tbuckley/cabot-search huggingface dataset:
PARticipation in inflammation
Authors: Shaun R. Coughlin, Eric Camerer
Journal: Journal of Clinical Investigation (2003)

In this issue of the JCI, Ferrell and colleagues report that mice lacking the proteinase-activated receptor-2 (PAR-2) were protected against a form of adjuvant-induced arthritis (1). Herein we discuss protease-activated receptors, their mechanism of activation, and the contexts in which they are thought to function. A useful unifying hypothesis emerges: protease-activated receptors link tissue injury to appropriate cellular responses, and such responses, while normally homeostatic, may contribute to disease.

Protease-activated receptor-1 (PAR-1), the prototypical PAR, was identified in a search for the receptors that mediate the activation of platelets and other cells by the coagulation protease thrombin. Known to be a seven transmembrane domain G-protein–coupled receptor, PAR-1 is activated by proteolysis (Figure ​(Figure1).1). Thrombin binds to PAR-1’s N-terminal exodomain and cleaves it after Arg41 to generate a new receptor N-terminus. The first six amino acids of this new N-terminus, SFLLRN, then serve as a tethered ligand that binds intramolecularly to the receptor’s heptahelical bundle to effect transmembrane signaling and G protein activation. Thus PARs are, in essence, peptide receptors that carry their own ligands, which lie hidden until revealed by receptor cleavage. The synthetic peptide SFLLRN, which mimics the PAR-1 tethered ligand, is a PAR-1 agonist and activates PAR-1 independent of thrombin and receptor cleavage. Such peptide agonists have provided a ready tool for probing the effects of PAR activation in vitro and in vivo.



Figure 1

Mechanism of PAR-1 activation. The N-terminus of PAR-1, a seven transmembrane domain G protein–coupled receptor, contains a protease cleavage site that, once cleaved by thrombin, results in a new N-terminus. The new N-terminal sequence, SFLLRN, ...



Four PARs are currently known (recent reviews include refs. 2–4). PAR-1, PAR-3, and PAR-4 can be activated by thrombin, and thrombin is almost certainly a physiological activator of these receptors in vivo. Several other proteases can cleave these receptors productively and may also contribute to their function in vivo. PAR-2 can be activated by multiple trypsin-like serine proteases including: trypsin itself, mast cell tryptase, neutrophil proteinase 3, tissue factor/factor VIIa/factor Xa, and membrane-tethered serine protease-1. However PAR-2 is not cleaved by thrombin.
Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer
Authors: L. Rubbia-Brandt, V. Audard, P. Sartoretti, A.D. Roth, C. Brezault, M. Le Charpentier, B. Dousset, P. Morel, O. Soubrane, S. Chaussade, G. Mentha, B. Terris
Journal: Annals of Oncology (2004)
Vertical subluxation of the axis in rheumatoid arthritis.
Authors: D R Swinson, E B Hamilton, J A Mathews, D A Yates
Journal: Annals of the Rheumatic Diseases (1972)

Involvement of the upper cervical spine in rheumatoid arthritis is now well documented and recognized as a common feature of the disease.Forward subluxation of the atlas on the axis on flexion of the neck is one of the most frequent and characteristic findings, occur- ring in 25 per cent. of a series of patients reported by Conlon, Isdale, and Rose (1966) and confirmed by Mathews (1969) in a tomographic study.Backward displacement of the atlas on the axis has been des- cribed in two cases of severe rheumatoid arthritis by Isdale and Corrigan (1970) and in one patient by Crellin, Maccabe, and Hamilton (1970).Minor degrees of vertical subluxation of the axis have been found in radiological studies by several authors including, Sharp and Purser (1961), Bland, Davis, London, Van Buskirk, Duarte, and Burlington (1963), and Martel (1961).Mathews (1969) found that the odontoid peg protruded above the level of the foramen magnum in 5 per cent. of his 76 cases.The particular danger of this lesion was emphasized by Ball and Sharp (1971) and compression of the brainstem and cord by a vertically subluxed odontoid peg was considered to be the main cause of death in the cases reported by David and Markley (1951), Storey (1958), and Martel and Abell (1963), although in the case reported by Webb, Hickman, and Brew (1968) death was due to massive thrombosis of the distorted vertebral arteries.Rana and Taylor (1971) described a case of vertical migration of the odontoid process associated with acute cord compression, which was relieved by skull traction and posterior occipito-atlanto-axial fusion.Another non-fatal case reported by Newman and Sweetman (1969) showed subjective improvement after occipito-cervical fusion.In general, the outlook for these patients, as judged by these case reports, is poor.Two patients are there- fore reported below who, despite alarming radio- logical signs, have survived with conservative care.A third patient who has improved after occipital decompression is also described. Case reportsCase 1, a 60-year old woman, had a 15-year history of severe classical rheumatoid arthritis.Despite treatment
The Hypotonic Upper Airway in Obstructive Sleep Apnea
Authors: ALAN R. SCHWARTZ, CHRISTOPHER P. O'DONNELL, JOSHUA BARON, NORMAN SCHUBERT, DANIEL ALAM, SHARYAR D. SAMADI, PHILIP L. SMITH
Journal: American Journal of Respiratory and Critical Care Medicine (1998)

The structural properties of the upper airway determine its collapsibility during periods of muscle hypotonia. Both rapid-eye-movement (REM) sleep and increases in nasal pressure (PN) produce hypotonia, which persists even after nasal pressure is abruptly reduced. To determine the factors that influence the collapsibility of the hypotonic airway, the critical pressure (Pcrit) and nasal resistance upstream to the site of pharyngeal collapse (RN) were measured in the first three breaths after abrupt reductions in PN during non-REM and REM sleep. PN was reduced abruptly from 15.2 ± 3.2 cm H2O (mean ± SD) for three breaths in 19 apneic patients. Upper-airway pressure–flow relationships were analyzed to determine Pcrit for each breath in non-REM and REM sleep. We found that Pcrit rose (collapsibility increased, p < 0.001) and RN fell (p = 0.02) between the first and third breath after the decrease in PN, whereas no difference in Pcrit was detected between sleep stages. In six patients, genioglossus-muscle electromyograms (EMGs) were recorded. Peak phasic activity rose between the first and third breath (p = 0.03), but tonic and peak phasic EMG activity fell in REM as compared with non-REM sleep (p < 0.001). We conclude that the hypotonic upper airway becomes most collapsible by the third breath after an abrupt decrease in PN, regardless of sleep stage and despite an increase in genioglossus-muscle activity. Our findings suggest that predominantly mechanical rather than neuromuscular factors modulate the properties of the pharynx after abrupt reductions in nasal pressure.
Hemoglobin Scavenger Receptor CD163 Mediates Interleukin-10 Release and Heme Oxygenase-1 Synthesis
Authors: P. Philippidis, J.C. Mason, B.J. Evans, I. Nadra, K.M. Taylor, D.O. Haskard, R.C. Landis
Journal: Circulation Research (2003)

The recently described hemoglobin scavenger receptor CD163 mediates the endocytosis of hemoglobin:haptoglobin (Hb:Hp) complexes and thereby counters Hb-induced oxidative tissue damage after hemolysis. Although CD163 has been indirectly associated with antiinflammatory and atheroprotective activity, no ligand-receptor-effector pathway has yet been described for this receptor. To understand the significance of CD163 and more clearly define downstream pathways linked to inflammatory resolution, we studied the expression and function of CD163 in human monocytes/macrophages using both in vitro and in vivo models. Differentiation of human blood monocytes into macrophages either by in vitro culture or in resolving cantharidin-induced skin blisters led to an equivalent increase (&gt;15×) in CD163 expression. Elevated CD163 levels were also noted on circulating monocytes in cardiac surgical patients during the resolution phase of the systemic inflammatory response to cardiopulmonary bypass surgery. In each case, binding of Hb:Hp to CD163-bearing cells elicited potent interleukin-10 secretion, and this was inhibited by the anti-CD163 antibody RM3/1. Release of interleukin-10, in turn, induced heme oxygenase-1 stress protein synthesis via an autocrine mechanism. Such induction of heme oxygenase-1 was observed in vivo 24 to 48 hours after the onset of cardiopulmonary bypass surgery. These results identify novel antiinflammatory and cytoprotective effector pathways in human monocytes/macrophages related to Hb scavenging and metabolism, which may have relevance in atheroprotection, wound healing, and patient recovery postoperatively.
Self-Reported Adherence to Treatment With Mood Stabilizers, Plasma Levels, and Psychiatric Hospitalization
Authors: Jan Scott, Marie Pope
Journal: American Journal of Psychiatry (2002)

The authors explored the relationship of adherence to treatment with mood stabilizers (lithium, carbamazepine, and sodium valproate) and plasma levels of these drugs to future psychiatric hospitalizations.They prospectively followed 98 patients with mood disorders who were prescribed mood stabilizers. These patients participated in an initial interview and completed a questionnaire regarding their adherence to the medications. Data on their plasma levels of these drugs were taken from assays done in the 3 months before the interview.Six of the 98 patients were not classified as to medication adherence or plasma levels. Twenty-nine (32%) of the remaining patients reported partial adherence to the medication regimen, and 33 (36%) had an index plasma level that was suboptimal. At 18 months, rates of admission to a psychiatric hospital were significantly higher in the 16 partially adherent patients with subtherapeutic plasma levels (N=13, 81%) than in the 46 adherent patients with therapeutic plasma levels (N=4, 9%). However, hospital admission was also more likely in partially adherent patients with therapeutic plasma levels than in adherent patients with subtherapeutic plasma levels.Adherence to medication regimens may be a proxy measure of other healthy behaviors.
Loss of MSH3 Protein Expression Is Frequent in MLH1-Deficient Colorectal Cancer and Is Associated with Disease Progression
Authors: Jens Plaschke, Stefan Krüger, Birgit Jeske, Franz Theissig, Friedmar R. Kreuz, Steffen Pistorius, Hans D. Saeger, Ingram Iaccarino, Giancarlo Marra, Hans K. Schackert
Journal: Cancer Research (2004)

Abstract Mononucleotide repeat sequences are particularly prone to frameshift mutations in tumors with biallelic inactivation of the mismatch repair (MMR) genes MLH1 or MSH2. In these tumors, several genes harboring mononucleotide repeats in their coding region have been proposed as targets involved in tumor progression, among which are also the MMR genes MSH3 and MSH6. We have analyzed the expression of the MSH3 and MSH6 proteins by immunohistochemistry in 31 colorectal carcinomas in which MLH1 was inactivated. Loss of MSH3 expression was identified in 15 tumors (48.5%), whereas all tumors expressed MSH6. Frameshift mutations at coding microsatellites were more frequent in MSH3 (16 of 31) than in MSH6 (3 of 31; Fisher’s exact test, P &amp;lt; 0.001). Frameshift mutations and allelic losses of MSH3 were more frequent in MSH3-negative tumors compared with those with normal expression (22 mutations in 30 alleles versus 8 mutations in 28 alleles; χ2, P = 0.001). Biallelic inactivation was evident or inferred for 60% of MSH3-negative tumors but none of the tumors with normal MSH3 expression. In contrast, we did not identify frameshift mutations in the (A)8 tract of MSH3 in a control group of 18 colorectal carcinomas in which the MMR deficiency was based on the inactivation of MSH2. As it has been suggested that mutations of MSH3 might play a role in tumor progression, we studied the association between MSH3 expression and disease stage assessed by lymph node and distant metastases status. Dukes stages C and D were more frequent in primary tumors with loss of MSH3 expression (9 of 13), compared with tumors with retained expression (1 of 14; Fisher’s exact test, P = 0.001), suggesting that MSH3 abrogation may be a predictor of metastatic disease or even favor tumor cell spread in MLH1-deficient colorectal cancers.
Do all anti-citrullinated protein/peptide antibody tests measure the same? Evaluation of discrepancy between anti-citrullinated protein/peptide antibody tests in patients with and without rheumatoid arthritis
Authors: B Vander Cruyssen, L Nogueira, J Van Praet, D Deforce, D Elewaut, G Serre, F De Keyser
Journal: Annals of the Rheumatic Diseases (2007)

Background: Different methods exist to demonstrate anti-citrullinated protein/peptide antibodies (ACPA). Aims: To evaluate discrepancy between four ACPA tests. Patients and methods: Population 1 consisted of patients with a new diagnostic problem, including 86 patients with rheumatoid arthritis (RA) and 450 patients without RA. Population 2 consisted of 155 patients with RA who had long-standing disease. Population 3 consisted of 188 patients with psoriatic arthritis and in population 4 there were 192 patients with systemic lupus erythematosus. Populations 1 and 2 were tested with the anti-human fibrinogen antibody (AhfibA) test, anti-CCP2 from Eurodiagnostica (CCP2-euro), anti-CCP2 from Pharmacia (CCP2-phar) and anti-CCP3 test by Inova (CCP3). Samples were annotated as discrepant if positive in one and negative in at least one other test. Each discrepant sample was re-analysed in a different run. Populations 3 and 4 were analysed in the CCP2-euro and AhFibA test. Results: In population 1, ACPA positivity was found in 17 of 450 (3.8%) patients without RA; 14 (82%) of these 17 samples were discrepant. In contrast, 61 of 86 (70.9%) patients with RA were ACPA positive of whom 18 of 61 (29.5%) were discrepant (70.9% vs. 29.5%, p&lt;0.001). The discrepancies between tests could be partly attributed to borderline results, inter-assay discrepancy and inter-test variability. They were more prevalent in patients with systemic lupus erythematosus who were ACPA positive than in those with psoriatic arthritis who were ACPA positive. Conclusions: Discrepancy between different ACPA tests was observed attributable to the occurrence of borderline results, inter-assay variability and mainly to inter-test variability. The lowest inter-test discrepancy is observed between tests that use the same substrate.
Selective Usage of D-Type Cyclins by Ewing’s Tumors and Rhabdomyosarcomas
Authors: Jingsong Zhang, Siwen Hu, Deborah E. Schofield, Poul H. B. Sorensen, Timothy J. Triche
Journal: Cancer Research (2004)

Abstract The genetic mechanisms that control proliferation of childhood musculoskeletal malignancies, notably Ewing’s tumor (ET) and rhabdomyosarcoma (RMS), remain largely unknown. Most human cancers appear to overexpress at least one of the G1 cyclins (cyclins D1, D2, D3, E1, and E2) to bypass normal regulation of cell cycle G1 progression. We compared the gene expression profiles of 7 ET and 13 RMS primary tumor samples and found overexpression of cyclin D1 in all 7 ET samples. In contrast, RMS samples expressed higher levels of cyclin D2, cyclin D3, and cyclin E1. This was confirmed by quantitative reverse transcription-polymerase chain reaction and Western blot. The relative roles of RAS-extracellular signal-regulated kinase 1/2 and phosphatidylinositol 3′-kinase (PI3K)-AKT pathways in the regulation of D-type cyclin expression in these tumors were then assessed. Inhibition of either pathway reduced expression of cyclins D1, D2, and D3 in RMS lines, whereas only PI3K inhibitors blocked cyclin D1, D2, and D3 expression in ET lines. Furthermore, PI3K-AKT appeared to regulate D-type cyclin transcription in RMS lines through FKHR and FKHRL1. Finally, the role of the ET-associated EWS-FLI1 fusion gene in regulating D cyclin expression was studied. Inhibition of EWS-FLI1 expression in the TC71 ET line decreased cyclin D1 levels but increased cyclin D3 levels. In contrast, induction of EWS-FLI1 expression in the RD RMS cell line increased cyclin D1 expression but decreased cyclin D3 expression. Our results demonstrate distinct regulation of D-type cyclins in ET and RMS and indicate that EWS-FLI1 can modulate the expression of D-type cyclins independent of cellular backgrounds.
Pseudoprune-Belly Syndrome in Vertebral Abnormalities, Anal Atresia, Cardiac Abnormalities, Tracheoesophageal Fistula and/or Esophageal Atresia, Renal Agenesis and Dysplasia, and Limb Defects Association
Authors: B ELY, R GUSTAFSON, W KARNSAKUL
Journal: Clinical Gastroenterology and Hepatology (2008)
Privatization and Its Discontents — The Evolving Chinese Health Care System
Authors: David Blumenthal, William Hsiao
Journal: New England Journal of Medicine (2005)

In this report, the authors describe the deterioration of China's health care system in the 1980s and 1990s in the context of privatization of the Chinese economy. They discuss the Chinese government's current efforts to address the crisis in order to improve access to and delivery of health care.
Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma.
Authors: M E Horowitz, T J Kinsella, L H Wexler, J Belasco, T Triche, M Tsokos, S M Steinberg, L McClure, D L Longo, R G Steis
Journal: Journal of Clinical Oncology (1993)

In an effort to improve outcome in patients with metastatic or high-risk localized Ewing's sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT).Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT.Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008).Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.
Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines
Authors: Wen Zhang, Aaron Braun, Zachary Bauman, Horatiu Olteanu, Peter Madzelan, Ruma Banerjee
Journal: Cancer Research (2005)

Abstract Methionine metabolism provides two key cellular reagents: S-adenosylmethionine and glutathione, derived from the common intermediate, homocysteine. A majority of cancer cells exhibit a methionine-dependent phenotype whereby they are unable to grow in medium in which methionine is replaced by its precursor, homocysteine. Additionally, CpG island hypermethylation of tumor suppressor gene promoters is observed in a background of global hypomethylation in cancerous cells. In this study, we have profiled the expression levels of the homocysteine junction enzymes, methionine synthase (MS), MS reductase (MSR), and cystathionine β-synthase (CBS) in the NCI60 panel of cancer cell lines. The doubling time of non–small lung cell cancer lines, which exhibit the lowest levels of MS within the panel, was significantly correlated with expression of MS. The ratio of MS to MSR varied over a 5-fold range in the different cell types, which may modulate methionine synthesis. Interestingly, markedly reduced CBS expression was seen in the methionine-dependent prostate cancer cell line, PC-3, but not in the methionine-independent cell line, DU-145. However, neither provision of the transsulfuration pathway product, cysteine, nor overexpression of CBS rescued the growth impairment, indicating that reduced CBS was not responsible for the methionine-dependent phenotype in this cell line.
Role of histidine 95 on pH gating of the cardiac gap junction protein connexin43.
Authors: J F Ek, M Delmar, R Perzova, S M Taffet
Journal: Circulation Research (1994)

We have studied the role of histidine 95 (H95) on the pH gating of the cardiac gap junction protein connexin43 (Cx43). Wild-type and mutant rat cardiac Cx43 channels were expressed in antisense-injected Xenopus oocytes. Junctional conductance was measured using the dual voltage-clamp technique, and intracellular acidification was induced by superfusion with a sodium acetate-containing solution balanced at a pH of 6.2. H95 was substituted by other amino acids by use of oligonucleotide-directed site-specific mutagenesis. Replacing H95 for the hydrophobic residues methionine or phenylalanine, for the charged basic residue arginine, or for the noncharged residue glutamine (H95Q) yielded nonfunctional channels. Functional expression of H95Q was rescued by placing a histidine residue in position 93 (H95Q-L93H), 94 (H95Q-A94H), or 97 (H95Q-F97H) but not in position 96. Further experiments showed that replacing H95 with either aspartate (an acidic residue) or tyrosine (a polar uncharged residue) led to the expression of functional channels with a reduced susceptibility to acidification-induced uncoupling, whereas lysine (a basic residue) was more susceptible to uncoupling than the wild-type protein. The susceptibility to acidification-induced uncoupling was enhanced for the H95Q-A94H mutant when compared with the wild-type mutant, but it was significantly reduced when histidine was placed at position 93 (H95Q-L93H). Our data indicate that a properly placed histidine residue is an important structural element for functional expression as well as for pH regulation of Cx43. The results suggest that the importance of H95 on pH gating may be associated with a possible protonation of this residue on acidification of the intracellular environment.(ABSTRACT TRUNCATED AT 250 WORDS)
Long-term efficacy and toxicity results of the FLUMIZ trial (fludarabine and mitoxantrone followed by yttrium-90 ibritumomab tiuxetan in untreated follicular lymphoma)
Authors: P.L. Zinzani, E. Derenzini, C. Pellegrini, L. Rigacci, A. Fabbri, L. Gandolfi, L. Argnani, B. Casadei, A. Pulsoni, M. Gobbi, A. Perotti, A. Zaccaria, M.T. Voso, M.G. Cabras, A. De Renzo
Journal: Annals of Oncology (2012)