tbuckley/cabot-search huggingface dataset:
Predictive Biomarkers of Response to Src Inhibitors in Lung Cancer. Getting to YES1
Authors: Howard Y. Li, Laurie L. Carr
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

small differences between these studies might be explained by differences in sample preparation; for example, Griese and colleagues used centrifugation of BAL to remove cells from the surfactant before analysis, which was not done in the prior studies.Importantly, esterified cholesterol is produced within alveolar macrophages in PAP, and thus they may have underestimated the true proportion of esterified cholesterol present in the alveolar macrophages from patients with PAP.One limitation of the study is that inhibitors of lipid oxidation were not included in the sample preparation and storage, which could have affected the concentration of oxidized lipid species.Such lipid species have specific roles in modulating macrophage functional processes, particularly oxidized derivatives of cholesterol (oxysterols), which act through the LXRa pathway (10).It is also unclear whether the lipidomic profile in individuals correlates with their clinical phenotype, including the presence or absence of fibrosis-this is an area that requires further exploration.Finally, assessing dynamic changes in the alveolar lipidome may be a novel method to monitor the therapeutic response to inhaled GM-CSF or emerging cholesterol-targeted strategies.
Longitudinal prediction of outcome in idiopathic pulmonary fibrosis using automated CT analysis
Authors: Joseph Jacob, Brian J. Bartholmai, Coline H.M. van Moorsel, Srinivasan Rajagopalan, Anand Devaraj, Hendrik W. van Es, Teng Moua, Frouke T. van Beek, Ryan Clay, Marcel Veltkamp, Maria Kokosi, Angelo de Lauretis, Eoin P. Judge, Teresa M. Jacob, Tobias Peikert, Ronald Karwoski, Fabien Maldonado, Elisabetta Renzoni, Toby M. Maher, Andre Altmann, Athol U. Wells
Journal: European Respiratory Journal (2019)

<b>Change in the vessel-related structures, a computer-derived CT variable, is a strong predictor of outcome in idiopathic pulmonary fibrosis and can increase power in future drug trials when used as a co-endpoint alongside forced vital capacity change</b>http://bit.ly/2M7DfKS
PS1388 RELATIVE EFFICACY OF APPROVED AND RECENTLY INTRODUCED TREATMENTS FOR NEWLY DIAGNOSED MULTIPLE MYELOMA: A NETWORK META-ANALYSIS
Authors: K. Weisel, K. Ramasamy, M. Owen, S. Dhanasiri, A. Frederickson, T. Facon
Journal: HemaSphere (2019)

Background: Carfilzomib (K)-based regimens improved progression-free survival (PFS) and overall survival (OS) in relapsed and refractory multiple myeloma (RRMM) patients (pts) in ASPIRE (K [27 mg/m2]-lenalidomide-dexamethasone [KRd] vs Rd) and ENDEAVOR (K [56 mg/m2]-dexamethasone [Kd56] vs bortezomib-dexamethasone [Vd]), regardless of age. Frailty scores have been developed based on age, comorbidities, and functional status (Palumbo Blood 2015;125:2068–74; Facon Blood 2015;126:4239). Aims: We assessed post-hoc pt outcomes by frailty status. Methods: PFS, OS, and safety were assessed by treatment arm and frailty score (based on age, medical history-derived Charlson Comorbidity Index, and ECOG performance status); frailty scores: 0 = fit, 1 = intermediate (int), and ≥2 = frail. Results: Pt frailty status was balanced between treatment arms in ASPIRE and ENDEAVOR. Median PFS and OS were longer with K-based regimens vs controls in ASPIRE and ENDEAVOR across frailty subgroups (Table). Rates of treatment-emergent adverse events are summarized in the Table.Summary/Conclusion: Kd56 and KRd consistently improved outcomes vs Vd and Rd, respectively, in all frailty subgroups as defined by the algorithm above. These findings support the favorable benefit-risk profile of KRd and Kd56 regardless of frailty score.
PB2309 INCIDENCE OF ALLOIMMUNIZATION IN SICKLE CELL DISEASE: EXPERIENCE OF A CENTER IN LISBON
Authors: R. Dutra, E. Araújo, M. Dias, J. Marco
Journal: HemaSphere (2019)

Background: Nowadays, red blood cell (RBC) transfusion is an indispensable option for the treatment and prevention of chronic complications of sickle cell disease (SCD). In SCD patients it has been reported at a rate of 18–76% of alloimmunization after transfusion. It has also been suggested, that transfusion is related to the formation of RBC autoantibodies, especially in patients with hemoglobinopathies. Interestingly, some authors correlate higher susceptibility to allo and autoimmunization in patients without the spleen. That could be one of the explanations why SCD patients have a higher incidence of RBC immunization. Aims: To determinate the rate of alloimmunization among the transfused SCD patients residing in Lisbon. The other objectives were to clarify among the same study population the incidence of positive direct antiglobulin (DAT) test and spleen absence and correlate both with alloimmunization. Methods: The subjects for the study were selected from the adult patients (≥18 years of age) of a tertiary hospital in Lisbon, between 01‐01‐2017 and 20‐02‐2018, that were transfused at least one time and monitored for the presence of irregular antibodies. A total of 61 patients met the inclusion criteria. Most of the routine immunohematological tests, i.e. blood group typing, indirect antiglobulin test (IAT) and DAT, were done using a microtube gel technique. Moreover, clinical assessment of the spleen status (absence or presence) were obtained from imagiological data. Results: In our study, we obtained a rate of alloimmunization of 21,3% (N = 13). 40% of the transfused SCD (N = 22) have in DAT positive and 50% of those/these have alloantibodies. We found in our population a significant association between positive DAT with alloimmunization (p &lt; 0.001). In 58 patients we succeed in obtaining their spleen status and among those without a spleen (N = 36) 25% became alloimmunized. Summary/Conclusion: In our study, the risk of alloimmunization was higher in patients who received more than 20 red blood cell units. Our alloimmunization rate is in agreement with the literature as well as the significant association of DAT with alloimmunization. Interestingly, 50% of those patients with DAT positive also have alloantibodies, supporting the idea that those patients develop autoantibodies due to transfusion therapy. This fact advocates some plausibility in screening for autoantibodies at regular intervals prior to each transfusion. There was no significant correlation between the presence or absence of a spleen and alloimmunization (p = 0.7475). In conclusion, this study is one of the few to approach the rate of alloimmunization in SCD patients. Therefore, it is necessary to have further studies in Portugal in order to study and to understand our heterogeneous SCD population.
AB0837 INFLUENCE OF AUTO-IMMUNE HEPATOPATHIES ON BONE MINERAL DENSITY
Authors: Hela Kchir, Dhouha Cherif, Dhia Kaffel, Dhilel Issaoui, Maha Mtir, Faten Limaiem, Nadia Maamouri
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Osteoporosis is a common complication of chronic liver diseases especially associated with Primary biliary cholangitis (PBC). Its occurrence during others autoiummune hepatopathies such us autoimmune hepatitis, primary sclerosing cholangitis has been described. <h3>Objectives</h3> The aim of our study was to assess the prevalence of osteoporosis in patients with autoimmune hepatopathies. <h3>Methods</h3> We carried out a retrospective study from January 1996 to December 2018, including all patients with auto-immune hepatopathy [autoimmune hepatitis/Primary biliary cholangitis (PBC)/Primary sclerosing cholangitis (PSC)/overlap syndrome]. Only patients who had bone mineral density (BMD) were selected. <h3>Results</h3> During the study period, 124 patients were included. The mean age of our patients was 55 years [18-87]. BMD has been realised in 51 patient [32 PBC/5AIH/3PSC/11 overlap Syndrome]. It was normal in 18 cases (35%), whereas 9 patients had osteopenia (18%) and 24 had osteoporosis (47%)[15PBC/2AIH/5overlap/2PSC]. The mean values of L2-L4 T-scores and femur total T-scores were -3.27 and -1.97, respectively., Osteoporotic patients had an average age of 58 years: 1 men, 3 premenopausal, and 20 postmenopausal women. The study of risk factors of osteoporosis has shown that 5patients underwent systemic corticosteroid. A tobacco intoxication has been noted in 1patient. Biochemical analysis indicated a high level of cytolysis (superior to twice normal value) in 14 patient. Cholestasis was noted in 10 patients. The mean values of bilirubin was 23mg/l. Among the 24 patients with osteoporosis, 10 had positif antinuclear antibodies, 17 had positif anti-mitochondrial antibodies and 5 had positif anti-smooth muscle antibodies. Eight of patients were at an advanced stages of liver fibrosis at the moment of diagnosis. <h3>Conclusion</h3> Our study has shown that autoimmune liver diseases has an influence on bone mineral density as a bone nineral loss was noted in more than half of the cases. It should be considered for all patients with auto immune hepatopathy especially with long duration of corticosteroid treatment. <h3>Disclosure of Interests</h3> None declared
Single-cell transcriptomics unveils gene regulatory network plasticity
Authors: Giovanni Iacono, Ramon Massoni-Badosa, Holger Heyn
Journal: Genome biology (2019)

Single-cell RNA sequencing (scRNA-seq) plays a pivotal role in our understanding of cellular heterogeneity. Current analytical workflows are driven by categorizing principles that consider cells as individual entities and classify them into complex taxonomies.We devise a conceptually different computational framework based on a holistic view, where single-cell datasets are used to infer global, large-scale regulatory networks. We develop correlation metrics that are specifically tailored to single-cell data, and then generate, validate, and interpret single-cell-derived regulatory networks from organs and perturbed systems, such as diabetes and Alzheimer's disease. Using tools from graph theory, we compute an unbiased quantification of a gene's biological relevance and accurately pinpoint key players in organ function and drivers of diseases.Our approach detects multiple latent regulatory changes that are invisible to single-cell workflows based on clustering or differential expression analysis, significantly broadening the biological insights that can be obtained with this leading technology.
Hyaluronan synthase 2–mediated hyaluronan production mediates Notch1 activation and liver fibrosis
Authors: Yoon Mee Yang, Mazen Noureddin, Cheng Liu, Koichiro Ohashi, So Yeon Kim, Divya Ramnath, Elizabeth E. Powell, Matthew J. Sweet, Yoon Seok Roh, I-Fang Hsin, Nan Deng, Zhenqiu Liu, Jiurong Liang, Edward Mena, Daniel Shouhed, Robert F. Schwabe, Dianhua Jiang, Shelly C. Lu, Paul W. Noble, Ekihiro Seki
Journal: Science Translational Medicine (2019)

Hyaluronan (HA), a major extracellular matrix glycosaminoglycan, is a biomarker for cirrhosis. However, little is known about the regulatory and downstream mechanisms of HA overproduction in liver fibrosis. Hepatic HA and HA synthase 2 (HAS2) expression was elevated in both human and murine liver fibrosis. HA production and liver fibrosis were reduced in mice lacking HAS2 in hepatic stellate cells (HSCs), whereas mice overexpressing HAS2 had exacerbated liver fibrosis. HAS2 was transcriptionally up-regulated by transforming growth factor-β through Wilms tumor 1 to promote fibrogenic, proliferative, and invasive properties of HSCs via CD44, Toll-like receptor 4 (TLR4), and newly identified downstream effector Notch1. Inhibition of HA synthesis by 4-methylumbelliferone reduced HSC activation and liver fibrosis in mice. Our study provides evidence that HAS2 actively synthesizes HA in HSCs and that it promotes HSC activation and liver fibrosis through Notch1. Targeted HA inhibition may have potential to be an effective therapy for liver fibrosis.
THU0073 HAVE THE CLINICAL CHARACTERISTICS OF RHEUMATOID ARTHRITIS AT PRESENTATION BECOME MILDER OVER TIME? RESULTS FROM A NATIONWIDE STUDY OVER THREE DECADES IN SWEDEN
Authors: Jon Einarsson, Tor Olofsson, Olafur Palsson, Johan K Wallman, Meliha C Kapetanovic
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> The course of rheumatoid arthritis (RA) has become milder during the last decades, which could at least partly be attributed to major advances in the pharmacological treatment of the disease and the implementation of "treat to target"-strategies (1,2). It has also been suggested that RA is already milder at presentation (3) <h3>Objectives</h3> To investigate whether the clinical status, markers of inflammation, functional status, and patient and evaluator reported disease activity measures in patients with newly diagnosed RA, have improved over the recent decades. <h3>Methods</h3> Baseline data on all DMARD-naïve patients with early RA (&lt;6 months duration) included in the nationwide Swedish Rheumatology Quality registry (SRQ) between 1991 and 2014 were retrieved. The RA diagnosis relied on the clinical judgement of the treating physician and the information comprised swollen and tender joints count (SJC; TJC), markers of inflammation (CRP; ESR), functional status (HAQ; 0-3), patient's and evaluator's assessment of global disease activity (PtGA; EGA) and patient's assessment of pain (on a visual analog scale, VAS; 0-100 mm). Baseline demographic and disease characteristics were compared between patients with disease onset 1991-2000 vs. those with onset 2011-2014, using Mann-Whitney U test and Pearson's chi-squared test. <h3>Results</h3> A total of 6559 early RA patients were included. Over the study period of 23 years the majority of the patients were women (68%), and the mean age at inclusion increased from 57,4 to 59,1 years. Results are summarised in Table 1. Mean CRP, ESR, TJC and SJC all decreased significantly between the two time periods compared, which was also the case for HAQ. In contrast, mean pain, PtGA and EGA increased significantly between the time periods. Furthermore, time from symptom onset to inclusion was shorter 2011-2014. <h3>Conclusion</h3> In Swedish patients with early RA, baseline joint counts and inflammatory markers improved over the last three decades. This could partly be explained by shorter symptom duration at diagnosis but also suggests that, at onset, RA might be an inherently milder disease today. However, pain and patient's global assessment and evaluator's global assessment of disease activity increased over the same period of time, possibly indicating changes in both patients' and evaluators' expectations for management of early RA today <h3>References</h3> [1] Gwinnutt, et al. Arthritis Rheumatol. 2017; 69:1566–75. [2] Matsumoto, et al. J Rheumatol. 2017; 44:1575–82. [3] Diffin, et al. J Rheumatol. 2014; 41:1590–9. <h3>Disclosure of Interests</h3> Jon Einarsson: None declared, Tor Olofsson: None declared, Olafur Palsson: None declared, Johan K Wallman Consultant for: Consultant for AbbVie, Celgene, Eli Lilly, Novartis, and UCB Pharma., Meliha C Kapetanovic: None declared
CHOP TREATMENT ENHANCES DEPENDENCY ON BCL-2, MCL-1 AND BCL-XL IN DIFFUSE LARGE B-CELL LYMPHOMA
Authors: M. De Jong, M. Langendonk, B. Reitsma, M. Nijland, G. Huls, A. van den Berg, E. Ammatuna, L. Visser, T. van Meerten
Journal: HemaSphere (2019)
Abstract 3106: The HoxD locus: Its contribution to the osteogenic phenotype and malignancy of Ewing sarcoma
Authors: Kristina von Heyking, Laura Roth, Miriam Ertl, Stefan Burdach, Günther H. Richter
Journal: Cancer Research (2014)

Abstract Ewing sarcoma (ES), an osteogenic malignancy that mainly affects children and young adults, is characterized by early metastasis to lung and bone. Microarray analysis revealed genes of the posterior HoxD locus to be clearly over-expressed in primary ES. Especially, genes such as HOXD10, HOXD11 and HOXD13 normally involved in bone formation and ossification pattern of bones are significantly over-expressed in ES. The expression of HOXD10, HOXD11 or HOXD13 seems not to be influenced via ES pathognomonic ews/ets translocations, since RNA interference of EWS-FLI1 or its over-expression in mesenchymal stem cells did not influence posterior HOXD expression. However, RNA knock down of the dickkopf 2 homolog DKK2, a canonical WNT/beta-catenin agonist and critical mediator of osteolytic tumor growth in ES (Hauer et al., 2013) resulted in a significant suppression of HOXD11 and HOXD13 expression. Subsequently, RNA interference of individual HoxD genes demonstrated posterior HOXD genes to suppress neuronal differentiation potential of ES. Furthermore, HOXD10, HOXD11 and HOXD13 were found to be critical for chondrogenic, however not for osteogenic differentiation, but promote the expression of bone-associated genes such as RUNX2. HOXD11 and HOXD13 further promote in vitro proliferation and contact independent growth of ES. Similarly, in vitro invasiveness of ES lines was dependent on HOXD10, HOXD11 as well as HOXD13 and seemed mediated via Matrix Metalloproteinase 1 (MMP1), since down-regulation of individual HoxD genes likewise resulted in a suppression of MMP1 expression. In line with these observations, knock down of HOXD11 or HOXD13 significantly suppressed metastasis in a xeno-transplant model in immune deficient Rag2-/-gammaC-/- mice. These data overall provide evidence that posterior HOXD genes are critical mediators of the differentiation phenotype of ES concurrently promoting their metastasis potential. Reference: Hauer K, Julia Calzada-Wack J, Steiger K, Grunewald TG, Baumhoer D, Plehm S, Buch T, Prazeres da Costa O, Esposito I, Burdach S, Richter GHS (2013). DKK2 mediates osteolysis, invasiveness and metastatic spread in Ewing sarcoma. Cancer Res. 73(2): 967-77. Citation Format: Kristina von Heyking, Laura Roth, Miriam Ertl, Stefan Burdach, Günther H. Richter. The HoxD locus: Its contribution to the osteogenic phenotype and malignancy of Ewing sarcoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3106. doi:10.1158/1538-7445.AM2014-3106
<i>Pseudomonas aeruginosa</i> eradication therapy and risk of acquiring <i>Aspergillus</i> in young children with cystic fibrosis
Authors: Sabariah Noor Harun, Nicholas H G Holford, Keith Grimwood, Claire E Wainwright, Stefanie Hennig
Journal: Thorax (2019)

Background While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. Aim To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. Methods Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. Results Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32–3.79) years and 3.69 (1.68–4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. Conclusion In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus .
Ambient air pollution, asthma drug response, and telomere length in African American youth
Authors: Eunice Y. Lee, Sam S. Oh, Marquitta J. White, Celeste S. Eng, Jennifer R. Elhawary, Luisa N. Borrell, Thomas J. Nuckton, Andrew M. Zeiger, Kevin L. Keys, Angel C.Y. Mak, Donglei Hu, Scott Huntsman, Maria G. Contreras, Lesly-Anne Samedy, Pagé C. Goddard, Sandra L. Salazar, Emerita N. Brigino-Buenaventura, Adam Davis, Kelley E. Meade, Michael A. LeNoir, Fred W. Lurmann, Esteban G. Burchard, Ellen A. Eisen, John R. Balmes
Journal: Journal of Allergy and Clinical Immunology (2019)
Surgical management and outcome of grade-C pancreatic fistulas after pancreaticoduodenectomy: A retrospective multicenter cohort study
Authors: Tao Ma, Xueli Bai, Wen Chen, Mengyi Lao, Gang Jin, Kailian Zheng, Deliang Fu, Feng Yang, Renyi Qin, Xu Li, Wenhui Lou, Lei Zhang, Kuirong Jiang, Pengfei Wu, Chenghao Shao, Anan Liu, Yinmo Yang, Yongsu Ma, Heshui Wu, Tingbo Liang
Journal: International Journal of Surgery (2019)
SAT0130 ANTI-CITRULLINATED PEPTIDE ANTI-BODIES TITERS DECREASE AFTER RITUXIMAB BUT NOT AFTER ABATACEPT OR TNF BLOCKERS TREATMENT: A REAL-LIFE ANALYSIS
Authors: Stéphane Hilliquin, Loriane Gutermann, Claire Goulvestre, Jerome Avouac, Maxime Dougados, Anna Moltó
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> There is an increasing body of evidence suggesting a direct pathophysiological role of ACPA in Rheumatoid Arthritis (RA). Therefore, on the top of clinical, biological and imaging remission, one target could be immunological remission, defined as the normalization of the ACPA titers after therapy. In this sense, data related to the capacity of different biologics to normalize ACPA are contradictory. <h3>Objectives</h3> To evaluate the changes in ACPA titers before and after treatment with different biologics. <h3>Methods</h3> RA patients treated with biologics were identified via the hospital's pharmacy and/or the Electronic Medical Record of the patients; thereafter, for each patient, ACPA titers before/after treatment were retrieved from the department of biology. To be included, patients had to be diagnosed with RA, to have received a biologic (either abatacept IV or SC, TNF-inhibitors(TNFi) (Infliximab iv and Etanercept SC), or Rituximab IV) and to have at least two dosages of ACPA (at least one before and one after biologic treatment). ACPA titers were compared before and after treatment in each of the treatment groups. A mixed model analysis including an interaction between the drug and time was also performed. <h3>Results</h3> Among the 328 selected RA patients 92 patients (female: 84%, mean age: 62 years) had enough biological data to be included for the analysis: 36 patients had received rituximab, 21 abatacept, 35 TNFi. Mean (Standard deviation) ACPA levels in the whole group before treatment was 924.8 (1164.6) UI/L. ACPA titers (summarized in figure 1) decreased significantly after Rituximab (from 1287 (1322) to 301(387) UI/L; p&lt;0.005) but not after Abatacept (from 857(1166) to 1352(1241) UI/L) or TNF blockers (from 593(881) to 1116(1398) UI/L). Modelisation of ACPA titers over follow-up (mixed models) revealed a significant interaction between drug and time, suggesting a drug effect of such variation (Figure) <h3>Conclusion</h3> In this real-life study, ACPA titers decrease slightly only after Rituximab therapy. These data suggest that there is potentially a huge unmet need in RA if the target is to achieve an immunological remission. <h3>Disclosure of Interests</h3> Stéphane Hilliquin: None declared, Loriane Gutermann: None declared, Claire Goulvestre: None declared, Jerome Avouac: None declared, maxime dougados Grant/research support from: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Consultant for: Eli Lilly and Company, Pfizer, AbbVie, and UCB Pharma, Anna Moltó: None declared