tbuckley/cabot-search huggingface dataset:
THU0629 TREATMENT PATTERNS WITH DISEASE MODIFYING ANTI-RHEUMATIC DRUGS IN UNITED STATES VETERANS WITH NEWLY DIAGNOSED RHEUMATOID ARTHRITIS, PSORIATIC ARTHRITIS, OR ANKYLOSING SPONDYLITIS
Authors: Jessica A. Walsh, Shaobo Pei, Gopi Penmetsa, Brian Sauer, Vikas Patil, Jodi Walker, Jerry Clewell, Kevin Douglas, Daniel Clegg, Grant Cannon, Ahmad Halwani
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Delays in treatment for inflammatory arthritis (IA) are associated with unfavorable outcomes, including impaired quality of life, irreversible joint damage, and disability. <h3>Objectives</h3> To characterize treatment initiation patterns in patients with newly diagnosed rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). <h3>Methods</h3> Incident IA cases were identified between January 1, 2007 and December 31, 2015, in patients enrolled in the Veteran Health Administration, using International Classification of Diseases codes and natural language processing. Patterns of treatment initiation and non-treatment with disease modifying anti-rheumatic drugs (DMARDs) were assessed in the 12-month follow-up period after the incident diagnosis. <h3>Results</h3> The population consisted of 12, 118 IA patients (9,711 RA, 1,472 PsA, 935 AS), with 91.3% males and a mean age of 63.7. In total, 58.2% of patients initiated a DMARD within 12 months after diagnosis (RA 60.0%, PsA 64.3%, AS 29.6%) (Figure). A DMARD was dispensed ≤30 days after IA diagnosis in 41.2% of patients and ≤90 days in 50.0% of patients. Rheumatology specialty care was accessed during the study period, prior to DMARD dispensation, by 82.7% of patients exposed to a non-biologic DMARD and 90.0% of patients exposed to a biologic DMARD. The percentage of IA patients with DMARD exposure during the 12-month follow-up period increased from 48.8% in 2008 to 66.4% in 2015. <h3>Conclusion</h3> Approximately one-half of patients received treatment with a DMARD within 90 days after their initial IA diagnosis. DMARD treatment rates during the initial 12 months after diagnosis increased between 2007 and 2015, but non-treatment remained common, particularly in patients with AS. Timely access to a rheumatology provider is likely important for early DMARD treatment. <h3>References</h3> [1] Ng, et al. BMJ Open. 3:e002468. <h3>Disclosure of Interests</h3> Jessica A. Walsh Grant/research support from: Abbvie, Pfizer , Consultant for: Abbvie, Celgene, Lilly, Novartis , Shaobo Pei: None declared, Gopi Penmetsa: None declared, Brian Sauer Grant/research support from: Amgen, Vikas Patil: None declared, Jodi Walker Shareholder of: Abbvie, Employee of: Abbvie, Jerry Clewell Shareholder of: Abbvie, Employee of: Abbvie, Kevin Douglas Shareholder of: Abbvie, Employee of: Abbvie, Daniel Clegg Grant/research support from: Amgen grant, Grant Cannon Grant/research support from: Amgen Inc., Ahmad Halwani Grant/research support from: Bristol-Myers Squibb, Kyowa Hakko Kirin, Roche, Abbvie, Genentech, Immune Design, miRagen, Amgen, Seattle Genetics, Takeda, Pharmacyclics
Abstract MP091: Hypertension is Associated With Increased Risk of Adverse Clinical Outcomes in Women With Peripartum Cardiomyopathy
Authors: Tasnim F Imran, Donya Mohebali, Diana Lopez, Natalie Bello, Sandy Truong, Ersilia Defilippis, Lauren Gilstrap, Marc Semigran, J Michael Gaziano, Luc Djousse, Robb Kociol
Journal: Circulation (2017)

Background: Peripartum cardiomyopathy (PPCM) is a rare condition that carries a high morbidity and mortality among young women. Studies examining the association of modifiable risk factors such as hypertension with outcomes in this population are sparse. Methods: We conducted a multi-center retrospective study across three major centers (BWH, BIDMC, MGH) to identify subjects with PPCM using the following criteria: ejection fraction &lt; 40%, development of heart failure within the last month of pregnancy or within 5 months of delivery and no other identifiable cause of heart failure with reduced ejection fraction. We defined adverse clinical outcome as a composite of heart failure hospitalizations, need for extra-corporeal membrane oxygenation, ejection fraction &lt;35%, cardiac transplantation or death during the follow-up period. Results: In all, 237 women met criteria for PPCM across the three centers between April 1995 and November 2015. Participants had a median age of 33.1 years (IQR: 28.6-38.0), gravida 2.0, para 2.0, mean left ventricular ejection fraction at diagnosis of 30%; 25% had chronic hypertension and 14% had preeclampsia. After a median follow-up of 3.2 years (IQR: 1.0-7.8), 59 events occurred. In a logistic regression model adjusting for age, number of prior pregnancies and number of deliveries, women with preeclampsia had an OR of 1.34 (95% CI: 1.05-1.72), p=0.02 as compared to those without preeclampsia. A similar association was observed for hypertension (Table). In sensitivity analysis, the association between preeclampsia and adverse outcomes persisted for blacks and other races, but not for whites. Conclusion: Our study suggests that hypertension or preeclampsia at diagnosis is associated with increased risk of heart failure hospitalizations, need for extra-corporeal membrane oxygenation, poor left ventricular function recovery, cardiac transplantation and death on follow-up in women with PPCM. Clinicians should consider aggressive treatment of hypertension in women of childbearing age.
Apolipoprotein E4, inhibitory network dysfunction, and Alzheimer’s disease
Authors: Ramsey Najm, Emily A. Jones, Yadong Huang
Journal: Molecular Neurodegeneration (2019)

Apolipoprotein (apo) E4 is the major genetic risk factor for Alzheimer's disease (AD), increasing risk and decreasing age of disease onset. Many studies have demonstrated the detrimental effects of apoE4 in varying cellular contexts. However, the underlying mechanisms explaining how apoE4 leads to cognitive decline are not fully understood. Recently, the combination of human induced pluripotent stem cell (hiPSC) modeling of neurological diseases in vitro and electrophysiological studies in vivo have begun to unravel the intersection between apoE4, neuronal subtype dysfunction or loss, subsequent network deficits, and eventual cognitive decline. In this review, we provide an overview of the literature describing apoE4's detrimental effects in the central nervous system (CNS), specifically focusing on its contribution to neuronal subtype dysfunction or loss. We focus on γ-aminobutyric acid (GABA)-expressing interneurons in the hippocampus, which are selectively vulnerable to apoE4-mediated neurotoxicity. Additionally, we discuss the importance of the GABAergic inhibitory network to proper cognitive function and how dysfunction of this network manifests in AD. Finally, we examine how apoE4-mediated GABAergic interneuron loss can lead to inhibitory network deficits and how this deficit results in cognitive decline. We propose the following working model: Aging and/or stress induces neuronal expression of apoE. GABAergic interneurons are selectively vulnerable to intracellularly produced apoE4, through a tau dependent mechanism, which leads to their dysfunction and eventual death. In turn, GABAergic interneuron loss causes hyperexcitability and dysregulation of neural networks in the hippocampus and cortex. This dysfunction results in learning, memory, and other cognitive deficits that are the central features of AD.
Abstract 18150: Ventricular Arrhythmia During Post Cardiac Arrest Care: Prognostic Importance and Influence of Pre-hospital Defibrillation - A TTM Substudy
Authors: Jakob H Thomsen, Jesper Kjærgaard, Niklas Nielsen, David Erlinge, Michael Wanscher, Yvan Gashe, Hans Friberg, Steen Pehrson, Lars Køber, Christian Hassager
Journal: Circulation (2015)

Background: Ventricular arrhythmias (VA) are life threatening, even in patients admitted to an intensive care unit following out-of-hospital cardiac arrest (OHCA). Post cardiac arrest care includes hemodynamic stabilization and targeted temperature management (TTM) and while most patients are stabilized, VA may occur. We assessed the prognosis of OHCA patients with in-hospital VA and whether the number of pre-hospital defibrillations was predictive of in-hospital arrhythmic events. Method: We studied 934 (99%) comatose OHCA survivors from the TTM-trial (year: 2010-13) with available data on VA during the first 2 days of post cardiac arrest care and the number of pre-hospital defibrillation used to achieve return of spontaneous circulation (ROSC). The TTM trial showed no benefit of TTM at 33°C over 36°C in terms of mortality and neurological outcome. Results: The prevalence of VA was 16% and did not differ between the TTM groups (33°C= 82 (17%) vs. 36°C= 67 (15%), p=0.23). Patients with VA had similar 180-day survival rates (VA= 52% vs. no-VA= 53%, plog-rank= 0.63, Figure) and odds of unfavorable neurological outcome (OR=1.04 (0.73-1.48, p=0.83), compared to patients without VA. The number of pre-hospital defibrillations ranged from 0 to &gt;20 and a twofold increase was associated with significantly higher odds of in-hospital VA, both combined (OR= 1.39 (1.22-1.59, p&lt;0.0001), and separately as risk of ventricular tachycardia (OR= 1.39 (1.20-1.60, p&lt;0.0001) and fibrillation (OR= 1.54 (1.23-1.93 p&lt;0.001). This remained significant when adjusting for STEMI, initial rhythm, age, sex, bystander CPR, time to ROSC and admission lactate. Conclusion: Risk of VA is directly related to the number of pre-hospital defibrillations, which may be of value in predicting patients at risk of arrhythmia. VA occurring during post cardiac arrest care has no significant impact on prognosis, which supports continued active treatment in patients with recurrent VA after OHCA.
PB2325 OUTCOMES OF ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION (ALLOHCT) FOR MYELOFIBROSIS (MF) – A SINGLE CENTER EXPERIENCE
Authors: R. K. Narra, R. Wu, A. Szabo, M. Hamadani, J. Jerkins, N. Shah, P. Hari, S. Chhabra
Journal: HemaSphere (2019)

Background: Allogeneic transplantation (alloHCT) is the only curative treatment modality for MF. Older age at diagnosis and age-related comorbidities make most patients ineligible for alloHCT, given concerns for non-relapse mortality (NRM). Utilization of alloHCT for MF is increasing recently with reduced intensity conditioning (RIC) approach. Herein, we report the outcomes of alloHCT for MF at Medical College of Wisconsin (MCW), Milwaukee, WI. Aims: Evaluate and report the outcomes of alloHCT for MF at Medical College of Wisconsin (MCW), Milwaukee, WI. Methods: We retrospectively reviewed the outcomes of 37 recipients of alloHCT for MF performed between 2009 and 2018. All patients with JAK2 mutation (68%) and/or constitutional symptoms received ruxolitinib for at least 4 months prior to HCT, and those with splenomegaly >22 cm received pre-transplant splenic radiation. Survival outcomes (overall [OS] and relapse-free survival [RFS]) were analyzed using Kaplan-Meier method and compared between groups using log-rank test. Results: Median age was 60 years (range, 40-74): 68% carried JAK2 driver mutation. 46% evolved from primary ET or PV and 11% had/developed MDS, in addition, pre-HCT. Three-quarters of the cohort had WHO grade 3 MF before HCT. 84% received ruxolitinib and 11% were treated with hypomethylating chemotherapy prior to transplant; 90% had splenomegaly, 35% received splenic radiation. Six patients had cirrhosis and portal hypertension (PHTN), and another 4 had PHTN without cirrhosis. Twenty-two patients (60%) received reduced intensity conditioning and all patients received peripheral blood transplant. Sixteen (43%) patients had matched sibling donor, and others had unrelated (n = 20) or haploidentical related donor (n = 1). HCT-CI score was ≥3 in 61%; 60% had KPS ≥90. The median follow-up of survivors was 30 months (range, 7.1-109). The 3-year OS and RFS were 87% and 84%, respectively. Only one patient relapsed (with acute myeloid leukemia) 15 months post-HCT. NRM at 2 years was 11%; causes of death were sepsis (n = 3) and GVHD (n = 1). Karyotype was the only predictor significantly associated with OS on univariate analysis (favorable/standard-risk vs. unfavorable, HR 5.3, p = 0.02).Summary/Conclusion: Despite advanced age (51% over 60 years; 24% over 65 years) and 61% with HCT-CI ≥ 3, we report high-quality single-center survival data in a carefully-selected MF patient population. We speculate that the use of ruxolitinib and splenic radiation pre-HCT, busulfan-based RIC regimen and higher CD34+ cell dose (median, 7.8 × 106/kg) contributed to the improved outcomes in this series.
SP0091 HOW TO SUPPORT YOURSELF QUITTING SMOKING
Authors: Marios Kouloumas
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> As a person living with Rheumatoid arthritis (RA) (a chronic inflammatory disease caused by both genetic and environmental factors) for the last 45 years (I have been diagnosed with RA at the age of 10 years old) I have been a smoker from the age of 14 years old. As I grew older, and was educated and involved concerning the management of my disease, I realized that smoking, besides its impact on my overall health, had a significant impact as one of the most important risk factors for RA that can increase the severity of the disease and to worsen symptoms. Smoking can also reduce the effect of treatments, including anti-TNF agents and disease-modifying anti-rheumatic drugs (DMARDs). Hence, quitting smoking will improve my overall health, reduce the severity of my disease and ensure that treatments work and reduce the risk for comorbidities e.g. cardiovascular disease and the progression of the disease (joint destructions). <h3>Objectives:</h3> To quit smoking after 40 years of being a smoker and to regain my health and quality of life as well as increase the efficacy of the RA treatments. <h3>Methods:</h3> To succeed I plan to be very well informed and to understand the reasons of quitting smoking as well as the negative impact of smoking and to realize that quitting smoking will improve my health and social life. To inform all people close to me including family members as well as friends and coworkers about my decision to quit smoking. Mentally being prepared to cope with the desire to smoke as well as ridding the thought of "just smoke one". It is also important to rid the mind and lose the connection of things associated with smoking, for example while drinking coffee. To ask for support if needed and to use tools to stop thoughts of smoking and to cope with the effects of nonsmoking and to try avoiding places that could increase my risk of starting to smoke again e.g. pubs <h3>Results:</h3> I have started to cut down on smoking and to minimize it and finally to fully quit smoking for the last 2 years. <h3>Conclusion:</h3> Although, if you ask all smokers how difficult it is to stop smoking, the answer will unanimously be "very hard", as a former smoker I can say that if you quit smoking, be aware of the reasons and the importance of quitting smoking and you will notice that after all it is not very difficult. Of course, when you set this goal it is important that in case of first time failure to not blame yourself and I can not stress enough how important a support system is for example that of your friends, family and especially your spouse. <h3>Disclosure of Interests:</h3> None declared
Кишечный микробиом и остеоартрит
Authors: O.Yu. Gubska, А.А. Kuzminetes, V.M. Hutsul, I.O. Lavrenchuk
Journal: GASTROENTEROLOGY (2019)

Изучение кишечного микробиома является очень актуальной темой, популярной среди исследователей. По ней проводится большое количество исследований. В настоящее время высокими темпами растет количество данных относительно кишечного микробиома человека как в здоровом состоянии, так и при различных патологических состояниях. С ростом накопленных данных расширяется понимание того, что микробиом является весьма сложной системой, части которой находятся в тесных взаимоотношениях с организмом хозяина, а также реагируют на факторы окружающей среды, в том числе на рацион питания и лекарства. Исследователи находят все больше данных относительно взаимного влияния приема медикаментов, кишечной микрофлоры и внекишечных заболеваний. Cтатья посвящена обзору данных, имеющихся в современной литературе, об особенностях состояния кишечной микрофлоры у больных остеоартритом, ее возможному влиянию на патогенез данного заболевания, а также изменениям, которые возникают в микробиоме на фоне лечения остеоартрита, в частности с помощью нестероидных противовоспалительных препаратов.
Driver mutations in USP8 wild-type Cushing’s disease
Authors: Silviu Sbiera, Luis Gustavo Perez-Rivas, Lyudmyla Taranets, Isabel Weigand, Jörg Flitsch, Elisabeth Graf, Camelia-Maria Monoranu, Wolfgang Saeger, Christian Hagel, Jürgen Honegger, Guillaume Assie, Ad R Hermus, Günter K Stalla, Sabine Herterich, Cristina L Ronchi, Timo Deutschbein, Martin Reincke, Tim M Strom, Nikita Popov, Marily Theodoropoulou, Martin Fassnacht
Journal: Neuro-Oncology (2019)

Medical treatment in Cushing's disease (CD) is limited due to poor understanding of its pathogenesis. Pathogenic variants of ubiquitin specific peptidase 8 (USP8) have been confirmed as causative in around half of corticotroph tumors. We aimed to further characterize the molecular landscape of those CD tumors lacking USP8 mutations in a large cohort of patients.Exome sequencing was performed on 18 paired tumor-blood samples with wild-type USP8 status. Candidate gene variants were screened by Sanger sequencing in 175 additional samples. The most frequent variant was characterized by further functional in vitro assays.Recurrent somatic hotspot mutations in another deubiquitinase, USP48, were found in 10.3% of analyzed samples. Several possibly damaging variants were found in TP53 in 6 of 18 samples. USP48 variants were associated with smaller tumors and trended toward higher frequency in female patients. They also changed the structural conformation of USP48 and increased its catalytic activity toward its physiological substrates histone 2A and zinc finger protein Gli1, as well as enhanced the stimulatory effect of corticotropin releasing hormone (CRH) on pro-opiomelanocortin production and adrenocorticotropic hormone secretion.USP48 pathogenic variants are relatively frequent in USP8 wild-type tumors and enhance CRH-induced hormone production in a manner coherent with sonic hedgehog activation. In addition, TP53 pathogenic variants may be more frequent in larger CD tumors than previously reported.
Functional PRAME Specific T Cells Can Be Cultured From CD8+ Cells From Healthy Donors but Not From Patients at First CR: Implications for Immunotherapeutic Strategies in AML.
Authors: Willemijn van den Ancker, Theresia M Westers, Hetty J Bontkes, Dewi Wulandari, Erik Hooijberg, Anita GM Stam, Saskia JAM Santegoets, Gert J Ossenkoppele, Tanja D de Gruijl, Arjan A van de Loosdrecht
Journal: Blood (2009)
Epigenetic polypharmacology: A new frontier for epi‐drug discovery
Authors: Daniela Tomaselli, Alessia Lucidi, Dante Rotili, Antonello Mai
Journal: Medicinal Research Reviews (2019)

Abstract Recently, despite the great success achieved by the so‐called “magic bullets” in the treatment of different diseases through a marked and specific interaction with the target of interest, the pharmacological research is moving toward the development of “molecular network active compounds,” embracing the related polypharmacology approach. This strategy was born to overcome the main limitations of the single target therapy leading to a superior therapeutic effect, a decrease of adverse reactions, and a reduction of potential mechanism(s) of drug resistance caused by robustness and redundancy of biological pathways. It has become clear that multifactorial diseases such as cancer, neurological, and inflammatory disorders, may require more complex therapeutic approaches hitting a certain biological system as a whole. Concerning epigenetics, the goal of the multi‐epi‐target approach consists in the development of small molecules able to simultaneously and (often) reversibly bind different specific epi‐targets. To date, two dual histone deacetylase/kinase inhibitors (CUDC‐101 and CUDC‐907) are in an advanced stage of clinical trials. In the last years, the growing interest in polypharmacology encouraged the publication of high‐quality reviews on combination therapy and hybrid molecules. Hence, to update the state‐of‐the‐art of these therapeutic approaches avoiding redundancy, herein we focused only on multiple medication therapies and multitargeting compounds exploiting epigenetic plus nonepigenetic drugs reported in the literature in 2018. In addition, all the multi‐epi‐target inhibitors known in literature so far, hitting two or more epigenetic targets, have been included.
PF240 COMBINED INHIBITION OF SHP1 AND SHP2 WITH PHORBOL ESTERS AS A DIFFERENTIATION THERAPY AGAINST ACUTE MYELOID LEUKEMIA
Authors: A. Pérez‐Fernández, G. López‐Ruano, R. Prieto‐Bermejo, C. Ijurko, M. Díez‐Campelo, F. Sánchez‐Guijo, Á. Hernández‐Hernández
Journal: HemaSphere (2019)

Background: The differentiation‐based therapy for acute promyelocytic leukemia (APL) is an inspiring example for the search of novel strategies aimed at treatment of other subtypes of acute myeloid leukemia (AML). Thus, the discovery of new molecular players in cell differentiation becomes a paramount research area to achieve this goal. Aims: To assess the involvement of the protein tyrosine phosphatases SHP1 and SHP2 on leukemic cells differentiation along with the therapeutic possibilities of their targeting to enhance the differentiation induction effect of phorbol esters. Methods: The oxidation status and enzymatic activity of SHP1 and SHP2 during PMA‐induced differentiation of HEL cells was evaluated. Additionally, the effects of RNAi‐mediated downregulation of these phosphatases on cell differentiation was studied. Afterwards, the impact of chemical inhibition of SHP1 and SHP2 on differentiation both in the presence and absence of phorbol esters was tested. Finally, the anti‐leukemic potential of phorbol esters and chemical inhibitors of SHP1 and SHP2 was addressed in several AML model cell lines, a xenograft mouse model and AML primary cells in vitro. Results: An increase of oxidation with a concomitant decrease of activity was observed for both phosphatases at the onset of PMA‐induced differentiation. Consistently, silencing of these proteins favored the process, with an enhanced effect upon their simultaneous downregulation. Moreover, the proteins SRC and β‐catenin were identified as downstream targets of SHP1 and SHP2 in this context. In agreement with these findings, chemical inhibition of the phosphatases promoted cell differentiation itself and enhanced the effect of phorbol esters. Interestingly, treatment with the phorbol ester prostratin and the dual inhibitor of SHP1 and SHP2 NSC87877 synergistically hampered the proliferation of AML cell lines, prolonged the survival of xenografted mice and reduced the clonogenic potential of AML primary cells. Summary/Conclusion: SHP1 and SHP2 are relevant mediators of differentiation in AML cells and their inhibition either alone or in combination with prostratin seems a promising differentiation‐based therapeutic strategy against different subtypes of AML beyond APL.