tbuckley/cabot-search huggingface dataset:
Efficacy and safety of NI-0101, an anti-toll-like receptor 4 monoclonal antibody, in patients with rheumatoid arthritis after inadequate response to methotrexate: a phase II study
Authors: Emmanuel Monnet, Ernest H Choy, Iain McInnes, Tamta Kobakhidze, Kathy de Graaf, Philippe Jacqmin, Geneviève Lapeyre, Cristina de Min
Journal: Annals of the Rheumatic Diseases (2019)

Anti-citrullinated protein antibodies (ACPAs) form immune complexes with citrullinated proteins binding toll-like receptor (TLR) 4, which has been proposed as a mediator of rheumatoid arthritis (RA). NI-0101 is a first-in-class humanised monoclonal antibody blocking TLR4, as confirmed by inhibition of in vivo lipopolysaccharide-induced cytokine release in healthy volunteers. This study was design to confirm preclinical investigations supporting a biomarker-driven approach for treatment of patients with RA who present positive for these immune complexes.Placebo-controlled, double-blind, randomised (2:1) trial of the tolerability and efficacy of NI-0101 (5 mg/kg, every 2 weeks for 12 weeks) versus placebo in ACPA-positive RA patients with inadequate response to methotrexate. Efficacy measures included Disease Activity Score (28-joint count) with C reactive protein (DAS28-CRP), European League Against Rheumatism (EULAR) good and moderate responses, and American College of Rheumatology (ACR) 20, ACR50 and ACR70 responses. Subgroup analyses defined on biomarkers were conducted. Pharmacokinetics, pharmacodynamics and safety were reported.90 patients were randomised (NI-0101 (61) and placebo (29)); 86 completed the study. No significant between-group difference was observed for any of the efficacy endpoints. Subgroup analyses using baseline parameters as covariants did not reveal any population responding to NI-0101. Treatment-emergent adverse events occurred in 51.7% of patients who received placebo versus 52.5% for NI-0101.We demonstrate for the first time that in RA, a human immune-mediated inflammatory disease, blocking the TLR4 pathway alone does not improve disease parameters. Successful targeting of innate immune pathways in RA may require broader and/or earlier inhibitory approaches.
SURG-10. GRADE TWO GLIOMA SURGERY - A LARGE SINGLE CENTRE REVIEW OF CLINICAL, HISTOLOGICAL, GENETIC AND SURGICAL OUTCOMES
Authors: Oliver Richards, Churl-Su Kwon, William Bolton, John Goodden, Paul Chumas
Journal: Neuro-Oncology (2019)

Abstract We analysed the surgical outcomes in a large series of operated grade two glioma patients with emphasis on surgical resection volumes, histology, genetics and survival. All adult glioma patients (200) operated between 2009 and 2016 with histological confirmation of grade two glioma from a single United Kingdom unit were included. Baseline clinical data was obtained along with radiological assessment of the extent of tumour resection, histological diagnosis, mutation status and survival data. Univariate and multivariate statistical analysis was performed. Preliminary analysis of an initial 63 patients had an average follow up of 51 months. A mean tumour resection of 73.9% (Range 14.4–100%), with an average pre-operative tumour volume of 42.2cm3 was achieved. 48 patients underwent awake surgery. There was no significant difference between pre-operative Karnofsky score (93.0) and post-operative (91.6) function. IDH-mutant diffuse astrocytoma (55.5%), IDH-mutant 1p19q co-deleted oligodendroglioma (33.3%) and IDH wildtype diffuse astrocytoma (14.3%) were the commonest histological diagnoses. 32 patients underwent post-operative adjuvant oncology treatment, with 22 requiring repeat operation. Extent of resection in repeat surgeries was 58.6%. Preliminary statistical analysis on this initial sample has demonstrated that every additional year of age at diagnosis however is associated with a 0.5% reduction in resection (p=0.02) and a 0.2% decline in Karnofsky performance (p=&amp;lt; 0.01). Patients with 1p19q co-deletion had a significant increase in progression free survival (PFS) (p=0.04). No significant variables were found to predict the risk of second surgery. Patients with eloquent tumour locations were significantly less likely to suffer post-operative neurological deficits (p&amp;lt; 0.01) Provisional analysis of our case series demonstrates an excellent extent of resection for our cohort of grade two glioma patients. 1p19q co-deletion in this group was significantly associated with improved PFS. Full analysis of the entire patient cohort will be available in time for presenting.
Dynamic micelles with detachable PEGylation at tumoral extracellular pH for enhanced chemotherapy
Authors: Guoqing Yan, Panpan Zhang, Jun Wang, Xin Wang, Rupei Tang
Journal: Asian Journal of Pharmaceutical Sciences (2020)

Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo, it also blocks uptake by tumor cells. This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times. Herein, the amphiphilic graft copolymers with pH-sensitive ortho ester-linked mPEG in side chains and polyurethanes in backbone, can self-assemble into the free and doxorubicin (DOX)-loaded micelles. The pH-sensitive micelles could undergo several characteristics as follows: (i) PEGylated shells for stability in sodium dodecyl sulfonate (SDS) solution; (ii) DePEGylation via degradation of ortho ester linkages at tumoral extracellular pH (6.5) for gradually dynamic size changes and effective release of DOX; and (iii) enhanced cellular uptake and cytotoxicity via positive DOX. Moreover, the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5Y multicellular spheroids (MCs) and strongly inhibit tumor growth in vitro and in vivo, and might be considered as promising and effective drug carriers in tumor therapy.
The association between pre-treatment serum 25-hydroxyvitamin D and survival in stage IV prostate cancer.
Authors: Pankaj G. Vashi, Digant Gupta, Kristen Trukova, Gwendolyn M Lambert, Carolyn Lammersfeld
Journal: Journal of Clinical Oncology (2013)

5036 Background: Emerging evidence in the literature suggests a positive association between serum 25-hydroxyvitamin D [25(OH)D], a standard indicator of vitamin D status, and survival in certain types of cancer. We investigated this relationship in newly diagnosed stage IV prostate cancer patients. Methods: A case series of 54 newly diagnosed stage IV prostate cancer patients underwent a baseline serum 25(OH)D evaluation prior to receiving any treatment at our institution between Jan 2008 and Dec 2010. We defined vitamin D insufficiency as serum 25(OH)D levels of &lt;=32 ng/ml. Patient survival was defined as the time between date of first patient visit and date of death from any cause/date of last contact. Cox regression was used to evaluate the prognostic significance of serum 25(OH)D after adjusting for age, prostate specific antigen (PSA) and functional status. Results: Mean age at diagnosis was 59.6 years. During a median follow-up of 23.6 months, 16 deaths occurred. The mean serum 25(OH)D was 30.1 ng/ml, among whom 38 (70.4%) were insufficient in vitamin D (&lt;=32 ng/ml). Mean overall survival was 49.4 months (95% CI: 38.1-60.7). Mean survival was 32.6 months and 62.4 months for patients in &lt;=32 ng/ml and &gt;32 ng/ml groups respectively (p = 0.02). On univariate analysis, patients with levels &gt;32 ng/ml had a significantly lower risk of mortality compared to those with levels &lt;=32 ng/ml (HR=0.19; 95% CI: 0.04-0.87; p=0.03). On multivariate analysis controlling for age, performance status and PSA, patients with levels &gt;32 ng/ml demonstrated significantly lower mortality (HR=0.13; 95% CI: 0.02-1.0; p=0.05) compared to those with levels &lt;=32 ng/ml. Conclusions: Higher circulating levels of serum 25(OH)D were positively associated with survival in patients with metastatic prostate cancer. While these results need to be confirmed in prospective clinical trials, our study adds to the growing body of literature on the prognostic role of serum vitamin D in cancer. Given the high prevalence of vitamin D insufficiency in prostate cancer and the fact that this insufficiency is easily correctable by supplementation, we recommend early vitamin D assessment and intervention for a potential impact on patient survival.
Integrative omics approaches provide biological and clinical insights: examples from mitochondrial diseases
Authors: Sofia Khan, Gulayse Ince-Dunn, Anu Suomalainen, Laura L. Elo
Journal: Journal of Clinical Investigation (2020)

High-throughput technologies for genomics, transcriptomics, proteomics, and metabolomics, and integrative analysis of these data, enable new, systems-level insights into disease pathogenesis. Mitochondrial diseases are an excellent target for hypothesis-generating omics approaches, as the disease group is mechanistically exceptionally complex. Although the genetic background in mitochondrial diseases is in either the nuclear or the mitochondrial genome, the typical downstream effect is dysfunction of the mitochondrial respiratory chain. However, the clinical manifestations show unprecedented variability, including either systemic or tissue-specific effects across multiple organ systems, with mild to severe symptoms, and occurring at any age. So far, the omics approaches have provided mechanistic understanding of tissue-specificity and potential treatment options for mitochondrial diseases, such as metabolome remodeling. However, no curative treatments exist, suggesting that novel approaches are needed. In this Review, we discuss omics approaches and discoveries with the potential to elucidate mechanisms of and therapies for mitochondrial diseases.
Rationale and design of the AFFIRM‐AHF trial: a randomised, double‐blind, placebo‐controlled trial comparing the effect of intravenous ferric carboxymaltose on hospitalisations and mortality in iron‐deficient patients admitted for acute heart failure
Authors: Piotr Ponikowski, Bridget‐Anne Kirwan, Stefan D. Anker, Maria Dorobantu, Jarosław Drozdz, Vincent Fabien, Gerasimos Filippatos, Teba Haboubi, Andre Keren, Irakli Khintibidze, Hans Kragten, Felipe A. Martinez, Theresa McDonagh, Marco Metra, Davor Milicic, José C. Nicolau, Marcus Ohlsson, Alexander Parhomenko, Domingo A. Pascual‐Figal, Frank Ruschitzka, David Sim, Hadi Skouri, Peter van der Meer, Ewa A. Jankowska
Journal: European Journal of Heart Failure (2019)
Regulation of mTOR by the tumor suppressor p53
Authors: Haiyan Zhang, Zhaohui Feng, Arnold J. Levine, Shengkan Jin
Journal: Cancer Research (2005)

2511  Normal cell growth and proliferation require an intricate coordination between the stimulatory signals arising from nutrients and growth factors and the inhibitory signals arising from intracellular stresses. In mammals, mTOR is a master molecule integrating nutrient and growth factor signals, and the tumor suppressor p53 plays a central role in sensing genotoxic stresses. Here we demonstrate that activation of p53 inhibits mTOR activity and regulates its downstream target programs. Etoposide treatment, which induces double-stranded DNA breaks and activates p53, decreases the activities of mTOR in wild type mouse embryo fibroblasts (MEFs) but not in p53−/− MEFs, as detected by the levels of the phosphorylated form of p70S6 kinase (p70S6K) at position thr-389, which is a specific mTOR phosphorylation site. Moreover, activation of a temperature sensitive form of p53 in a human cell line by temperature shift dramatically inhibits mTOR activity, while similar temperature shift has little effect on mTOR in the parental cell line that does not harbor the temperature sensitive p53. Other downstream targets of mTOR are also similarly affected. The levels of the phosphorylated form of 4EBP1 at thr-37, another mTOR specific phosphorylation target, decrease dramatically upon p53 activation. Autophagy, a known process that is negatively regulated by mTOR, is activated by p53 activation. The mechanism by which p53 regulates mTOR is apparently independent of its cell cycle regulation, since p53 activation inhibits mTOR in p21−/− MEFs similarly as it does in wild type MEFs. The inhibition of mTOR by p53 requires the TSC1/TSC2 complex, a known upstream negative regulator of mTOR. Neither etoposide treatment, nor overexpression of p53 by transient transfection, downregulates mTOR in TSC1−/− or TSC2−/− MEFs. Furthermore, p53 activation leads to rapid induction of the activity of AMPK, an AMP dependent kinase and a positive regulator of TSC2. Consistent with the role of AMPK in the p53-dependent mTOR regulation, treatment with an AMPK specific inhibitor blocks the effect of p53 on mTOR in both MEFs and the p53 temperature sensitive cell line. Thus p53 can regulate mTOR and consequently its downstream cellular programs, including autophagy, which is a novel tumor suppression mechanism. This regulation involves AMPK activation and requires the TSC1/TSC2 complex, a process that mimics energy deprivation, and this novel regulation by p53 might contribute to its tumor suppression function.
Effects of cryopreservation on antiviral responses of primary airway epithelial cells
Authors: Styliani Taka, Chrysa Nikopoulou, Alexandros Polyzos, Spyridon Megremis, Chrysanthi L. Skevaki, Eirini Roumpedaki, Aikaterini Trochoutsou, Dimitris Thanos, Nikolaos G. Papadopoulos
Journal: Allergy (2019)

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Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses
Authors: Lam C. Tsoi, Elke Rodriguez, Dora Stölzl, Ulrike Wehkamp, Jingru Sun, Sascha Gerdes, Mrinal K. Sarkar, Matthias Hübenthal, Chang Zeng, Ranjitha Uppala, Xianying Xing, Frederieke Thielking, Allison C. Billi, William R. Swindell, Alanna Shefler, Jiahan Chen, Matthew T. Patrick, Paul W. Harms, J. Michelle Kahlenberg, Bethany E. Perez White, Emanual Maverakis, Johann E. Gudjonsson, Stephan Weidinger
Journal: Journal of Allergy and Clinical Immunology (2019)
The integrative memory model is detailed, but skimps on false memories and development
Authors: Glen E Bodner, Daniel M Bernstein
Journal: Behavioral and Brain Sciences (2019)

Abstract The integrative memory model combines five core memory systems with an attributional system. We agree with Bastin et al. that this melding is the most novel aspect of the model. But we await further evidence that the model's substantial complexity informs our understanding of false memories or of the development of recollection and familiarity.
Interactions with the integrative memory model
Authors: Christine Bastin, Gabriel Besson, Emma Delhaye, Adrien Folville, Marie Geurten, Jessica Simon, Sylvie Willems, Eric Salmon
Journal: Behavioral and Brain Sciences (2019)

Abstract The integrative memory model formalizes a new conceptualization of memory in which interactions between representations and cognitive operations within large-scale cerebral networks generate subjective memory feelings. Such interactions allow to explain the complexity of memory expressions, such as the existence of multiples sources for familiarity and recollection feelings and the fact that expectations determine how one recognizes previously encountered information.
Prevalence of Human Papillomavirus Infection by Number of Vaccine Doses Among US Women
Authors: Kalyani Sonawane, Alan G. Nyitray, Gizem S. Nemutlu, Michael D. Swartz, Jagpreet Chhatwal, Ashish A. Deshmukh
Journal: JAMA Network Open (2019)

These findings support previous observational studies and post hoc analyses of vaccine trials that demonstrated comparable effectiveness of 1 dose to 2 or 3 doses. 4The limitations of our study include a cross-sectional design that precluded us from evaluating the timing of HPV vaccination compared with potential exposure.Furthermore, any conclusion regarding efficacy by individual number of doses cannot be drawn given the self-reported immunization history that may be prone to recall bias. 6If ongoing trials confirm sufficient efficacy and sustained duration of protection from a single-dose regimen, vaccine initiation (as opposed to the series completion) will become a more achievable metric of population coverage.
История Самуила Фельдмана — ученого, хирурга и музыканта (1874–1954)
Authors: M.P. Chaban, Z.I. Shevtsova, V.V. Gaponov
Journal: GASTROENTEROLOGY (2019)

В статье представлен жизненный путь и профессиональная деятельность врача-хирурга, ученого, преподавателя, организатора, общественного деятеля Самуила Лазаревича Фельдмана. Будучи участником четырех войн, он сделал большой вклад в развитие научной и клиничной работы в мирное и военное время на Екатеринославщине — Днепропетровщине.
Abstract 11992: Molecular Basis of Cardiomyopathy Due to Frequent Ventricular Ectopy: Roles of Calcium Mishandling and CaMKII
Authors: Tao Liu, Xiaoyan Qi, Feng Xiong, Jiening Xiao, Edward Gerstenfeld, Stanley Nattel
Journal: Circulation (2018)

Introduction: Frequent premature ventricular contractions (PVCs) can cause contractile dysfunction/cardiomyopathy; underlying mechanisms are poorly understood. Hypothesis: Frequent PVCs cause cardi...
Chronic inflammatory arthritis following checkpoint inhibitor therapy for cancer: game changing implications
Authors: Leonard Calabrese, Xavier Mariette
Journal: Annals of the Rheumatic Diseases (2020)

The use of immune checkpoint inhibitor (ICI) therapy for cancer is now a pillar of oncological therapeutics and growing, with an estimated 43.5% of all tumours falling within current labelling indications for use.1 Eventually as the accessibility to ICI therapy increases, these data have staggering implications, given that an estimated number of new cancers in Europe and the USA exceeds 5 million individuals yearly.2 As a byproduct of this tidal wave of newly exposed patients to various forms of immunotherapy with estimates that 10%–20% or more who may develop serious immune related adverse events (irAEs),3 it is inevitable that the evaluation and care of such patients will pose a challenge to existing healthcare systems and likely create a space for a new specialty to manage such. From a rheumatological perspective, let us now consider that an estimated 3%–7% of ICI exposed patients may develop inflammatory arthritis (IA),4 5 making it seem inevitable that ICI associated IA will become ever more commonplace, giving us pause to ask ourselves what our current understanding of this disorder is and how prepared we are to manage it.

These irAEs are heterogeneous and appear to differ in their presentations, similarity to existing constructs of autoimmune diseases and their natural history. To help focus the discussion regarding these complications and based on the available data on IrAEs, we propose a classification of them into three main categories (box 1). Most irAEs are self-limiting in nature and while they may have lasting clinical effects such as ongoing requirement for hormone replacement therapy in some endocrinopathies, the inflammatory phase of these illnesses is largely self-limiting with few exceptions, with less than 10% requiring additional therapy after suppression with glucocorticoids.6 A second category is the development of a classical autoimmune disease in subjects who were …
Abstract 15513: EPRS Promotes Cardiac Fibrosis by Regulating Proline-Rich Pro-Fibrotic Protein Synthesis
Authors: Jiangbin Wu, Kadiam C Venkata Subbaiah, Feng Jiang, Omar Hedaya, Wai Hong W Tang, Peng Yao
Journal: Circulation (2019)

Introduction: Increased synthesis of pro-fibrotic proteins is a common feature of cardiac fibrosis. However, critical factors and mechanisms for translational control of cardiac fibrosis remain unc...
Association of Time Since Injury to the First Clinic Visit With Recovery Following Concussion
Authors: Anthony P. Kontos, Kendra Jorgensen-Wagers, Alicia M. Trbovich, Nathan Ernst, Kouros Emami, Brandon Gillie, Jonathan French, Cyndi Holland, R. J. Elbin, Michael W. Collins
Journal: JAMA Neurology (2020)

Recovery after concussion varies, with adolescents taking longer (approximately 30 days) than adults. Many factors have been reported to influence recovery, including preinjury factors, perceptions about recovery, comorbid conditions, and sex. However, 1 factor that may play a role in recovery but has received little attention from researchers is the timeliness of clinical evaluation and care.
Peripheral blood microRNAs expression profile: A fingerprint for metastatic prostate cancer.
Authors: Vanessa Medina Villaamil, Guadalupe Aparicio, Isabel Santamarina Cainzos, Francisco Gomez-Veiga, Manuel Valladares Ayerbes, Maria Quindós Varela, Luis M. Antón Aparicio
Journal: Journal of Clinical Oncology (2013)

e22171 Background: We previously have studied differentially microRNA expression levels related to hormone refractory and sensitive prostate cancer cell lines (VCap and LNCap respectively). Now, we investigated circulating miRNAs differentially expressed between metastatic prostate adenocarcinomas (mPA) and healthy controls (HC) that may serve as novel diagnostic and/or prognosis markers. Methods: Using SYBR-green-based custom microRNA RT-qPCR arrays technology (Exiqon), we compared the expression levels of miRNAs in blood samples from 18 HC and 48 mPA. Results: Among a panel of 92 candidates we found 41 underexpressed (UE) and 8 overexpressed (OE) miRNAs. The level of significance was p&lt;0.05. Conclusions: Among the UE miRNAs are miR-203 and 129 which regulate a cohort of metastatic genes. Among the OE is miR-200a, a member of miR-200 family which directly targeted β-catenin mRNA and miR-135b which induce invasion and distant metastasis. The knowledge of miRNAs involved in mPA progression could provide us a profile that could identify patients for adjuvant therapy or even propose new target drugs to avoid disease progression or treat mPA. Our group is actively involved in the study of selected OE miRNAs for their potential as circulating markers for mPA. [Table: see text]
Training for a First-Time Marathon Reverses Age-Related Aortic Stiffening
Authors: Anish N. Bhuva, Andrew D’Silva, Camilla Torlasco, Siana Jones, Niromila Nadarajan, Jet Van Zalen, Nish Chaturvedi, Guy Lloyd, Sanjay Sharma, James C. Moon, Alun D. Hughes, Charlotte H. Manisty
Journal: Journal of the American College of Cardiology (2020)
Abstract 19701: Trends in Inappropriate Sensing of the Subcutaneous Implantable Defibrillator
Authors: Tom F Brouwer, Anne-Floor Quast, Kirsten Kooiman, Sarah Baalman, Reinoud Knops
Journal: Circulation (2017)

Introduction: High rates of inappropriate shocks by the subcutaneous implantable cardioverter-defibrillator (S-ICD) have been reported. Dual zone programming and improvements in the rhythm discrimi...