tbuckley/cabot-search huggingface dataset:
Late-breaking abstract: A phase 2a study of benralizumab in adults with COPD
Authors: Christopher Brightling, Mona Bafadhel, Eugene Bleecker, Reynold Panettieri, Dewei She, Christine K Ward, Xiao Xu, Rene van der Merwe
Journal: European Respiratory Journal (2014)

RATIONALE: Benralizumab is a humanized, afucosylated, anti-interleukin-5 receptor alpha monoclonal antibody shown to deplete blood and airway eosinophils in subjects with asthma. We investigated the effects of benralizumab in adults with chronic obstructive pulmonary disease (COPD) and elevated airway eosinophils.  METHODS: Subjects with moderate-to-severe COPD, >3% sputum eosinophils, and >1 acute exacerbation (AECOPD) in the previous year were randomized in a double-blind, placebo (PBO)-controlled, multicenter study. Subjects received PBO or 100 mg benralizumab subcutaneously on weeks 1, 4, 8, 16, 24, 32, 40, and 48. Endpoints included moderate-to-severe AECOPD rate at week 56 (primary), forced expiratory volume in 1 second (FEV1), COPD-specific Saint George9s Respiratory Questionnaire (SGRQ-C), and adverse events. Efficacy analyses were conducted on the per-protocol population.  RESULTS: 101 subjects were randomized to PBO (n=50) or benralizumab (n=51). Benralizumab depleted both peripheral blood and sputum eosinophils. The primary endpoint of AECOPD rate reduction vs. PBO at week 56 was not met, however pre-bronchodilator FEV1 change from baseline was -0.059L with PBO (n=42), and 0.128L with benralizumab (n=37, P=.01). A pre-specified subgroup analysis demonstrated that in subjects with baseline eosinophils >300/uL, improvements at week 56 were greater for AECOPD rate (58% reduction, P=0.28), FEV1 (0.318L, P=0.22), and SGRQ-C symptom domain (-13.1 points, P=0.26) for benralizumab (n=14) compared to PBO (n=7). The safety profile was similar to previous studies.  CONCLUSIONS: Benralizumab did not reduce the exacerbation rate in subjects with COPD, but significantly improved lung function with an acceptable safety profile.
Interleukin 12 Stimulates IFN-γ–Mediated Inhibition of Tumor-Induced Regulatory T-Cell Proliferation and Enhances Tumor Clearance
Authors: Xuefang Cao, Karen Leonard, Lynne I. Collins, Sheng F. Cai, Joshua C. Mayer, Jacqueline E. Payton, Michael J. Walter, David Piwnica-Worms, Robert D. Schreiber, Timothy J. Ley
Journal: Cancer Research (2009)

To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor-dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN-gamma mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-gamma-independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN-gamma signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12-IFN-gamma axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo.
Molecular Markers of Early Pancreatic Cancer
Authors: Michael Goggins
Journal: Journal of Clinical Oncology (2005)

Pancreatic cancer is a deadly disease and the fourth most common cause of cancer death in the United States. Since chemotherapy and radiotherapy have thus far largely failed to significantly improve the survival of patients with pancreatic ductal adenocarcinoma, there is considerable interest in identifying better diagnostic markers of pancreatic neoplasia. Not only could better markers improve the early diagnosis of pancreatic cancer and allow more patients to undergo curative surgical resection, but also could potentially be used for patients at high risk of developing pancreatic cancer to identify precancerous lesions while they are amenable to cure. A wealth of information has recently become available about gene expression, DNA methylation, and proteomics alterations that occur in pancreatic cancers creating hope that better diagnostic markers of pancreatic cancer will be soon forthcoming.
Positive Selection of Extrathymically Developed T Cells by Self-antigens
Authors: Hisakata Yamada, Toshiharu Ninomiya, Asako Hashimoto, Koji Tamada, Hiroaki Takimoto, Kikuo Nomoto
Journal: The Journal of Experimental Medicine (1998)

Most T cells develop through the thymus, where they undergo positive and negative selection. Some peripheral T cells are known to develop in the absence of thymus, but there is insufficient information about their selection. To analyze the selection of extrathymically developed T cells, we reconstituted thymectomized male or female recipient mice with bone marrow cells of mice transgenic for male H-Y antigen–specific T cell receptor (TCR). It was revealed that the T cells bearing self-antigen–specific TCR were not deleted in thymectomized male recipients. More importantly, the absence of H-Y antigen–specific T cells in thymectomized female recipients suggests positive selection of extrathymically developed T cells by the self-antigen. The extrathymically developed T cells in male mice expressed interleukin (IL)-2 receptor β chain (IL-2Rβ) and intermediate levels of CD3 (CD3int) but were natural killer cell (NK)1.1−. They rapidly produced interferon γ but not IL-4 after TCR cross-linking. Furthermore, a similar pattern of cytokine production was observed in CD3intIL-2Rβ+NK1.1− cells in normal mice which have been shown to develop extrathymically. These results suggest that extrathymically developed CD3intIL-2Rβ+NK1.1− cells in normal mice are also positively selected by self-antigens.
Duodenal bile acid conjugation patterns and dietary sulphur amino acids in the newborn.
Authors: M J Brueton, H M Berger, G A Brown, L Ablitt, N Iyngkaran, B A Wharton
Journal: Gut (1978)

Patterns of glycine and taurine conjugation of bile acids in duodenal juice have been studied in 20 low birth weight babies at 12 and 22 days of age. They were fed from birth on one of three feeds containing different amounts of taurine and its precursors, cysteine and methionone. Taurine conjugation predominated in those fed on human milk throughout the first three weeks of life. In those fed on SMA or S26 infant feeding formulae, both of which contain very little taurine, concentrations of glycine conjugates were found to exceed those of taurine conjugates by the 12th day. The low glycine-taurine conjugate ratios previously described in newborn babies are, therefore, probably related to the taurine content of the milk which they received. Glycine-taurine conjugate ratios less than 1.0 occur in breast fed infants during the first three weeks of life.
Activation of Raf-1 and mitogen-activated protein kinase in murine macrophages partially mimics lipopolysaccharide-induced signaling events.
Authors: J Hambleton, M McMahon, A L DeFranco
Journal: The Journal of Experimental Medicine (1995)

Lipopolysaccharide (LPS), a highly conserved component of the outer membrane of gram-negative bacteria, stimulates macrophages to release various cytokine and eicosanoid mediators of the immune response. The mechanism by which LPS stimulates these cells is poorly characterized. One of the most rapid LPS-stimulated events is the phosphorylation and activation of the p42 and p44 isoforms of mitogen-activated protein (MAP) kinase. We wished to examine the role of MAP kinase in LPS-induced signaling in murine macrophages by activating MAP kinase independently of LPS. An expression vector encoding a Raf-1:estrogen receptor (ER) chimeric protein was transfected into the murine macrophage cell line RAW 264.7. Activation of this chimeric protein (delta Raf-1:ER) by estradiol resulted in rapid and prolonged activation of MAP kinase, as expected from previous results implicating Raf-1 as an upstream activator of this signaling cascade. LPS stimulation induced accumulation of MAP kinase phosphatase 1 messenger RNA, whereas delta Raf-1:ER activation did not, perhaps accounting for the more prolonged activation of MAP kinase seen in response to delta Raf-1:ER activation. Similarly, activation of DNA binding by the transcription factor, nuclear factor (NF) kappa B, as assessed by electrophoretic mobility shift assay, occurred in response to LPS stimulation but not in response to delta Raf-1:ER activation or phorbol myristate acetate (PMA) stimulation. Using an enzyme-linked immunosorbent assay for murine tumor necrosis factor alpha (TNF-alpha), we found that LPS and PMA stimulation and delta Raf-1:ER activation induced secretion of TNF-alpha, although the amount of TNF-alpha secreted in response to delta Raf-1:ER activation and PMA stimulation was approximately 20-fold less than that secreted in response to LPS. Correspondingly, accumulation of TNF-alpha messenger RNA was weakly induced by delta Raf-1:ER activation or PMA stimulation, whereas strong induction was noted in response to LPS. These results suggest that Raf-1 or PMA activation of MAP kinase in murine macrophages is sufficient for a small amount of TNF-alpha production and secretion in the absence of NF-kappa B activation, but LPS stimulation involves additional signaling events, such as NF-kappa B activation, that augment the response seen with activation of MAP kinase alone.
The Effect of Cinnamon on A1C Among Adolescents With Type 1 Diabetes
Authors: Justin A. Altschuler, Samuel J. Casella, Todd A. MacKenzie, Kevin M. Curtis
Journal: Diabetes Care (2007)

The purpose of this study was to determine the effect of cinnamon on glycemic control in adolescents with type 1 diabetes.Using a prospective, double-blind, placebo-controlled design, 72 adolescent type 1 diabetic subjects were treated in an outpatient setting with cinnamon (1 g/day) or an equivalent-appearing placebo for 90 days. A1C, total daily insulin intake, and adverse events were recorded and compared between groups.There were no significant differences in final A1C (8.8 vs. 8.7, P = 0.88), change in A1C (0.3 vs. 0.0, P = 0.13), total daily insulin intake, or number of hypoglycemic episodes between the cinnamon and placebo arms.Cinnamon is not effective for improving glycemic control in adolescents with type 1 diabetes.
Cytomegalovirus-specific immunity and protection against viremia and disease in HIV-infected patients in the era of highly active antiretroviral therapy
Authors: A. Weinberg, C. Tierney, M.A. Kendall, R.J. Bosch, J. Patterson-Bartlett, A. Erice, M.S. Hirsch, B. Polsky
Journal: Journal of Infection (2006)
CYP2B6*6 is an independent determinant of inferior response to fludarabine plus cyclophosphamide in chronic lymphocytic leukemia
Authors: Gillian G. Johnson, Ke Lin, Trevor F. Cox, Melanie Oates, David R. Sibson, Richard Eccles, Bryony Lloyd, Laura-Jayne Gardiner, Daniel F. Carr, Munir Pirmohamed, Jonathan C. Strefford, David G. Oscier, David Gonzalez de Castro, Monica Else, Daniel Catovsky, Andrew R. Pettitt
Journal: Blood (2013)
GONADOTROPIN-RELEASING HORMONE AND ITS ANALOGS
Authors: P. Michael Conn, Ph.D, William F. Crowley
Journal: Annual Review of Medicine (1994)

▪ Abstract GnRH and its analogues have led to exciting new avenues of therapy in virtually every subspecialty of internal medicine as well as in gynecology, pediatrics, and urology. Since their discovery in 1971, it has been demonstrated that GnRH and its analogues enable medical professionals to influence the hypothalamic-pituitary-gonadal axis in two distinct classes of therapeutic applications. The first provides natural sequence GnRH in a pulsatile fashion via portable infusion pumps to mimic the normal physiology of hypothalamic GnRH secretion and restores reproductive potential to infertile men and women with disorders of endogenous GnRH secretion. The second mode uses long-acting GnRH agonists administered in a depot delivery to produce a paradoxical desensitization of pituitary gonadotropin secretion which, in turn, results in a complete ablation of the reproductive axis. This biochemical castration induced by GnRH agonist administration is a safe, effective, complete, and reversible method of removing the overlay of gonadal steroids from a variety of diseases which they are known to exacerbate. These diseases include endometriosis and uterine fibroids in women, prostate cancer in men, and precocious puberty in both sexes. This review examines the physiologic and pharmacologic principles underlying the advances produced by these agents, the mechanism of action of GnRH and its analogues at the cellular level, and the individual therapeutic applications to which these analogues have been applied. Because virtually every subspecialty of medicine will be touched by the GnRH analogues, this review provides an overview and background of their use.
PRAS40 Is a Functionally Critical Target for EWS Repression in Ewing Sarcoma
Authors: Lin Huang, Yuji Nakai, Iku Kuwahara, Ken Matsumoto
Journal: Cancer Research (2012)

Ewing sarcoma family tumors (ESFT) are highly aggressive and highly metastatic tumors caused by a chromosomal fusion between the Ewing sarcoma protein (EWS) with the transcription factor FLI-1. However, expression of the EWS/FLI-1 chimeric oncogene by itself is insufficient for carcinogenesis, suggesting that additional events are required. Here, we report the identification of the Akt substrate PRAS40 as an EWS target gene. EWS negatively regulates PRAS40 expression by binding the 3' untranslated region in PRAS40 mRNA. ESFT cell proliferation was suppressed by treatment with an Akt inhibitor, and ESFT cell proliferation and metastatic growth were suppressed by siRNA-mediated PRAS40 knockdown. Furthermore, PRAS40 knockdown was sufficient to reverse an increased cell proliferation elicited by EWS knockdown. In support of a pathologic role for PRAS40 elevation in EFST, we documented inverse protein levels of EWS and PRAS40 in ESFT cells. Together, our findings suggest that PRAS40 promotes the development of ESFT and might therefore represent a novel therapeutic target in this aggressive disease.
Harnessing Transporters to Clear Uremic Toxins
Authors: Orson W. Moe
Journal: Journal of the American Society of Nephrology (2009)

The constancy of the milieu interieur described by Claude Bernard is an absolute prerequisite for the health of the organism. The primacy of the kidney in whole organism homeostasis is best exemplified by the disturbance in the composition and amount of body fluid and solute when this organ fails to function. In simplistic terms, one can envision renal failure as the inability to remove what should be excreted and inability to add what should be added to the body. The inability to excrete the appropriate amount of water and various solutes is well studied and serves as a marker in clinical practice to evaluate the degree of dysfunction and adequacy of therapy. There are also many additional substances that are not properly excreted in renal failure, the accumulation of which contributes to the uremic state, but these are less well studied in terms of their metabolism, mechanism of action, or mode of excretion.

The expanding group of proven and putative uremic toxins has recently been highlighted by the European Uremic Toxin Work Group (http://EUTox.info) and the count has reached over 110 moieties.1 This highly diverse group of substances ranges from inorganic solutes to organic substances including acids, guanidine, peptides, indoles, nucleotides, peptides, and others.2 The chemical properties of these moieties are as expansive as their identities, with a broad range of molecular weight (outside the …
Ebola viral load at diagnosis associates with patient outcome and outbreak evolution
Authors: Marc-Antoine de La Vega, Grazia Caleo, Jonathan Audet, Xiangguo Qiu, Robert A. Kozak, James I. Brooks, Steven Kern, Anja Wolz, Armand Sprecher, Jane Greig, Kamalini Lokuge, David K. Kargbo, Brima Kargbo, Antonino Di Caro, Allen Grolla, Darwyn Kobasa, James E. Strong, Giuseppe Ippolito, Michel Van Herp, Gary P. Kobinger
Journal: Journal of Clinical Investigation (2015)

BACKGROUND. Ebola virus (EBOV) causes periodic outbreaks of life-threatening EBOV disease in Africa. Historically, these outbreaks have been relatively small and geographically contained; however, the magnitude of the EBOV outbreak that began in 2014 in West Africa has been unprecedented. The aim of this study was to describe the viral kinetics of EBOV during this outbreak and identify factors that contribute to outbreak progression.
Salvage mechanisms for regeneration of adenosine triphosphate in rat cardiac myocytes
Authors: J. W DOW, J. BOWDITCH, S. V NIGDIKAR, A. K BROWN
Journal: Cardiovascular Research (1987)

Since mitochondrial oxidative phosphorylation does not produce sufficient adenosine triphosphate for rapid restoration of contractile function in myocardium reoxygenated after ischaemia alternative non-oxidative routes by which purine nucleosides or bases may be used to increase the cytoplasmic adenine nucleotide pool were studied. Comparative rates of uptake and salvage of adenosine, adenine, and hypoxanthine were determined using myocytes isolated from adult rat heart. For each precursor reactions limiting the overall rate at which substrate in the extracellular fluid is incorporated into the intracellular adenosine triphosphate pool were identified. Adenosine was salvaged at twice the rate seen with adenine in the presence of ribose, whereas the rate of salvage of hypoxanthine, in the presence of ribose, was only 5% of that for adenosine. Adenine may be an advantageous substrate since high concentrations of adenine are not inhibitory to salvage and do not influence cardiac haemodynamics. Salvage of hypoxanthine appeared to be limited by the rate of adenylosuccinate synthetase, which was present at less than 1% of the adenylosuccinase rate in rat, rabbit, and beef heart. In addition, since salvage of bases is dependent on the availability of phosphoribosylpyrophosphate rates of synthesis of phosphoribosylpyrophosphate were measured in whole myocytes from ribose and in cytoplasmic extracts from ribose and from ribose-5-phosphate. Metabolic sites were identified at which interventions designed to accelerate salvage rates might best be directed.
Pulmonary veno-occlusive disease in myeloproliferative disorder
Authors: E. Willems, J-L. Canivet, B. Ghaye, L. de Leval, M. Radermecker, J-C. Preiser, Y. Beguin
Journal: European Respiratory Journal (2008)

The present study reports a case of biopsy-proven pulmonary veno-occlusive disease as a cause of severe pulmonary hypertension in a patient suffering from a chronic myeloproliferative disorder. The pulmonary disease evolved favourably under treatment with defibrotide, a pro-fibrinolytic medication used in hepatic veno-occlusive disease.
Regional changes in intracellular potassium and sodium activity after healing of experimental myocardial infarction in cats.
Authors: S Kimura, A L Bassett, M S Gaide, P L Kozlovskis, R J Myerburg
Journal: Circulation Research (1986)

After healing of experimental myocardial infarction in cat hearts, endocardial cells demonstrate persistent regional electrical changes. These include long action potential duration in surviving cells over the infarct scar, and short action potential duration and low membrane potential in border zone cells between the scar and normal tissue. We studied the basis for these electrophysiological changes by measuring intracellular potassium and sodium activity with ion-sensitive microelectrodes in normal, border, and infarct zone cells of the cat left ventricle 2-6 months after ligation of multiple distal tributaries of the left anterior descending and circumflex coronary arteries. In normal zone cells, intracellular potassium activity was 89.6 +/- 12.3 mM (mean +/- SD, n = 9), and sodium activity was 10.8 +/- 2.2 mM (n = 5). Neither was significantly different from infarct zone cells (91.2 +/- 15.0 and 10.5 +/- 3.0 mM, respectively). In contrast, border zone cells had significantly reduced intracellular potassium activity (71.4 +/- 5.1 mM, P less than 0.01, compared to normal and infarct zone cells) and increased intracellular sodium activity (19.1 +/- 5.9 mM, P less than 0.05, compared to normal and infarct zone cells). The membrane potential in border zone cells was more positive to calculated potassium equilibrium potential, and less sensitive to the change in the extracellular potassium concentration in the range between 2 and 10 mM, compared to normal and infarct zone cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Expression and role of the nerve growth factor NGF in severe pulmonary hypertension
Authors: Florence Coste, Christian Toussaint, Mathilde Dubois, Arnaud Courtois, Christelle Guibert, Roger Marthan, Jean-Pierre Savineau, Bernard Muller, Véronique Freund-Michel
Journal: European Respiratory Journal (2014)

Introduction:  Our previous studies showed an increased NGF expression in animal models of pulmonary hypertension (PH) and suggested a role for NGF in various aspects of this disease. We have studied here expression of NGF and its receptors in human PH, and investigated whether administrating anti-NGF blocking antibodies in vivo prevented some pathological aspects in a rat PH model.   Methods:  NGF and inflammatory cytokine secretion was assessed by ELISA in human pulmonary arteries (PA) from controls or from patients with secondary PH. Expression of NGF receptors (TrkA and p75NTR) was assessed by Western blotting. In the rat, PH was induced by monocrotaline (MCT, J1, 60mg/kg ip), with or without administration of anti-NGF blocking antibodies (J0, J2, J7, 10μg/kg ip). Pulmonary arterial pressure (Pap) and Fulton index were assessed at J28. PA medial wall thickness was evaluated on lung sections after hematoxylin and eosin staining. PA reactivity to phenylephrine or prostaglandin F2α (PGF2α) was assessed ex vivo.   Results:  Significant increase in expression of NGF and its receptors was observed in PA from patients with secondary PH compared to controls. In the MCT-treated rat, anti-NGF blocking antibodies significantly reduced Pap, Fulton index, cytokine secretion, PA medial wall thickness, and totally prevented PA hyperreactivity to phenylephrine or PGF2α.   Conclusion:  Our data show that expression of NGF and its receptors are increased in human PH. Moreover, administration of anti-NGF blocking antibodies in the rat in vivo partially prevented PH by modulating PA hyperreactivity, inflammation and remodelling. These results therefore confirm that targeting NGF may be of therapeutical interest in this disease.