tbuckley/cabot-search huggingface dataset:
PS1145 TARGETED ACTIVATION OF THE PROTEIN PHOSPHATASES SHP-1 AND PP2A ABROGATES CONSTITUTIVE ACTIVATION OF SURVIVAL PATHWAYS IN LARGE GRANULAR LYMPHOCYTE LEUKEMIA (LGLL)
Authors: M.A. Pagano, E. Tibaldi, A.M. Brunati, G. Calabretto, A. Teramo, G. Zagotto, G. Ribaudo, V.R. Gasperini, V. Trimarco, C. Vicenzetto, G. Barilà, M. Facco, G. Semenzato, R. Zambello
Journal: HemaSphere (2019)

Background: Interleukin-1 receptor-associated kinase 4 (IRAK4) plays a critical role in Toll-like receptor (TLR) signal transduction and innate immune responses. Recruitment and subsequent activation of IRAK4 upon TLR stimulation is mediated by the myeloid differentiation primary response 88 (MYD88) adaptor protein. Around 3% of chronic lymphocytic leukemia (CLL) patients have activating mutations of MYD88, a driver mutation in this disease. Aims: Here, we studied the effects of TLR activation and the pharmacological inhibition of IRAK4 with ND2158, an IRAK4 competitive inhibitor, as a therapeutic approach in CLL. Methods: TLR stimulation was performed with an agonist mix of Pam3CSK4, HKLM, FSL1 and ODN2006. Cytokine secretion and CLL proliferation were assessed by Luminex system and carboxyfluorescein succinimidyl ester staining, respectively. For in vivo studies, the Eμ-TCL1 adoptive transfer mouse model was used. Results: Our in vitro studies demonstrated that ND2158 preferentially killed CLL cells in a dose-dependent manner. We further observed a decrease in NF-κB and STAT3 signaling, cytokine secretion, proliferation and migration of primary CLL cells from MYD88-mutated and –unmutated cases. In the Eμ-TCL1 adoptive transfer mouse model of CLL, ND2158 delayed tumor progression and modulated the activity of myeloid and T cells. Summary/Conclusion: Our findings show the importance of TLR signaling in CLL development and suggest IRAK4 as a therapeutic target for this disease.
OP0085 CAN WE AVOID THE LOSS OF BONE MINERAL DENSITY ONE YEAR AFTER DENOSUMAB DISCONTINUATION? THE REOLAUS BONE PROJECT
Authors: Bérengère Aubry-Rozier, Giovanni Liebich, Delphine Stoll, Elena Gonzalez-Rodriguez, Didier Hans, Olivier Lamy
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Denosumab discontinuation (DD) induces bone turnover markers (BTMs) increase, bone mineral density (BMD) decrease, and increased risk of spontaneous vertebral fractures. Prescribing a bisphosphonate after DD could avoid this rebound effect. <h3>Objectives</h3> The objective of the ReoLaus (Rebound Effect Observatory in Lausanne) Bone Project is to follow bone parameters after DD. We report the determinants associated to BMD loss 1 year after DD. <h3>Methods</h3> 170 patients are followed in ReoLaus. Patients with a BMD follow-up &gt; 1 year after DD with a standardized management were included. We defined as significant a lumbar spine BMD loss (Loosers group) over 3.96% at one year after DD as compared with values at the end of the denosumab treatment 18 months after last injection. <h3>Results</h3> 71 post-menopausal women stopped denosumab after 7.7±2.2 injections: age 63.8±8.1 years, BMI 23.8±4.5, 0.96 prevalent fractures/patient, 8.45% previously exposed to corticoids, 22.54% to anti-aromatases. 17.25 months after last denosumab injection 30 patients were classified as Loosers and 41 as Stable. At denosumab introduction Loosers were younger (61.4±7.3 vs 65.5±8.2 years, p=0.034) with higher sCTX level (644.7 vs. 474.1 ng/ml, p=0.005). The rate of BP given less than 2 years before denosumab was not different, but none of the Loosers had received zoledronate vs. 12% of the Stable (p=0.047). Other pre-denosumab characteristics were not different. Number of denosumab injections, BTMs and BMD values were comparable in both groups during denosumab treatment. First BTMs values measured 7.5 months (median) after last denosumab injection and before bisphosphonates were not different (sCTX: Loosers, 592 ng/ml; Stable, 379 ng/ml, p=0.06). At DD 59% received zoledronate, 24% alendronate, 3% others, and 14% nothing (p=0.39 between groups). BTMs 12.8 months post-BP were higher in Loosers as compared to Stable (sCTX 537 vs. 336 ng/ml, p=0.009). Incidence of new fractures was low (0.18/patient) without between group's difference. <h3>Conclusion</h3> In our sub-cohort, being younger, having high BMTs and not having received zoledronate before denosumab introduction increases the risk of a BMD loss, even if a bisphosphonate is prescribed at DD. Our results support the use of denosumab after a bisphosphonate to restrain the BMD loss at its discontinuation. <h3>Disclosure of Interests</h3> Bérengère Aubry-Rozier Speakers bureau: Lilly Pfizer Amgen Novartis, Giovanni Liebich: None declared, Delphine Stoll: None declared, Elena Gonzalez-Rodriguez: None declared, Didier Hans Shareholder of: co owner of TBS, medimaps group, Speakers bureau: Amgen Lilly, Olivier Lamy Speakers bureau: Amgen Lilly
AB1147 VERTEBRAL FRACTURE ASSESSMENT : A SIMPLE TOOL TO DETECT VERTEBRAL FRACTURE IN THE OSTEOPOROSIS ASSESSMENT OF PATIENTS WITH TYPE2 DIABETES MELLITUS
Authors: Nassima Hanouchine, Salah Ouhadj, Chafia Dahou-Makhloufi
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Vertebral fracture assessment ( VFA) has several benefits, including substantially lower radiation dose, lower cost, higher patient convenience, and less operator-dependent variance,VFA can be directly assessed during bone mineral density ( BMD) measurement Objectives: evaluate the accuracy of VFA performed in the supine position by using conventional visual radiography of the spine as the reference standard in patients with type 2 diabetes mellitus <h3>Methods</h3> A total of 207 patients with type 2 diabetes mellitus (mean age, 46,59 ±7,53years; range, 21–60 years) consisting of 102 women and 105 men,who were suspected of having osteoporosis and who underwent VFA in the supine position and radiography of the spine were evaluated. VFA was analyzed by using a six-marker point method to describe the shape and deformity of each vertebra. Visual radiography of the lateral spine was performed by an experienced radiologist. The agreement between VFA and visual radiography, was assessed by using weighted ƙ statistics. <h3>Results</h3> Visual radiography helped identify 51 (24.6%) patients with at least one vertebral fracture versus 49(23,67%) with VFA. Most fractures were present in T7, T12, and L1. Excellent agreement was found between VFA and visual radiography, with 97. 3% concordance and ƙ 0.89. Sensitivity, specificity, and positive and negative predictive values calculated by lesion level for VFA compared with visual assessment were 90.2%, 98.08%, 93.88%, and 96.84%, respectively. <h3>Conclusion</h3> VFA performed with patients with type 2 diabetes, in the supine position, is an accurate method to help detect vertebral fractures when compared with conventional spine radiography. VFA permits combination of fracture assessment with bone mineral density measurement in a single session <h3>References</h3> [1] -Jacobs-Kosmin D, Sandorfi N, Murray H, Abruzzo JL. Vertebral deformities identified by vertebral fracture assessment: associations with clinical characteristics and bone mineral density. J Clin Densitom 2005;8: 267–272. [2] -Binkley N, Krueger D, Gangnon R, Genant HK, Drezner MK. Lateral vertebral assessment: a valuable technique to detect clinically significant vertebral fractures. Osteoporos Int 2005;16:1513–1518. [3] -Schousboe JT, DeBold CR. Reliability and accuracy of vertebral fracture assessment with densitometry compared to radiography in clinical practice. Osteoporos Int 2006;17: 281–289 <h3>Disclosure of Interests</h3> None declared
Identification of Latrophilin-2 as a Novel Cell-Surface Marker for the Cardiomyogenic Lineage and Its Functional Significance in Heart Development
Authors: Choon-Soo Lee, Hyun-Jai Cho, Jin-Woo Lee, Jaewon Lee, Yoo-Wook Kwon, Taekwon Son, Hanseul Park, Jongpil Kim, Hyo-Soo Kim
Journal: Circulation (2019)
SP0173 CASE 2 DISCUSSANT: IMMUNOSUPPRESSION OR ANTIBIOTICS – WHEN TO CHOOSE WHAT?
Authors: Christopher Denton
Journal: Annals of the Rheumatic Diseases (2019)

<h3></h3> Gastrointestinal tract involvement is almost universal in systemic sclerosis but in most patients is relatively mild with symptoms of gastro-oesophageal dysmotility and reflux or lower bowel symptoms of constipation. A minority of cases have severe involvement, and this can be life-threatening. The key issues related to severe disease are attacks of pseudo-obstruction with complications such as pneumatosis coli and perforation of infection. Additional issues include malnutrition and intestinal failure that may require long term home parenteral supplementation. Finally, the most severe lower tract involvement can result in intractable diarrhoea, persistent anorectal incompetence and complications of severe chronic constipation such as sigmoid volvulus. Management is challenging and requires interaction with gastroenterology and nutritional expert colleagues. Some newer approaches that have been beneficial include long term intravenous immunoglobulin therapy although in general response to immunosuppression are relatively modest. This discussion will focus on treatment with immunomodulation and use of antibiotic therapy to treat small intestinal bacterial overgrowth and also to manage other infective problems and the potential impact on intestinal dysbiosis. <h3>Disclosure of Interests:</h3> Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer
SP0087 TREATMENT: HOW TO IMPLEMENT IT AND HOW TO MONITOR ADHERENCE?
Authors: Kassim Javaid Muhammad
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> The key to achieving the benefits of an FLS on the population and the patient level is to ensure enough high-risk patients are initiated and then adhere to therapy. There is a low rate of primary and secondary adherence by patients with osteoporosis. Treatment initiation requires co-developed decision making with patients and clinicians balancing locally agreed intervention thresholds with effective and efficient risk and treatment communication. Treatment adherence depends on patient, treatment and healthcare service characteristics. <h3>Objectives:</h3> Describe the current status of treatment recommendation in the UK Describe the current methods for imrpoving adherence globally <h3>Methods:</h3> Review of the data from the UK Fracture Liaison Service Database and IOF Capture the Fracture audits. <h3>Disclosure of Interests:</h3> Kassim Javaid Muhammad Shareholder of: Zebra Medical Vision, Grant/research support from: Amgen, Kyowa Kirin Hakin, Consultant for: Amgen, Internis, Consilient Health,Mereo Biopharma, Kyowa Kirin Hakin, UCB, Speakers bureau: Amgen, Lilly UK, Internis, UCB
AB0360E SLEEP DISORDER OR DEPRESSION IN KOREAN RHEUMATOID ARTHRITIS, AND ITS ASSOCIATION WITH DISEASE ACTIVITY
Authors: Kyeong Mon Son, Seoung Hun Kang, Young Il Seo, Hyun Ah Kim
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Rheumatoid arthritis is a chronic autoimmune disease. Psychological stress and mood disorders such as sleep disorder or depression are more frequent in patient with RA. <h3>Objectives</h3> The aim of this study was to evaluate the relationship between disease activities and sleep disorder or depression in Korean patients with RA. <h3>Methods</h3> The study enrolled 334 patients with RA who visited Hallym University Sacred Heart Hospital (South Korea). The diagnosis of insomnia and depression is based in patient questionnaire such as Pittsburg sleep quality index (PSQI) and Beck depression inventory (BDI). Insomnia was defined as PSQI&gt;5 and depression was defined as BDI ≥13. Patients were divided into two groups (insomnia vs no-insomnia, depression vs no-depression) and the clinical aspects were compared by Mann-Whitney U-test. Age, gender, erythrocyte sedimentation rate (ESR), 28 joint disease activity score (DAS28), DAS28-P score (the subjective components of the DAS28 relative to the total components), tender joint count (TJC) and swollen joint count (SJC), quality of life measured with health assessment questionnaire (HAQ) were analyzed. <h3>Results</h3> The median (inter-quartile range) disease duration was 6 (4–9) years and the mean DAS28 score was 3.6±1.1. Seventy percent of the patient had insomnia and 8% had depression. Compared with patients without insomnia, insomnia patients had a higher DAS28 (3.7±1.16 <i>vs</i>. 3.21±1.0, <i>P</i>&lt;0.001), higher pain DAS28-P (0.37±0.17 <i>vs</i>. 0.32±0.16, <i>P</i>=0.004), higher TJC (4.63±5.68 <i>vs</i>. 2.38±3.45, <i>P</i>&lt;0.001) and higher HAQ score (0.49±0.53 vs 0.18±0.36,<i> P</i>&lt;0.001). Compared with no depression patients, depression patients had a higher DAS28 (4.07±1.37 <i>vs</i>. 3.51±1.11, <i>P</i>&lt;0.001), higher pain DAS28-P (0.44±0.17 <i>vs</i>. 0.35±0.44, <i>P</i>=0.015), higher TJC (6.59±6.57 <i>vs</i>. 3.71±5.02, <i>P</i>=0.006), higher SJC(1.81±5.2 <i>vs</i>. 0.67±1.28, <i>P</i>=0.003), and higher HAQ score(0.63±0.51 vs 0.38±0.5,<i> P</i>=0.021). On univariable logistic regression analysis, insomnia was positively associated with age, DAS28, DAS28-P and BDI score. After adjustment, insomnia was positively associated with sex (female), age, BDI and DAS28 score. On univariable logistic regression analysis, depression was positively associated with PSQI, DAS28 and DAS28-P score. After adjustment, depression was positively associated with PSQI and DAS28-P score. <h3>Conclusion</h3> Rheumatoid arthritis patient with the sleep disorder or depression had worse clinical symptoms than those without. Rheumatologist should take sleep disorder or depression into consideration on evaluation of disease severity in RA patients. <h3>Disclosure of Interests</h3> None declared
PB1807 RESULTS OF TREATMENT BY REGIMENS R‐MPV/TBC FOR PATIENTS WITH PRIMARY CNS LYMPHOMA
Authors: E. Zvonkov, D. Koroleva, N. Gabeeva, A. Smolyaninova, O. Gavrilina, O. Shchetsova, A. Gubkin, A. Kovrigina, G. Galstyan, G. Klyasova, T. Savenko, E. Parovichnikova, V. Savchenko
Journal: HemaSphere (2019)

Background: High‐dose MTX‐containing chemotherapy and autologous stem sell transplantation (HDC‐ASCT) is a potentially curable options for patients with primary central nervous system lymphoma (PCNCL). In our prospective study, pts with newly diagnosed PCNSL were treated with R‐MPV (rituximab, methotrexate, vincristine and procarbazine) chemotherapy, followed by consolidation HDC‐ASCT with TBC (thiotepa, busulfan and cyclophosphamide). After completion of therapy all pts reseived maintenance treatment with temozolomide every 3 months for a total of 2 years. Aims: To assess the efficacy and safety of regimens R‐MPV/TBC for patients with PCNSL. Methods: A total 19 pts were enrolled in prospective study between 2015 to 2019 years. The median age was 43 years (range, 20 to 62 years), with a total of 2 (10%) ≥ 60 years of age. Male:female = 13:7. In four pts (21%) the ECOG status was ≥ 2. The MSKCC prognostic class was as follows: 17 pts (91%), class 1; 2 pts (9%), class 2; 0 pts, class 3. Results: Following 3‐5 R‐MPV cycles 16 pts were in CR and 3 pts in PR. All pts were undegro stem‐sell harvest after the second cycle. All pts eventually received HDC‐ASCT with TBC. Treatment‐related mortality was 0%. All pts achieved haemotopoietic regeneration: the median times neutrophil and platelet recovery were 9 and 14 days, respectively. Seventeen pts are alive and well in complete remission at a median follow‐up of 12 months (range 1‐40). Two pts with progressive disease (+6 months) went on to received second‐line treatment: both had received chemotherapy and WBRT. Summary/Conclusion: Regimens R‐MPV/TBC was associated with favorable safety and high preliminary efficacy.
Abstract 3124: Skeletonized Internal Thoracic Artery Harvest Reduces Pain And Dysesthesia And Improves Sternal Perfusion Following Coronary Artery Bypass Surgery: A Randomized, Double-Blinded, Within-Patient Comparison
Authors: Munir Boodhwani, B. Khanh Lam, Howard J Nathan, Thierry G Mesana, Marc Ruel, Wanzhen Zeng, Frank W Sellke, Fraser D Rubens
Journal: Circulation (2006)

Background Observational studies suggest that skeletonization of the internal thoracic artery (ITA) can improve conduit flow and length, reduce deep sternal infections and post-operative pain. We p...
No evidence for phylostratigraphic bias impacting inferences on patterns of gene emergence and evolution
Authors: Tomislav Domazet-Lošo, Anne-Ruxandra Carvunis, M. Mar Albà, Martin Sebastijan Šestak, Robert Bakarić, Rafik Neme, Diethard Tautz
Journal: Molecular Biology and Evolution (2016)

Phylostratigraphy is a computational framework for dating the emergence of DNA and protein sequences in a phylogeny. It has been extensively applied to make inferences on patterns of genome evolution, including patterns of disease gene evolution, ontogeny and de novo gene origination. Phylostratigraphy typically relies on BLAST searches along a species tree, but new simulation studies have raised concerns about the ability of BLAST to detect remote homologues and its impact on phylostratigraphic inferences. Here, we re-assessed these simulations. We found that, even with a possible overall BLAST false negative rate between 11-15%, the large majority of sequences assigned to a recent evolutionary origin by phylostratigraphy is unaffected by technical concerns about BLAST. Where the results of the simulations did cast doubt on previously reported findings, we repeated the original analyses but now excluded all questionable sequences. The originally described patterns remained essentially unchanged. These new analyses strongly support phylostratigraphic inferences, including: genes that emerged after the origin of eukaryotes are more likely to be expressed in the ectoderm than in the endoderm or mesoderm in Drosophila, and the de novo emergence of protein-coding genes from non-genic sequences occurs through proto-gene intermediates in yeast. We conclude that BLAST is an appropriate and sufficiently sensitive tool in phylostratigraphic analysis that does not appear to introduce significant biases into evolutionary pattern inferences.
Targeting Glutamine Metabolism and Redox State for Leukemia Therapy
Authors: Mark A. Gregory, Travis Nemkov, Hae J. Park, Vadym Zaberezhnyy, Sarah Gehrke, Biniam Adane, Craig T. Jordan, Kirk C. Hansen, Angelo D’Alessandro, James DeGregori
Journal: Clinical Cancer Research (2019)

Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically.AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized.We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells in vitro and in vivo.Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.
Being obese before conception triples odds of obese or overweight offspring, review finds
Authors: Susan Mayor
Journal: BMJ (2019)

Women who are obese before becoming pregnant have more than three times the odds of having obese or overweight offspring when compared with women of a healthy weight, a systematic review and meta-analysis has found.1

“This research has identified the need for early intervention in the prevention of childhood obesity, starting before conception,” said the study authors, led by Nicola Heslehurst of Newcastle University, …
Abstract 17904: Deficiency of Yes-associated Protein Promotes Cardiac Dysfunction in Response to Pressure Overload in the Mouse Heart
Authors: Jaemin Byun, Dominic P Del Re, Peiyong Zhai, Akihiro Shirakabe, Junichi Sadoshima
Journal: Circulation (2015)

Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, plays an important role in regulating cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiomyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, it remains unclear whether YAP mediates hypertrophy of individual CMs under stress conditions in vivo. We hypothesized that endogenous YAP plays an essential role in mediating hypertrophy and survival of CMs in response to pressure overload (PO). Three-month-old YAP+/fl;α-MHC-Cre (YAP-cKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). Two weeks later, YAP-cKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.27±0.38, 6.93±0.29) compared to sham (5.08±0.14, 4.07±0.33). LV CM cross sectional area was similarly increased by TAC in YAP-cKO and control mice compared to their respective shams. Induction of fetal-type genes, such as Anf and Myh7, was also similar in YAP-cKO and control mice. YAP-cKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 75, 76%). YAP-cKO mice had significantly decreased LV function after TAC compared to Sham-control mice (EF: 51%, 76%, p&lt;0.05) and TAC-control mice (75%, p&lt;0.05). LV end diastolic pressure (LVEDP, mmHg) was significantly increased (19.3 ±3.2, 9.8±1.6, p&lt;0.05), and LV +dP/dt (mmHg/s, 7250±588, 9500±453, p&lt;0.01) and -dP/dt (mmHg/s, 6000±433, 7781± 314, p&lt;0.05) were significantly decreased in YAP-cKO compared to in control mice after TAC. LV end diastolic diameter (mm) was significantly greater in YAP-cKO than in control mice after TAC (3.95±0.11, 3.35±0.15, p&lt;0.05), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cKO compared to in control mice. Since cardiac hypertrophy in YAP-cKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.