tbuckley/cabot-search huggingface dataset:
The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space
Authors: Johanna Klughammer, Barbara Kiesel, Thomas Roetzer, Nikolaus Fortelny, Amelie Nemc, Karl-Heinz Nenning, Julia Furtner, Nathan C. Sheffield, Paul Datlinger, Nadine Peter, Martha Nowosielski, Marco Augustin, Mario Mischkulnig, Thomas Ströbel, Donat Alpar, Bekir Ergüner, Martin Senekowitsch, Patrizia Moser, Christian F. Freyschlag, Johannes Kerschbaumer, Claudius Thomé, Astrid E. Grams, Günther Stockhammer, Melitta Kitzwoegerer, Stefan Oberndorfer, Franz Marhold, Serge Weis, Johannes Trenkler, Johanna Buchroithner, Josef Pichler, Johannes Haybaeck, Stefanie Krassnig, Kariem Mahdy Ali, Gord von Campe, Franz Payer, Camillo Sherif, Julius Preiser, Thomas Hauser, Peter A. Winkler, Waltraud Kleindienst, Franz Würtz, Tanisa Brandner-Kokalj, Martin Stultschnig, Stefan Schweiger, Karin Dieckmann, Matthias Preusser, Georg Langs, Bernhard Baumann, Engelbert Knosp, Georg Widhalm, Christine Marosi, Johannes A. Hainfellner, Adelheid Woehrer, Christoph Bock
Journal: Nature Medicine (2018)
New insights into the pathogenesis and treatment of sarcopenia in chronic heart failure
Authors: Jiayu Yin, Xiang Lu, Zhiyuan Qian, Weiting Xu, Xiang Zhou
Journal: Theranostics (2019)

Sarcopenia is an age-related geriatric syndrome that is characterized by a progressive loss of muscle mass, strength and function.Chronic heart failure (CHF), the final stage of various cardiovascular diseases, may be closely correlated with the occurrence of sarcopenia.Accumulating evidence has demonstrated that CHF can promote the development of sarcopenia through multiple pathophysiological mechanisms, including malnutrition, inflammation, hormonal changes, oxidative stress, autophagy, and apoptosis.Additionally, CHF can aggravate the adverse outcomes associated with sarcopenia, including falls, osteoporosis, frailty, cachexia, hospitalization, and mortality.Sarcopenia and CHF are mutually interacting clinical syndromes.Patients with these two syndromes seem to endure a double burden, with no particularly effective way to hinder their progression.However, the combination of physical exercise, nutritional supplements, and drug therapy may counteract the development of these maladies.In this review, we will summarize the latest progress in the pathogenesis and treatment of sarcopenia in patients with CHF.
PS1173 PROTEIN CASEIN KINASE 2 IS INVOLVED IN CHRONIC MYELOID LEUKEMIA RESISTANCE TO IMATINIB AND ALSO TO DASATINIB
Authors: O. Mitrovský, D. Myslivcová, T. Lopotová Macháčková, H. Klamová, M. Žáčková
Journal: HemaSphere (2019)

Background: Protein casein kinase 2 (CK2) is a Ser/Thr kinase, which is ubiquitously expressed in eukaryotic cells. It phosphorylates a broad number of proteins, regulates a number of key signaling pathways and promotes cell proliferation and survival. Although CK2 does not belong to the “oncogenic kinases”, it is overexpressed in many solid tumours and also in hematological malignancies. Previous results by Donella‐Deana et al. indicated CK2 association with resistance to imatinib in CML cell lines. In our study, we explored the role of CK2 in cell resistance to imatinib as well as to dasatinib, both in CML cell lines and in patient samples. Aims: We aimed 1) to verify the involvement of CK2 kinase in the resistance to imatinib, in cell line model and in patient samples and 2) to investigate possible role of CK2 in the resistance to dasatinib. Methods: Sublines resistant to either 2 nM dasatinib or 2 μM imatinib were derived from established CML cell lines JURL‐MK1, MOLM‐7, and K562. Sensitive and resistant cells were then treated with the CK2 inhibitor CX‐4945, imatinib, or dasatinib, individually or in selected combinations. Alternatively, siRNAs against CK2 subunits were used. Cell viability was determined using Alamar test. Protein levels and phosphorylation were measured using western blots. CK2 activity was assessed through phosphorylation of its substrates [(pS/pT)DXE] and of its natural target, Cdc37. To evaluate the extent of apoptosis, PARP and caspase 3 cleavage was analysed. Results: We have successfully established JURL‐MK1, MOLM‐7 and K562 sublines resistant to either 2 nM dasatinib or 2 μM imatinib. We found increased protein levels of CK2 kinase and increased phosphorylation levels of CK2 substrates in all resistant cells as compared to sensitive cells. All cells were treated with imatinib, dasatinib and CK2 inhibitor CX‐4945 and their combinations. Despite the loss of response to TKIs, the resistant cells remained sensitive to CK2 inhibition. CX‐4945 reduced CK2 substrates phosphorylation and also cell proliferation in both type of resistant cells. It also increased apoptotic indicators (cleaved PARP, caspase 3) and the dead cell fraction. Preliminary results showed a decrease of cell viability and/or apoptosis induction also in primary cells from four patients resistant to imatinib or dasatinib. Leukocytes from healthy donors were not affected by any of the inhibitors tested. Summary/Conclusion: Altogether, our results suggest that CK2 kinase is involved in CML resistance to both imatinib and dasatinib. Further research is necessary to fully understand the role of CK2 in CML and its potential to become a new target of therapy.
Endothelial Forkhead Box Transcription Factor P1 Regulates Pathological Cardiac Remodeling Through Transforming Growth Factor-β1–Endothelin-1 Signal Pathway
Authors: Jie Liu, Tao Zhuang, Jingjiang Pi, Xiaoli Chen, Qi Zhang, Ying Li, Haikun Wang, Yajing Shen, Brian Tomlinson, Paul Chan, Zuoren Yu, Yu Cheng, Xiangjian Zheng, Muredach Reilly, Edward Morrisey, Lin Zhang, Zhongmin Liu, Yuzhen Zhang
Journal: Circulation (2019)

Pathological cardiac fibrosis and hypertrophy, the common features of left ventricular remodeling, often progress to heart failure. Forkhead box transcription factor P1 (Foxp1) in endothelial cells (ECs) has been shown to play an important role in heart development. However, the effect of EC-Foxp1 on pathological cardiac remodeling has not been well clarified. This study aims to determine the role of EC-Foxp1 in pathological cardiac remodeling and the underlying mechanisms.Foxp1 EC-specific loss-of-function and gain-of-function mice were generated, and an angiotensin II infusion or a transverse aortic constriction operation mouse model was used to study the cardiac remodeling mechanisms. Foxp1 downstream target gene transforming growth factor-β1 (TGF-β1) was confirmed by chromatin immunoprecipitation and luciferase assays. Finally, the effects of TGF-β1 blockade on EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes were further confirmed by pharmacological inhibition, more specifically by RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.Foxp1 expression is significantly downregulated in cardiac ECs during angiotensin II-induced cardiac remodeling. EC-Foxp1 deletion results in severe cardiac remodeling, including more cardiac fibrosis with myofibroblast formation and extracellular matrix protein production, as well as decompensated cardiac hypertrophy and further exacerbation of cardiac dysfunction on angiotensin II infusion or transverse aortic constriction operation. In contrast, EC-Foxp1 gain of function protects against pathological cardiac remodeling and improves cardiac dysfunction. TGF-β1 signals are identified as Foxp1 direct target genes, and EC-Foxp1 deletion upregulates TGF-β1 signals to promote myofibroblast formation through fibroblast proliferation and transformation, resulting in severe cardiac fibrosis. Moreover, EC-Foxp1 deletion enhances TGF-β1-promoted endothelin-1 expression, which significantly increases cardiomyocyte size and reactivates cardiac fetal genes, leading to pathological cardiac hypertrophy. Correspondingly, these EC-Foxp1 deletion-mediated profibrotic and prohypertrophic phenotypic changes and cardiac dysfunction are normalized by the blockade of TGF-β1 signals through pharmacological inhibition and RGD-peptide magnetic nanoparticle target delivery of TGF-β1-siRNA to ECs.EC-Foxp1 regulates the TGF-β1-endothelin-1 pathway to control pathological cardiac fibrosis and hypertrophy, resulting in cardiac dysfunction. Therefore, targeting the EC-Foxp1-TGF-β1-endothelin-1 pathway might provide a future novel therapy for heart failure.
AB1405-HPR REDUCED HAND FUNCTION AFFECTS ACTIVITY PERFORMANCE AND QUALITY OF LIFE IN PERSONS WITH SIBM
Authors: Malin Regardt
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Reduced hand function is common in persons with (IBM) (1). Information regarding how hand function deficits affect activities of daily living and quality of life is limited (2,3). There is a need to improve treatment and increase knowledge on how to assess different aspects of sIBM. <h3>Objectives</h3> To investigate how hand function can influence activities of daily living and quality of life in persons with sIBM. <h3>Methods</h3> Data collection have been performed in both USA and in Sweden. In total 62 persons with IBM participated in this study (USA n= 36, Sweden n= 26), median age were (IQR) n=70 (66-75) years with a median disease duration (IQR) 6 (2-8) year. The majority were men n=39 (63%). Hand strength was measured with the Jamar dynamometer and dexterity by the Purdue Pegboard. Activity limitation measured by the Disability of the Arm, Shoulder and Hand (DASH) and Myositis Activities Profile (MAP). Quality of life by SF-36. <h3>Results</h3> Hand strength and dexterity in IBM was reduced in both women and men (p&lt;0.001). Percentage of reference values were (right hand/left hand) in Women 42%/25%, Men 30%/27%. Persons with IBM had limitations in daily activities when compared to reference values (p&lt;0.001). The most limited activities were: Activities of moving around (extremely difficult), Recreation (Very difficult), Movement (moderately difficult) and Household activities (moderately difficult) Persons with IBM had reduced quality of life in SF-36 domains; Physical Function, Role Physical, General Health, Vitality, Social Function and Mental Health. Hand strength correlated moderately with activity limitation measures by DASH (p&lt;0.001) and MAP subscales; Movement, Activities of moving around, Personal hygiene, Housework, Social activities, Work/School and Recreation (p&lt;0.001) and moderately to SF-36-dimension Physical Function (p&lt;0.001). Dexterity correlated moderately to DASH (p&lt;0.001) and all subscales of MAP (p&lt;0.001) and moderately to SF-36 dimensions Physical Function and Social Function (p&lt;0.001). <h3>Conclusion</h3> Persons with IBM have reduced hand function and limitations in daily activities and quality of life. Suggesting the importance to include measures on both hand function, activity limitation and quality of life. The expertise on activity and occupational science of an occupational therapist may contribute to the assessment and treatment of persons with IBM. <h3>References</h3> [1] Lindberg C, Oldfors A. Prognosis and prognostic factors in sporadic inclusion body myositis. Acta Neurol Scand. 2012;125(5):353-8. [2] Eriksson M, Lindberg C. Hand function in 45 patients with sporadic inclusion body myositis. Occup Ther Int. 2012;19(2):108-16. [3] Cox FM, Titulaer MJ, Sont JK, Wintzen AR, Verschuuren JJ, Badrising UA. A 12-year follow-up in sporadic inclusion body myositis: an end stage with major disabilities. Brain. 2011;134(Pt 11):3167-75. <h3>Disclosure of Interests</h3> None declared
PF443 ADOPTIVE IMMUNOTHERAPY OF INVASIVE ASPERGILLOSIS BY T CELLS VACCINES AGAINST ASPERGILLOSIS IN MOUSE MODEL
Authors: H. Xing, D. Chen, M. Wang, W. Tian, H. Sun, Z. Jiang
Journal: HemaSphere (2019)

Background: Invasive aspergillosis is a common cause of life‐threatening infection in immunocompromised patients, especially those who require aggressive immunosuppressive treatment, as Aspergillus fumigatus is the most common pathogen. Despite advances in early diagnosis and new antifungal agents, the majority of cases still associated with high morbidity and unacceptable mortality. The reconstitution of specific immunity against A. fumigatus during periods of severe immunosuppression has the potential to impact enormously on the health and well being of patients. Aims: To screened the amino acid sequences of A. fumigatus recombinant protein ASP f16 by bioinformation software and determine the potential CTL epitopes processed and presented by mature DCs to prime specific CTL cells. Methods: We confirmed the killing ability of Asp f16 peptides specific CTLs against A. fumigatus by conidiacidal and hyphae killing assays, which indicated that CTLs culture supernatant contains substances that killed fresh A. fumigatus conidia and CTLs have killing activity directly against the hyphae in vitro. In our study, we also accessed the evaluation of the protection against A. fumigatus in vivo by adoptive transfer peptides specific CTLs to an invasive aspergillosis model of HLA A0201 transgenic mouse. Results: The results demonstrated the adoptive transfer of ASP f16 peptides specific CTLs significantly altered the course of the Aspergillus infection, as indicated by statistical significantly extended survival hours after the infection and reduced fungal burden in the lung tissue, as opposed to mice not receiving T cells or receiving nonrelated peptides (NPM1) specific T cells, which all died faster with extensive fungal growth. Summary/Conclusion: Generate Asp f16 specific CTL clones in vitro and adoptive transfer to the recipients when they’re susceptive to or involved in IA, will be a promising potential option to protect the recipients against the fatal fungal infection.
Impact of the WHO Framework Convention on Tobacco Control on global cigarette consumption: quasi-experimental evaluations using interrupted time series analysis and in-sample forecast event modelling
Authors: Steven J Hoffman, Mathieu J P Poirier, Susan Rogers Van Katwyk, Prativa Baral, Lathika Sritharan
Journal: BMJ (2019)

To evaluate the impact of the WHO Framework Convention on Tobacco Control (FCTC) on global cigarette consumption.Two quasi-experimental impact evaluations, using interrupted time series analysis (ITS) and in-sample forecast event modelling.71 countries for which verified national estimates of cigarette consumption from 1970 to 2015 were available, representing over 95% of the world's cigarette consumption and 85% of the world's population.The FCTC is an international treaty adopted in 2003 that aims to reduce harmful tobacco consumption and is legally binding on the 181 countries that have ratified it. Main outcomes were annual national estimates of cigarette consumption per adult from 71 countries since 1970, allowing global, regional, and country comparisons of consumption levels and trends before and after 2003, with counterfactual control groups modelled using pre-intervention linear time trends (for ITS) and in-sample forecasts (for event modelling).No significant change was found in the rate at which global cigarette consumption had been decreasing after the FCTC's adoption in 2003, using either ITS or event modelling. Results were robust after realigning data to the year FCTC negotiations commenced (1999), or to the year when the FCTC first became legally binding in each country. By contrast to global consumption, high income and European countries showed a decrease in annual consumption by over 1000 cigarettes per adult after 2003, whereas low and middle income and Asian countries showed an increased annual consumption by over 500 cigarettes per adult when compared with a counterfactual event model.This study finds no evidence to indicate that global progress in reducing cigarette consumption has been accelerated by the FCTC treaty mechanism. This null finding, combined with regional differences, should caution against complacency in the global tobacco control community, motivate greater implementation of proven tobacco control policies, encourage assertive responses to tobacco industry activities, and inform the design of more effective health treaties.
THU0304 PREVALENCE AND MANAGEMENT OF CARDIOVASCULAR RISK FACTORS IN ANCA-ASSOCIATED VASCULITIS: A CROSS-SECTIONAL STUDY IN THE NETHERLANDS AND CANADA
Authors: Eline Houben, Arielle Mendel, Joost van der Heijden, Suat Simsek, Willem Bax, Simon Carette, Alexandre Voskuyl, Christian Pagnoux, Erik Penne
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Patients with ANCA-associated vasculitis (AAV) are at increased risk of cardiovascular (CV) disease.(1) <h3>Objectives:</h3> The aim of the present study was to determine the prevalence of CV risk factors in patients with AAV and to evaluate the management of CV risk factors according to current guidelines. <h3>Methods:</h3> A cross-sectional study was performed in patients with AAV in the Netherlands and Canada. Information on traditional CV risk factors, as well as markers of inflammation and kidney function, were collected. Their prevalence and treatment were studied and compared with recommendations in current guidelines. <h3>Results:</h3> A total of 144 consecutive patients with AAV were included (71 from the Netherlands; 73 from Canada). Mean age was 62 ± 15 years, and 56% were male. The mean disease duration was 7.0 ± 6.6 years; 69% had granulomatosis with polyangiitis, 17% microscopic polyangiitis and 14% eosinophilic granulomatosis with polyangiitis. Mean body mass index was 28 ± 6 kg/m<sup>2</sup> and 65 patients (45%) had an estimated glomerular filtration rate &lt;60 ml/min. The mean C-reactive protein was 6.5 ± 12.3 mg/l. Dyslipidemia was present in 69% and hypertension in 72%. In 36% and 25% of the included patients, blood pressure and dyslipidemia, respectively, were not managed in accordance with national guidelines. <h3>Conclusion:</h3> Patients with AAV have a high prevalence of traditional CV risk factors. Whether past or persistent inflammation and chronic kidney disease further increases the CV risk remains to be studied. Strict adherence to CV risk management guidelines should be encouraged. <h3>Reference:</h3> [1] Houben E, Penne EL, Voskuyl AE, van der Heijden JW, Otten RHJ, Boers M, et al. Cardiovascular events in anti-neutrophil cytoplasmic antibody-associated vasculitis: a meta-analysis of observational studies. Rheumatology (Oxford) 2018; 57: 555-62. <h3>Disclosure of Interests:</h3> None declared
AB0370 EFFICACY AND SAFETY OF BIOLOGIC TREATMENT IN ELDERLY RHEUMATOID ARTHRITISPATIENTS: A WIDE COHORT STUDY
Authors: Cristian Caimmi, Federica Martinis, Ilaria Montanari, Alice Dellaidotti, Elena Fracassi, Ombretta Viapiana, Domenico Biasi, Maurizio Rossini, Antonio Carletto
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> Given the data on efficacy and safety of biologic treatment in rheumatoid arthritis (RA), more and more patients older than 65 years are starting these drugs. <h3>Objectives</h3> This study aims to evaluate safety and efficacy of biologics in elderly patients. Methods: four-hundred and thirteen patients with RA were enrolled and divided in two group, i.e. older or younger than 65 years old. Data on disease characteristics, treatment and adverse reactions were collected. In addition, comorbidities were evaluated by the Rheumatic Disease Comorbidity index (RDCI). <h3>Results</h3> Seventy-seven patients were male and 87 were older than 65 years. The elderly patients had a higher RDCI as compared to those younger than 65 years (1.0 ± 3.0 vs. 0.0 ± 10 respectively, p&lt;0.001). Mean DAS28 at the beginning of biologic treatment was 4.46 ± 1.16. Most of patients started etanercept (41.4%) or adalimumab (26.9%) and 37.1% were on monotherapy. None of these variables were statistically different between age groups. The figure shows the differences in retention rate of first biologic at 60 months in the two groups that was found to be significantly higher in older than younger patients (43.3 vs. 48.5, p=0.023). This result was confirmed also after correcting for comorbidities as defined by RDCI (p=0.014). On the contrary, no differences were found in retention rate on any biologic (i.e. not only first line) between age groups (p=0.509). The main reason for biologic treatment discontinuation was inefficacy in both groups (74.7% in &lt;65 years old and 58.6% in ≥65years old, p=0.161). The most common side effects in elderly patients were hematological complications (30.4%) while in younger patients muco-cutaneous (32.4%) adverse reactions. Infections were a reason for discontinuation in 17.4% in old patients and 20.6% in younger ones (p=1.000). <h3>Conclusion</h3> RA patients aged over 65 years have been found to have even a better retention rate at first biologic than youngers one, probably because of less strict targets in disease control and a more frequent follow up. In addition, safety has been found to be as good as in younger patients. Comorbidities do not seem to affect retention rate. <h3>Disclosure of Interests</h3> Cristian Caimmi: None declared, Federica Martinis: None declared, Ilaria Montanari: None declared, Alice Dellaidotti: None declared, Elena Fracassi Speakers bureau: Novartis, Ombretta Viapiana Speakers bureau: Novartis, Abbvie, Eli-Lilly, Sanofi Genzyme, Domenico Biasi: None declared, Maurizio Rossini: None declared, Antonio Carletto Speakers bureau: Roche, Novartis, MSD, Abbvie, Bristol, Jannsen, Celgene, Pfizer
Infectious Disease Dynamics Inferred from Genetic Data via Sequential Monte Carlo
Authors: R.A. Smith, E.L. Ionides, A.A. King
Journal: Molecular Biology and Evolution (2017)

Genetic sequences from pathogens can provide information about infectious disease dynamics that may supplement or replace information from other epidemiological observations. Most currently available methods first estimate phylogenetic trees from sequence data, then estimate a transmission model conditional on these phylogenies. Outside limited classes of models, existing methods are unable to enforce logical consistency between the model of transmission and that underlying the phylogenetic reconstruction. Such conflicts in assumptions can lead to bias in the resulting inferences. Here, we develop a general, statistically efficient, plug-and-play method to jointly estimate both disease transmission and phylogeny using genetic data and, if desired, other epidemiological observations. This method explicitly connects the model of transmission and the model of phylogeny so as to avoid the aforementioned inconsistency. We demonstrate the feasibility of our approach through simulation and apply it to estimate stage-specific infectiousness in a subepidemic of human immunodeficiency virus in Detroit, Michigan. In a supplement, we prove that our approach is a valid sequential Monte Carlo algorithm. While we focus on how these methods may be applied to population-level models of infectious disease, their scope is more general. These methods may be applied in other biological systems where one seeks to infer population dynamics from genetic sequences, and they may also find application for evolutionary models with phenotypic rather than genotypic data.
National mycology laboratory diagnostic capacity for invasive fungal diseases in 2017: Evidence of sub-optimal practice
Authors: Silke Schelenz, Katie Owens, Rebecca Guy, Riina Rautemaa-Richardson, Rohini J. Manuel, Malcolm Richardson, Caroline Moore, David A. Enoch, Christianne Micallef, Philip Howard, Samir G. Agrawal, Elizabeth M. Johnson, Berit Muller-Pebody
Journal: Journal of Infection (2019)
Accuracy of Parent-Measured and Parent-Estimated Heights and Weights in Determining Child Weight Status
Authors: Punam Ohri-Vachaspati, Francesco Acciai, Derek DeLia, Kristen Lloyd, Michael J. Yedidia
Journal: JAMA Pediatrics (2019)

This cohort study assesses whether parent measurements of children’s height and weight are more accurate than their respective estimates for determining weight status and how both compare with professionally measured data.