tbuckley/cabot-search huggingface dataset:
FISH+CD34+CD38- cells detected in newly diagnosed acute myeloid leukemia patients can predict the clinical outcome
Authors: Libing Wang, Lei Gao, Sheng Xu, Shenglan Gong, Li Chen, Shuqing Lü, Jie Chen, Huiying Qiu, Xiaoqian Xu, Xiong Ni, Xianmin Song, Weiping Zhang, Jianmin Yang, Min Liu, Xiaoxia Hu, Jianmin Wang
Journal: Journal of Hematology & Oncology (2013)

In acute myeloid leukemia (AML), the leukemia initiating cells (LICs) or leukemia stem cells (LSCs) is found within the CD34+CD38- cell compartment. The LICs subpopulation survives chemotherapy and is most probable the cause of minimal residual disease (MRD), which in turn is thought to cause relapse. The aim of this study was to determine the prognostic value of the percentage of LICs in blasts at diagnosis. The percentage of LICs in the blast population was determined at diagnosis using a unique Flow-FISH analysis, which applies fluorescent in situ hybridization (FISH) analysis on flow cytometry sorted cells to distinguish LICs within the CD34+CD38- cell compartment. Fourty-five AML patients with FISH-detectable cytogenetic abnormalities treated with standardized treatment program were retrospectively included in the study. Correlations with overall survival (OS), events-free survival (EFS) and cumulative incidence of relapse (CIR) were evaluated with univariate and multivariate analysis. The percentage of LICs is highly variable in patients with acute myeloid leukemia, ranged from 0.01% to 52.8% (median, 2.1%). High LIC load (≥1%) negatively affected overall survival (2-year OS: 72.57% vs. 16.75%; P = 0.0037) and events-free survival (2-year EFS: 67.23% vs. 16.33%; P = 0.0018), which was due to an increased cumulative incidence of relapse (2-year CIR: 56.7% vs. 18.0%; P = 0.021). By multivariate analysis, high LIC load retained prognostic significance for OS and EFS. In the present study, we established the Flow-FISH protocol as a useful method to distinguish normal and leukemic cells within the CD34+CD38- cell subpopulation. The high percentage of LICs at diagnosis was significantly correlated with increased risk of poor clinical outcome.
Early Recovery of Regional Performance in Salvaged Ischemic Myocardium following Coronary Artery Occlusion in the Dog
Authors: John R. Darsee, Robert A. Kloner, Eugene Braunwald
Journal: Journal of Clinical Investigation (1981)

Although numerous agents have been shown experimentally to protect ischemic myocardium, a critical unanswered question is whether function is preserved in the salvaged tissue. Accordingly, 38 openchest dogs had measurements of percent segment length shortening (%SS) and velocity of segment length shortening either in midmyocardial or subepicardial and subendocardial ischemic segments before and after 60 min of left anterior descending coronary artery occlusion during 5 h of reperfusion; 10 additional dogs were subjected to 3 h of coronary occlusion followed by 72 h of reperfusion. 15 min after coronary artery occlusion, radiolabeled microspheres were injected into the left atrium for measurement of regional myocardial blood flow, and dogs were treated with 1 mg/kg i.v. (n = 23) of an anti-inflammatory drug, flurbiprofen or an equal volume of saline (n = 25). The ischemic myocardium-at-risk for necrosis was determined by injecting methylene blue dye into the left atrium with the coronary artery reoccluded at the end of the reperfusion period, slicing the left ventricle into thin transverse sections, and measuring the areas of each slice that were not perfused (pink unstained tissue) by methylene blue. The quantity of necrotic tissue in each transverse section was measured by planimetry after incubation of the slices in triphenyltetrazolium chloride, and by direct histological examination in dogs with 72 h of reperfusion.
PTU-101 We’re Not Immune To Immunisations In Ibd
Authors: L Macken, F Chedgy, J Medcalf, A Li
Journal: Gut (2014)

<h3>Introduction</h3> Immunomodulator therapy is commonplace in the management of inflammatory bowel disease, IBD. The European Crohn’s and Colitis Organisation, ECCO, published guidelines in 2009 recommending every patient with IBD be considered for varicella, human papilloma virus, influenza, pneumococcal and hepatitis B vaccination. This study examines current immunisation practices in an IBD population at a District General Hospital. <h3>Methods</h3> 100 consecutive patients with IBD attending general gastroenterology outpatient clinics were asked to complete a questionnaire. All subtypes of IBD were included. Information regarding IBD related medication, recent infections and immunisation status were collected. The results were analysed using the statistical package for the social sciences, SPSS software. <h3>Results</h3> 100 questionnaires were collected; 3 were excluded, 2 due to duplication of patients, 1 was submitted blank. The patients’ median age was 52 (17–86), with a male to female ratio of 36:64%. Of IBD subtypes, 52 had Crohn’s disease, CD, 42 ulcerative colitis, UC, and 3 had colitis of undetermined type or aetiology, CUTE. 91 (94%) of patients had been on prescribed medication for IBD in the last 6 months. Of those, a majority (69%) had taken mesalazine, nearly half (42%) thiopurines, a quarter (24%) steroids and 15% anti tumour necrosis factor, anti-TNF. Of the 97 patients, 64% had been on an immunosuppressing medication in the previous 6 months, 29% of which reported having had an infection in the preceding 12 months. Chest and urinary tract infections were the most commonly reported in 33% and 22% of those reporting an infection respectively. 39% of patients on immunosuppressants reported a doctor discussing vaccinations with them. 74% of immunosuppressed patients had received an immunisation of any sort. 92% of these had received influenza vaccine, 40% Pneumovax, 21% hepatitis B vaccination, and 1 (2%) human papilloma virus. Of note, all patients who reported a chest infection had received the influenza vaccine and two thirds had received Pneumovax. <h3>Conclusion</h3> A significant number of patients diagnosed with IBD will require immunosuppressing medications at some point during their care. Despite ECCO guidelines advising all patients with IBD be considered for a vaccination program at initial diagnosis, only three quarters had received any vaccinations whatsoever. Interestingly, in our small cohort, influenza and pneumococcal vaccinations did not seem to protect against self reported chest infections. Traditionally the role of vaccination has been seen as a function of primary care. Increasing awareness of the need for vaccination in primary care may improve adherence. Ultimately, with the increasing use of immunomodulators and their inherent infection risks, perhaps more responsibility should be taken on by the IBD clinician? <h3>Disclosure of Interest</h3> None Declared.
The impact of Crohn's disease genes on healthy human gut microbiota: a pilot study
Authors: Christopher Quince, Elin E Lundin, Anna N Andreasson, Dario Greco, Joseph Rafter, Nicholas J Talley, Lars Agreus, Anders F Andersson, Lars Engstrand, Mauro D'Amato
Journal: Gut (2013)

We read with interest the paper by Rehman et al 1 reporting the contribution of Nod2 genotype to the composition of gut microbiota in mice and Crohn's disease (CD) patients. This was followed by a similar description for another CD-predisposing gene, FUT2.2 To date, 163 CD- and ulcerative colitis-risk loci have been identified, and while most of the known causative genes are involved in immune functions and response to infections, their effects on the composition of the gut microbiota are mostly unknown. Studies like those mentioned above are therefore very important, since the relative abundance of specific enteric bacteria has been clearly shown to be of pathogenetic relevance in mouse models of colitis.3 By studying genotype–microbiota correlations in healthy individuals, key information could also be sought for devoid of potentially confounding effects from disease status and therapeutic treatment.

We studied the impact of 30 unequivocal CD-risk loci, each tagged by a single nucleotide polymorphism (SNP), on the mucosa-associated …
IL-29 Is Produced by T <sub>H</sub> 17 Cells and Mediates the Cutaneous Antiviral Competence in Psoriasis
Authors: Kerstin Wolk, Katrin Witte, Ellen Witte, Martin Raftery, Georgios Kokolakis, Sandra Philipp, Günther Schönrich, Katarzyna Warszawska, Stefan Kirsch, Susanna Prösch, Wolfram Sterry, Hans-Dieter Volk, Robert Sabat
Journal: Science Translational Medicine (2013)

Psoriasis, but not atopic dermatitis patients, express elevated antiviral proteins in lesional skin because of the T H 17 cytokine IL-29.
Mechanism of association between BMI and dysfunction of the gastro-oesophageal barrier in patients with normal endoscopy
Authors: Mohammad H Derakhshan, Elaine V Robertson, Jonathan Fletcher, Gareth-Rhys Jones, Yeong Yeh Lee, Angela A Wirz, Kenneth E L McColl
Journal: Gut (2011)

<h3>Introduction</h3> The association between body mass index (BMI) and gastro-oesophageal pressure gradient (GOPG) is incompletely understood. We examined the association between BMI and gastro-oesophageal (GO) barrier function and the effect of mechanically increasing intra-abdominal pressure on GO physiology. <h3>Methods</h3> (A) 103 dyspeptic patients with normal endoscopy underwent 24 h pH-metry and upper gastrointestinal manometry. Relationships between BMI and acid reflux, intragastric pressure (IGP), GOPG and lower oesophageal sphincter (LOS) pressure were calculated using bivariate correlations. (B) In 18 healthy volunteers, the effects of increasing IGP by abdominal belt on GO manometry were studied. <h3>Results</h3> (A) There was a linear correlation between BMI and oesophageal acid exposure in erect (R=0.35, p&lt;0.001) and supine (R=0.40, p&lt;0.001) positions. BMI was strongly associated with IGP (inspiration: R=0.66, p&lt;0.001; expiration: R=0.78, p&lt;0.001) and inspiratory GOPG (R=0.50, p&lt;0.001). There were a positive correlation between BMI and inspiratory LOS pressure relative to atmospheric pressure (R=0.29, p=0.016) and a negative correlation with LOS pressure relative to IGP on expiration (R=−0.25, p=0.018). Logistic regression models using all significant manometric variables and relevant interactions revealed marked decline in the magnitude and significance of relationship between BMI and oesophageal acid exposure in supine (from OR 1.12 (95% CI 1.03 to 1.22), p=0.009, to 1.00 (0.86 to 1.17), p=0.999) and upright positions (from 1.11 (1.02 to 1.20), p=0.020, to 1.03 (0.89 to 1.18), p=0.717). (B) Application of the constricting abdominal belt produced similar manometric changes to those associated with increased BMI. However, the belt did not reproduce the reduced LOS pressure relative to IGP. <h3>Conclusion</h3> The association between reflux and BMI may be largely explained by effects of increased intra-abdominal pressure. However, the reduced LOS pressure associated with BMI may be mediated by another mechanism or effects of chronic rather than acute elevation of intra-abdominal pressure.
Inhibition of Glioblastoma Angiogenesis and Invasion by Combined Treatments Directed Against Vascular Endothelial Growth Factor Receptor-2, Epidermal Growth Factor Receptor, and Vascular Endothelial-Cadherin
Authors: Katrin Lamszus, Marc A. Brockmann, Carmen Eckerich, Peter Bohlen, Chad May, Ulrich Mangold, Regina Fillbrandt, Manfred Westphal
Journal: Clinical Cancer Research (2005)

Abstract Purpose: Inhibition of angiogenesis can influence tumor cell invasion and metastasis. We previously showed that blockade of vascular endothelial growth factor receptor-2 (VEGFR-2) with the monoclonal antibody DC101 inhibited intracerebral glioblastoma growth but caused increased tumor cell invasion along the preexistent vasculature. In the present study, we attempted to inhibit glioma cell invasion using a monoclonal antibody against the epidermal growth factor receptor (EGFR), which in the context of human glioblastomas, has been implicated in tumor cell invasion. In addition, we analyzed whether blockade of vascular endothelial (VE)-cadherin as a different antiangiogenic target could also inhibit glioblastoma angiogenesis and growth. Experimental Designs: Nude mice who received intracerebral glioblastoma xenografts were treated using monoclonal antibodies against VEGFR-2 (DC101), EGFR (C225), and VE-cadherin (E4G10) either alone or in different combinations. Results: Increased tumor cell invasion provoked by DC101 monotherapy was inhibited by 50% to 66% by combined treatment with C225 and DC101. C225 inhibited glioblastoma cell migration in vitro, but had no effect on the volume of the main tumor mass or on tumor cell proliferation or apoptosis in vivo, either alone or in combination with DC101. The anti-VE-cadherin monoclonal antibody E4G10 was a weaker inhibitor of tumor angiogenesis and growth than DC101, and also caused a weaker increase in tumor cell invasion. Conclusions: Inhibition of angiogenesis achieved by blocking either VEGFR-2 or VE-cadherin can cause increased glioma cell invasion in an orthotopic model. Increased tumor cell invasion induced by potent inhibition of angiogenesis with DC101 could be inhibited by simultaneous blockade of EGFR.
Exposure of thyroid slices to thyroid-stimulating hormone induces refractoriness of the cyclic AMP system to subsequent hormone stimulation.
Authors: S J Shuman, U Zor, R Chayoth, J B Field
Journal: Journal of Clinical Investigation (1976)

These studies evaluated the influence of an initial exposure of thyroid slices to thyroid-stimulating hormone (TSH) on the subsequent responsiveness to the hormone. Bovine thyroid slices were incubated with or without 50 mU/ml TSH for varying periods and then incubated in hormone-free medium for varying periods. Subsequently, slices were incubated for 20 min with 10 mM theophylline and with or without TSH. Cylic AMP was measured after the third incubation. Phosphodiesterase and adenylate cylase were assayed in homogenates prepared from slices after the second incubation. In some experiments prostaglandin E1, puromycin, thyroxine, and triiodothyronine and propylthiouracil were included in the media. In other experiments, low does of TSH (1 AND 10 mU/ml) were used instead of 50 mU/ml. Slices previously exposed to TSH have decreased responsiveness of the adenylate cyclase-cylic AMP system. Such refractoriness is hormone specific since initial exposure to prostaglandin E1 decreases the subsequent response to this substance but not to TSH. Refractoriness to TSH develops only when the first incubation is at least 30 min. It is not reversed by 5 h of incubation without hormone. Incubation of thyroid slices with puromycin does not eliminate refractoriness. The decreased response to TSH cannot be explained by release of thyroxine, triiodothyronine, or iodide from the slices. Phosphodiesterase activity is not increased during the refractory period. The decreased cyclic AMP response to TSH is associated with diminished response of adenylate cyclase activity to the hormone. Guanosine triphosphate (1 mM) increased adenylate cyclase activity in both control and TSH treated tissue, but the effect was significantly less in the latter. Although with guanosine triphosphate, TSH increased adenylate cyclase activity in TSH treated tissue, the enzyme activity was still less than that present in control tissue incubated with guanosine triphosphate and TSH. NaF caused an equivalent stimulation of adenylate cyclase in both control and TSH treated tissue. These results suggest that the refractoriness represents an alteration in hormone binding or the coupling of the bound hormone to the adenylate cyclase activity rather than any modification of the catalytic site of the enzyme.
Oral Bisphosphonate Use and Total Knee/Hip Implant Survival: Validation of Results in an External Population‐Based Cohort
Authors: Daniel Prieto‐Alhambra, Arief Lalmohamed, Bo Abrahamsen, Nigel K. Arden, Anthonius de Boer, Peter Vestergaard, Frank de Vries
Journal: Arthritis & Rheumatology (2014)

Aseptic loosening is the most common cause of revision arthroplasty. Bisphosphonates could minimize this through their antiresorptive effects. This study was undertaken to investigate the association between bisphosphonate use and implant survival.A retrospective cohort study was conducted within the Danish nationwide registries (5.5 million residents). Using procedure codes of the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, we identified patients age ≥40 years undergoing total joint replacement in 1998-2007. We excluded users of disease-modifying antirheumatic drugs as well as patients with rheumatoid arthritis, Paget's disease, or hip fracture. Participants were classified as bisphosphonate users if they had been receiving treatment for ≥6 months. A time-varying exposure was used to avoid immortal time bias. Up to 6 bisphosphonate nonusers undergoing arthroplasty were matched to each bisphosphonate user, using propensity scores. Stratified Cox regression was performed to model implant survival according to bisphosphonate use. Further, we studied the associations of implant survival with duration of use, adherence (medication possession ratio), and timing of therapy initiation (preoperative/postoperative).Of 95,392 patients with a primary total joint replacement, 80,342 (84.2%) were eligible. We identified 1,590 bisphosphonate users (2.0%), and 1,558 of them (98.0%) were matched to 8,966 bisphosphonate nonusers. Twenty-seven of the 1,558 bisphosphonate users (1.73%) and 399 of the 8,966 matched nonusers (4.45%) underwent revision surgery during the study followup period (at a median 2.61 years after the first surgery [interquartile range 1.04-5.41 years]). Cox regression showed a reduced risk of revision surgery in bisphosphonate users (hazard ratio 0.41 [95% confidence interval 0.27-0.61]). This association was strongest in patients with the longest duration of treatment and/or the best adherence.Oral bisphosphonate users have a 59% reduced risk of revision surgery. This association is only present when bisphosphonates are started after arthroplasty surgery. Confirmation in randomized controlled trials is urgently needed.
Telomere length in chronic obstructive pulmonary disease
Authors: Eman Sobh, Magd Galal, Entesar Sayed, Mona Hilmy Alryes, Manal Refaat, Abeer Ashmawy
Journal: European Respiratory Journal (2013)

Background:  Telomere length (TL) is considered a biomarker of cellular aging. Chronic obstructive pulmonary disease (COPD) is found to be associated with premature aging and the senescence hypothesis is now accepted as a molecular pathway for COPD development.   Objectives:  to measure TL in patients with COPD and to study its relation to demographic data, spirometric-indices and arterial blood gases parameters.   Methods:  We measured TL using quantitative polymerase chain reaction, in 20 patients with severe to very severe COPD and 11 nonsmokers with normal lung function; both patients and controls were age and sex-matched males.   Measurements and Main Results:  Telomere length was significantly shorter in patients with COPD than in controls (P  2  sat %, pH (P  2  (P  1  %, FEF 25-75  % (P    Conclusions:  Our data support accelerated cellular senescence in COPD represented by shortening of telomere length, TL was positively correlated with air flow limitation and it may be related to impaired physical activities in COPD patients, which is a manifestation of aging process.
LRP: a multifunctional scavenger and signaling receptor
Authors: Joachim Herz, Dudley K. Strickland
Journal: Journal of Clinical Investigation (2001)

Multiligand receptorsLigand families and subgroups and their binding sites on LRP LRP recognizes at least 30 different ligands (Table 1) that represent several families of proteins.These include lipoproteins, proteinases, proteinaseinhibitor complexes, ECM proteins, bacterial toxins, viruses, and various intracellular proteins.
Inflammation and Carotid Artery—Risk for Atherosclerosis Study (ICARAS)
Authors: Martin Schillinger, Markus Exner, Wolfgang Mlekusch, Schila Sabeti, Jasmin Amighi, Robert Nikowitsch, Ewald Timmel, Bernhard Kickinger, Christoph Minar, Matthias Pones, Wolfgang Lalouschek, Helmut Rumpold, Gerald Maurer, Oswald Wagner, Erich Minar
Journal: Circulation (2005)

Compelling evidence suggests that inflammation is fundamentally involved in the pathogenesis of atherosclerosis; however, temporal correlation between inflammation and morphological features of atherosclerosis progression has not been demonstrated unequivocally.We prospectively studied 1268 consecutive patients who were initially asymptomatic with respect to carotid artery disease. Patients underwent serial carotid ultrasound investigations at baseline and after a follow-up interval of a median of 7.5 months (range 6 to 9 months), with measurement of carotid flow velocities and categorization of carotid arteries as 0% to 29%, 30% to 49%, 50% to 69%, 70% to 89%, or 90% to 99% stenosed or occluded. High-sensitivity C-reactive protein (hs-CRP) and serum amyloid A (SAA) were measured at baseline and follow-up. Progression of carotid atherosclerosis was found in 103 (8.1%) of 1268 patients. Hs-CRP and SAA, respectively, at baseline (P=0.004 and P=0.014) and follow-up (P<0.001 and P<0.001) and the change from baseline to follow-up (P<0.001 and P<0.001) were significantly associated with progressive atherosclerosis. Adjusted ORs (95% CI) for atherosclerosis progression with increasing quintiles of baseline hs-CRP were 1.65 (0.71 to 3.84), 1.87 (0.8 to 4.37), 3.32 (1.49 to 7.39), and 3.65 (1.65 to 8.08), and with increasing quintiles of baseline SAA, they were 0.86 (0.38 to 1.92), 0.99 (0.49 to 1.99), 1.72 (0.91 to 3.28), and 2.28 (1.24 to 4.20), respectively, compared with the lowest quintiles.These findings supply evidence for a close temporal correlation between inflammation and morphological features of rapidly progressive carotid atherosclerosis, which suggests that elevation or increase of the inflammatory biomarkers hs-CRP and SAA identifies the presence of active atherosclerotic disease.
Leptin Corrects Host Defense Defects after Acute Starvation in Murine Pneumococcal Pneumonia
Authors: Peter Mancuso, Gary B. Huffnagle, Mihal A. Olszewski, John Phipps, Marc Peters-Golden
Journal: American Journal of Respiratory and Critical Care Medicine (2005)

Leptin is an adipocyte-derived hormone that declines dramatically during fasting and plays a pivotal role in the neuroendocrine response to starvation. Previously, we employed leptin-deficient (ob/ob) mice to identify an important role for leptin in the host defense against Klebsiella pneumonia.To assess the effects of fasting on the innate immune response against pneumococcal pneumonia and to determine the effects of maintaining circulating leptin levels on host defense in fasted mice.C57BL/6 mice were either fed ad libitum or fasted for 48 h and given an intraperitoneal injection of saline or recombinant leptin (1 microg/g of body weight) twice daily for 48 h before bacterial challenge. Mice were challenged with 10(5) cfu of Streptococcus pneumoniae via the intranasal route.Lung homogenate S. pneumoniae burden was nearly 20-fold greater in the fasted as compared with fed mice. The impairment in bacterial clearance observed in fasted animals was associated with reduced bronchoalveolar lavage neutrophil counts and interleukin-6 and macrophage inflammatory protein-2 levels. Alveolar macrophages from fasted animals also exhibited defective phagocytosis and killing of S. pneumoniae and reduced calcium-ionophore-stimulated leukotriene B(4) synthesis in vitro. In contrast, the provision of exogenous leptin to fasted animals restored bacterial clearance, bronchoalveolar lavage levels of neutrophils and cytokines, alveolar macrophage bacterial killing, and leukotriene B(4) synthesis.These results suggest that reduced leptin levels substantially contribute to the suppression of pulmonary antibacterial host defense during starvation and that administration of this adipokine may be of therapeutic benefit clinically.