tbuckley/cabot-search huggingface dataset:
AB1313 NMR SPECTROSCOPY REVEALS ALTERATIONS OF URINARY ACETATE AND CITRATE LEVELS FOLLOWING CYCLOPHOSPHAMIDE THERAPY IN PATIENTS WITH LUPUS NEPHRITIS
Authors: Sujata Ganguly, Umesh Kumar, Nikhil Gupta, Anupam Guleria, Sanjukta Majumdar, Sanat Phatak, Smriti Chaurasia, Amita Aggarwal, Dinesh Kumar, Ramnath Misra
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background:</h3> Metabolomics, the study of global alterations in small metabolites is a useful tool to look for novel biomarkers. Recently, we reported a reprogramming of the serum metabolomic profile on nuclear magnetic resonance(NMR) spectroscopy following treatment in Lupus Nephritis (LN) <b>[1]</b>. <h3>Objectives:</h3> We explored urinary parameters using NMR Spectroscopy in patients with biopsy proven proliferative lupus nephritis. Change in parameters after 6 months Cyclophosphamide induction treatment and its correlation with disease activity was assessed. <h3>Methods:</h3> Urine obtained from Lupus Nephritis (n=18, F=16,M=2) at diagnosis and following induction therapy with cyclophosphamide, and healthy controls (n=18, median age 35,all females) were stored at -80 °C. Metabolomic profiling was done using high resolution 800 MHz 1D 1H NMR spectroscopy. Urinary ratio of metabolites was calculated- (Metabolitex1000)/Creatinine. Disease activity was measured using SLEDAI. Metabolomic profiles were compared between groups and correlated with clinical parameters using SPSS. <h3>Results:</h3> Urinary metabolomic fingerprint of LN patients differed from healthy controls by having significantly raised urinary acetate/creatinine(LN=41.84±100.6, HC=12.36±9.40, p=&lt;0.002) and reduced urinary citrate/creatinine.(LN=34.22±54.8, HC=114.5±70.09, p=&lt;0.0001). Urinary citrate (88.68±98.33) increased after 6 months of Cyclophosphamide, while urinary acetate showed a trend towards decrease(14.77±9.98). AUC for urinary citrate/creatinine and acetate/creatinine were 0.9136 and 0.8086. The urinary acetate levels correlated with SLEDAI (r=0.337,p=0.048). Urinary citrate levels correlated with C3 (r=0.362,p=0.03) and negatively correlated with uPCR (r=0.346, p=0.039). <h3>Conclusion:</h3> The decreased urinary citrate mirrors the finding seen in serum of the patients done earlier which reflects dampened aerobic glycolysis and oxidative phosphorylation.(1) Raised urinary acetate levels possibly reflects proximal renal tubular injury leading to increased urinary excretion(2). Change in levels with treatment show that urinary metabolomics parameters are potential noninvasive biomarkers for diagnosis and monitoring treatment response in LN <h3>References</h3> [1] Guleria A, et al. NMR based serum metabolomics reveals reprogramming of lipid dysregulation following Cyclophosphamide based induction therapy in lupus nephritis. J Proteome Res. 2018, 17 (7), 2440–2448. [2] Gartland KP, Bonner FW, Nicholson JK. Investigations into the biochemical effects of region-specific nephrotoxins. Molecular Pharmacology. 1989 Feb 1;35(2):242-50. <h3>Disclosure of Interests:</h3> None declared
Site-specifically labeled <sup>89</sup>Zr-DFO-trastuzumab improves immuno-reactivity and tumor uptake for immuno-PET in a subcutaneous HER2-positive xenograft mouse model
Authors: Lotte K. Kristensen, Camilla Christensen, Mette M. Jensen, Brian J. Agnew, Christina Schjöth-Frydendahl, Andreas Kjaer, Carsten H. Nielsen
Journal: Theranostics (2019)

Antibody-based PET tracers are exceptionally well-suited for determination of the in vivo biodistribution and quantification of therapeutic antibodies. The continued expansion in antibody-based therapeutics has accordingly driven the development towards more robust conjugation strategies in order to reliably predict the performance of such agents. We therefore aimed to evaluate the effect of site-specific labeling by enzymatic remodeling on the stability, immuno-reactivity and tumor-targeting properties of the monoclonal antibody (mAb) trastuzumab and compare it to conventional, random labeling in a HER2-positive xenograft mouse model. Methods: Trastuzumab was conjugated with the p-SCN-Bn-Desferrioxamine (SCN-Bn-DFO) chelator randomly on lysine residues or site-specifically on enzymatically modified glycans using either β-galactosidase or endoglycosidase S2 prior to 89Zr radiolabeling. 89Zr-DFO-trastuzumab was injected into SK-OV-3 tumor-bearing NMRI nude mice. The antibody dose was titrated with either 100 µg or 500 µg of unlabeled trastuzumab. Mice underwent small animal PET/CT imaging 24, 70 and 120 hours post-injection for longitudinal assessment. Parallel experiments were conducted with an isotype control matched antibody. In vivo imaging was supported by conventional ex vivo biodistribution and HER2 immuno-histochemistry. Furthermore, site-specifically labeled 89Zr-DFO-trastuzumab was evaluated in a panel of subcutaneous patient-derived xenograft (PDX) models. Additionally, the affinity, in vitro stability and immuno-reactivity were assessed for all tracers. Results: Site-specific labeling significantly increased PET tumor uptake (One-way ANOVA, p<0.0001) at all time-points when compared to random labeling. Mean tumor uptakes were 6.7 ± 1.7, 13.9 ± 3.3 and 15.3 ± 3.8 % injected dose per gram tissue (%ID/g) at 70 hours post-injection, for random, β-galactosidase or endoglycosidase S2 labeled probes, respectively. Co-injection with unlabeled trastuzumab increased the circulation time of tracers but did not alter tumor uptake notably. Site-specific probes presented with a superior in vitro stability and immuno-reactivity compared to the randomly labeled probe. Ex vivo biodistribution confirmed the data obtained by in vivo PET imaging, and site-specific 89Zr-DFO-trastuzumab successfully detected HER2-positive tumors in PDX mouse models. Conclusion: 89Zr-DFO-trastuzumab is well-matched for specific immuno-PET imaging of HER2-positive tumors and site-specific labeling of trastuzumab by the SiteClickTM technology minimizes the impact of the DFO chelator on immuno-reactivity, stability and biodistribution. These findings support further development of site-specifically radiolabeled mAbs for immuno-PET.
Performance of neural network basecalling tools for Oxford Nanopore sequencing
Authors: Ryan R. Wick, Louise M. Judd, Kathryn E. Holt
Journal: Genome biology (2019)

Basecalling, the computational process of translating raw electrical signal to nucleotide sequence, is of critical importance to the sequencing platforms produced by Oxford Nanopore Technologies (ONT). Here, we examine the performance of different basecalling tools, looking at accuracy at the level of bases within individual reads and at majority-rule consensus basecalls in an assembly. We also investigate some additional aspects of basecalling: training using a taxon-specific dataset, using a larger neural network model and improving consensus basecalls in an assembly by additional signal-level analysis with Nanopolish. Training basecallers on taxon-specific data results in a significant boost in consensus accuracy, mostly due to the reduction of errors in methylation motifs. A larger neural network is able to improve both read and consensus accuracy, but at a cost to speed. Improving consensus sequences ('polishing') with Nanopolish somewhat negates the accuracy differences in basecallers, but pre-polish accuracy does have an effect on post-polish accuracy. Basecalling accuracy has seen significant improvements over the last 2 years. The current version of ONT's Guppy basecaller performs well overall, with good accuracy and fast performance. If higher accuracy is required, users should consider producing a custom model using a larger neural network and/or training data from the same species.
Abstract 17780: Pulmonary Arterial Aldosterone Levels Associate with Impaired Cardiac Reserve Capacity During Exercise in Left Ventricular Systolic Heart Failure Patients
Authors: Thomas E Stephens, Bradley A Maron, Laurie A Farrell, Joseph Loscalzo, Jane A Leopold, Gregory D Lewis
Journal: Circulation (2014)

Elevated pulmonary arterial aldosterone levels (PA-ALDO) are associated with decreased exercise capacity in pulmonary hypertension patients despite normal left ventricular (LV) function. Pulmonary endothelial ALDO synthesis occurs in vitro under experimental conditions akin to LV systolic heart failure (HFrEF); however, the relevance of PA-ALDO to the clinical profile of HFrEF is not known. Therefore, we analyzed PA and radial arterial plasma in control and HFrEF patients to assess for transpulmonary ALDO release and determine if circulating ALDO is related to hemodynamic indices of cardiac reserve capacity during exercise. Data from 20 controls (51 ± 13 y, 13 females, LVEF=0.66 ± 0.9, volume of oxygen uptake at peak exercise [pVO2]=94.1 ± 11.5 % predicted) and 42 consecutive HFrEF patients (57 ± 13 y, 20 females, LVEF=0.36 ± 0.1, pVO2=47.1 ± 2.5 % predicted) undergoing invasive cardiopulmonary exercise testing were analyzed. At rest, HFrEF patients had increased PA-ALDO (714 ± 450 vs. 380 ± 187 ng/dl, P&lt;0.001) and radial ALDO levels (796 ± 483 vs. 371 ± 175 ng/dl, P&lt;0.001) compared to controls. Transpulmonary ALDO release (radial ALDO - PA-ALDO) was increased significantly in HFrEF at rest (+82 ± 20, P=0.02) and a trend was present with exercise (+62 ± 21, P=0.08). Although in controls, transpulmonary ALDO release levels were not significantly increased at rest (-9 ± 8, P=NS) or with exercise (+48 ± 13, P=NS), levels differed significantly between groups at rest and exercise (P&lt;0.05 for both). By contrast, an incremental increase at peak exercise was present in PA-ALDO by 16.3% (P&lt;0.01) and 9.2% (P&lt;0.02) for controls and HFrEF patients, respectively, but there was no significant change in levels between groups. We next explored the relationship between ALDO and cardiovascular reserve capacity measures. After controlling for age and weight in the overall cohort, resting PA-ALDO levels correlated with pVO2 (Spearman coefficient -0.37, P&lt;0.01), peak cardiac output (-0.36, P&lt;0.01), and resting mean PA pressure (0.36, P&lt;0.01). Collectively, these findings identify transpulmonary ALDO release as a novel characteristic of HFrEF and suggest that increased PA-ALDO in patients merits further investigation as a potential marker of impaired cardiac reserve capacity.
Abstract 13786: Cardiac Arrest Increases Oxygen Consumption Without Increase of Carbon Dioxide Generation in Rats
Authors: Koichiro Shinozaki, Lance B Becker, Kota Saeki, Junhwan Kim, Tai Yin, Tong Da, Xuanwen Li, Joshua W Lampe
Journal: Circulation (2017)

Introduction: It has been accepted that a metabolic alteration occurs after cardiac arrest (CA). Hypothesis: CA alters the global metabolic rate in Post-CA. In order to test the hypothesis, we meas...
PB1965 CLINICAL UTILITY OF RETICULOCYTE HEMOGLOBIN EQUIVALENT TO DIFFERENTIATE BETWEEN FUNCTIONAL IRON DEFICIENCY ANEMIA AND TRUE ANEMIA AND DIFFERENT FROM ANEMIA OF OTHER CAUSES OF CHRONIC DISEASE.
Authors: E.M. Lourenco, N. Thomas, D.V. ANTIA
Journal: HemaSphere (2019)

Background: Iron Restricted Erythropoiesis can be: 1.Absolute iron deficiency 2. Iron sequestration [impaired iron trafficking] 3. Functional iron deficiency [FID] 4. Heriditary conditions with impaired iron transport &amp; utilization. Anaemia of chronic disease [ACD] is defined as hypoproliferative anaemia of no apparent cause. Ret He is hemoglobin content equivalent of reticulocytes.Monitors iron supply during erythropoiesis over last 2‐3 days, increases within 2‐4 days of iron therapy Aims: To compare Ret He and % Hypo values with standard biochemical markers of iron metabolism: serum iron, TIBC, Transferrin saturation, serum ferritin, sTfR [Soluble Transferrin Receptor] levels and to assess in diagnosing iron deficiency. Methods: [n = 120] analysed [15 M: 10 F ratio,age 10 – 87 yrs] CBC samples [K2 EDTA] analysed on Sysmex XN1000 series.Ret He and Hypo He % identified in the reticulocyte channel by Fluorescence flowcytometry using polymethine dye Patients with Haemoglobin &lt; 10 g/dl tested [1]:Normal patients [n = 25] 20.8 %. [2]: IDA Patients [n = 45] 37.5 %. [3]: CKD Patients on haemodialysis treated with variety of erythropoietin doses [n = 12] 10 %. [4]: CKD Patients [n = 7] 5.8 %. [5]: ACD Patients [n = 31] 25.8 %. Ret‐He: Sensitivity: 97.87 %,Specificity: 96.15 %,PPV: 98.92 %,NPV: 92.59 % Results: 20 % Normal patients Ret He 33 pg In 5% of ACD,IDA co‐existented so differentiate ACD and ACD/IDA as iron supplementation is beneficial for ACD/IDA patients but deleterious for ACD patients. 37 % IDA Patients Ret He was &lt; 23.6 pg. 3.3 %patients of thalassemia with IDA, Ret‐He: 19.5pg. STfR elevated in IDA cases, but was normal in ACD &amp;FID cases Hypo He % in FID [&gt; 5%],IDA [&gt;10%] ACD [&lt;5 %]. Hypo He % measure is time average marker of iron restricted erythropoiesis [20‐120 days]. 10% CKD patients on erythropoietin doses Ret‐He &lt; 25.5 pg presents FID Normal Range for Ret He: 31‐35 pg. Summary/Conclusion: Serum Iron, TIBC, % T Sat. Screens anemia but Ret He detects &amp; gives expended information at cellular levels so assess true status of iron and predictor of marrow iron stores image Detects IDA, FID, ACD which helps differential diagnosis Ret He &lt; 23.6 pg. suggest classical iron deficiency &amp; also predicts FID in those receiving ESA [erythropoietin stimulating agent] therapy. Indicates a non responder to rHuEPO/ ESA or FID
Positron emission tomography scan (PET) in human T-cell lymphotropic virus-1 (HTLV) associated adult T-cell leukemia lymphoma (ATLL): Single center experience.
Authors: Gurinder Singh Sidhu, Mohan Preet, Rabia Latif, Constantine A Axiotis, Albert S. Braverman
Journal: Journal of Clinical Oncology (2012)

e18504 Background: Serologic positivity for HTLV and ATLL are endemic amongst Caribbean populations. Kings County and University Hospital of Brooklyn serve population with large number of immigrants from this region. ATLL in this population is mostly of aggressive (leukemia/lymphomatous) type. Responses to chemotherapy (CT) are brief, and 90% succumb to ATLLwithin 18 months (m) of presentation. Lactic dehydrogenase (LDH) levels are high, but PET is not used in routine staging. Methods: Records of all patients with ATLL presenting to these institutions between 2001-11 were reviewed. The results of PET, including maximum standard uptake value (SUVmx) were recorded for scans obtained before (12) and after (19) initial CT, and at relapse (13). Results: Of 95 T cell lymphoma patients, 73 had ATLL. PET was performed in 26 of the 73 patients; 20 of the 26 had ATLL, 5 had other T cell lymphomas. Infusional etoposide, vincristine, doxorubicin and prednisone (EPOCH) was the CT of 17 of the 20 ATLL patients; relapse occurred after a median of 9.5 m, often followed by salvage CT. Of the 6 male and 6 female patients scanned pre-CT, the median SUVmx was 9.9; range 2.9-33. Their initial median LDH level was 390 (321-683). The median overall survival (OS) was 11.5 (1-24 m). Thirteen patients had 19 post-CT scans, with a median SUVmx of 3.0; only one SUVmx was elevated (8.4); that patient had progressive disease, but the others variously displayed complete and partial remissions, or progression. Their median OS was 13 m (range 4-39 m). Their median LDH at presentation was 523. Eight patients had 13 scans at relapse, with a median SUVmx of 10.6, range 3.7-21. Their median OS was 17 m (range 12-21). OS and SUVmx were not correlated. Conclusions: Like Hodgkin’s and large B cell lymphomas, the pre-CT PET SUVmx levels of ATLL patients were significantly elevated; most fell to normal or slightly elevated levels after CT. PET is thus likely to have some value in staging ATTL. Our results suggest that PET response of ATLL patients to CT correlates poorly with durable relapse-free survival. The latter parameter is probably dependent on factors other than proliferative rate or control of aerobic glycolysis.
PB2423 THE DIAGNOSTIC RELIABILITY OF TESTS DETECTION OF LUPUS ANTICOAGULANT
Authors: V. Krasivska, O. Stasysyn
Journal: HemaSphere (2019)

Background: Antiphospholipid syndrome (APS) is an acquired autoimmune disorder that manifests clinically as recurrent venous or arterial thrombosis and/or fetal loss. Characteristic laboratory abnormalities in APS include persistently elevated levels of antiphospholipid antibodies (lupus anticoagulant (LA), anticardiolipin antibody, and/or anti-beta2-glycoprotein I) Aims: Finding the most informative coagulologic tests for the detection of LA in patients with suspected APS by identifying diagnostic laboratory eligibility criteria (sensitivity, specificity, accuracy and likelihood ratio) for each of these tests Methods: In 233 patients with suspected APS the presence of lupus anticoagulant (LA) was examined on the basis of a three-step test carried out in accordance with the current guidelines. We used clotting time with diluted viper venom time (DVVT), activated partial thromboplastin time (APTT) with LA -sensitive reagent and prothrombin time (PT) with diluted to 50 and 500 times thromboplastin. We calculated sensitivity (Se), specificity (Sp) and accuracy (Ac) for each of these tests Results: APS was diagnosed in 44,6% of patients. LA was identified in 42,5% of all the patients, which is 95,2% of all patients with APS. On the first stage a considerable Sp >75,0% (χ2 > 60,0; p < 0,001) of all phospholipid - dependent coagulation test. Ac of the first stage tests does not go <75,0% which indicates a fairly big part of true positive and true negative results of the all examined patients. However, due to low Se it's impossible to narrow the quantity of patients with the APS possibility. On the mix-stage we observed the low Se and high Sp of index of circulating anticoagulant (ICA) all the tests (χ2 > 44,74; p < 0,001). On the confirmatory stage Se for LA ratio of all the test was 61,5% - 74,4% and Sp LA ratio – 95,4% - 98,4% (χ2 > 87,42; p < 0,001). Ac of all the tests was >87,8% Summary/Conclusion: Coagulation tests of the first stage have a high diagnostic reliability due to considerable Sp and Ac. Low Se does not give a considerable certainty of anticoagulant absence if the coagulation time is within the norm. On the second stage with ICA >15,0% LA can be suspected with high probability, but the low Se does not allow us to confidently differentiate the deficiency of clotting factor from the presence of pathological inhibitors. The highest significant diagnostic efficacy was found in the confirmatory stage.
SAT0101 INTRAHOSPITAL MORTALITY IN PATIENTS WITH RHEUMATOID ARTHRITIS: OBSERVATIONAL STUDY AT THE NATIONAL LEVEL OVER A 17-YEAR PERIOD (TREND-AR STUDY)
Authors: Ramón Mazzucchelli, Elia Perez-Fernandez, Carmen Barbadillo, Natalia Crespí-Villarías, Manuel Fernandez-Prada, María Galindo-Izquierdo, Alberto García-Vadillo, Hilda Godoy, Angeles Herranz Varela, Cristina Macía-Villa, Concepción Morado Quiroga, Jose Luis Morell Hita, Javier Quirós, Virginia Villaverde, Cristina Martinez-Prada, María Espinosa
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> There have been important changes in the management of RA in the last 20 years, such as T2T strategy or new biologic agents. The potential impact of these therapeutic strategies on important objectives such as intrahospital mortality due to different causes is not known. <h3>Objectives</h3> To analyze the incidence and tendency of mortality by different causes (global, cardiovascular, infectious, neoplasm, and others) in patients with RA, in Spain, during the period 1999-2015. <h3>Methods</h3> Retrospective cohort study based on the exploitation of the database that collects a minimum basic set of data (MBDS) of all income in patients with RA. Period: 1999 to 2015. We analyzed cases of intrahospital death and the main diagnosis of these cases. The causes of death were identified by the presence of the corresponding ICD 9 codes in the main diagnostic fields. The causes of death in the hospital, global, by sex and in periods 1999-2001, 2003-2006, 2007-2010 and 2011-2015 are described. The results are expressed in absolute numbers and in proportion to the total number of deaths. <h3>Results</h3> There was a total of 338,343 hospital admissions in patients with RA during the 17 years of the study period, corresponding to a total of 176,097 patients (117,985 women and 58,112 men). There was a total of 18,641 hospital exitus (5.5% of the incomes). 63.4% were women. The mean age was 76.4 (SD 10.1) (in females of 77.2 (SD 10.2) and in men of 75.1 (SD 9.9) p &lt;.001). The mean of Charlson index was 3.2 (SD 2.4). The mean age was increased linearly from 73.5 (1999-2002) to 78.23 (2011-215). The following table shows the causes of death grouped by sex and period: <h3>Conclusion</h3> The main causes of intrahospital mortality in patients with RA in Spain were cardiovascular (24%), infections (20%), respiratory-non-infectious (15%) and neoplasms (12%). The average age of death increased 5 years in the study period. The deaths from infections, respiratory and neoplasms have increased, while those of digestive origin and AR extrarticular have decreased. <h3>Disclosure of Interests</h3> None declared
Abstract 16624: Impact of Troponin I Cut-Off Values on the Incidence of Myocardial Infarction With Non-ST-Segment Elevation: From a Higher Sensitivity to a True Greater Predictive Value?
Authors: Alessandra P Porretta, Marcello Di Valentino, Costanzo Limoni, Augusto Gallino
Journal: Circulation (2013)

Background: The diagnosis of myocardial infarction with non-ST-segment elevation (NSTEMI) is the result of a rule-out strategy, which strongly relies on cardiac biomarker elevations. However, the d...
Statins in nephrotic syndrome: A new weapon against tissue injury
Authors: Michele Buemi, Lorena Nostro, Eleonora Crascì, Antonio Barillà, Vincenzo Cosentini, Carmela Aloisi, Tito Sofi, Susanna Campo, Nicola Frisina
Journal: Medicinal Research Reviews (2005)

Abstract The nephrotic syndrome is characterized by metabolic disorders leading to an increase in circulating lipoproteins levels. Hypertriglyceridemia and hypercholesterolemia in this case may depend on a reduction in triglyceride‐rich lipoproteins catabolism and on an increase in hepatic synthesis of Apo B‐containing lipoproteins. These alterations are the starting point of a self‐maintaining mechanism, which can accelerate the progression of chronic renal failure. Indeed, hyperlipidemia can affect renal function, increase proteinuria and speed glomerulosclerosis, thus determining a higher risk of progression to dialysis. 3‐hydroxy‐3‐methylglutaryl‐coenzyme A (HMG‐CoA) reductase is the rate‐limiting enzyme in cholesterol synthesis from mevalonate and its inhibitors, or statins, can therefore interfere with the above‐mentioned consequences of hyperlipidemia. Statins are already well known for their effectiveness on primary cardiovascular prevention, which cannot be explained only through their hypolipemic effect. As far as kidney diseases are concerned, statin therapy has been shown to prevent creatinine clearance decline and to slow renal function loss, particularly in case of proteinuria, and its favorable effect may depend only partially on the attenuation of hyperlipidemia. Statins may therefore confer tissue protection through lipid‐independent mechanisms, which can be triggered by other mediators, such as angiotensin receptor blockers. Possible pathways for the protective action of statins, other than any hypocholesterolemic effect, are: cellular apoptosis/proliferation balance, inflammatory cytokines production, and signal transduction regulation. Statins also play a role in the regulation of the inflammatory and immune response, coagulation process, bone turnover, neovascularization, vascular tone, and arterial pressure. In this study, we would like to provide scientific evidences for the pleiotropic effects of statins, which could be the starting point for the development of new therapeutical strategies in different clinical areas. © 2005 Wiley Periodicals, Inc.