tbuckley/cabot-search huggingface dataset:
PB1661 CHARACTERIZATION OF A DUX4‐IGH INHIBITOR AS A POSSIBLE TREATMENT FOR ACUTE LYMPHOBLASTIC LEUKEMIA
Authors: M. Salome’, C. Caronni, V. Runfola, R. Giambruno, D. Campolungo, C. Ghirardi, D. Gabellini
Journal: HemaSphere (2019)

Background: B cell acute lymphoblastic leukemia (B‐ALL) is the most common pediatric cancer and the major cause of cancer‐related death before the age of 20. In up to 7% of cases, the disease is caused by rearrangements of the Double Homeobox 4 ( DUX4 ) transcription factor to the immunoglobulin heavy chain (IGH) locus, giving rise to the oncogenic fusion protein DUX4‐IGH. While ectopic expression of wild type DUX4 induces apoptosis, DUX4‐IGH has transforming ability in cellular and animal models. These opposite biological activities are mirrored by the ability of DUX4 and DUX4‐IGH to drive the transcription of non‐overlapping sets of target genes, despite the two proteins share the same DNA binding domain (dbd). Aims: Through proteomics, we identified a specific DUX4‐IGH inhibitor. Preliminary data indicate that the inhibitor directly binds to DUX4‐IGH dbd blocking the activation of target genes. Based on this evidence, I aim to test the antileukemic activity of the inhibitor. Methods: Human cell lines and primary murine bone barrow progenitor cells will be lentivirally transduced to induce the expression of DUX4‐IGH alone or in combination with its inhibitor, and the effects on proliferation, transformation, clonogenic potential and self‐renewal ability in B‐cell differentiation conditions will be evaluated. To test the efficacy of DUX4‐IGH inhibition in leukemia development, I will employ murine bone marrow transplantation assays and patient derived xenografts of DUX4‐IGH B‐ALL and assess disease latency in the presence or absence of the DUX4‐IGH inhibitor. Results: Preliminary data indicate that the activity of DUX4‐IGH is restricted to B‐cells, supporting the need of a B‐cell specific co‐factor. Importantly, lentiviral expression of the DUX4‐IGH inhibitor in NALM6 cells that carry a DUX4‐IGH translocation reduce the endogenous levels of DUX4‐IGH targets. I expect to see a significant inhibition of DUX4‐IGH driven transformation in the presence of its inhibitor, associated with reduced proliferation, clonogenic and self‐renewal potential in cell culture systems. I predict that the inhibitor will rescue differentiation potential and block or significantly delay leukemia development in mice injected with DUX4‐IGH expressing pro‐B cells. Summary/Conclusion: Pre‐clinical validation of the DUX4‐IGH inhibitor will help defining effective therapeutic strategies for DUX4‐IGH B‐ALL patients, improving clinical outcome and lowering treatment toxicity.
THU0549 SURGICAL MANAGEMENT IN JUVENILE IDIOPATHIC ARTHRITIS: A MONOCENTRIC EXPERIENCE OF 257 PROSTHESIS
Authors: Irene Pontikaki, Carolina Artusi, Marco DI Marco, Alessandro Sinelli, Martina Cornalba, Marcello Truzzi, Silvia De Martinis, Roberto Viganò
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Juvenile idiopathic arthritis (JIA) includes all forms of inflammatory arthritis, with onset before the 16<sup>th</sup> birthday, lasting more than 6 weeks. Although conservative management with nonsteroidal anti-inflammatory drugs and disease-modifying antirheumatic drugs can be effective, a significant number of young adults affected by JIA requires a major surgical procedure, including different types of prosthetic devices. <h3>Objectives</h3> This article presents a monocentric experience of an interdisciplinary team of rheumatologists and orthopedic surgeons for JIA and the outcome of patients subjected to prosthesis implantation. <h3>Methods</h3> Data were collected through a retrospective analysis of 583 patients attending to our transitional care center for JIA between 1999 and 2018, in the context of a once-week rheumatologic counseling with the orthopedic surgeons. Descriptive statistics were used to evaluate the baseline and follow-up data. <h3>Results</h3> On a total of 257 prosthesis implantations, 137 were total hip prosthesis, 101 total knee prosthesis and 19 total ankle prosthesis. The 10-year implant survival rate was 97%, with good results in term of function and comfort for the patients. Complications were observed in 9% of patients, including intraoperative fractures, periprosthetic joint infections and wound dehiscence. The majority of patients were treated with biologic therapy before surgery. <h3>Conclusion</h3> Prosthesis implantation in JIA patients is a complicated and difficult procedure, related to the management of the biologic therapy, the low quality of bone, the remarkable stiffness and deformity of the joints. Long-term results were good, even in patients with severe arthritis, showing drastic reduction of joint pain and an improvement of functionality. The risk of complications results to be modest compared to a great survival rate and a valid recovery of joint range of motion. The interdisciplinary team composed by rheumatologists and orthopedic surgeons for the all follow-up of these patients is a cornerstone to obtain the perfect schedule for prosthetic implantation. <h3>References</h3> [1] C. Mertelsmann-Voss et al. US Trends in Rates of Arthroplasty for Inflammatory Arthritis Including Rheumatoid Arthritis, Juvenile Idiopathic Arthritis, and Spondyloarthritis. Arthritis &amp; Rheumatology, June 2014. [2] M. P. Abdel et al. Surgical Management of the Juvenile Idiopathic Arthritis Patient with Multiple Joint Involvement. Orthopedic Clinics of North America, 2014-10-01. <h3>Disclosure of Interests</h3> None declared
PB1830 CLINICAL IMPACTS OF INFLAMMATORY MARKERS IN PATIENTS WITH LIMITED STAGE UPPER AERODIGESTIVE TRACT NK/T CELL LYMPHOMA
Authors: J.‐S. Chung, D.‐Y. Kim, M.‐K. Song, Y.‐D. Joo
Journal: HemaSphere (2019)

Background: In localized extranodal natural killer/T cell lymphoma (ENKTCL), traditional prognostic models had a limited prognostic value to predict survivals. Especially, clinical data is limited to find out what the most meaningful inflammatory marker among them is and determine whether the meaningful inflammatory marker would be useful to reinforce prognostic limitations of the traditional prognostic models in ENKTCL Aims: The present study was performed to find out the most meaningful factor among available inflammatory markers and to evaluate whether the inflammatory marker would improve predictive ability of traditional models in patients with limited stage UAT ENKTCL. Methods: We evaluated prognostic value of inflammatory makers in 157 patients with limited stage upper aerodigestive tract (UAT) ENKTCL. Diagnosis of ENKTCL was according to the presence of histologic findings and immunophenotypes such as CD3+, CD20‐, CD56+ and positive Epstein‐barr virus by fluorescence in situ hybridization. Statistical Analysis Chi‐square test or Fisher's exact test were used as appropriate to analyze categorical variables. Progression‐free survival (PFS) and overall survival (OS) were estimated using the Kaplan‐Meier method and the 2‐tailed log‐rank test. PFS was defined as the time between the beginning of salvage therapy until disease progression or death. Meanwhile, OS was defined as the time from the start of salvage therapy until death. Cox proportional hazard model was used to evaluate prognostic impacts of several prognostic factors. Hazard ratios (HRs) of prognostic factors were used to measure the differential risks of progression and death. Receiver operating characteristic (ROC) curves were prepared to estimate the accuracy of predicting the ideal cut‐off values of continuous variables. The statistical analysis was carried out with SPSS software version 18.0 (SPSS Inc., Chicago, IL, USA). A p‐value &lt; 0.05 was considered significant. Results: Among several inflammatory markers, mean platelet volume (MPV) was most meaningful predictive value for progression‐free survival (PFS) and overall survival (OS). Ideal cut‐off value of MPV was 8.8 in Receiver operating characteristic analysis. In univariate and multivariate analysis, only two factors such as low MPV (&lt; 8.8) (PFS, HR = 2.483, 95% CI = 1.182‐4.601, p = 0.009; OS, HR = 3.412, 95% CI = 1.949‐6.990, p = 0.008) and high international prognostic index (IPI) score (IPI ≥ 2) (PFS, HR = 3.339, 95% CI = 1.323‐8.430, p = 0.011; OS, HR = 3.317, 95% CI = 1.046‐6.892, p = 0.010) were significantly associated with both PFS and OS. interestingly, the MPV value could significantly subdivide low IPI score group (PFS, p = 0.006; OS, p = 0.021). Summary/Conclusion: We found that Low MPV and high IPI can significantly predict poor prognosis in localized ENKTCL. image
Cost-effectiveness of Shared Telemedicine Appointments in Young Adults With T1D: CoYoT1 Trial
Authors: Wen Wan, Aviva G. Nathan, M. Reza Skandari, Parmida Zarei, Mark W. Reid, Jennifer K. Raymond, Elbert S. Huang
Journal: Diabetes Care (2019)

OBJECTIVE Young adults with type 1 diabetes (T1D) often struggle to achieve glycemic control and maintain routine clinic visits. We aimed to evaluate the societal cost-effectiveness of the Colorado young adults with T1D (CoYoT1) Clinic, an innovative care model of shared medical appointments through home telehealth. RESEARCH DESIGN AND METHODS Patients self-selected into the CoYoT1 (N = 42) or usual care (N = 39) groups. RESULTS Within the trial, we found no significant differences in 9-month quality-adjusted life; however, the control group had a larger decline from baseline in utility than the CoYoT1 group, indicating a quality of life (QoL) benefit of the intervention (difference in difference mean ± SD: 0.04 ± 0.09; P = 0.03). There was no significant difference in total costs. The CoYoT1 group had more study-related visits but fewer nonstudy office visits and hospitalizations. CONCLUSIONS The CoYoT1 care model may help young adults with T1D maintain a higher QoL with no increase in costs.
Vaccine Reduces Pneumonia in Kenya
Authors: M.J. Friedrich
Journal: JAMA (2019)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Abstract 449: GRK2-S670A Mice Reveal Cardioprotection Post Ischemia-reperfusion
Authors: Priscila Y Sato, J K Chuprun, Christopher J Traynham, Anna Maria Lucchese, Ancai Yuan, Erhe Gao, Walter J Koch
Journal: Circulation Research (2016)

β-adrenergic receptors (βARs) are critical regulators of cardiac contractility whose function are drastically impaired during heart failure (HF). Activated βARs are regulated via phosphorylation by G-protein coupled receptor kinase-2 (GRK2) and subsequent interaction with β-arrestin. Numerous studies have shown that GRK2 is elevated in human HF and animal models demonstrate that it contributes to HF pathogenesis after ischemic injury (IR). Further, our lab has uncovered non-canonical actions of GRK2 that are involved in HF development. One such novel action of GRK2 is within mitochondria where we have shown increased GRK2 localization after oxidative stress. Our lab has shown that in the heart, phosphorylation of GRK2 via Map kinase at residue Ser670 promotes binding to Hsp90 and further enhances translocation of GRK2 to the mitochondria after oxidative stress such as ischemia. To determine the ultimate role of this pathway in the post-ischemic heart we have generated novel GRK2-S670A mice where all endogenous GRK2 cannot be phosphorylated at this residue. Baseline characterization of these mice along with their controls, show a minimal phenotype, however we have found significant differences post-IR. Compared to control mice (NLC), GRK2-S670A have significantly less infarction size 24 hrs after IR and echocardiography and hemodynamics revealed significantly improved cardiac function in GRK2-S670A mice post-IR. GRK2-S670A mice showed improved ejection fraction (52.83%+/- 2.826 S670A vs 42.38%+/- 1.603 NLC) and smaller infarcted areas (9.942%+/- 1.763 S670A vs 20.78%+/- 3.579 NLC) when compared to NLC mice. Further, we found that mitochondrial GRK2 protein levels were lower in the GRK2-S670A mice at the area at risk (0.1428+/-0.02485 S670A vs 0.2327+/- 0.023 NLC). Overall, our data suggest that phosphorylation at Ser670 of GRK2 might act as a “biological switch” in cardiomyocytes, where un-phosphorylated GRK2 is readily available in the cytoplasm to desensitize receptors such as βARs, but upon phosphorylation, GRK2 translocates to the mitochondria leading to detrimental effects including cell death. This mechanism suggests a novel way to develop pharmacological interventions to aid in the treatment of HF.
Contrasting Paternal and Maternal Genetic Histories of Thai and Lao Populations
Authors: Wibhu Kutanan, Jatupol Kampuansai, Metawee Srikummool, Andrea Brunelli, Silvia Ghirotto, Leonardo Arias, Enrico Macholdt, Alexander Hübner, Roland Schröder, Mark Stoneking
Journal: Molecular Biology and Evolution (2019)

The human demographic history of Mainland Southeast Asia (MSEA) has not been well studied; in particular, there have been very few sequence-based studies of variation in the male-specific portions of the Y chromosome (MSY). Here, we report new MSY sequences of ∼2.3 mB from 914 males and combine these with previous data for a total of 928 MSY sequences belonging to 59 populations from Thailand and Laos who speak languages belonging to three major Mainland Southeast Asia families: Austroasiatic, Tai-Kadai, and Sino-Tibetan. Among the 92 MSY haplogroups, two main MSY lineages (O1b1a1a* [O-M95*] and O2a* [O-M324*]) contribute substantially to the paternal genetic makeup of Thailand and Laos. We also analyze complete mitochondrial DNA genome sequences published previously from the same groups and find contrasting pattern of male and female genetic variation and demographic expansions, especially for the hill tribes, Mon, and some major Thai groups. In particular, we detect an effect of postmarital residence pattern on genetic diversity in patrilocal versus matrilocal groups. Additionally, both male and female demographic expansions were observed during the early Mesolithic (∼10 ka), with two later major male-specific expansions during the Neolithic period (∼4-5 ka) and the Bronze/Iron Age (∼2.0-2.5 ka). These two later expansions are characteristic of the modern Austroasiatic and Tai-Kadai groups, respectively, consistent with recent ancient DNA studies. We simulate MSY data based on three demographic models (continuous migration, demic diffusion, and cultural diffusion) of major Thai groups and find different results from mitochondrial DNA simulations, supporting contrasting male and female genetic histories.
AB0266 THREE NOVEL BIOMARKERS PRDICTING THE SHORT-TERM RESPONSE TO IFX + MTX + LEFTRIPLE THERAPY IN RA
Authors: Jian Chen, Mengshi Tang, Lichang Xu, LI Shu, XI Xie, fen li
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> For rheumatoid arthritis (RA), nearly one-third of patients still have poor response to biological agents. In addition, infliximab, methotrexate and leflunomide are the most widely used three drugs in the clinic, but there remains no unified and precise indicators capable to predict the clinical response to their combination therapy. <h3>Objectives</h3> The purpose of this experiment is to identify a protein biomarker panel for predicting the outcome of RA patients who have received a triple therapy combining of infliximab, methotrexate and leflunomide (IFX+MTX+LEF). <h3>Methods</h3> All incorporated RA patients with DAS28-CRP&gt;5.1 accepted IFX+MTX+LEF therapy. At 14th week, they were divided into good responder (GR), moderate responder (MR), and non-responder (NR) in accordance with the EULAR response criteria. After removal of the 14 high-abundance proteins, serum samples from patients (4 GR and 4 NR) at baseline and 14th week, and 4 healthy subjects (HS) were screened for candidate biomarkers via isobaric tags for relative and absolute quantification (iTRAQ). After an in-depth technical feasibility analysis, Parallel Reaction Monitoring (PRM) was performed in 20 RA patients and 20 HS for further validation <h3>Results</h3> A total of 590 proteins were identified by iTRAQ, and 51 proteins of which showed significant differences between NR and GR (Figure 1). PRM showed that levels of catalase, epididymal secretory protein Li 282, and hemoglobin subunit δ of the GR+MR group at baseline was higher than that of the NR group (Figure 1), and they were involved in the process of oxidative stress. <h3>Conclusion</h3> The RA patients with higher pre-treatment levels of the three proteins responded better to IFX+MTX+LEF triple therapy at 14th week; Inhibitor of oxidative stress might be a new therapeutic target of RA in the future. <h3>References</h3> [1] Tracey D, Klareskog L, Sasso E H, Salfeld J G and Tak P P. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther, 2008, 117(2):244-279. [2] Isaacs J D, Ferraccioli G. The need for personalised medicine for rheumatoid arthritis. Ann Rheum Dis, 2011, 70(1):4-7. <h3>Disclosure of Interests</h3> None declared
The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions
Authors: Yanli Wang, Fan Song, Bo Zhang, Lijun Zhang, Jie Xu, Da Kuang, Daofeng Li, Mayank N. K. Choudhary, Yun Li, Ming Hu, Ross Hardison, Ting Wang, Feng Yue
Journal: Genome biology (2018)

Here, we introduce the 3D Genome Browser, http://3dgenome.org , which allows users to conveniently explore both their own and over 300 publicly available chromatin interaction data of different types. We design a new binary data format for Hi-C data that reduces the file size by at least a magnitude and allows users to visualize chromatin interactions over millions of base pairs within seconds. Our browser provides multiple methods linking distal cis-regulatory elements with their potential target genes. Users can seamlessly integrate thousands of other omics data to gain a comprehensive view of both regulatory landscape and 3D genome structure.
S1642 DEVELOPMENT OF A CLINICAL PREDICTION RULE FOR VENOUS THROMBOEMBOLISM IN PATIENTS WITH ACUTE LEUKEMIA
Authors: F. Al-Ani, Y.P. Wang, A. Lazo-Langner
Journal: HemaSphere (2019)

Background: Risk factors for venous thromboembolism (VTE) in patients with solid tumors are well studied, however studies in patients with acute leukemia (AL) are lacking. Identifying risk factors for VTE in leukemia patients would help to develop tailored VTE prophylaxis or surveillance strategies. Aims: To develop a clinical prediction model for VTE in AL patients. Methods: We conducted a retrospective cohort study of adult patients diagnosed with acute myeloid leukemia and acute lymphoblastic leukemia diagnosed between June 2006 and June 2017 at a tertiary care center in Canada. Outcome of interest was occurrence of imaging-confirmed VTE including proximal upper and lower extremity deep vein thrombosis, pulmonary embolism or thrombosis of unusual sites, including cerebral and splanchnic. Participants were followed until VTE occurrence, death or last follow up. Groups’ characteristics were compared using chi-square, Fisher's exact, or Student's T-tests as appropriate. Potential predictors were evaluated using single variable logistic regression and confirmed with multiple variable logistic regression. The final risk score was derived based on weighed variables and compared using survival analysis. Internal validation was conducted using non-parametric bootstrapping. Results: A total of 501 leukemia patients (427 myeloid and 74 lymphoblastic; 260 males) were included. Venous thromboembolism occurred in 77(15.3%) patients (44 upper extremity DVT, 28 lower extremity DVT or PE, 5 cerebral vein thrombosis. Median time from AL diagnosis to VTE was 64 days (interquartile range 22–130). The cumulative incidence of VTE was 9.6% (n = 48) (95%CI: 7.30–12.47) at 3 months, 12.8% (n = 64) (95%CI: 10.13–15.98) at 6 months, and 14% (n = 71) (95%CI: 11.39–17.50) at 12 months from the AL diagnosis. Of a total of 20 potential predictors, 7 were included in the multi-variable model. The final prediction score that was derived and validated included: previous history of venous thromboembolism (3 points), lymphoblastic leukemia (2 points), and platelet count > 50 x 109/L at the time of diagnosis (1 point). The overall cumulative incidence of venous thromboembolism was 44% in the high risk group (≥ 3 points) versus 10.5% in the low risk group (0–2 points) and it was consistent at 3 (28.8% vs 6.3%), 6 (41.1% vs 7.9%), and 12 (42.5% vs 9.3%) months (Figure; Log-rank p < 0.001).Summary/Conclusion: We derived and internally validated a predictive score of venous thromboembolism risk in acute leukemia patients. FA-A is a fellow of the Canadian Venous Thromboembolism Clinical Trials and Outcomes Research (CanVECTOR) Network; ALL-L is an investigator of the CanVECTOR Network. This study was funded by the CanVECTOR Network which receives grant funding from the Canadian Institutes of Health Research (Funding Reference: CDT-142654).