tbuckley/cabot-search huggingface dataset:
08.35 Thrombospondin-1 is elevated in the plasma of patients with antiphospholipid syndrome and is correlated with free active tgf-b1 levels, il-1b and il-17a
Authors: Markos D Patsouras, Athanassios G Tzioufas, Panayiotis G Vlachoyiannopoulos
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Antiphospholipid syndrome (APS) is an acquired thombophillia characterised by recurrent thromboembolism and pregnancy morbidity. Thrombospondin (TSP-1) is a r glycoprotein secreted by platelets upon activation with proinflammatory, antiangiogenic and proapoptotic properties. TSP-1 activates TGF-b<sub>1</sub> and has been shown to be involved in TH-17 response. We aimed to investigate Thrombospondin-1 in APS. <h3>Materials and methods</h3> Plasma, serum, and total IgG were isolated from 90 patients with APS, 46 healthy controls (HC) and 26 SLE patients. Monocytes and CD4<sup>+</sup> T-cells were isolated from 4 HC. Human Umbilical Vein Endothelial Cells were isolated from 2 APS patients and 5 HC and cultured with plasma or total IgG from HC or APS patients. Monocytes were stimulated with total IgG and these supernatants were used to stimulate CD4<sup>+</sup> T-cells. Plasma and cell culture supernatant TSP-1, IL-1β, IL-17A and free active TGF-β<sub>1</sub> levels were determined using an ELISA. <h3>Results</h3> APS patients had higher plasma levels of TSP-1 than HCs and SLE patients (APS: mean 390 ng/ml vs HC: 144.3 vs SLE: 153.0) Patient plasma free active TGF-β1 levels were higher and strongly correlated with TSP-1 (r=0,827). Among the APS patients those with TSP-1 levels&gt;600 ng/ml had IL-1b and IL-17A in their plasma. APS HUVECs and HC HUVECs cultured with APS plasma expressed higher levels of TSP-1 copmared to their controls. (APS=139.4 ng/ml vs HC=22.8 ng/ml p=0,0009). Monocytes stimulated with APS total IgG produced higher levels of IL-1b and TSP-1 compared to their controls (700pg/ml vs 50pg/ml and 500 ng/ml vs 200 ng/ml respectively). APS stimulated supernatants induced IL-17A expression from T-cells (250pg/ml) whereas the HC had no effect. Regarding the clinical aspects of APS, there was significant difference between the patients with pregnancy morbidity alone (130.1 ng/ml) and those with miscarriages and thrombosis (403.2 ng\ml). <h3>Conclusions</h3> Preliminary results suggest that APS patients have higher TSP-1 plasma levels which correlate with free active TGF-β1. Monocytes and HUVECs treated with APS plasma and APS IgG produce higher levels of TSP-1 and IL-1b and these supernatants induce the IL-17A expression from T-cells. All these suggest a possible involvement of TSP-1 in thrombus formation, inflammation and inhibition of angiogenesis that needs further study.
Abstract 17899: Prognostic Value of Persistent Hyponatremia in Patients With Chronic Heart Failure: A Prospective Comparative Study With Cardiac I-123 Metaiodobenzylguanidine Imaging
Authors: Masahiro Seo, Takahisa Yamada, Takashi Morita, Yoshio Furukawa, Syunsuke Tamaki, Yusuke Iwasaki, Masato Kawasaki, Atsushi Kikuchi, Takumi Kondo, Masashi Ishimi, Hideyuki Hakui, Tatsuhisa Ozaki, Yoshihiro Sato, Iyo Ikeda, Eiji Fukuhara, Masatake Fukunami
Journal: Circulation (2015)

Backgrounds: Hyponatremia is associated with not only mortality, but also excessive neurohumoral drive including sympathetic overactivation in patients (pts) with chronic heart failure (CHF). However, the prognostic significance of persistent hyponatremia (per-hypoNa) remains to be unclear in CHF pts. Cardiac metaiodobenzylguanidine (MIBG) imaging, which is useful for the estimation of cardiac sympathetic nerve activity, provides prognostic information in CHF pts. We sought to investigate whether per-hypoNa would provide the additional prognostic information to MIBG imaging in CHF pts. Methods: We studied 103 CHF outpatients with LVEF &lt;40% in our prospective cohort study. The cardiac MIBG heart-to-mediastinum ratio (H/M) washout rate (WR) were calculated from the chest anterior view images obtained at 20 and 200 min after isotope injection. We also measured serum sodium concentration at entry and every 6month for the initial 3 years. Per-hypoNa was defined that hyponatremia (&lt;137mEq/L) was observed for more than 6 months. Results: During a follow up period of 8.0±4.0 years, 41 pts died. At multivariate Cox analysis, per-hypoNa (p=0.01) and abnormal WR (p=0.007) were significantly independently associated with the mortality, although H/M showed the significant association with the mortality at the univariate analysis. Pts with per-hypoNa had a significantly higher risk of mortality than pts without per-hypoNa (67% vs 35%, p=0.03). Pts with both per-hypoNa and abnormal WR had a significantly greater risk of mortality than pts with either per-hypoNa or abnormal WR (80% vs 48% p=0.01, adjusted HR 2.8[1.2-6.5]). Furthermore, pts with either per-hypoNa or abnormal WR also had a significantly greater risk of mortality than pts with neither per-hypoNa nor abnormal WR (48% vs 22% p=0.009, adjusted HR 2.6 [1.2-5.4]). Conclusion: The combination of persistent hyponatremia and cardiac MIBG imaging could provide the improved prediction of mortality in CHF pts.
Apoptosis mediated by extracellular matrix proteins and p53 prevents full in vitro transformation of human fibroblasts.
Authors: Aatur Singhi, Mark Jackson, Shu Liu, Vadim Krivokrysenko, Katerina Gurova, George Stark, Andrei Gudkov
Journal: Cancer Research (2007)

3047   Much of our current understanding of the pathogenesis of cancer comes from studies performed in rodent cells and animal tumor models. However, human cells are more resistant to both immortalization and transformation. In fact, the same basic genetic changes required for neoplastic transformation in rodent cells have consistently failed to yield tumorigenic transformants in human cells. This indicates fundamental differences in the biology of human and rodent cells and the need to establish more representative model systems to study human tumorigenesis. Recently, several studies have been undertaken to create experimentally transformed human cancer cells in vitro. We describe a novel set of genes capable of full transformation of human cells involving hTERT, E1A, RasV12 combined with inactivation of p53. Full inactivation of p53 could be substituted by Bcl-2 indicating the key role of apoptotic function of p53 in this model of transformation suppression. Further, microarray analyses of human cells undergoing malignant transformation at different stages have identified p53 downstream targets important for transformation. As a result, we have identified the extracellular matrix proteins, Cyr61/CCN1 and CTGF/CCN2 to be both p53-responsive genes and mediators of p53-dependent transformation. Suppression of either Cyr61/CCN1 or CTGF/CCN2 was able to mimic p53 inactivation, resulting in full transformation of human fibroblasts in vitro. These results demonstrate the development of a new human transformation model system, where apoptosis plays a critical role in tumor suppression and the identification of extracellular matrix proteins that may mediate p53-dependent transformation.
Diabetes Presentation in Infancy: High Risk of Diabetic Ketoacidosis
Authors: Lisa R. Letourneau, David Carmody, Kristen Wroblewski, Anna M. Denson, May Sanyoura, Rochelle N. Naylor, Louis H. Philipson, Siri Atma W. Greeley
Journal: Diabetes Care (2017)

Diabetes in childhood has been associated with increased morbidity and mortality, but the risks for diabetes in infancy remain unclear. Cases with onset of hyperglycemia in the first 6 months of life consist predominantly of monogenic diabetes, whereas type 1 autoimmune diabetes accounts for the majority of cases beyond this threshold. Regardless of etiology, diabetes symptoms tend to be difficult to recognize in an infant, putting patients at increased risk for delays in diagnosis, which may lead to higher blood glucose levels and diabetic ketoacidosis (DKA) at presentation. Here, we report a high degree of morbidity among a cohort of subjects with infancy-onset diabetes.

We examined diagnosis records from 88 cases with diabetes onset ≤13 months of age collected through the University of Chicago Monogenic Diabetes Registry (1). We assessed laboratory values and sign/symptoms, and if a causal mutation for diabetes was detected, participants were subdivided by similar mutation subtypes. Data were managed using REDCap electronic data capture tools and analyzed using Stata version 14 (StataCorp, 2015).

The majority of participants were male ( n = 46, …
Abstract 057: β-arrestin1-Biased β1-adrenergic Receptor Signaling Regulates MicroRNA Processing
Authors: Il-man Kim, Yongchao Wang, Kyoung-mi Park, Christopher J Traynham, Lan Mao, Walter J Koch, Howard A Rockman
Journal: Circulation Research (2013)

MicroRNAs (miRs) are small, non-coding RNAs that function to post-transcriptionally regulate gene expression. First transcribed as long primary transcripts (pri-miRs), they are processed in the nucleus by Drosha into hairpin intermediates (pre-miRs) and further processed in the cytoplasm by Dicer into mature miRs where they regulate cellular processes following activation by a variety of signals such as those stimulated by β-adrenergic receptors (βARs). Initially discovered to desensitize βAR signaling, β-arrestins are now appreciated to transduce multiple effector pathways independent of G protein-mediated second messenger accumulation, a concept known as biased signaling. We previously showed that the β-arrestin-biased βAR agonist carvedilol activates cellular pathways in the heart. Here, we tested the hypothesis that carvedilol could activate β-arrestin-mediated miR maturation, thereby providing a novel potential mechanism for its cardioprotective effects. In human cells and mouse hearts, carvedilol (Carv) upregulates a subset of mature and pre-miRs but not their pri-miRs in a β1AR-, G protein-coupled receptor kinase (GRK) 5/6- and β-arrestin1-dependent manner (see figure). Mechanistically, β-arrestin1 regulates miR processing by forming a nuclear complex with hnRNPA1, a component of the Drosha microprocessor complex (see figure). In conclusion, our findings indicate a novel function for β1AR-mediated β-arrestin1 signaling in miR biogenesis, which may be linked to its cell survival mechanism and beneficial adaptive remodeling in the failing heart.
Phase Ib trial of the CpG-A Oligonucleotide CMP-001 combined with pembrolizumab (Pembro) in patients with advanced melanoma.
Authors: Mohammed M. Milhem, Hassane M. Zarour, Nashat Y. Gabrail, David J. Mauro, Norman M. Greenberg, William J. Slichenmyer, Arthur M. Krieg
Journal: Journal of Clinical Oncology (2016)

TPS9593 Background: We are developing CMP-001 to facilitate activation of the innate immune response within a tumor that will enhance response to anti-PD-1/L1 therapy. CMP-001 is comprised of a CpG-A oligodeoxynucleotide (ODN) formulated within a virus-like particle. The CpG ODN is a TLR9 agonist that activates plasmacytoid dendritic cells leading to the production of high local concentrations of Type I interferons and subsequent activation of anti-tumor CD8+ T cells that express PD-1. In syngeneic mouse models intratumoral delivery of CMP-001 in combination with systemic anti-PD-1 antibody improved tumor growth control and promoted regression in injected and un-injected tumors when compared to either agent alone. These data provide the rationale to study this combination in cancer patients. CMP-001 has been previously studied in over 700 human subjects for non-oncology indications. Adverse events noted in prior studies were primarily grade 1/2 fever, chills, flu-like symptoms and local injection-site reactions following subcutaneous administration. Methods: A Phase Ib study of CMP-001 given in combination with pembro has recently opened for enrollment at study sites in the U.S. Eligible subjects must have received pembro for advanced melanoma and present with either progressive disease, or stable disease after at least 12 weeks of pembro therapy. Subjects are permitted to have received prior treatment with anti-CLTA-4 antibody and must have received prior treatment with a BRAF inhibitor if known to have BRAF V600E+ tumors. CMP-001 is administered by intratumoral injection weekly for seven weeks, followed by q6 week dosing. Planned dose levels for CMP-001 are 1, 3, 10 and 24 mg. Pembro will continue at 2 mg/kg q3 weeks. A 3+3 design will be used during dose escalation. One or more expansion cohorts of approximately 12 subjects per cohort are planned with optional tumor biopsies pre- and on-treatment. Clinical trial information: NCT02680184.Study Objectives Primary Secondary Exploratory Recommended Phase II Dose Safety Profile Plasma cytokine levels Pharmacodynamic response of chemokine IP-10 in serum Markers of immune activation in tumor tissue Antitumor activity
08.44 Clinical and immunological characteristics of antiphospholipid syndrome in patients with incomplete systemic lupus erythematosus
Authors: Simeon Monov, Daniela Monova, Russka Shumnalieva, Rasho Rashkov, Marta Baleva
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Abstract</h3> The aim of our study is to investigate the features of the clinical course and the immunological characteristics of anti-phospholipid syndrome (APS) in patients with incomplete systemic lupus erythematosus (SLE). <h3>Material and methods</h3> 58 patients (aged from 19 to 39 years, mean age 28.57±5.37 years) with incomplete SLE according to the 1997 update of the 1982 American College of Rheumatology Revised Criteria for classification of SLE were included in the study. 53 of them were women and 5 men (sex ratio 10.6:1) and the disease duration was between 1 and 8 years (mean disease duration 3.29±1.27 years). Clinical, immunological and instrumental investigations were performed in all patients. The disease activity (DA) was determined by SLE DA index (SLEDAI) with 24 descriptors. <h3>Results</h3> APS was found in 12 (6.96%) of the studied patients. The main clinical features of APS in the studied patients with incomplete SLE were: pulmonary infarctions – in 2 (16.67%), peripheral thrombosis (a/v) – in 5 (41.67%), miscarriages/stillbirths – in 10 (83.33%). The mean immunological abnormalities were: positive aCL – in 12 (100%), positive a-β<sub>2</sub>GP1 – in 2 (16.67%), and positive LAC – in 5 (41.67%). Thrombocytopenia was found in 10 of the patients (17.24%). <h3>Conclusion</h3> 1. In patients with incomplete SLE there was a variety of systemic abnormalities; 2. According to the criteria of SLE the incomplete SLE may have a high disease activity; 3. Adding the anti-phospholipid antibodies to the diagnostic criteria of SLE is a reason some of the patients with incomplete SLE to be diagnosed as having complete SLE.
Combinatorial Effect of HDAC6i and Ibrutinib Therapy in CLL Murine Model
Authors: Kamira Karen Maharaj, John J. Powers, Susan Deng, Alex Achille, Mibel Pabon-Saldana, Renee Fonseca, Steven N Quayle, Simon S Jones, Eva Sahakian, Javier Pinilla-Ibarz
Journal: Blood (2016)
Effect of LIM-kinase 1 on cancer invasion and metastasis
Authors: Weigang Wang, Jeffrey Wyckoff, Xiaoming Chen, Ghassan Mouneimne, Mazen Sidani, John Condeelis
Journal: Cancer Research (2005)

2528  Guanine-rich strands of DNA can form four-stranded structures termed G-quadruplexes, which are built up from stacks of hydrogen bonded guanine quartets. Quadruplexes can adopt a variety of folds, dependent on, in particular the nature and length of the loop sequences. The extreme 5’ ends of eukaryotic chromosomes, which consists of G-rich single stranded DNA repeats, such as T2AG3 in humans, is capable of forming G-quadruplexes, some of which have been characterised by X-ray crystallography and NMR. There is increasing interest in quadruplexes occurring in other regions of the genome containing G-rich sequences, where they might be involved in the regulation of transcription or translation, especially where their stability is enhanced by specific ligand binding. The putative quadruplex sequences that have been identified have varying numbers of guanine bases and different loop compositions, suggesting wide variability in overall fold and detailed structure. We have embarked on a programme of computational and crystallographic studies to determine the rules governing quadruplex folding (Hazel et al, J. Am. Chem. Soc, in press). We present crystallographic and modeling data that investigate the role of loop composition in determining G-quadruplex structures. Single crystals have been obtained on both G4T3G4 and G4T2AG4 sequences, and X-ray diffraction data has been collected to high resolution (1.5 and 1.8 A respectively). The crystal structures are currently being solved. Unit cell dimensions are consistent with G-quadruplex formation ((a, b, c (A),alpha, beta, gamma(°))=30, 37, 44, 90, 90, 90 and 101, 26, 81, 90, 97, 90, for G4T3G4 and G4T2AG4 respectively). The G4T3G4 structure has exact crystallographic symmetry, with a two-fold axis through the centre of the molecule, indicating that the structure does not adopt the diagonal loop structure of the Oxytricha G4T4G4 structure. Preliminary analysis of the crystallographic data on these two G-quadruplexes with T3 and T2A loops indicates that they do not fold in the same way as quadruplexes with a T4 loop. These new structures will broaden our understanding of the influence of loop size and composition on the folding of quadruplexes, in conjunction with simulations of their flexibility using molecular dynamics simulations. The derivation of rules guiding the folding of quadruplexes will enable the design of ligands targeted specifically to potential G-quadruplex forming sequences.
03.08 High vitamin d levels may downregulate inflammation in behçet’s disease patients
Authors: Fahd Adeeb, Maria Usman Khan, Austin Stack, Alexander D. Fraser
Journal: Annals of the Rheumatic Diseases (2017)

<h3>Background</h3> Vitamin D has been shown to be directly or indirectly involved in the regulation of proliferation, differentiation, and function of immune cells. Many studies have revealed higher levels of Vitamin D deficiency among patients with autoimmune diseases compared to controls. <h3>Aim</h3> Aim of the study was to evaluate the serum 25-hydroxyvitamin D (25(OH)D) levels in Behçet's disease (BD) patients in the midwest region of Ireland, and to correlate with its disease activity. <h3>Methods</h3> All BD patients attending our rheumatology service and satisfying the ISGBD/ICBD criteria were included in the study and compared in a 1:5 ratio with samples taken from controls matched for age, gender- and the month of the year. Exclusion criteria included other rheumatological or bone/skeletal diseases, a history of chronic kidney disease or other chronic systemic diseases, malignancies, limited physical activity, and if on vitamin D supplementation or medications that could have affected vitamin D metabolism including calcium supplements, cytotoxic drugs, anticonvulsants, bisphosphonates and thyroxine but not glucocorticoids and disease-modifying anti-rheumatic drugs. The total serum 25(OH)D was measured by using competitive chemiluminescence immunoassays (DiaSorin, Dietzenbach, Germany). Levels&lt;20 ng/ml were defined as deficient, between 20–40 ng/ml as insufficient. <h3>Results</h3> 19 Caucasian BD patients were included in the study (5 male, 14 female, median age of 37.5 years (interquartile range (IQR), 24.3–51.2 years). The median 25(OH)D of BD patients and controls were 45 ng/ml (IQR,33–65 ng/ml) and 22 ng/ml (IQR, 15–31 ng/ml) respectively. The median 25(OH)D was relatively lower in active BD patients in comparison to inactive patients: 35 ng/ml (IQR, 22.75–47.25 ng/ml) compared to 50 ng/ml (IQR, 35–67 ng/ml). Overall, none of the patients had Vit D deficiency, however 6 patients had Vit D insufficiency. <h3>Conclusion</h3> In contrast to many previous studies in other BD cohorts and other autoimmune diseases our study suggests the mean 25(OH)D levels was significantly higher in this BD group. In patients with active disease however serum levels were relatively low compared to the inactive group which is in concordance with the literature. Our findings suggest vitamin D may be a potential suppressor of inflammation in BD, however larger studies are needed to support this thesis and to conclusively understand its role in the inflammatory pathway.
PREVENTION OF MUSCULOSKELETAL INJURIES AMONG DUTCH HOCKEY PLAYERS: DEVELOPMENT AND PILOT-IMPLEMENTATION OF THE KNHB INTERVENTION
Authors: Vincent Gouttebarge, Victor Zuidema
Journal: British Journal of Sports Medicine (2017)

Background Musculoskeletal injuries in the lower limbs are common in pivoting team sports such as field hockey. Consequently, the Royal Dutch Hockey Federation (KNHB) aims to prevent the occurrence of these injuries among hockey players. Objective To develop an evidence-based intervention to prevent musculoskeletal injuries in the lower limbs among youth/adult hockey players and to explore its feasibility and limited efficacy. Design The KNHB intervention was developed in accordance to a scientific framework (Intervention Mapping). Then, a pilot-implementation based on a single-group repeated-measures design was conducted. Setting Royal Dutch Hockey Federation (KNHB). Patients (or Participants) A total of 168 hockey coaches/trainers were enrolled in a pilot-implementation of 12 weeks. Interventions (or Assessment of Risk Factors) The KNHB intervention was developed according to (i) scientific literature, (ii) view of experts in hockey and injury prevention, and (iii) needs of hockey players and hockey coaches/trainers. The KNHB intervention is an age- and gender-specific warming-up programme involving more than 50 exercises divided in three phases of 4–5 minutes (preparation, motor skills, hockey skills). The KNHB intervention is available through a website and an application for smartphone/tablet in which all exercises are described with texts, pictures and video's. Main Outcome Measurements Use/feasibility of the KNHB intervention as well as level of knowledge and skills of hockey coaches/trainers about injury prevention and the KNHB intervention (Visual Analogue Scale). Results The KNHB intervention was positively evaluated, while more than 80% of the hockey coaches/trainers thought that the website and application for smartphone/table were of added value. Calculated effect size (d=0,23 between T0 and T1; d=0,34 between T0 and T2) showed a moderate effect on level of knowledge and skills of hockey coaches/trainers. Conclusions The KNHB intervention is feasible and leads to more knowledge and skills among hockey coaches/trainers. Its effect on injuries needs to be evaluated.