tbuckley/cabot-search huggingface dataset:
Dual Role for Nitric Oxide in the Regulation of Plasma Volume and Albumin Escape During Endotoxin Shock in Conscious Rats
Authors: János G. Filep, Aline Delalandre, Micheline Beauchamp
Journal: Circulation Research (1997)

To assess the role of nitric oxide (NO) produced by the constitutive (cNOS) and inducible NO synthase (iNOS) in the regulation of vascular functions, we compared the effects of aminoguanidine, a relatively selective inhibitor of iNOS, and NG-nitro-L-arginine methyl ester (L-NAME), a nonselective NOS inhibitor on blood pressure, plasma volume, and albumin escape during the early and delayed phases of endotoxin shock in conscious, chronically catheterized rats. Red blood cell volume and plasma volume were determined by using chromium-51-tagged erythrocytes and iodine-125-labeled albumin, respectively. Injection of lipopolysaccharide (LPS) 10 mg/kg i.v. resulted in a fall in blood pressure, hemoconcentration, and increased total-body albumin escape, which is reflected by a 25% reduction in plasma volume. When LPS was injected into animals pretreated with L-NAME (7.4 mumol/kg i.v. 15 minutes before LPS), losses in plasma volume and albumin escape were significantly greater than in rats that received LPS alone, despite that L-NAME attenuated the hypotensive action of LPS. Aminoguanidine pretreatment (162 mumol/kg) had no effect on the early responses to LPS, whereas it was as potent as L-NAME in reversing hypotension when injected 70 minutes after LPS. Aminoguanidine treatment also prevented further losses in plasma volume and markedly attenuated total-body and organ albumin escape rates elicited by LPS. L-NAME produced only a slight attenuation of LPS-induced losses in plasma volume and albumin escape in most organs studied, whereas it potentiated albumin extravasation in the lung. These results demonstrate that inhibition of cNOS potentiates, whereas inhibition of iNOS markedly attenuates, losses in plasma volume and albumin escape elicited by LPS, and suggest that selective inhibitors of iNOS may be more effective than nonselective inhibitors of all forms of NOS in the therapy of septic shock.
CYCLOOXYGENASES 1 AND 2
Authors: J. R. Vane, Y. S. Bakhle, R. M. Botting
Journal: The Annual Review of Pharmacology and Toxicology (1998)

▪ Abstract Cyclooxygenase (COX), first purified in 1976 and cloned in 1988, is the key enzyme in the synthesis of prostaglandins (PGs) from arachidonic acid. In 1991, several laboratories identified a product from a second gene with COX activity and called it COX-2. However, COX-2 was inducible, and the inducing stimuli included pro-inflammatory cytokines and growth factors, implying a role for COX-2 in both inflammation and control of cell growth. The two isoforms of COX are almost identical in structure but have important differences in substrate and inhibitor selectivity and in their intracellular locations. Protective PGs, which preserve the integrity of the stomach lining and maintain normal renal function in a compromised kidney, are synthesized by COX-1. In addition to the induction of COX-2 in inflammatory lesions, it is present constitutively in the brain and spinal cord, where it may be involved in nerve transmission, particularly that for pain and fever. PGs made by COX-2 are also important in ovulation and in the birth process. The discovery of COX-2 has made possible the design of drugs that reduce inflammation without removing the protective PGs in the stomach and kidney made by COX-1. These highly selective COX-2 inhibitors may not only be anti-inflammatory but may also be active in colon cancer and Alzheimer's disease.
Field evaluation of a rapid point-of-care assay for targeting antibiotic treatment for trachoma control: a comparative study
Authors: Claude-Edouard C Michel, Anthony W Solomon, Jose PV Magbanua, Patrick A Massae, Ling Huang, Jonaice Mosha, Sheila K West, Elpidio CB Nadala, Robin Bailey, Craig Wisniewski, David CW Mabey, Helen H Lee
Journal: The Lancet (2006)
Pharmacogenomic Discovery Approaches: Will the Real Genes Please Stand Up?
Authors: Richard A. Walgren, Melissa A. Meucci, Howard L. McLeod
Journal: Journal of Clinical Oncology (2005)

Genetic inheritance plays a significant role in the interindividual variability of drug response. The field of pharmacogenomics seeks to identify genetic factors that influence drug response, including both those that are inherited and those that arise within tumors, and use this information to improve drug therapy. Candidate gene approaches have led to clinical tests for toxicity avoidance (eg, TPMT, UGT1A1) and efficacy prediction (eg, epidermal growth factor receptor-activating mutations). However, the "right" genes are not known for most anticancer drugs. Strategies for uncovering pharmacogenomic associations vary widely from monogenic candidate gene approaches to polygenic genome-wide approaches. This review will place in context clinically relevant pharmacogenomic discovery approaches, including the relative strengths and weaknesses and the challenges inherent with achieving the goal of individualized therapy.
Radiation-Induced Changes in Gene Expression Involve Recruitment of Existing Messenger RNAs to and away from Polysomes
Authors: Xing Lü, Lorena de la Peña, Christopher Barker, Kevin Camphausen, Philip J. Tofilon
Journal: Cancer Research (2006)

Although ionizing radiation has been shown to influence gene transcription, little is known about the effects of radiation on gene translational efficiency. To obtain a genome-wide perspective of the effects of radiation on gene translation, microarray analysis was done on polysome-bound RNA isolated from irradiated human brain tumor cells; to allow for a comparison with the effects of radiation on transcription, microarray analysis was also done using total RNA. The number of genes whose translational activity was modified by radiation was approximately 10-fold greater than those whose transcription was affected. The radiation-induced change in a gene's translational activity was shown to involve the recruitment of existing mRNAs to and away from polysomes. Moreover, the change in a gene's translational activity after irradiation correlated with changes in the level of its corresponding protein. These data suggest that radiation modifies gene expression primarily at the level of translation. In contrast to transcriptional changes, there was considerable overlap in the genes affected at the translational level among brain tumor cell lines and normal astrocytes. Thus, the radiation-induced translational control of a subset of mRNAs seems to be a fundamental component of cellular radioresponse.
Silencing of the <i>miR-17∼92</i> Cluster Family Inhibits Medulloblastoma Progression
Authors: Brian L. Murphy, Susanna Obad, Laure Bihannic, Olivier Ayrault, Frederique Zindy, Sakari Kauppinen, Martine F. Roussel
Journal: Cancer Research (2013)

Medulloblastoma, originating in the cerebellum, is the most common malignant brain tumor in children. Medulloblastoma consists of four major groups where constitutive activation of the Sonic Hedgehog (SHH) signaling pathway is a hallmark of one group. Mouse and human SHH medulloblastomas exhibit increased expression of microRNAs encoded by the miR-17~92 and miR-106b~25 clusters compared with granule progenitors and postmitotic granule neurons. Here, we assessed the therapeutic potential of 8-mer seed-targeting locked nucleic acid (LNA)-modified anti-miR oligonucleotides, termed tiny LNAs, that inhibit microRNA seed families expressed by miR-17~92 and miR-106b~25 in two mouse models of SHH medulloblastomas. We found that tumor cells (medulloblastoma cells) passively took up 8-mer LNA-anti-miRs and specifically inhibited targeted microRNA seed-sharing family members. Inhibition of miR-17 and miR-19a seed families by anti-miR-17 and anti-miR-19, respectively, resulted in diminished tumor cell proliferation in vitro. Treatment of mice with systemic delivery of anti-miR-17 and anti-miR-19 reduced tumor growth in flank and brain allografts in vivo and prolonged the survival of mice with intracranial transplants, suggesting that inhibition of the miR-17~92 cluster family by 8-mer LNA-anti-miRs might be considered for the treatment of SHH medulloblastomas.
Fetal Ventricular Mass Determination on Three-Dimensional Echocardiography
Authors: Aarti Hejmadi Bhat, Virginia Corbett, Nathan Carpenter, Nick Liu, Ruolan Liu, Anna Wu, Graham Hopkins, Roya Sohaey, Carey Winkler, Christine S. Sahn, Valerie Sovinsky, Xiaokui Li, David J. Sahn
Journal: Circulation (2004)

Estimation of ventricular volume and mass is important for baseline and serial evaluation of fetuses with normal or abnormal hearts. Direct measurement of chamber wall volumes and mass can be made without geometric assumptions by 3D fetal echocardiography. Our goals were to determine the feasibility of using fast nongated 3D echocardiography for fetal volumetric and mass assessments, to validate the accuracy of the ultrasound system and the measurement technique, and if satisfactory, to develop normal values for fetal ventricular mass during the second and third trimesters.This was a prospective outpatient study of 90 consecutive normal pregnancies during routine obstetric services at Oregon Health & Science University (Portland). Optimized 3D volumes of the fetal thorax and cardiac chambers were rapidly acquired and later analyzed for right and left ventricular mass by radial summation technique from manual epicardial and endocardial traces. Experiments to validate the ultrasound system and measurement technique were performed with modified small balloon models and in vivo and ex vivo small animal experiments. Our study established the feasibility of fetal ventricular mass measurements with 3D ultrasound technology and developed normal values for right and left ventricular mass from 15 weeks' gestation to term.Nongated fast 3D fetal echocardiography is an acceptable modality for determination of cardiac chamber wall volume and mass with good accuracy and acceptable interobserver variability. The method should be especially valuable as an objective serial measurement in clinical fetal studies with structurally or functionally abnormal hearts.
Total Soluble HLA Class I and Soluble HLA-G in Multiple Myeloma and Monoclonal Gammopathy of Undetermined Significance
Authors: Xavier Leleu, Gaëlle Le Friec, Thierry Facon, Laurence Amiot, Renée Fauchet, Bernadette Hennache, Valérie Coiteux, Ibrahim Yakoub-Agha, Sylvain Dubucquoi, Hervé Avet-Loiseau, Claire Mathiot, Régis Bataille, Jean-Yves Mary
Journal: Clinical Cancer Research (2005)

Serum beta2-microglobulin, the light chain of the HLA class I molecular complex, remains one of the best survival prognostic factors in multiple myeloma, but other HLA class I molecules might be of interest in monoclonal gammopathies. In this study, we evaluate total soluble HLA class I (HLA-Is) and soluble HLA-G (HLA-Gs) in 103 patients with newly diagnosed multiple myeloma, 30 patients with monoclonal gammopathy of undetermined significance (MGUS), and 30 healthy subjects, studying their prognostic value in multiple myeloma. In multiple myeloma patients, HLA-Is and HLA-Gs median values were 0.8 microg/mL and 28 ng/mL, respectively. Median HLA-Is concentration was higher in stage II and III multiple myeloma patients than in stage I multiple myeloma, MGUS, and control patients. Median HLA-Gs was significantly lower in healthy controls than in MGUS and multiple myeloma patients. A high level of HLA-Is (> or =2.1 microg/mL) was predictive of short survival (P = 0.017). For each given level of beta2-microglobulin, the relative risk of death was higher for patients with HLA-Is > or = 2.1 microg/mL than in patients with a lower level (P = 0.047). HLA-Gs, a marker of monoclonal gammopathy, was of no prognostic value, but the addition of HLA-Is to beta2-microglobulin produced an efficient prognostic score (P < 0.0001). HLA-Is is a new marker of multiple myeloma tumor load and provides additional survival prognostic information to beta2-microglobulin.
N-Nitrosodimethylamine Blood Levels in Patients With Chronic Renal Failure: Modulation of Levels by Ethanol and Ascorbic Acid
Authors: S. R. Dunn, M. L. Simenhoff, P. S. Lele, S. Goyal, J. W. Pensabene, W. Fiddler
Journal: JNCI Journal of the National Cancer Institute (1990)

Journal Article N-Nitrosodimethylamine Blood Levels in Patients With Chronic Renal Failure: Modulation of Levels by Ethanol and Ascorbic Acid Get access S. R. Dunn, S. R. Dunn * Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA * Correspondence to: Stephen R. Dunn, Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, PA 19107. Search for other works by this author on: Oxford Academic PubMed Google Scholar M. L. Simenhoff, M. L. Simenhoff Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA Search for other works by this author on: Oxford Academic PubMed Google Scholar P. S. Lele, P. S. Lele Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA Search for other works by this author on: Oxford Academic PubMed Google Scholar S. Goyal, S. Goyal Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA Search for other works by this author on: Oxford Academic PubMed Google Scholar J. W. Pensabene, J. W. Pensabene Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA Search for other works by this author on: Oxford Academic PubMed Google Scholar W. Fiddler W. Fiddler Department of Medicine, Division of Nephrology, Jefferson Medical College, Thomas Jefferson UniversityPhiladelphia, PA Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 82, Issue 9, 2 May 1990, Pages 783–787, https://doi.org/10.1093/jnci/82.9.783 Published: 02 May 1990 Article history Received: 01 August 1989 Revision received: 15 February 1990 Accepted: 23 February 1990 Published: 02 May 1990
Urgent steps to tackle antibiotic resistance are needed despite government review, say MPs
Authors: A. O'Dowd
Journal: BMJ (2014)

MPs have called for urgent action to tackle the growing problem of antibiotic resistance despite recent promises of a large review announced by the government.

A new report by MPs on the House of Commons science and technology committee has described the problem of growing resistance to antibiotics in the United Kingdom and worldwide as “one of the greatest risks to modern medicine faced by this generation.”1 

The report, published on 7 July, said, “For too long, antibiotics have been used as if they were a bottomless pit of cure-all miracle treatments.” However, antibiotics were ineffective against viruses and other diseases that are not caused by bacteria, it warned, adding that their …
C/EBPbeta-2 confers EGF-independent growth and disrupts the normal acinar architecture of human mammary epithelial cells
Authors: Linda Bundy, Sam Wells, Linda Sealy
Journal: Molecular Cancer (2005)

The transcription factor, C/EBPbeta, is a key regulator of growth and differentiation in the mammary gland. There are three different protein isoforms of C/EBPbeta. C/EBPbeta-1 and -2 are transactivators, and differ by only 23 N-terminal amino acids present in beta-1 only. C/EBPbeta-3 (LIP) lacks the transactivation domain and represses transcription. Elevated C/EBPbeta-2 expression causes MCF10A normal human mammary epithelial cells to become transformed, undergo an epithelial to mesenchymal transition (EMT), and acquire an invasive phenotype. C/EBPbeta is a downstream transcriptional target of Ras signaling pathways and is required for Ras transformation of some cell types. Ras signaling pathways are activated in mammary epithelial cells by the ErbB receptor tyrosine kinase family. Therefore, we considered whether elevated C/EBPbeta-2 expression would resemble ErbB RTK activation in MCF10A cells.We show that elevated C/EBPbeta-2 expression confers EGF-independent growth in MCF10A mammary epithelial cells. However, MCF10A cells expressing C/EBPbeta-3 are not EGF-independent, and high C/EBPbeta-3 or LIP expression is incompatible with growth. C/EBPbeta-2 overexpression disrupts the normal acinar architecture of MCF10A cells in basement membrane cultures and induces complex multiacinar structures with filled lumen, similar to the consequences of aberrant ErbB2 activation.Given the ability of C/EBPbeta-2 to confer EGF-independent growth to mammary epithelial cells as well as its capability for disrupting normal epithelial architecture and causing EMT, it is worth considering whether inhibitors which target ErbB family signaling pathways could be less effective in mammary epithelial cells with elevated nuclear C/EBPbeta-2 expression.
Distinct and Separable Roles of the Complement System in Factor H-Deficient Bone Marrow Chimeric Mice with Immune Complex Disease
Authors: Jessy J. Alexander, O.G.B. Aneziokoro, Anthony Chang, Bradley K. Hack, Adam Markaryan, Alexander Jacob, Roger Luo, Michael Thirman, Mark Haas, Richard J. Quigg
Journal: Journal of the American Society of Nephrology (2006)

Plasma complement factor H (Cfh) is a potent complement regulator, whereas Cfh on the surface of rodent platelets is responsible for immune complex processing. For dissection between the two, bone marrow chimeras between Cfh-deficient (Cfh−/−) and wild-type C57BL/6 mice were created. Platelet Cfh protein was tracked with the Cfh status of the bone marrow donor, indicating that platelet Cfh is of intrinsic origin. In an active model of immune complex disease, Cfh−/− mice that were reconstituted with wild-type bone marrow had levels of platelet-associated immune complexes comparable to those of wild-type mice and were protected against the excessive glomerular deposition of immune complexes seen in Cfh−/− mice, yet these mice still developed glomerular inflammation. In contrast, wild-type mice with Cfh−/− bone marrow had reduced platelet-associated immune complexes and extensive glomerular deposition of complement-activating immune complexes, but they did not develop glomerular pathology. The large quantities of glomerular C3 in wild-type mice with Cfh−/− bone marrow were in the form of iC3b and C3dg, whereas active C3b remained in Cfh−/− recipients of wild-type bone marrow. These data show that plasma Cfh limits complement activation in the circulation and other accessible sites such as the glomerulus, whereas platelet Cfh is responsible for immune complex processing.
Rituximab-associated hepatitis B virus (HBV) reactivation in lymphoproliferative diseases: meta-analysis and examination of FDA safety reports
Authors: A.M. Evens, B.D. Jovanovic, Y.-C. Su, D.W. Raisch, D. Ganger, S.M. Belknap, M.-S. Dai, B.-C. C. Chiu, B. Fintel, Y. Cheng, S.-S. Chuang, M.-Y. Lee, T.-Y. Chen, S.-F. Lin, C.-Y. Kuo
Journal: Annals of Oncology (2010)
Hemodynamic effects of isoproterenol and norepinephrine in acute cardiac tamponade
Authors: Noble O. Fowler, John C. Holmes
Journal: Journal of Clinical Investigation (1969)

The hemodynamic effects of isoproterenol infusion, 0.5 mug/kg per min were evaluated in eight intact anesthetized dogs during cardiac tamponade. During tamponade, the mean of pericardial pressures was increased from - 1.5 to 12.5 mm Hg, and the mean of right atrial pressures was increased from 1 to 12.4 mm Hg. Mean cardiac output fell from 144.8 to 44.8 ml/kg per min (P < 0.001), and rose to 105.6 ml/kg per min (P < 0.001) with isoproterenol. Mean cardiac stroke volume fell from 20.3 to 6.1 ml during tamponade (P < 0.001) and rose to 12.1 ml with isoproterenol (P < 0.001). The heart rate increased from 193.3 beats/min during tamponade to 217.5 beats/min with isoproterenol (P < 0.05). During isoproterenol infusion, the mean right atrial pressure and mean pericardial pressure decreased significantly. With cardiac tamponade, the mean blood pressure fell from 157.5 to 126.1 mm Hg (P < 0.01) and did not change significantly with isoproterenol, 11 additional animals were studied with norepinephrine infusion during tamponade. There were no consistent hemodynamic effects with infusions of 0.5 and 1 mug/kg per min. With norepinephrine 2, 5, and 10 mug/kg per min cardiac output rose in some experiments. Isoproterenol infusion increased the cardiac output during tamponade principally by increasing cardiac stroke volume and to a lesser degree by increasing the heart rate. It is postulated that the increased stroke volume resulted from an increased ejection fraction with greater decrease in end-systolic than end-diastolic ventricular volume. These effects are consistent with the known positive inotropic, peripheral vasodilator, and positive chronotropic effects of isoproterenol.
JNK1 Mediates Degradation HIF-1α by a VHL-Independent Mechanism that Involves the Chaperones Hsp90/Hsp70
Authors: Dongyun Zhang, Jingxia Li, Max Costa, Jimin Gao, Chuanshu Huang
Journal: Cancer Research (2010)

Abstract Hypoxia-inducible factor-1α (HIF-1α) is a master transcription factor that is critical for the regulation of a variety of cellular functions. HIF-1α is rapidly degraded under normoxic conditions by ubiquitin-mediated proteasome pathway controlled by the tumor suppressor von Hippel Lindau (VHL). Several recent studies reveal that heat-shock proteins (Hsp) can regulate HIF-1α protein degradation by a VHL-independent pathway. Here, we demonstrate that the stress kinase c-Jun NH2-terminal kinase 1 (JNK1) is required for Hsp-dependent regulation of HIF-1α. Stabilization of HIF-1α was impaired in JNK1−/− cells but could be rescued by JNK1 reconstitution under hypoxic conditions. These effects could be phenocopied in other cell settings by JNK1 silencing. Accordingly, HIF-1 transcriptional activity and target gene expression were dramatically reduced in JNK1−/− cells. Further, decreased levels of endogenous Hsp90/Hsp70 proteins in JNK1−/− cells affected the protective roles of these chaperones in stabilizing newly synthesized HIF-1α, whereas enforced expression of Hsp90/Hsp70 in JNK1−/− cells increased HIF-1α stability relative to parental control cells. Furthering this connection, we also found that defective expression of the Hsp90 acetyltransferase HDAC6 in JNK1−/− cells was associated with reduced Hsp90 chaperone activity. Taken together, our studies define a novel function for JNK1 in regulating HIF-1α turnover by a VHL-independent mechanism. Cancer Res; 70(2); 813–23