tbuckley/cabot-search huggingface dataset:
FRI0334 PERFORMANCE OF THE SCLERODERMA SKIN PATIENT-REPORTED OUTCOME (SSPRO) IN A PHASE 2 TRIAL WITH LENABASUM
Authors: Ada Man, Nancy Dgetluck, Brian Conley, Barbara White
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Skin thickening is a distressing feature of systemic sclerosis (SSc). The severity and extensiveness of skin thickening, as traditionally assessed by mRSS, may not directly correlate with its effect on patients' health related quality of life (HRQoL). The Scleroderma Skin Patient-reported Outcome (SSPRO) was specifically developed to assess the skin-related HRQoL in SSc. No skin-specific PRO in SSc has been prospectively validated in a clinical trial. <h3>Objectives</h3> Validate the SSPRO prospectively in a clinical trial. <h3>Methods</h3> The SSPRO, Patient Global Assessment (PtGA), Physician Global Assessment (MDGA), HAQ-DI, mRSS, FVC% predicted, PROMIS-29 questionnaire, and ACR CRISS were assessed prospectively in a Phase 2 study of lenabasum in dcSSc. SSPRO has 18 items that assess four SSc skin-related HRQoL domains. The Phase 2 study of lenabasum had a 4-month double-blinded portion (N = 41 completers) followed by an open-label extension (N = 38 entered). Spearman correlations of baseline values and change values were determined for SSPRO and other outcome measures. Mean change in SSPRO scores were determined in subjects with increasing levels of improvement in other efficacy outcomes. <h3>Results</h3> At baseline, SSPRO correlated moderately with all other outcome measures except for FVC%, as expected, with strongest correlations with PtGA, HAQ-DI, and PROMIS-29 pain interference and social role domains (Table 1). The mean change in SSPRO scores at 3 and 12 months correlated mostly moderately (r = 0.25 to 0.62) with the mean change in other outcome scores, but correlations were low or inconsistent with mRSS, FVC%, and PROMIS-29 anxiety domain (Table 1). Significance of correlations in some outcomes was hampered by small magnitudes of change. Mean SSPRO generally increased in subjects with increasing levels of improvement in HAQ-DI, PtGA, mRSS, and ACR CRISS, although less consistently with mRSS and ACR CRISS at 3 months (Table 2). <h3>Conclusion</h3> SSPRO score correlates with both physician and patient-reported outcomes at baseline, though correlations with the latter were stronger. Change in SSPRO reflects changes in how the patient feels (PtGA, PROMIS-29 pain interference and depression domains) and functions (HAQ-DI, PROMI-29 physical function and social role domains) and less consistently with physician-assessed outcomes. Subjects with improvement ≥ MID levels of –0.250 in HAQ-DI, -1 in PtGA, and –5 in mRSS had SSPRO improvements of -22 to -23 points at 12 months. <h3>Disclosure of Interests</h3> Ada Man Consultant for: Advisory Board Fee: Abbvie, Janssen, Boeringer Ingelheim, Nancy Dgetluck Employee of: Corbus Pharmaceuticals, Inc., Brian Conley Employee of: Corbus Pharmaceuticals, Inc., Barbara White Shareholder of: Corbus Pharmaceuticals, Inc., Employee of: Corbus Pharmaceuticals, Inc.
PS1012 PREDICTING A PML‐RARA FUSION GENE IN PATIENTS WITH ACUTE MYELOID LEUKEMIA BY CONVOLUTIONAL NEURAL NETWORKS
Authors: C.‐J. Liu, Y.‐C. Liu, W. Yuan, K.‐H. Yu
Journal: HemaSphere (2019)

Background: Acute myeloid leukemia (AML) is a prevalent hematological malignancy worldwide. The estimated incidence of AML was 2.4 per 100,000 standard population in Taiwan in 2016. Bone marrow studies are essential for the initial workup in most cases. However, these examinations require a thorough evaluation of the histopathology slides by hematopathologists. Acute promyelocytic leukemia (APL) is a subtype of AML. APL has completely different initial treatment and prognosis from the other subtypes of AML. Convolutional neural network (CNN) is the state‐of‐the‐art technology of image recognition and has been shown to successfully predict common gene mutations by using cancer pathology images (Nicolas et al. 2018 Nature Medicine). Aims: We planned to use the whole‐slide scanning images of bone marrow aspiration smears to examine the utility of CNN in predicting APL in AML patients. Methods: We collected the whole‐slide scanning images of patients with newly diagnosed AML at Taipei Veterans General Hospital between November 2009 and September 2017. The final cohort consisted of 261 AML cases. The patients’ age, sex, bone marrow blast percentage, cytogenetics and molecular studies, such as FLT3‐ITD and NPM1 and outcomes, were collected. The cohort was split into a training set (80%) and a testing set (20%). In addition, two AML cohorts from Far Eastern Memorial Hospital ( n = 19) and Kaohsiung Veterans General Hospital ( n = 29) were served as external validation cohorts. Inception V3 was used as the baseline model. Stochastic gradient descent was employed to refine the weights in the CNNs using the training set. The finalized model was tested on the held‐out test set. Prediction accuracy and the area under the receiver operating characteristic curves (AUCs) were analyzed to evaluate the performance of the algorithms. All CNN models were trained using Keras version 2.1.5 with Tensorflow 1.7.0, and statistical analysis was performed with R version 3.5.1. Results: The median age of the AML patients at diagnosis was 65 (range 17–96) years and 58.9% of them were male. CNN classified APL from the other subtypes of AML with high accuracy (AUC 0.92). In addition, CNN also could predict other chromosomal abnormalities, such as complex karyotypes, and molecular abnormalities, such as NPM1 mutation. Furthermore, CNN successfully predicted patients’ overall survival by using its classification. Summary/Conclusion: CNN successfully predicted genetic alterations of AML patients by using the histopathology images of the bone marrow aspiration smears. These results demonstrated the utility of convolutional neural networks in predicting common genetic mutations. Our developed methods are generalizable to other hematological malignancies or other cancers. image
THU0291 THE CHARACTERISTICS OF PEDIATRIC BEHÇET’S DISEASE IN TURKEY VERSUS ISRAEL
Authors: Yonatan Butbul, Ezgi Deniz Batu, Hafize Emine Sonmez, Betül Sözeri, Nuray Aktay Ayaz, Limor Baba, Gil Amarilyo, Seval Simsek, Liora Harel, Şerife Gül Karadağ, Yelda Bilginer, Seza Özen
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Behçet's disease (BD) is a variable vessel vasculitis affecting all sizes of vasculature in both the arterial and venous systems. Children with BD comprises 3-24% of all BD patients. <h3>Objectives</h3> To compare the demographics, presentation, clinical manifestations, disease activity, and treatment in pediatric Behçet's disease in Turkey versus Israel. <h3>Methods</h3> Three centers from Turkey and two centers from Israel participated in this study. The diagnosis of BD was before 16 years of age and based on expert opinion at each center. BD current activity form (BDCAF) was used for assessing disease activity. <h3>Results</h3> A total of 205 patients were included (165 from Turkey; 40 from Israel). HLA-B51 positivity (68.3% vs 46.2%, p=0.028), male gender (52.1% vs 30%, p=0.012), and skin involvement (especially necrotic folliculitis) (55.2% vs 22.5%, p&lt;0.001) were more frequent among patients from Turkey compared to the ones from Israel. The first disease-related symptom was oral aphthosis in both groups followed by genital aphthosis and arthralgia/arthritis in patients from Turkey and Israel, respectively. The median BDCAF values were worse at the first visit for patients from Turkey than those from Israel (4 vs 2, p&lt;0.001). The most commonly prescribed drug was colchicine in the whole group (96.6%). Significantly more patients were treated with corticosteroids (50% vs 28.5%, p=0.006), methotrexate (17.5% vs 3%, p=0.002), infliximab (10% vs 1.8%, p=0.026), and nonsteroidal anti-inflammatory drugs (12.5% vs 1.8%, p=0.007) in Israel than Turkey. For the classification of BD in the whole group, ICBD criteria had the highest sensitivity (73.2%) followed by PED-BD (pediatric BD) (47.8%) and ISG (The International Study Group) (42%) criteria sets. <h3>Conclusion</h3> This is the largest cohort of pediatric BD reported to date. The disease manifestations and disease activity significantly differ among pediatric BD patients from Turkey and Israel which emphasizes the effect of the ethnicity on disease phenotype. <h3>Reference</h3> [1] Kone-Paut I, et al. Consensus classification criteria for paediatric Behcet's disease from a prospective observational cohort: PEDBD. Ann Rheum Dis 2016;75:958-64. <h3>Disclosure of Interests</h3> Yonatan Butbul: None declared, Ezgi Deniz Batu: None declared, Hafize Emine Sonmez: None declared, Betül Sözeri: None declared, Nuray Aktay Ayaz: None declared, Limor Baba: None declared, Gil Amarilyo: None declared, Seval Simsek: None declared, Liora Harel: None declared, Şerife Gül Karadağ: None declared, Yelda Bilginer: None declared, Seza Özen Consultant for: Seza Ozen is receiving consultancy fees from Novartis, Speakers bureau: Roche
KDM2B promotes IL-6 production and inflammatory responses through Brg1-mediated chromatin remodeling
Authors: Qingqing Zhou, Yunkai Zhang, Bo Wang, Wenhui Zhou, Yong Bi, Wanwan Huai, Xi Chen, Yihan Chen, Zhongmin Liu, Xingguang Liu, Zhenzhen Zhan
Journal: Cellular and Molecular Immunology (2019)
Apolipoprotein A-I mimetics mitigate intestinal inflammation in a COX2-dependent inflammatory disease model
Authors: David Meriwether, Dawoud Sulaiman, Carmen Volpe, Anna Dorfman, Victor Grijalva, Nasrin Dorreh, R. Sergio Solorzano-Vargas, Jifang Wang, Ellen O’Connor, Jeremy Papesh, Muriel Larauche, Hannah Trost, Mayakonda N. Palgunachari, G.M. Anantharamaiah, Harvey R. Herschman, Martin G. Martin, Alan M. Fogelman, Srinivasa T. Reddy
Journal: Journal of Clinical Investigation (2019)

Cyclooxygenase 2 (Cox2) total knockout and myeloid knockout (MKO) mice develop Crohn's-like intestinal inflammation when fed cholate-containing high-fat diet (CCHF). We demonstrated that CCHF impaired intestinal barrier function and increased translocation of endotoxin, initiating TLR/MyD88-dependent inflammation in Cox2-KO but not WT mice. Cox2-MKO increased proinflammatory mediators in LPS-activated macrophages, and in the intestinal tissue and plasma upon CCHF challenge. Cox2-MKO also reduced inflammation resolving lipoxin A4 (LXA4) in intestinal tissue, whereas administration of an LXA4 analog rescued disease in Cox2-MKO mice fed CCHF. The apolipoprotein A-I (APOA1) mimetic 4F mitigated disease in both the Cox2-MKO/CCHF and piroxicam-accelerated Il10–/– models of inflammatory bowel disease (IBD) and reduced elevated levels of proinflammatory mediators in tissue and plasma. APOA1 mimetic Tg6F therapy was also effective in reducing intestinal inflammation in the Cox2-MKO/CCHF model. We further demonstrated that APOA1 mimetic peptides (a) inhibited LPS and oxidized 1-palmitoyl-2-arachidonoyl-sn-phosphatidylcholine–dependent (oxPAPC-dependent) proinflammatory responses in human macrophages and intestinal epithelium, and (b) directly cleared proinflammatory lipids from mouse intestinal tissue and plasma. Our results support a causal role for proinflammatory and inflammation-resolving lipids in IBD pathology and a translational potential for APOA1 mimetic peptides for the treatment of IBD.
PF331 COST‐EFFECTIVENESS OF EMICIZUMAB VERSUS BY‐PASSING AGENTS IN PATIENTS WITH HAEMOPHILIA A AND FVIII INHIBITORS IN FRANCE
Authors: B. Polack, M. Trossaert, C. Godard, M. Cousin, S. Baffert, A. Pruvot, J.‐M. Pinguet
Journal: HemaSphere (2019)

Background: The development of an anti‐FVIII inhibitor is the most serious complication of haemophilia A. On February 23, 2018, Emicizumab obtained a European Marketing Authorization for the prevention of bleeding episodes in patients with haemophilia A who developed an anti‐FVIII inhibitor. In France, emicizumab is reimbursed by National Insurance since February 7 th 2019. As part of its inscription on the list of products reimbursed by French National Health Insurance, emicizumab has been evaluated by health authorities (HAS): The Transparency Committee granted a major added medical benefit (ASMR II), and a medico‐economic analysis was evaluated by the Health Economic and Public Health Committee. Aims: The purpose of this analysis is to evaluate the Incremental Cost‐Effectiveness Ratio (ICER) of emicizumab compared to the current management by Bypassing Agents (BPA) taking into account the final price that has just being published. Methods: The analysis is based on a Markov model with two health states (alive, dead) over a 5‐year time horizon. Emicizumab is compared with current BPA management (aPCC and rFVIIa) in prophylaxis or on‐demand, according to their real‐life use in the FranceCoag Network cohort (RFC). The ICER is expressed in euros per QALY (Quality‐Adjusted Life Year). Bleeding rates are derived from the HAVEN 1 clinical trial for emicizumab and BPA on‐demand, and an indirect comparison for BPA prophylaxis. Quality of life data are derived from the HAVEN 1 trial. The costs of treatment acquisition, adverse events and hospitalizations were taken into account. Deterministic and probabilistic sensitivity analyzes were performed to evaluate the uncertainty around the result. Results: Emicizumab prophylaxis is a dominant strategy, in children and adult patients: it is more effective and less costly than the current BPA strategy. Over 5 years, the mean total cost per patient was 2,3 M€ in patients treated with emicizumab, versus 2,7 M€ with BPA, associated to 3,3 and 2,4 QALYs respectively. Thus, emicizumab brings 0,9 additional QALYs per patients for a saving of almost 426 000€. Exploration of uncertainty does not alter these results. Summary/Conclusion: The health economic analysis shows the cost‐effectiveness of emicizumab versus BPA in France. The methodology used was accepted by the CEESP in its Opinion of October 9, 2018. The limitations of this analysis are mainly based on the lack of data to model the consequences of the reduction of bleeding on the long‐term evolution of arthropathy and disability.
Use of nanocurcumin to inhibit proliferation and metastases of hepatocellular carcinoma via NF-κB mediated matrix metalloproteinase-9 downregulation.
Authors: Yang Xu, Bo Hu, Robert Anders, Anirban Maitra, Jia Fan
Journal: Journal of Clinical Oncology (2013)

e22103 Background: Curcumin regulates the expression and secretion of MMPs, and has potent anti-cancer properties in several human cancer cell lines and animal carcinogenesis models. In this study we try to investigate the effects of polymeric nanoparticle encapsulated formulation of curcumin– nanocurcumin (NC) on Hepatocellular carcinoma (HCC) in vitro and in vivo. Methods: The effects of NC alone and in combination with sorafenib (SO) were investigated on HCC cell lines, Huh7 and MHCCLM3 in vitro by using proliferation and invasion assay, western blot, qRT-PCR, enzyme-linked immunosorbent assay and immunohistochemistry staining, and the subcutaneous and orthotopic HCC xenograft nude mice models (MHCCLM3) were used to evaluate primary tumor growth and metastasis after treatments. Results: NC alone (or combined with SO)inhibited HCC cell proliferation (p&lt;0.05) and invasion in vitro (p&lt;0.01), and remarkably decreased both the subcutaneous and orthotopic primary tumor growth and lung metastases in vivo. NC and/or SO could down-regulating the expressions of Matrix Metalloproteinase-9 (MMP9), p-ERK1 and NF-kB/p65 (p&lt;0.05). Conclusions: NC showed potent anti-invasion and metastasis properties in HCC via NF-κB mediated MMP9 down-regulation, which may provide a new strategy to the treatment of HCC patients and prevention of tumor recurrence after operation.
Abstract 238: Ability to Activate the Eicosanoid and Polyunsaturated Fatty Acid Pathways Predicts Survival After Cardiac Arrest
Authors: Mary Ann Peberdy, Dayanjan S Wijesinghe, Joseph P Ornato, Leroy R Thacker, Clifton W Callaway, Jon C Rittenberger, Michael W Donnino, Michael N Cocchi, David F Gaieski, Benjamin S Abella, Charles E Chalfant
Journal: Circulation (2013)

Background: Cardiac arrest (CA) and ROSC are associated with profound oxidative stress and systemic inflammation which is, in part, modulated by eicosanoid pathways. Docosahexaenoic acid (DHA) has anti-inflammatory properties, reduces cytokines, and is the precursor for D-resolvins and protectins which actively resolve inflammation. 5-Hydroxyeicosatetraenoic acid (5-HETE) is produced by the oxidation of arachadonic acid and is considered a “biomarker” of the inflammatory status of the body. It is linked to outcomes in trauma and sepsis. Hypothesis: DHA and 5-HETE levels after ROSC will be associated with outcome after CA Methods: Ninety-two pts from the 4 center Characterization of Mitochondrial Injury After Cardiac Arrest (COMICA) study had serial plasma samples analyzed for DHA and 5-HETE by mass spectroscopy at Time 0 (T0) upon arrival to the hospital, and 12, 24, 36, and 48 hours post ROSC. A repeated measures ANOVA was fit with a between subjects factor (Group: Survived, Expired), a within subjects factor (Time: 0, 12, 24, 38, 48) and the interaction between these two factors. Values are presented as mean ± SEM. Results: The figure shows the relationship between 5-HETE and DHA, respectively, vs. time in pts who survived and died. There was a significant Group x Time interaction for both DHA and 5HETE (p=0.0055 and p=0.0016). Post-Hoc tests revealed that the T0 5HETE level was significantly higher in those who survived vs. expired (p = 0.0003). There was a strong trend (p=0.058) for the T0 DHA level to be higher in survivors. Conclusions: Non-survivors have lower levels of 5-HETE and DHA than survivors immediately following hospital admission after ROSC from CA. Severe oxidative stress may deplete the lipid precursor pool. Survivors appear to have an intact polyunsaturated fatty acid system that is associated with recovery. Lipid biomarkers may serve as an early marker of outcome and potential area for therapeutic intervention after CA.
PF612 ONCE‐WEEKLY (70 MG/M2) VERSUS TWICE‐WEEKLY (56 MG/M2) DOSING OF CARFILZOMIB FOR PATIENTS WITH RELAPSED AND/OR REFRACTORY MULTIPLE MYELOMA
Authors: P. Moreau, A.K. Stewart, M.‐A. Dimopoulos, D. Siegel, T. Facon, J. Berenson, N. Raje, J.G. Berdeja, R.Z. Orlowski, H. Yang, H. Ma, Z. Klippel, A. Zahlten‐Kumeli, K. Mezzi, K. Iskander, M.‐V. Mateos
Journal: HemaSphere (2019)

Background: Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m 2 (Kd70 QW) or twice‐weekly at 56 mg/m 2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW. Aims: We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials. Methods: Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW. Results: Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69). Summary/Conclusion: This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56. © 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.
Localizing and Classifying Adaptive Targets with Trend Filtered Regression
Authors: Mehreen R Mughal, Michael DeGiorgio
Journal: Molecular Biology and Evolution (2018)

Identifying genomic locations of natural selection from sequence data is an ongoing challenge in population genetics. Current methods utilizing information combined from several summary statistics typically assume no correlation of summary statistics regardless of the genomic location from which they are calculated. However, due to linkage disequilibrium, summary statistics calculated at nearby genomic positions are highly correlated. We introduce an approach termed Trendsetter that accounts for the similarity of statistics calculated from adjacent genomic regions through trend filtering, while reducing the effects of multicollinearity through regularization. Our penalized regression framework has high power to detect sweeps, is capable of classifying sweep regions as either hard or soft, and can be applied to other selection scenarios as well. We find that Trendsetter is robust to both extensive missing data and strong background selection, and has comparable power to similar current approaches. Moreover, the model learned by Trendsetter can be viewed as a set of curves modeling the spatial distribution of summary statistics in the genome. Application to human genomic data revealed positively selected regions previously discovered such as LCT in Europeans and EDAR in East Asians. We also identified a number of novel candidates and show that populations with greater relatedness share more sweep signals.