tbuckley/cabot-search huggingface dataset:
Adrenomedullin Is Expressed in Pancreatic Cancer and Stimulates Cell Proliferation and Invasion in an Autocrine Manner via the Adrenomedullin Receptor, ADMR
Authors: Vijaya Ramachandran, Thiruvengadam Arumugam, Rosa F. Hwang, Joel K. Greenson, Diane M. Simeone, Craig D. Logsdon
Journal: Cancer Research (2007)

Abstract The current study investigated adrenomedullin as a potential autocrine regulator of pancreatic cancer cell function. Adrenomedullin was localized in the neoplastic epithelium of 90% (43 of 48) of human pancreatic adenocarcinomas analyzed by immunohistochemistry and was expressed by 100% (8 of 8) of pancreatic cancer cell lines analyzed by reverse transcription-PCR. Pancreatic cancer cell lines also secreted adrenomedullin into the culture medium as determined by ELISA (5 of 5). Exogenous adrenomedullin treatment of Panc-1, BxPC3, and MPanc96 cells in vitro stimulated cell proliferation, invasion, and nuclear factor κB activity, indicating the ability of the cells to respond to adrenomedullin. Treatment of the cell cultures with an adrenomedullin antagonist inhibited basal levels of proliferation and nuclear factor κB activity, supporting the autocrine function of this molecule. Furthermore, increasing adrenomedullin levels by gene transfer to Panc-1 cells increased, whereas adrenomedullin small hairpin RNA silencing in MPanc96 cells inhibited tumor growth and metastasis in vivo. Adrenomedullin is able to act through at least two different receptors, adrenomedullin receptor (ADMR) and calcitonin receptor–like receptor (CRLR). Reverse transcription-PCR and Western blotting indicated that pancreatic cancer cells expressed only ADMR but not CRLR. In contrast, cells found in the tumor microenvironment, primary human pancreatic stellate and endothelial (HUVEC) cells, expressed both ADMR and CRLR. Small hairpin RNA silencing of ADMR in pancreatic cancer cells blocked adrenomedullin-induced growth and invasion, indicating that this receptor is involved in the autocrine actions of adrenomedullin. These data indicate that adrenomedullin acting via ADMR increases the aggressiveness of pancreatic cancer cells and suggests that these molecules may be useful therapeutic targets. [Cancer Res 2007;67(6):2666–75]
Urinary excretion of pyridinium crosslinks of collagen in patients with osteoporosis and the effects of bone fracture.
Authors: A M McLaren, L D Hordon, H A Bird, S P Robins
Journal: Annals of the Rheumatic Diseases (1992)

Values for the urinary excretion of pyridinium crosslinks of collagen, pyridinoline and deoxypyridinoline, in a group of 30 elderly women with femoral fractures associated with osteoporosis and a group of 20 women without recent fracture but with overt or suspected osteoporosis were compared with 27 control subjects matched for age. Relative to the control group, the excretion of the crosslinks was significantly higher in the group with fractures and the group with osteoporosis. Fractures contributed markedly to the excretion of pyridinium crosslinks as the patients with fractures showed significantly higher excretion of pyridinoline and deoxypyridinoline than the group without recent fractures. This was confirmed by the fact that excretion of pyridinium crosslinks in patients with accidental bone fractures was significantly higher than for healthy control subjects matched for age and sex. The crosslinks appear to provide valid indices of bone resorption, but the effects of bone fracture must be considered in the clinical application of this technique.
Periprocedural Cardiac Marker Elevation After Percutaneous Coronary Artery Revascularization&lt;subtitle&gt;Importance and Implications&lt;/subtitle&gt;
Authors: E. Magnus Ohman
Journal: JAMA (1997)

Up to 1 million patients annually may be undergoing percutaneous coronary revascularization with procedures including angioplasty, stent implantation, and atherectomy by the end of this decade.<sup>1</sup>Periprocedural myocardial infarction (MI) may occur in up to 14% of patients undergoing these procedures.<sup>2,3</sup>In the late 1980s, transient elevations of cardiac enzymes, such as creatine kinase (CK), were shown to occur relatively often despite a lack of symptoms indicative of MI.<sup>4-6</sup>Limited, short-term follow-up of small numbers of patients suggested that there was no increased risk of late adverse events in patients with such elevations.<sup>4,5</sup> See also p 461. In the early 1990s, several new antithrombotic therapies and devices were tested prospectively in patients undergoing percutaneous interventions.<sup>2,7</sup>Transient elevations in cardiac markers, some similar to levels seen in a typical MI, were shown to occur in 20% to 40% of patients.<sup>8-10</sup>Later examination of several large
Inhibition of prostaglandin E2 secretion. Failure to abolish autoregulation in the isolated dog kidney.
Authors: G J Kaloyanides, R E Ahrens, J A Shepherd, G F DiBona
Journal: Circulation Research (1976)

We studied the role of renal prostaglandins in the regulation of glomerular filtration rate (GFR) and renal blood flow (RBF) in the isolated dog kidney. Indomethacin or meclofenamate, 2 mg/kg of body weight, suppressed renal prostaglandin E2 (PGE2) secretion, measured by radioimmunoassay, to zero within 20 minutes; the effect persisted for the duration of the study. When renal arterial pressure (PRA) was maintained at 104 mm Hg both drugs caused a sharp decrease in sodium excretion and RBF with redistribution of flow from inner to outer cortes we examined autoregulation of GFR and RBF over the pressure ranges of 150-100 and 150-75 mm Hg, respectively, after inhibition of PGE2 secretion and under control conditions. deltaGFR/deltaPRA (ml/min per mm Hg) was 0.020 +/- 0.017 in the indomethacin group, 0.152 +/- 0.055 in the meclofenamate group, and 0.086 +/- 0.017 in the control group. The change in GFR for the indomethacin group was significantly less than that for meclofenamate (P less than 0.01) and control groups (P less than 0.025); the latter two groups were not statistically different from each other (P greater than 0.1). There was no significant difference (P greater than 0.1) between the three groups with respect to deltaRBF/deltaPRA, which measured 0.288 +/- 0.046, 0.370 +/- 0.112, and 0.438 +/- 0.123 ml/min per mm Hg in the indomethacin, meclofenamate and control groups, respectively. Renal was lowered from 150 to 75 mm Hg. The observation that inhibition of prostaglandin synthesis promotes a redistribution of RBF from inner to outer cortex suggests that renal prostaglandins may participate in the regulation of medullary blood flow. However, since autoregulation of GFR and RBF remained intact despite inhibition of prostaglandin secretion, these data argue against a role for renal prostaglandins in regulating whole kidney GFR and RBF.
Reversible Severe Congestive Cardiomyopathy in Three Cases of Hypophosphatemia
Authors: JOHN R. DARSEE
Journal: Annals of Internal Medicine (1978)

Three patients presented with severe congestive cardiomyopathy of unknown cause. All three had a profound depression of serum phosphorus levels resulting from the chronic ingestion of large quantities of a phosphorus-binding antacid. Results of physical examination and echocardiograms were consistent with cardiomegaly and severe myocardial dysfunction, and chest films showed enlargement of the cardiac silhouette with interstitial pulmonary edema. Serum phosphorus was restored to normal levels, and within 2 to 5 weeks the results of physical examination and echocardiogram of each patient returned to normal. We conclude that these patients had reversible hypophosphatemic cardiomyopathy and show the importance of inorganic phosphorus in myocardial metabolism and function. Serum phosphorus measurements should be a part of the routine evaluation of patients with congestive cardiomyopathy because, at least in some patients, hypophosphatemia appears to be a reversible cause of this disorder.
Acyl peptide hydrolase degrades monomeric and oligomeric amyloid-beta peptide
Authors: Rina Yamin, Cheng Zhao, Peter B O'Connor, Ann C McKee, Carmela R Abraham
Journal: Molecular Neurodegeneration (2009)

Abstract Background The abnormal accumulation of amyloid-beta peptide is believed to cause malfunctioning of neurons in the Alzheimer's disease brain. Amyloid-beta exists in different assembly forms in the aging mammalian brain including monomers, oligomers, and aggregates, and in senile plaques, fibrils. Recent findings suggest that soluble amyloid-beta oligomers may represent the primary pathological species in Alzheimer's disease and the most toxic form that impairs synaptic and thus neuronal function. We previously reported the isolation of a novel amyloid-beta-degrading enzyme, acyl peptide hydrolase, a serine protease that degrades amyloid-beta, and is different in structure and activity from other amyloid-beta-degrading enzymes. Results Here we report the further characterization of acyl peptide hydrolase activity using mass spectrometry. Acyl peptide hydrolase cleaves the amyloid-beta peptide at amino acids 13, 14 and 19. In addition, by real-time PCR we found elevated acyl peptide hydrolase expression in brain areas rich in amyloid plaques suggesting that this enzyme's levels are responsive to increases in amyloid-beta levels. Lastly, tissue culture experiments using transfected CHO cells expressing APP751 bearing the V717F mutation indicate that acyl peptide hydrolase preferentially degrades dimeric and trimeric forms of amyloid-beta. Conclusion These data suggest that acyl peptide hydrolase is involved in the degradation of oligomeric amyloid-beta, an activity that, if induced, might present a new tool for therapy aimed at reducing neurodegeneration in the Alzheimer's brain.
Base Pairing Constraints Drive Structural Epistasis in Ribosomal RNA Sequences
Authors: Julien Y. Dutheil, Fabrice Jossinet, Eric Westhof
Journal: Molecular Biology and Evolution (2010)

It has long been accepted that the structural constraints stemming from the 3D structure of ribosomal RNA (rRNA) lead to coevolution through compensating mutations between interacting sites. State-of-the-art methods for detecting coevolving sites, however, while reaching high levels of specificity and sensitivity for Watson–Crick (WC) pairs of the helices defining the secondary structure, only scarcely reveal tertiary interactions occurring at the level of the 3D structure. In order to understand the relative failure of coevolutionary methods to detect such interactions, we analyze 2,682 interacting sites derived from high-resolution structures, which include a comprehensive data set of rRNA sequences from Archaea and Bacteria. We report a striking difference in the amount of coevolution between WC and non-WC pairs. In order to understand this pattern, we derive fitness landscapes from the geometry of base pairing interactions and construct neutral networks of substitutions for each type of interaction. These networks show that coevolution is a property of WC pairs because, unlike non-WC pairs, their landscapes exhibit fitness valleys, a single mutation in a WC pair resulting in a fitness drop. Second, we used the inferred neutral networks to estimate the level of constraint acting on each type of base pair and show that it correlates negatively with the observed rate of substitutions for all non-WC pairs. WC pairs appear as outliers, fixing more substitutions than expected according to their level of constraint. We here propose that the rate of substitution in WC pairs is due to coevolution resulting from constraints acting at intermediate levels of organization, namely the one of the helical stem with its forming WC pairs. In agreement with this hypothesis, we report a significant excess of intrahelical, inter-WC pairs coevolution compared with interhelices pairs. Altogether, these results show that detailed biochemical knowledge is required and has to be incorporated into evolutionary reasoning in order to understand the fine patterns of variation at the molecular level. They also demonstrate that coevolutionary analysis provides almost exclusively 2D information and only little 3D signal.
15-Hydroxyprostaglandin Dehydrogenase is a Target of Hepatocyte Nuclear Factor 3β and a Tumor Suppressor in Lung Cancer
Authors: Guosheng Huang, Rosana Eisenberg, Min Yan, Stefano Monti, Earl Lawrence, Pingfu Fu, Jaclyn Walbroehl, Ester Löwenberg, Todd Golub, Jaime Merchan, Daniel G. Tenen, Sanford D. Markowitz, Balazs Halmos
Journal: Cancer Research (2008)

Abstract The forkhead transcription factor hepatocyte nuclear factor 3β (HNF3β) is essential in foregut development and the regulation of lung-specific genes. HNF3β expression leads to growth arrest and apoptosis in lung cancer cells and HNF3β is a candidate tumor suppressor in lung cancer. In a transcriptional profiling study using a conditional cell line system, we now identify 15-PGDH as one of the major genes induced by HNF3β expression. 15-PGDH is a critical metabolic enzyme of proliferative prostaglandins, an antagonist to cyclooxygenase-2 and a tumor suppressor in colon cancer. We confirmed the regulation of 15-PGDH expression by HNF3β in a number of systems and showed direct binding of HNF3β to 15-PGDH promoter elements. Western blotting of lung cancer cell lines and immunohistochemical examination of human lung cancer tissues found loss of 15-PGDH expression in ∼65% of lung cancers. Further studies using in vitro cell-based assays and in vivo xenograft tumorigenesis assays showed a lack of in vitro but significant in vivo tumor suppressor activity of 15-PGDH via an antiangiogenic mechanism analogous to its role in colon cancer. In summary, we identify 15-PGDH as a direct downstream effector of HNF3β and show that 15-PGDH acts as a tumor suppressor in lung cancer. [Cancer Res 2008;68(13):5040–8]
Long-term Efficacy of Platelet Glycoprotein IIb/IIIa Integrin Blockade With Eptifibatide in Coronary Stent Intervention
Authors: J. Conor O'Shea
Journal: JAMA (2002)

ContextIn the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, treatment with eptifibatide, a platelet glycoprotein IIb/IIIa integrin blocker, was found to reduce the ischemic complications of nonurgent coronary stent implantation at 48 hours and 30 days.ObjectiveTo determine whether eptifibatide treatment continues to provide durable, long-term benefit after coronary stent intervention.Design and SettingThe ESPRIT trial was a randomized, double-blind, placebo-controlled, parallel-group, crossover-permitted trial conducted from June 1999 through February 2000 at 92 tertiary care centers in the United States and Canada.ParticipantsA total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation.InterventionPatients were randomly assigned to receive placebo (n = 1024) or eptifibatide (two 180-µg/kg boluses, 10 minutes apart, with a continuous infusion of 2.0 µg/kg per minute; n = 1040), started immediately before stent implantation and continued for 18 to 24 hours. Patients also received aspirin, heparin, and a thienopyridine.Main Outcome MeasuresComposite rates of death or myocardial infarction (MI) and death, infarction, or target vessel revascularization during the 12 months after enrollment.ResultsComplete follow-up data were available for 988 patients given eptifibatide (95.0%) and 976 patients given placebo (95.3%). By 12 months, the composite of death or MI had occurred in 8.0% of eptifibatide-treated patients and in 12.4% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.48-0.83; P = .001). The composite rate of death, MI, or target vessel revascularization was 17.5% in eptifibatide-treated patients vs 22.1% in placebo-treated patients (HR, 0.76; 95% CI, 0.63-0.93; P = .007).ConclusionsLong-term outcomes of nonurgent coronary stent implantation appear to be improved through blockade of the platelet glycoprotein IIb/IIIa integrin with eptifibatide.
Expiratory capnography in asthma: evaluation of various shape indices
Authors: B You, R Peslin, C Duvivier, V D Vu, J P Grilliat
Journal: European Respiratory Journal (1994)

The shape of the capnogram is modified by airway obstruction, and the evaluation of this deformation, using measurable indices, could allow an indirect measurement of bronchial patency. A previous study undertaken in asthmatic subjects showed a good correlation between a capnographic index (end-tidal slope) and a spirometric parameter (forced expiratory volume in one second as a percentage of predicted (FEV1 %pred)) and suggested the study of other indices. The correlations between capnographic and spirometric indices were measured in 10 healthy subjects and 30 asthmatic patients. The usefulness of eight descriptive indices, analysing the successive phases of the capnogram, was assessed by measuring their reproducibility and their sensitivity to airway obstruction. The intraindividual and interindividual variabilities (Vi and VI) and the noise/signal ratio (Vi/VI) were measured by comparing the results of two successive capnographic measurements in 14 asthmatic subjects. The results show an increasing noise/signal ratio along the expiration (between 23 and 62%). Significant correlations between spirometry and capnography were found with all indices, but the strongest were observed with indices analysing the intermediate phase of the capnogram, that is the angle between the ascending phase (E2) and the alveolar plateau (E3). The correlations show that the analysis of the capnogram's shape is a quantitative method for evaluating the severity of bronchospasm. This ability, added to specific advantages (noninvasiveness, effort-independency, measurements during tidal breathing) opens new fields of application to capnography, such as measurement of bronchospasm in children and computerized monitoring of asthma.
Nervous Factor in Juvenile Asthma
Authors: A. K. Clarkson
Journal: BMJ (1937)

DTHCELBURNL 845 ConclusionsIt would appear, therefore, that the chance of curing a patient witL thrombocytopenic purpura by the adminis- tration of ascorbic acid is, from the evidence at present available, 33 1 / 3 per cent.There is a rather higher chance that x rays may be of value-twenty-five favourable reports against twenty unfavourable have been found.Observations on snake-venom therapy at present show eighteen patients benefited and twenty-four with no improvement.There is no evidence that liver extract is of value.Hypercalcaemia has been tried in too few cases to permit of any conclusion.Transfusion has its greatest value in tiding an acute case over the preliminary stage and in pre-operative preparation.Splenectomy to-day has an immediate mortality rate of 7 per cent.or rather less, and the majority of patients who recover from operation have a reasonable chance of permanent improvement.I am grateful to Professor F. R. Fraser for permission to make use of his clinical notes, and to
Looking back at genomic medicine in 2011
Authors: Charles Auffray, Timothy Caulfield, Muin J Khoury, James R Lupski, Matthias Schwab, Timothy Veenstra
Journal: Genome Medicine (2012)

Genomic medicine, in its broadest sense of being medical developments informed by 'omic' advances, has continued to move towards the clinic in 2011.To mark the end of the year and the beginning of 2012, the editors of the six sections within Genome Medicine were invited to provide their highlights of the past year and to hint at the developments that we are likely to see in the near future.Six different areas of progress are covered here, but the core of genomic medicine continues to be intrinsically linked to improvements in the underlying technology, and two obvious examples are sequencing and mass spec trometry.Technological advances have enabled larger studies and more complex analyses, allowing researchers and clinicians to track changes within a single cell and yet spot patterns across a whole population and within an entire physiological system.e foundations laid in 2011 should help the field to tackle the challenges of translating genomic medicine to the clinic in 2012.
Generation of primary human intestinal T cell transcriptomes reveals differential expression at genetic risk loci for immune-mediated disease
Authors: Tim Raine, Jimmy Z Liu, Carl A Anderson, Miles Parkes, Arthur Kaser
Journal: Gut (2014)

<h3>Objective</h3> Genome-wide association studies (GWAS) have identified genetic variants within multiple risk loci as predisposing to intestinal inflammatory diseases, including Crohn9s disease, ulcerative colitis and coeliac disease. Most risk variants affect regulation of transcription, but a critical challenge is to identify which genes and which cell types these variants affect. We aimed to characterise whole transcriptomes for each common T lymphocyte subset resident within the gut mucosa, and use these to infer biological insights and highlight candidate genes of interest within GWAS risk loci. <h3>Design</h3> We isolated the four major intestinal T cell populations from pinch biopsies from healthy subjects and generated transcriptomes for each. We computationally integrated these transcriptomes with GWAS data from immune-related diseases. <h3>Results</h3> Robust, high quality transcriptomic data were generated from 1 ng of RNA from precisely sorted cell subsets. Gene expression patterns clearly differentiated intestinal T cells from counterparts in peripheral blood and revealed distinct signalling pathways for each intestinal T cell subset. Intestinal-specific T cell transcripts were enriched in GWAS risk loci for Crohn9s disease, ulcerative colitis and coeliac disease, but also specific extraintestinal immune-mediated diseases, allowing prediction of novel candidate genes. <h3>Conclusions</h3> This is the first report of transcriptomes for minimally manipulated intestinal T lymphocyte subsets in humans. We have demonstrated that careful processing of mucosal biopsies allows the generation of transcriptomes from as few as 1000 highly purified cells with minimal interindividual variation. Bioinformatic integration of transcriptomic data with recent GWAS data identified specific candidate genes and cell types for inflammatory pathologies.
Plant and Animal Glycolate Oxidases Have a Common Eukaryotic Ancestor and Convergently Duplicated to Evolve Long-Chain 2-Hydroxy Acid Oxidases
Authors: Christian Esser, Anke Kuhn, Georg Groth, Martin J. Lercher, Veronica G. Maurino
Journal: Molecular Biology and Evolution (2014)

Glycolate oxidase (GOX) is a crucial enzyme of plant photorespiration. The encoding gene is thought to have originated from endosymbiotic gene transfer between the eukaryotic host and the cyanobacterial endosymbiont at the base of plantae. However, animals also possess GOX activities. Plant and animal GOX belong to the gene family of (L)-2-hydroxyacid-oxidases ((L)-2-HAOX). We find that all (L)-2-HAOX proteins in animals and archaeplastida go back to one ancestral eukaryotic sequence; the sole exceptions are green algae of the chlorophyta lineage. Chlorophyta replaced the ancestral eukaryotic (L)-2-HAOX with a bacterial ortholog, a lactate oxidase that may have been obtained through the primary endosymbiosis at the base of plantae; independent losses of this gene may explain its absence in other algal lineages (glaucophyta, rhodophyta, and charophyta). We also show that in addition to GOX, plants possess (L)-2-HAOX proteins with different specificities for medium- and long-chain hydroxyacids (lHAOX), likely involved in fatty acid and protein catabolism. Vertebrates possess lHAOX proteins acting on similar substrates as plant lHAOX; however, the existence of GOX and lHAOX subfamilies in both plants and animals is not due to shared ancestry but is the result of convergent evolution in the two most complex eukaryotic lineages. On the basis of targeting sequences and predicted substrate specificities, we conclude that the biological role of plantae (L)-2-HAOX in photorespiration evolved by co-opting an existing peroxisomal protein.