tbuckley/cabot-search huggingface dataset:
Dexamethasone modulation of tumour necrosis factor-alpha (cachectin) release by activated normal human alveolar macrophages
Authors: N Martinet, P Vaillant, T Charles, J Lambert, Y Martinet
Journal: European Respiratory Journal (1992)

Recurrent infections of the lower respiratory tract are a frequent and serious side-effect of chronic corticosteroid treatment. Since alveolar macrophages (AM) are currently thought to play a central role in the protection of the lower respiratory tract against infectious agents, it is likely that a steroid-induced deficiency of AM is involved in this process. In this respect, when activated, AM are major producers of tumour necrosis factor-alpha (TNF or cachectin), a versatile cytokine with several biological properties including antiviral and anti-infectious activities. A deficit of TNF production induced by corticosteroid may be one mechanism of the sensitivity to infections. Thus normal human AM obtained by bronchoalveolar lavage were pretreated with dexamethasone (DXM) before activation with lipopolysaccharides (LPS) and the amounts of TNF released in culture were quantified. Pretreatment with DXM resulted in a marked decrease of TNF release in a dose-dependent fashion. In contrast, when AM were activated with LPS before DXM treatment, TNF release by AM was suppressed in a more limited fashion. Thus DXM suppression of LPS-activated AM ability to release TNF may play a role in the susceptibility to infections of patients chronically treated with corticosteroids.
Inhibition of Vascular Smooth Muscle Cell Migration by Cytochrome P450 Epoxygenase-Derived Eicosanoids
Authors: Jianxin Sun, XinXin Sui, J. Alyce Bradbury, Darryl C. Zeldin, Michael S. Conte, James K. Liao
Journal: Circulation Research (2002)

Vascular smooth muscle cell (SMC) migration and proliferation contribute to neointimal hyperplasia and restenosis after vascular injury. The epoxyeicosatrienoic acids (EETs), which are products of cytochrome P450 (CYP) epoxygenases, possess vasodilatory, antiinflammatory, and fibrinolytic properties. To determine whether these compounds also possess antimigratory and antiproliferative properties, we stimulated rat aortic SMCs with either 20% serum or platelet-derived growth factor (PDGF-BB, 20 ng/mL). In a concentration-dependent manner, treatment with EETs, particularly 11,12-EET, inhibited SMC migration through a modified transwell filter by 53% to 60%. EETs, however, have no inhibitory effects on PDGF-stimulated SMC proliferation. Adenoviral-mediated overexpression of the CYP isoform, CYP2J2, in SMCs also inhibited serum- and PDGF-induced SMC migration by 32% and 26%, respectively; both effects of which were reversed by the CYP inhibitors SKF525A or clotrimazole, but not by the K Ca channel blocker, charybdotoxin, or the cyclooxygenase inhibitor, diclofenac. The effect of EETs correlated with increases in intracellular cAMP levels. Indeed, forskolin and 8-bromo-cAMP exert similar inhibitory effects on SMC migration as 11,12-EET and the effects of 11,12-EET were blocked by cAMP and protein kinase A (PKA) inhibitors. These findings indicate that EETs possess antimigratory effects on SMCs through the cAMP-PKA pathway and suggest that CYP epoxygenase-derived eicosanoids may play important roles in vascular disease and remodeling.
Effects of Acute Hypoxia and Lipopolysaccharide on Nitric Oxide Synthase-2 Expression in Acute Lung Injury
Authors: Jackeline Agorreta, Mercedes Garayoa, Luis M. Montuenga, Javier J. Zulueta
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

The potential role of nitric oxide synthase-2 (NOS2) in acute lung injury (ALI) has gained increasing attention. This study evaluates the effects of hypoxia, an important feature of ALI, on NOS2 expression in a rat model of ALI caused by exposure to hypoxia and LPS. Exposure to hypoxia alone had no effect on the expression of NOS2 in rat lungs. LPS treatment resulted in a significant increase in NOS2 in the lungs, which was further enhanced by concomitant exposure to hypoxia. Immunohistochemical analysis and in situ hybridization showed no changes in the expression of NOS2 in lung resident cells under any conditions. The increase in NOS2 levels is mainly due to the influx of NOS2-expressing inflammatory cells. By morphologic analysis, these inflammatory cells were identified as neutrophils, lymphocytes, and monocytes. In vitro experiments of lung epithelial and endothelial cell lines showed no detectable expression of NOS2 with any of the treatments. In a macrophage cell line, LPS-induced NOS2 expression was not affected by the concomitant exposure to hypoxia. In conclusion, LPS increases NOS2 expression in rat lungs through the recruitment of NOS2-producing leukocytes. Simultaneous exposure to LPS and hypoxia results in a greater influx of inflammatory cells that further enhances NOS2 expression.
Immunohistochemistry Versus Microsatellite Instability Testing in Phenotyping Colorectal Tumors
Authors: Noralane M. Lindor, Lawrence J. Burgart, Olga Leontovich, Richard M. Goldberg, Julie M. Cunningham, Daniel J. Sargent, Catherine Walsh-Vockley, Gloria M. Petersen, Michael D. Walsh, Barbara A. Leggett, Joanne P. Young, Melissa A. Barker, Jeremy R. Jass, John Hopper, Steve Gallinger, Bharati Bapat, Mark Redston, Stephen N. Thibodeau
Journal: Journal of Clinical Oncology (2002)

PURPOSE: To compare microsatellite instability (MSI) testing with immunohistochemical (IHC) detection of hMLH1 and hMSH2 in colorectal cancer. PATIENTS AND METHODS: Colorectal cancers from 1,144 patients were assessed for DNA mismatch repair deficiency by two methods: MSI testing and IHC detection of hMLH1 and hMSH2 gene products. High-frequency MSI (MSI-H) was defined as more than 30% instability of at least five markers; low-level MSI (MSI-L) was defined as 1% to 29% of loci unstable. RESULTS: Of 1,144 tumors tested, 818 showed intact expression of hMLH1 and hMSH2. Of these, 680 were microsatellite stable (MSS), 27 were MSI-H, and 111 were MSI-L. In all, 228 tumors showed absence of hMLH1 expression and 98 showed absence of hMSH2 expression: all were MSI-H. CONCLUSION: IHC in colorectal tumors for protein products hMLH1 and hMSH2 provides a rapid, cost-effective, sensitive (92.3%), and extremely specific (100%) method for screening for DNA mismatch repair defects. The predictive value of normal IHC for an MSS/MSI-L phenotype was 96.7%, and the predictive value of abnormal IHC was 100% for an MSI-H phenotype. Testing strategies must take into account acceptability of missing some cases of MSI-H tumors if only IHC is performed.
Long Noncoding RNA <i>HOTAIR</i> Regulates Polycomb-Dependent Chromatin Modification and Is Associated with Poor Prognosis in Colorectal Cancers
Authors: Ryunosuke Kogo, Teppei Shimamura, Koshi Mimori, Kohichi Kawahara, Seiya Imoto, Tomoya Sudo, Fumiaki Tanaka, Kohei Shibata, Akira Suzuki, Shizuo Komune, Satoru Miyano, Masaki Mori
Journal: Cancer Research (2011)

The functional impact of recently discovered long noncoding RNAs (ncRNAs) in human cancer remains to be clarified. One long ncRNA which has attracted attention is the Hox transcript antisense intergenic RNA termed HOTAIR, a long ncRNA expressed from the developmental HOXC locus located on chromosome 12q13.13. In cooperation with Polycomb complex PRC2, the HOTAIR long ncRNA is reported to reprogram chromatin organization and promote breast cancer metastasis. In this study, we examined the status and function of HOTAIR in patients with stage IV colorectal cancer (CRC) who have liver metastases and a poor prognosis. HOTAIR expression levels were higher in cancerous tissues than in corresponding noncancerous tissues and high HOTAIR expression correlated tightly with the presence of liver metastasis. Moreover, patients with high HOTAIR expression had a relatively poorer prognosis. In a subset of 32 CRC specimens, gene set enrichment analysis using cDNA array data revealed a close correlation between expression of HOTAIR and members of the PRC2 complex (SUZ12, EZH2, and H3K27me3). Our findings suggest that HOTAIR expression is associated with a genome-wide reprogramming of PRC2 function not only in breast cancer but also in CRC, where upregulation of this long ncRNA may be a critical element in metastatic progression.
The UMKC Medical Education Experiment
Authors: E. Grey Dimond
Journal: JAMA (1988)

IN SEPTEMBER 1969, after a two-day visit to Kansas City, a survey team representing the Liaison Committee on Medical Education gave this opinion: The'educational program of the University of Missouri—Kansas City [UMKC] School of Medicine, if developed as presently proposed, will constitute a significant departure from the typical pattern of education in American medical schools. As such, it should be viewed as an experiment in medical education. In the opinion of the survey team, the experiment should be permitted to continue with the knowledge and consent of the Liaison Committee on Medical Education. The survey team's awareness that it was authorizing a major departure in medical education was made clear in the next paragraph: The University has consciously undertaken the development of a different kind of medical school, with a major emphasis upon education of the student to provide medical care, with early and continuous involvement of the student with
Streptozocin and o,p'DDD in the treatment of adrenocortical cancer patients: Long-term survival in its adjuvant use
Authors: T.S. Khan, H. Imam, C. Juhlin, B. Skogseid, S. Gröndal, S. Tibblin, E. Wilander, K. Öberg, B. Eriksson
Journal: Annals of Oncology (2000)
Inhibitory effect of a cholecystokinin antagonist on the proliferative response of the pancreas to pancreatobiliary diversion.
Authors: P Watanapa, E F Efa, K Beardshall, J Calam, C E Sarraf, M R Alison, R C Williamson
Journal: Gut (1991)

Since pancreatobiliary diversion probably stimulates pancreatic growth by increasing cholecystokinin secretion, the effect of the cholecystokinin antagonist CR-1409 on this adaptive response was tested. Male Wistar rats (n = 108) weighing 220-250g were randomised to receive either pancreatobiliary diversion (n = 60) or sham diversion (n = 48) and thereafter to receive either saline injections or CR-1409 (10 mg/kg/day, subcutaneously). Rats were killed at four, seven, and 14 days postoperatively, when blood was obtained for cholecystokinin assay and the pancreas was assessed for proliferative activity by three techniques: nucleic acid and protein assay, bromodeoxyuridine labelling, and metaphase arrest after vincristine administration (1 mg/kg, intraperitoneally). Pancreatobiliary diversion increased plasma cholecystokinin concentrations by 91% at seven days and 137% at 14 days, irrespective of CR-1409 treatment. Total pancreatic RNA content was doubled by pancreatobiliary diversion at four days (2.15 v 1.07 mg/100 g body weight: p less than 0.001) and at seven days (3.43 v 1.76 mg/100 g: p less than 0.001), and trebled at 14 days (4.27 v 1.32 mg/100 g: p less than 0.001). Pancreatobiliary diversion increased bromodeoxyuridine labelling index from 1.1 to 3.7% at seven days and the cell birth rate from 0.09 to 0.06%. CR-1409 completely abolished this proliferative response and partly prevented the rise in RNA. The results confirm pancreatic hypertrophy and increased acinar cell proliferation after pancreatobiliary diversion. CR-1409 prevents this adaptive growth, probably by blocking cholecystokinin receptors. Bromodeoxyuridine labelling and the metaphase arrest technique may be used to assess pancreatic cell kinetics.
Schindler disease: the molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes an infantile neuroaxonal dystrophy.
Authors: A M Wang, D Schindler, R Desnick
Journal: Journal of Clinical Investigation (1990)

Schindler disease is a recently recognized infantile neuroaxonal dystrophy resulting from the deficient activity of the lysosomal hydrolase, alpha-N-acetylgalctosaminidase (alpha-GalNAc). The recent isolation and expression of the full-length cDNA encoding alpha-GalNAc facilitated the identification of the molecular lesions in the affected brothers from family D, the first cases described with this autosomal recessive disease. Southern and Northern hybridization analyses of DNA and RNA from the affected homozygotes revealed a grossly normal alpha-GalNAc gene structure and normal transcript sizes and amounts. Therefore, the alpha-GalNAc transcript from an affected homozygote was reverse-transcribed, amplified by the polymerase chain reaction (PCR), and sequenced. A single G to A transition at nucleotide 973 was detected in multiple subclones containing the PCR products. This point mutation resulted in a glutamic acid to lysine substitution in residue 325 (E325K) of the alpha-GalNAc polypeptide. The base substitution was confirmed by dot blot hybridization analyses of PCR-amplified genomic DNA from family members with allele-specific oligonucleotides. Furthermore, transient expression of an alpha-GalNAc construct containing the E325K mutation resulted in the expression of an immunoreactive polypeptide which had no detectable alpha-GalNAc activity.
Race, Gender, and Incident Dialysis Patients’ Reported Health Status and Quality of Life
Authors: Nancy G. Kutner, Rebecca Zhang, Donna Brogan
Journal: Journal of the American Society of Nephrology (2005)

Patient-reported physical and mental health status, along with disease-specific concerns ("quality of life") reported by patients, provide information about experience on dialysis that can help to improve patient care. Among prevalent hemodialysis (HD) patients, blacks have been shown to report higher health status and quality of life scores than whites, but whether similar race differences characterize incident patients who start regular dialysis is not known. Health status and quality of life, measured by the Kidney Disease Quality of Life-Short Form, reported by black men, black women, white men, and white women who initiated HD and peritoneal dialysis (PD) in the Dialysis Morbidity and Mortality Study (DMMS) Wave 2 were examined. After adjustment for patients' sociodemographic and clinical characteristics, the only race differences observed were that among HD patients, black women scored highest on the burden of kidney disease measure (lower perceived burden), and among PD patients, black men had the lowest satisfaction with care scores. It is possible that differences between blacks' and whites' reported health status and quality of life become more evident as patients' dialysis vintage increases, a hypothesis that requires following a well-characterized incident cohort over time. These findings add to existing evidence that minority patients on dialysis report less satisfaction with their care than do white patients, an important area for continued study.
Thrombotic thrombocytopenic purpura: reducing the risk?
Authors: Michael C. Berndt, Robert K. Andrews
Journal: Journal of Clinical Investigation (2011)

von Willebrand factor (vWF) has a key role in initiating platelet aggregation, and thereby thrombus formation, that is dependent on its ability to form appropriately sized multimers. Ultralarge multimers promote the formation of the microvascular thrombi that are hallmarks of the life-threatening condition thrombotic thrombocytopenic purpura (TTP). In this issue of the JCI, Chen et al. show that the drug N-acetylcysteine (NAC) can decrease the size of vWF multimers in vitro and in vivo, resolving thrombi in mice. These data suggest that NAC could potentially be used to treat thrombotic conditions such as TTP.
Hypomorphic Mutation in the Site-1 Protease Mbtps1 Endows Resistance to Persistent Viral Infection in a Cell-Specific Manner
Authors: Daniel L. Popkin, John R. Teijaro, Brian M. Sullivan, Shuzo Urata, Sophie Rutschmann, Juan Carlos de la Torre, Stefan Kunz, Bruce Beutler, Michael Oldstone
Journal: Cell Host & Microbe (2011)
Getting to the heart of the matter
Authors: D. Pyne, K. Barakat, M. T Rothman
Journal: Annals of the Rheumatic Diseases (1999)

Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle–associated protein). Taken together, our data redefine the AVRs as Tie2 signaling–dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.
Randomized Phase III Trial Comparing ABVD Plus Radiotherapy With the Stanford V Regimen in Patients With Stages I or II Locally Extensive, Bulky Mediastinal Hodgkin Lymphoma: A Subset Analysis of the North American Intergroup E2496 Trial
Authors: Ranjana H. Advani, Fangxin Hong, Richard I. Fisher, Nancy L. Bartlett, K. Sue Robinson, Randy D. Gascoyne, Henry Wagner, Patrick J. Stiff, Bruce D. Cheson, Douglas A. Stewart, Leo I. Gordon, Brad S. Kahl, Jonathan W. Friedberg, Kristie A. Blum, Thomas M. Habermann, Joseph M. Tuscano, Richard T. Hoppe, Sandra J. Horning
Journal: Journal of Clinical Oncology (2015)

The phase III North American Intergroup E2496 Trial (Combination Chemotherapy With or Without Radiation Therapy in Treating Patients With Hodgkin's Lymphoma) compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) with mechlorethamine, doxorubicin, vincristine, bleomycin, vinblastine, etoposide, and prednisone (Stanford V). We report results of a planned subgroup analysis in patients with stage I or II bulky mediastinal Hodgkin lymphoma (HL).Patients were randomly assigned to six to eight cycles of ABVD every 28 days or Stanford V once per week for 12 weeks. Two to 3 weeks after completion of chemotherapy, all patients received 36 Gy of modified involved field radiotherapy (IFRT) to the mediastinum, hila, and supraclavicular regions. Patients on the Stanford V arm received IFRT to additional sites ≥ 5 cm at diagnosis. Primary end points were failure-free survival (FFS) and overall survival (OS).Of 794 eligible patients, 264 had stage I or II bulky disease, 135 received ABVD, and 129 received Stanford V. Patient characteristics were matched. The overall response rate was 83% with ABVD and 88% with Stanford V. At a median follow-up of 6.5 years, the study excluded a difference of more than 21% in 5-year FFS and more than 16% in 5-year OS between ABVD and Stanford V (5-year FFS: 85% v 79%; HR, 0.68; 95% CI, 0.37 to 1.25; P = .22; 5-year OS: 96% v 92%; HR, 0.49; 95% CI, 0.16 to 1.47; P = .19). In-field relapses occurred in < 10% of the patients in each arm.For patients with stage I or II bulky mediastinal HL, no substantial statistically significant differences were detected between the two regimens, although power was limited. To the best of our knowledge, this is the first prospective trial reporting outcomes specific to this subgroup, and it sets a benchmark for comparison of ongoing and future studies.
A Clinical Report of the Use of Low-Molecular-Weight Dextran in a Rotating Oxygenator
Authors: J. C. A. Raison
Journal: Thorax (1962)

Increasing use of heart-lung machines accentuates the desirability of reducing demands on blood donors by the addition of other priming fluids.Neptune, Bougas, and Panico (1960) described a machine requiring no priming blood, and Zuhdi, McCollough, Carey, Krieger, and Greer (1961) accepted haemodilution by 5% dextrose solution during hypothermic perfusion.Recently Long, Sanchez, Varco, and Lillehei (1961) have used low molecular weight dextran during perfusion, and demonstrate by elegant studies of the microcirculation that reduction in " sludging" of red cells results in improved peripheral circulation.Drake and Lewis (1961) are unable to confirm this effect but note the prevention of haemoconcentration during hypo- thermia as a benefit.Finsterbusch, Long, Sellers, Amplatz, and Lillehei (1961) found improved renal flow during perfusion using low molecular weight dextran.All these studies used low flow perfusion rates.Unusual foaming characteristics when using dextrans in bubble oxygenators may be acceptable because of the debubbling methods already necessary but might provide special difficulties in the use of a rotating oxygenator, particularly at high flow rates.A clinical trial of these features has been successfully carried out.
Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study
Authors: G Jones, A Sebba, J Gu, M B Lowenstein, A Calvo, J J Gomez-Reino, D A Siri, M Tomšič, E Alecock, T Woodworth, M C Genovese
Journal: Annals of the Rheumatic Diseases (2009)

Background: The anti-interleukin (IL) 6 receptor antibody tocilizumab inhibits signalling of IL6, a key cytokine in rheumatoid arthritis (RA) pathogenesis. Objective: To evaluate through the AMBITION study the efficacy and safety of tocilizumab monotherapy versus methotrexate in patients with active RA for whom previous treatment with methotrexate/biological agents had not failed. Methods: This 24-week, double-blind, double-dummy, parallel-group study, randomised 673 patients to either tocilizumab 8 mg/kg every 4 weeks, or methotrexate, starting at 7.5 mg/week and titrated to 20 mg/week within 8 weeks, or placebo for 8 weeks followed by tocilizumab 8 mg/kg. The primary end point was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 24. Results: The intention-to-treat analysis demonstrated that tocilizumab was better than methotrexate treatment with a higher ACR20 response (69.9 vs 52.5%; p&lt;0.001), and 28-joint Disease Activity Score (DAS28) &lt;2.6 rate (33.6 vs 12.1%) at week 24. Mean high-sensitivity C-reactive protein was within the normal range from week 12 with tocilizumab, whereas levels remained elevated with methotrexate. The incidence of serious adverse events with tocilizumab was 3.8% versus 2.8% with methotrexate (p = 0.50), and of serious infections, 1.4% versus 0.7%, respectively. There was a higher incidence of reversible grade 3 neutropenia (3.1% vs 0.4%) and increased total cholesterol ⩾240 mg/dl (13.2% vs 0.4%), and a lower incidence of alanine aminotransferase elevations &gt;3×–&lt;5× upper limit of normal (1.0% vs 2.5%), respectively. Conclusion: Tocilizumab monotherapy is better than methotrexate monotherapy, with rapid improvement in RA signs and symptoms, and a favourable benefit–risk, in patients for whom treatment with methotrexate or biological agents has not previously failed. Trial registration number: NCT00109408