillaries, measured by NFC with disease activity (EScSG activity score) and vascular involvement (digital ulcers (DUs) or history of DUs) in a single-centre cohort of patients with SSc. <h3>Methods</h3> 68 patients with SSc fulfilling the ACR/EULAR 2013 classification criteria were included. NFC and extensive assessment per the recommendations of EUSTAR were performed in all patients. 54 patients had a follow-up (FU) at 6 months. 8 digits were examined (II to V of both hands) by NFC; 4 images for each finger were saved. The NFC images were assessed by two experienced raters independently, scoring the mean number of capillaries in all fingers (m_nr/pat), in the 3rd finger of the dominant hand (m_nr/3rd dom) and in the 4th finger of the non-dominant hand (m_nr/4th non-dom) for each patient. "Early', 'active' and 'late' Cutolo patterns were also recorded. <h3>Results</h3> 2176 images were scored at baseline and 1728 at FU. The m_nr/pat at baseline ranged between 3.4–9.1, mean(SD) 5.6 (1.7) for rater 1, respectively 3.3–8.9, 5.2 (1.4) for rater 2. There was good to excellent correlation (Spearman's rho) at baseline and FU of the m_nr/pat with m_nr/3rd dom, m_nr/4th non-dom and Cutolo patterns, and fair correlation of m_nr/3rd dom with m_nr/4th non-dom and Cutolo patterns. We found significant differences of all mean scores of capillaries between patients with and without history of DUs (Mann Whitney U test) (table 1). Using linear regression adjusted for age, gender and history of DUs, mean number of capillaries was associated with disease activity at FU (table 2). <h3>Conclusions</h3> The mean number of capillaries had a good association with the history of DUs and predicted disease activity at 6 months follow-up. The m_nr/pat performed better in our analysis than the m_nr/3rd dom and m_nr/4th non-dom, however these could be used alternatively in clinical practice as they are less time consuming. <h3>Acknowledgements</h3> <i>This work is part of the QUANTICAP project</i> <h3>Disclosure of Interest</h3> None declared
FRI0100 Multi-omics analysis identifies a gene signature associated with the clinical response to anti-tnf therapy in rheumatoid arthritis
Authors: A. Aterido, J. Tornero, F. Blanco, B. Fernández-Gutiérrez, A. González, J.D. Cañete, J. Maymó, M. Alperi-López, À. Olivé, H. Corominas, V. Martínez-Taboada, I. González, A. Fernández-Nebro, A. Erra, S. Sánchez-Fernández, M. López-Lasanta, M. López-Corbeto, R. Tortosa, L. Codó, S. Marsal, A. Julià
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Tumour Necrosis Factor (TNF) inhibitors have improved the management of many patients with rheumatoid arthritis (RA). However,~30% of anti-TNF treated patients do not show a significant clinical improvement. To date, little is known on the biological mechanisms underlying the differential response to anti-TNF agents. <h3>Objectives</h3> We sought to identify genetic variation associated with the anti-TNF response in RA using a sequential multi-omics approach. <h3>Methods</h3> First, we aimed to identify gene coexpression modules (GCMs) associated with anti-TNF response. For this objective, we extracted the RNA from synovial biopsies of 13 RA patients starting anti-TNF therapy and determined the expression profiles using Illumina microarrays. GCMs were identified using the WGCNA approach. The association between GCMs and anti-TNF response was performed using the eigengene of each GCM. Clinical response was defined using the EULAR criteria at week 14. To analyse the association of GCMs with anti-TNF response at the genetic level, we used 348 anti-TNF treated RA patients from Spain. The statistical analysis was performed using GWAS data and the set-based test in PLINK. The GCMs that were significantly associated with anti-TNF response were subsequently tested for validation in an independent cohort of 2706 anti-TNF treated RA patients. The functional implication of the validated GCMs was studied via pathway and cell type epigenetic enrichment analyses. <h3>Results</h3> We identified 148 GCMs in the RA synovium. From these, 15 GCMs were found to be associated with anti-TNF response (p&lt;0.05). At the genetic level, we found two of the 15 GCMs to be associated with the adalimumab (ADL) and infliximab response (p&lt;0.05) in the Spain cohort. In the independent cohort, we replicated the association of the GCM associated with ADL response (p=0.01). The validated GCM was found to be enriched in genes that participate in the nucleotides metabolism (p=2.41e-5). The epigenetic analysis revealed that ADL-associated variants are enriched in epigenetic marks from immune cell types like Tregs (p=0.04). <h3>Conclusions</h3> Our study shows the existence of a drug-specific genetic basis for the anti-TNF response. Therefore, this molecular diversity should be considered for biomarker research in RA. <h3>Disclosure of Interest</h3> None declared
Acute Infection and Myocardial Infarction
Authors: Daniel M. Musher, Michael S. Abers, Vicente F. Corrales-Medina
Journal: New England Journal of Medicine (2019)

Among patients who are hospitalized for pneumococcal pneumonia, the incidence of myocardial infarction is 7 to 8%. The true incidence of postinfection myocardial infarction may be higher than estimated, given the practice of attributing elevated troponin levels to "troponin leak."
A Single -195 C &lt; G HBG1 Promoter Mediated By CRISPR/Cas9 Genome Editing Induces Fetal Hemoglobin Synthesis in Hudep-2
Authors: Priscila Keiko Matsumoto Martin, Dulcinéia Martins de Albuquerque, Carolina Lanaro, Ryo Kurita, Yukio Nakamura, Fernando F. Costa
Journal: Blood (2018)
Prognostic Value of Interim and End-of-Treatment PET-CT in Patients with Mature T-Cell and NK-Cell Lymphomas: A 10-Year Single Institution Study
Authors: Akihiro Kitadate, Kota Fukumoto, Hiroki Kobayashi, Yoshiaki Abe, Kentaro Narita, Daisuke Miura, Masami Takeuchi, Kosei Matsue
Journal: Blood (2018)
Postprogression Outcomes for Osimertinib versus Standard-of-Care EGFR-TKI in Patients with Previously Untreated EGFR-mutated Advanced Non–Small Cell Lung Cancer
Authors: David Planchard, Michael J. Boyer, Jong-Seok Lee, Arunee Dechaphunkul, Parneet K. Cheema, Toshiaki Takahashi, Jhanelle E. Gray, Marcello Tiseo, Suresh S. Ramalingam, Alexander Todd, Astrid McKeown, Yuri Rukazenkov, Yuichiro Ohe
Journal: Clinical Cancer Research (2019)

In the phase III FLAURA study, third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) osimertinib significantly improved progression-free survival (PFS) versus standard-of-care (SoC) EGFR-TKI (gefitinib or erlotinib) in patients with previously untreated EGFR (exon 19 deletion or L858R) mutation-positive advanced non-small cell lung cancer (NSCLC). Interim overall survival (OS) data were encouraging, but not formally statistically significant at current maturity (25%). Here we report exploratory postprogression outcomes.Patients were randomized 1:1 to receive osimertinib (80 mg orally, once daily) or SoC EGFR-TKI (gefitinib 250 mg or erlotinib 150 mg, orally, once daily). Treatment beyond disease progression was allowed if the investigator judged ongoing clinical benefit. Patients receiving SoC EGFR-TKI could cross over to receive osimertinib after independently confirmed objective disease progression with documented postprogression T790M-positive mutation status.At data cutoff (June 12, 2017), 138 of 279 (49%) and 213 of 277 (77%) patients discontinued osimertinib and SoC EGFR-TKI, respectively, of whom 82 (59%) and 129 (61%), respectively, started a subsequent treatment. Median time to discontinuation of any EGFR-TKI or death was 23.0 months [95% confidence interval (CI), 19.5-not calculable (NC)] in the osimertinib arm and 16.0 months (95% CI, 14.8-18.6) in the SoC EGFR-TKI arm. Median second PFS was not reached (95% CI, 23.7-NC) in the osimertinib arm and 20.0 months (95% CI, 18.2-NC) in the SoC EGFR-TKI arm [hazard ratio (HR), 0.58; 95% CI, 0.44-0.78; P = 0.0004].All postprogression endpoints showed consistent improvement with osimertinib versus SoC EGFR-TKI, providing further confidence in the interim OS data.
THU0473 Trend of mortality after osteoporotic hip fracture in a period of 17 years
Authors: R. Mazzucchelli, O. Guzón-Illescas, E. Pérez-Fernandez, M. Peña, J. Quirós, N. Crespí_Villarías, A. García-Vadillo
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> It is known that the mortality after a hip fracture is increased with respect to the general population. However, the trend of mortality is a controversial issue. <h3>Objectives</h3> The objective of this study is to analyse the incidence, trend and factors associated with mortality in patients with osteoporotic hip fracture. <h3>Methods</h3> This is a retrospective cohort study using the Minimum Basic Data Set (MBDS) of our hospital that collects a minimum data set at hospital discharge. We identified patients older than 45 years who suffered an osteoporotic hip fracture during the period from 1999 to 2015. (3992 hip fractures). The demographic data and comorbidities were obtained from the exploitation of the MBDS and the Income Nursing Assessment Form (subgroup of 810 patients). The identification of the deceased was obtained by consulting the MBDS and the INDEF (National Death Index facilitated by the Ministry of Health). A survival analysis was performed (regression of Cox and Kaplan-Meier). The incidence rate, standardised mortality index (SMI) was calculated with respect to the mortality of the general population of Madrid (mortality data of the general population obtained INE), trend (Poisson regression) and risk (Hazard Ratio) for the different clinical and demographic variables. <h3>Results</h3> The cumulative incidence of mortality was 72.69% in the study period. The crude mortality rate at 1, 3, 6 months and 1 and 3 years was 9.2%, 17.4%, 24.6%, 33% and 56%, respectively. In men it was 13.7%, 25%, 32.7%, 43.3% and 65.6% and in women 7.9%, 15.7%, 22.3%, 30%, 53.2%. The median overall survival was 886 days (95% CI: 836–951), with 576 for men and 998 for women. A statistically significant reduction in median survival was observed throughout the study period. The IME was 8.3 (95% CI: 7.98–8.59); (similar values in men and women). The clinical-demographic variables that showed a statistically significant association with mortality are shown in the following table 1 (HR and p-value): Other variables that showed statistical association were: presence of auditory and visual alterations, incontinence (urinary and faecal) and the total score on the Norton scale and the Downton scale. <h3>Conclusions</h3> We found an increase in mortality (or decrease in median survival) of patients with hip fracture during the last 17 years. An oncrease in mortality has been observed in patients with hip fracture related to age, male sex, diabetes, hepatic disease and living in a nursing home. <h3>Disclosure of Interest</h3> None declared
FRI0668 Item response theory to standardize patient reported physical function outcomes; linking 10 commonly used questionnaires to a common metric
Authors: M. Oude Voshaar, H. Vonkeman, D. Courvoisier, A. Finckh, L. Gossec, Leung Ying Ying, K. Michaud, G. Pinheiro, E. Soriano, N. Wulfraat, A. Zink, M. van de laar
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background:</h3> Physical function is a core outcome domain in clinical trials in various inflammatory rheumatic diseases. It is also included in the recently developed International Consortium for Health Outcomes Measurement (ICHOM) standard set for patients with inflammatory arthritis. Physical function patient reported outcome measures (PROMs) are commonly collected in patient registries and are used by decision makers in ways that require outcomes to be aggregated across different data sources. A major barrier to such initiatives is that many different physical function PROMs are in widespread use, and results cannot be meaningfully compared across them, if the traditional scoring procedures based on summing of the individual item scores are used. This is because summed scores depend on both patient- and item characteristics. To facilitate standardization of physical function outcome measurement, we developed a common metric for ten commonly used physical function PROMs using item response theory (IRT), that can be used to adjust PROM scores for item characteristics. <h3>Methods:</h3> Data of 16.386 patients with inflammatory arthritis from the United States National Databank of Rheumatic Disease, the Swiss Clinical Quality Management Registry, the National Database of the German Collaborative Arthritis Centres, the Dutch Rheumatoid Arthritis Monitoring Study, and several smaller observational studies were used to map the items of 10 commonly used physical function PROMs on a continuous latent physical function variable. The resulting common metric was cross-validated in an independent dataset of 243 patients with gout, osteoarthritis or polymyalgia rheumatica, in which four of the linked PROMs were administered <h3>Results:</h3> Our analyses supported that all 97 items of the 10 included PROMs relate to a single underlying physical function variable and that responses to each item could be described by the generalized partial credit IRT model. In the cross-validation analyses we found congruent mean scores for four different PROMs when the IRT based scoring procedures were used. <h3>Conclusions:</h3> We showed that scores obtained using the IRT based common metric developed in this study can be used to make physical function outcomes obtained using different physical function PROMs comparable. <h3>Disclosure of Interest:</h3> None declared
FRI0395 Sle disease activity index glucocorticoid index (SLEDAI-2KG) identifies more responders than sledai-2k
Authors: Z. Touma, D. Gladman, J. Su, N.M. Anderson, M.B. Urowitz
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) is one of the most commonly used disease activity indices in clinical practice and research but this index doesn't account for severity within each descriptor. Moreover, in clinical trials, the use of standard of care (SoC), which includes glucocorticoid (GC) often confounds trial results. We developed and validated a novel lupus disease activity index, SLEDAI-2K GC (SLEDAI-2KG), that describes disease activity while accounting for GC dose. SLEDAI-2KG has the same descriptors as SLEDAI-2K in addition to a new descriptor "GC" with different weight scores based on the dose of GC. Furthermore, SLEDAI-2KG has a low administration burden and a simple scoring system similar to SLEDAI-2K. <h3>Objectives</h3> We aimed to compare the performance of SLEDAI-2K and SGI in identifying responders in response to SoC. <h3>Methods</h3> Patients have been followed prospectively according to a standard protocol between January 2011 and January 2014, at a single lupus centre, with active disease (SLEDAI-2K≥6), on prednisone ≥10 mg/day, and with follow up visits within 5–24 months were studied. Treatment was determined based on the judgment of the treating rheumatologist. Response to SoC therapy, at first follow up visit, was assessed by SLEDAI- 2K and SLEDAI-2KG. Responders were defined based on the decrease in SLEDAI-2K and SGI score by ≥4. The performance of SLEDAI-2K and SGI was also compared using different cut-off points; 5, 6 and 7. Descriptive analysis was used. <h3>Results</h3> 111 patients met the inclusion criteria of the study and were further analysed. Patients' characteristics are represented in table 1. SLEDAI-2KG identified more responders at 6 months (94% vs. 84%) and at 12 months (92% vs. 76%) compared to SLEDAI-2K by cut off of 4. SLEDAI-2KG also identified more responders with cut off points 5, 6 and 7 (table 2). <h3>Conclusions</h3> The novel index, SLEDAI-2KG, is superior to SLEDAI-2K in identifying responders at 6 and 12 months accounting for steroid dose and thus adjusting for severity within each descriptor of SLEDAI-2K. SLEDAI-2KG has the ability to enhance analyses in clinical trials to differentiate between responders on minimal and moderate/large doses of GC. <h3>Disclosure of Interest</h3> Z. Touma Grant/research support from: GlaxoSmithKline, D. Gladman: None declared, J. Su: None declared, N. Anderson: None declared, M. Urowitz Grant/research support from: GlaxoSmithKline
Single-Center Experience With Catheter-Based Tricuspid Valve Replacement for Tricuspid Regurgitation
Authors: Mara Gavazzoni, Alberto Pozzoli, Michel Zuber, Edwin C. Ho, Felix Christian Tanner, Ioannis Kapos, Mizuki Miura, Luca Vicentini, Francesco Maisano, Maurizio Taramasso
Journal: JACC. Cardiovascular imaging (2019)
Hematologic Malignancies Arising in Patients with Germ Cell Tumors: Secondary Somatic Differentiation of Hematopoietic Malignancies from Germ Cell Precursors
Authors: Justin Taylor, Mark Donoghue, Raajit K. Rampal, Roni Tamari, Martin S. Tallman, Darren R. Feldman, Barry S Taylor, Omar I Abdel-Wahab
Journal: Blood (2018)
SAT0278 Nsaids reduces radiographic progression in sacloiliac joints in early axial spondyloarthritis
Authors: D. Rumiantceva, T. Dubinina, O. Rumyantseva, A. Demina, S. Erdes
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> According to the ASAS-EULAR management recommendations for axial spondyloarthritis (axSpA) patients (pts) suffering from pain and stiffness should use an NSAIDs as first-line drug and for pts who respond well to NSAIDs continuous use is preferred if symptomatic otherwise. Two studies have suggested that the continuous use of NSAIDs in patients with an elevated CRP results in reduced progression of structural damage in the spine in comparison to on-demand use.<sup>1; 2</sup> But up-to-date the question of the effect of NSAIDs on radiographic progression in early axSpA remains open. <h3>Objectives</h3> To compare continuous and on-demand treatment groups on radiographic progression sacloiliac joints (SIJ) in axSpA. <h3>Methods</h3> The research included 68 pts with early axSpA<sup>ASAS criteria, 2009</sup> from Moscow CORSAR cohort with disease duration &lt;5 years, age onset &lt;45 years and at least 2 years follow up (FUP). 33 (48,5%) males, pts mean age was 28,5 (5,8) y., average disease duration – 24,1 (15,4) mo, 63 (92,6%) pts were HLA-B27 positive. Pts were randomised into two treatment groups: group 1 – continuous uses of NSAIDs; group 2 – on-demand uses of NSAIDs. The dosages of NSAIDs accounted by the ASAS NSAID index. At baseline 6 pts received TNF inhibitors, after 2 y. FUP 14 pts receives TNF inhibitors. <h3>Results</h3> No significantly differences in axSpA disease activity between two groups at baseline (table 1) and after 2 y. FUP (table 2). At group &amp;x2116;1 8,2% pts has radiographic progression in SIJ (from nr-axSpA to AS), at group &amp;x2116;2%–13,3% pts (<b>p=0,000</b>). <h3>Conclusions</h3> The frequency of NSAIDs treatment does not affect on the activity of axSpA. Continuouly uses of NSAIDs reduces radiographic progression in sacloiliac joints in pts with early axSpA. <h3>References</h3> [1] Wanders A, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum2005;52:1756–65. [2]Kroon F. et al. Continuous NSAID use reverts the effects of inflammation on radiographic progression in patients with ankylosing spondylitis. Ann Rheum Dis2012;71:1623–9. <h3>Disclosure of Interest</h3> None declared
OCT Appraisal of Residual Thrombus Burden in Patients With STEMI Undergoing Intraprocedural Versus Post-Stenting Prolonged Bivalirudin Infusion
Authors: Andrea Picchi, Hector M. Garcia-Garcia, Gennaro Sardella, Marianna Adamo, Enrico Frigoli, Ugo Limbruno, Stefano Rigattieri, Roberto Diletti, Giacomo Boccuzzi, Marco Zimarino, Marco Contarini, Filippo Russo, Paolo Calabro, Giuseppe Andò, Ferdinando Varbella, Stefano Garducci, Cataldo Palmieri, Carlo Briguori, Kayode O. Kuku, Martina Rothenbühler, Alexios Karagiannis, Marco Valgimigli
Journal: JACC. Cardiovascular imaging (2019)