tbuckley/cabot-search huggingface dataset:
The Intermountain Risk Score (including the red cell distribution width) predicts heart failure and other morbidity endpoints
Authors: Benjamin D. Horne, Heidi T. May, Abdallah G. Kfoury, Dale G. Renlund, Joseph B. Muhlestein, Donald L. Lappé, Kismet D. Rasmusson, T. Jared Bunch, John F. Carlquist, Tami L. Bair, Kurt R. Jensen, Brianna S. Ronnow, Jeffrey L. Anderson
Journal: European Journal of Heart Failure (2010)
Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial
Authors: Jorma Paavonen, David Jenkins, F Xavier Bosch, Paulo Naud, Jorge Salmerón, Cosette M Wheeler, Song-Nan Chow, Dan L Apter, Henry C Kitchener, Xavier Castellsague, Newton S de Carvalho, S Rachel Skinner, Diane M Harper, James A Hedrick, Unnop Jaisamrarn, Genara AM Limson, Marc Dionne, Wim Quint, Bart Spiessens, Pascal Peeters, Frank Struyf, Susan L Wieting, Matti O Lehtinen, Gary Dubin
Journal: The Lancet (2007)
A Role for Prostaglandin E in Defective Insulin Secretion and Carbohydrate Intolerance in Diabetes Mellitus
Authors: R. Paul Robertson, Mei Chen
Journal: Journal of Clinical Investigation (1977)

Prostaglandin E2 (PGE2) infusion in normal humans inhibited acute insulin responses to a glucose (5 g i.v.) pulse (response before PGE2 = 593 ± 104%; during PGE2 = 312±55%; mean±SE, mean change 3-5 min insulin,% basal, P < 0.005). This effect was associated with a decrease in glucose disappearance rates (KG before PGE2 = 0.73±0.07; during PGE2 = 0.49±0.06%/min, P < 0.025). Acute insulin responses to arginine (2 g i.v.) were not affected by PGE2 (response before PGE2 = 592±164%; during PGE2 = 590±118%; P = NS). Infusion of sodium salicylate (SS), an inhibitor of endogenous prostaglandin synthesis, augmented acute insulin responses to glucose in normals (response before SS = 313±62%; during SS = 660±86%; P < 0.001). In adult-onset diabetes with fasting hyperglycemia, SS restored absent acute insulin responses to glucose (20 g i.v.) pulses (response before SS = 5±6%; during SS = 97±24%; P < 0.005). This was accompanied by a fourfold augmentation in second phase insulin secretion (second phase before SS = 1,696±430%; during SS = 5,176±682%; change 10-60 min insulin, μU/ml·min,% basal, P < 0.001) and by acceleration of glucose disappearance rates (KG before SS = 0.56±0.06; during SS = 1.02±0.17%/min, P < 0.005). These findings uniquely demonstrate that (a) PGE2 inhibits glucose-induced acute insulin responses and decreases glucose disposal in nondiabetic humans and (b) SS restores acute insulin responses, augments second phase insulin secretion, and accelerates glucose disposal in hyperglycemic, adultonset diabetics. It is hypothesized that endogenous PGE synthesis may play a role in defective insulin secretion and glucose intolerance in diabetes mellitus.
Interleukin-8 gene expression by a pulmonary epithelial cell line. A model for cytokine networks in the lung.
Authors: T J Standiford, S L Kunkel, M A Basha, S W Chensue, J P Lynch, G B Toews, J Westwick, R M Strieter
Journal: Journal of Clinical Investigation (1990)

Cellular constituents of the alveolar-capillary wall may be key participants in the recruitment of polymorphonuclear leukocytes to the lung through the generation of the novel neutrophil chemotactic peptide interleukin-8 (IL-8). This interaction appears to occur via the ability of human alveolar macrophage (AM)-derived monokines, tumor necrosis factor (TNF), and interleukin-1 (IL-1) to induce gene expression of IL-8 from pulmonary type II-like epithelial cells (A549). Northern blot analysis demonstrated that steady-state IL-8 mRNA expression, by either TNF- or IL-1 beta-treated A549 cells, occurred in both a dose- and time-dependent fashion. Similarly, extracellular antigenic IL-8, as assessed by specific ELISA, was expressed from TNF- or IL-1 beta-stimulated epithelial cells in a time-dependent fashion with maximal IL-8 antigen detected at 24 h poststimulation. Immunohistochemical staining utilizing rabbit anti-human IL-8 antibody identified immunoreactive, cell-associated IL-8 antigen as early as 8 h post-TNF or IL-1 beta stimulation. A549-generated neutrophil chemotactic bioactivity paralleled IL-8 steady-state mRNA levels. Signal specificity was demonstrated in this system as IL-8 mRNA or protein expression by lipopolysaccharide (LPS)-treated A549 cells was not different from unstimulated cells. Although LPS did not serve as a direct stimulus for the production of IL-8 by type II-like epithelial cells, the condition media from LPS-challenged AM induced a significant expression of IL-8 mRNA by the A549 cells. 24-h conditioned media from LPS-treated cells was as potent as either IL-1 beta or TNF in generating steady-state IL-8 mRNA by A549 cells. Preincubation of LPS-treated AM-conditioned media with anti-human TNF or IL-1 beta neutralizing antibodies resulted in significant abrogation of IL-8 gene expression by A549 pulmonary epithelial cells. These findings demonstrate potential cell-to-cell communication circuits that may be important between AMs and pulmonary epithelial cells during the recruitment phase of acute lung inflammation.
Notch Signaling in Leukemia
Authors: Jon C. Aster, Warren S. Pear, Stephen C. Blacklow
Journal: Annual Review of Pathology Mechanisms of Disease (2008)

Recent discoveries indicate that gain-of-function mutations in the Notch1 receptor are very common in human T cell acute lymphoblastic leukemia/lymphoma. This review discusses what these mutations have taught us about normal and pathophysiologic Notch1 signaling, and how these insights may lead to new targeted therapies for patients with this aggressive form of cancer.
Agenesis of paranasal sinuses and nasal nitric oxide in primary ciliary dyskinesia
Authors: M. Pifferi, A. Bush, D. Caramella, M. Di Cicco, M. Zangani, I. Chinellato, P. Macchia, A.L. Boner
Journal: European Respiratory Journal (2010)

Agenesis of paranasal sinuses has only been described in case reports of patients with primary ciliary dyskinesia (PCD). As agenesis of paranasal sinuses may contribute to low nasal nitric oxide levels, a common finding in PCD, we speculated that this condition might frequently occur in PCD patients. Patients referred for PCD evaluation were consecutively recruited for 30 months. In addition to standard diagnostic testing for PCD, a computed tomography (CT) scan of paranasal sinuses was performed in all subjects. 86 patients (46 children aged 8–17 yrs) were studied. PCD was diagnosed in 41 subjects and secondary ciliary dyskinesia (SCD) was diagnosed in the remaining 45 subjects. Frontal and/or sphenoidal sinuses were either aplastic or hypoplastic on CT scans in 30 (73%) out of 41 PCD patients, but in only 17 (38%) out of 45 with SCD (p = 0.002). There was a significant inverse correlation between the score for aplasia/hypoplasia of each paranasal sinus and nasal NO values in the PCD patients (p = 0.008, r = −0.432) but not in SCD (p = 0.07, r = −0.271). The findings of aplasia/hypoplasia of the frontal and or sphenoidal sinuses may be part of the spectrum of PCD and this finding should prompt exclusion of this condition.
Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients
Authors: Simone Susser, Christoph Welsch, Yalan Wang, Markus Zettler, Francisco S. Domingues, Ursula Karey, Eric Hughes, Robert Ralston, Xiao Tong, Eva Herrmann, Stefan Zeuzem, Christoph Sarrazin
Journal: Hepatology (2009)

Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS) 3/4A protease inhibitor that is currently being evaluated in combination with peginterferon alfa-2b and ribavirin in phase 3 studies. The clinical resistance profile of boceprevir is not characterized in detail so far. The NS3 protease domain of viral RNA was cloned from HCV genotype 1–infected patients (n = 22). A mean number of 47 clones were sequenced before, at the end, and after treatment with 400 mg boceprevir twice or three times daily for 14 days for genotypic, phenotypic, and viral fitness analysis. At the end of treatment, a wild-type an NS3 protease sequence was observed with a mean frequency of 85.9%. In the remaining isolates, five previously observed resistance mutations (V36M/A, T54A/S, R155K/T, A156S, V170A) and one mutation (V55A) with unknown resistance to boceprevir were detected either alone or in combination. Phenotypic analysis in the HCV replicon assay showed low (V36G, T54S, R155L; 3.8- to 5.5-fold 50% inhibitory concentration [IC50]), medium (V55A, R155K, V170A, T54A, A156S; 6.8- to 17.7-fold IC50) and high level (A156T; >120-fold IC50) resistance to boceprevir. The overall frequency of resistant mutations and the level of resistance increased with greater declines in mean maximum HCV RNA levels. Two weeks after the end of treatment, the frequency of resistant variants declined and the number of wild-type isolates increased to 95.5%. With the exception of V36 and V170 variants all resistant mutations declined by more than 50%. Mathematical modeling revealed impaired replicative fitness for all single mutations, whereas for combined mutations a relative increase of replication efficiency was suggested. Conclusion: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross-resistance to telaprevir. (HEPATOLOGY 2009.)
TGF-β1–Containing Exosomes from Injured Epithelial Cells Activate Fibroblasts to Initiate Tissue Regenerative Responses and Fibrosis
Authors: Fernanda T. Borges, Sonia A. Melo, Berna C. Özdemir, Noritoshi Kato, Ignacio Revuelta, Caroline A. Miller, Vincent H. Gattone, Valerie S. LeBleu, Raghu Kalluri
Journal: Journal of the American Society of Nephrology (2012)

Hypoxia is associated with tissue injury and fibrosis but its functional role in fibroblast activation and tissue repair/regeneration is unknown. Using kidney injury as a model system, we demonstrate that injured epithelial cells produce an increased number of exosomes with defined genetic information to activate fibroblasts. Exosomes released by injured epithelial cells promote proliferation, α-smooth muscle actin expression, F-actin expression, and type I collagen production in fibroblasts. Fibroblast activation is dependent on exosomes delivering TGF-β1 mRNA among other yet to be identified moieties. This study suggests that TGF-β1 mRNA transported by exosomes constitutes a rapid response to initiate tissue repair/regenerative responses and activation of fibroblasts when resident parenchyma is injured. The results also inform potential utility of exosome-targeted therapies to control tissue fibrosis.
Topical Microbicides to Prevent HIV: Clinical Drug Development Challenges
Authors: Craig W. Hendrix, Ying Jun Cao, Edward J. Fuchs
Journal: The Annual Review of Pharmacology and Toxicology (2008)

Microbicides, substances applied topically to prevent sexual HIV infection, are needed to empower receptive sexual partners with effective prevention methods. Several large microbicide trials, however, failed to demonstrate efficacy, thus motivating a reevaluation of the current microbicide development paradigm, which has been largely empirically based. Microbicide use occurs in a highly complex environment involving multi-level interactions, behavioral and biochemical, among host, virus, and drug, yet many details of these interactions remain unknown. Fundamental information regarding virus and drug distribution over time in sexually receptive body compartments that is necessary to design a microbicide able to outdistance and outlast the virus is largely absent. Recent efforts have been made to establish a simple conceptual framework for obtaining the knowledge that is likely to inform a more mechanistic, model-based development paradigm. These efforts have also advanced the development of numerous methodological approaches to obtain the knowledge needed to improve microbicide development.
Screening for HIV-Associated Tuberculosis and Rifampicin Resistance before Antiretroviral Therapy Using the Xpert MTB/RIF Assay: A Prospective Study
Authors: Stephen D. Lawn, Sophie V. Brooks, Katharina Kranzer, Mark P. Nicol, Andrew Whitelaw, Monica Vogt, Linda-Gail Bekker, Robin Wood
Journal: PLoS Medicine (2011)

The World Health Organization has endorsed the Xpert MTB/RIF assay for investigation of patients suspected of having tuberculosis (TB). However, its utility for routine TB screening and detection of rifampicin resistance among HIV-infected patients with advanced immunodeficiency enrolling in antiretroviral therapy (ART) services is unknown.Consecutive adult HIV-infected patients with no current TB diagnosis enrolling in an ART clinic in a South African township were recruited regardless of symptoms. They were clinically characterised and invited to provide two sputum samples at a single visit. The accuracy of the Xpert MTB/RIF assay for diagnosing TB and drug resistance was assessed in comparison with other tests, including fluorescence smear microscopy and automated liquid culture (gold standard) and drug susceptibility testing. Of 515 patients enrolled, 468 patients (median CD4 cell count, 171 cells/µl; interquartile range, 102-236) produced at least one sputum sample, yielding complete sets of results from 839 samples. Mycobacterium tuberculosis was cultured from 81 patients (TB prevalence, 17.3%). The overall sensitivity of the Xpert MTB/RIF assay for culture-positive TB was 73.3% (specificity, 99.2%) compared to 28.0% (specificity, 100%) using smear microscopy. All smear-positive, culture-positive disease was detected by Xpert MTB/RIF from a single sample (sensitivity, 100%), whereas the sensitivity for smear-negative, culture-positive TB was 43.4% from one sputum sample and 62.3% from two samples. Xpert correctly identified rifampicin resistance in all four cases of multidrug-resistant TB but incorrectly identified resistance in three other patients whose disease was confirmed to be drug sensitive by gene sequencing (specificity, 94.1%; positive predictive value, 57%).In this population of individuals at high risk of TB, intensive screening using the Xpert MTB/RIF assay increased case detection by 45% compared with smear microscopy, strongly supporting replacement of microscopy for this indication. However, despite the ability of the assay to rapidly detect rifampicin-resistant disease, the specificity for drug-resistant TB was sub-optimal.
Abstract 4787: Interaction between environmental exposure and HPV infection on developing lung cancer among Taiwanese nonsmokers.
Authors: Yawen Cheng, Nan-Yung Hsu, Huei Lee
Journal: Cancer Research (2013)

Abstract Majority of investigation is focused on lung tumorigenesis in smokers, little in nonsmokers. Previously, Benzo[a]pyrene (B[a]P)-DNA adducts levels in nonsmoking female patients were higher than in nonsmoking male patients. However, p53 mutation rate in female patients did not differ from male patients. Moreover, HPV16/18 infection rate in female patients was much higher than in male patients. We therefore hypothesized that HPV infection could synergistically increased chromosomal instability (CIN) induced by B[a]P-DNA adducts and might contribute to lung tumorigenesis. Herein, three HPV-positive and five HPV-negative lung cancer cells were enrolled to test the hypothesis. FISH analysis was used to determine the micronuclei formation when these cells were treated with various concentrations of B[a]P for different time-intervals. The efficacy of micronuclei and DNA adduct formation induced by B[a]P in HPV-positive cells were significantly higher than HPV-negative cells. Mechanistically, the micronuclei and DNA adduct formation are dependent on HPV E6 oncoprotein expression. We next questioned whether B[a]P-induced CIN enhanced by E6 could be through altering DNA repair gene expressions. The promoter hypermethylation and mRNA expression of six DNA repair genes including hMLH1, hMSH2, BRCA1, and BRCA2, and XRCC3, and XRCC5 were evaluated by MSP and real-time RT-PCR, and data indicated that XRCC3 and XRCC5 expressions in E6-positive cells were markedly lower than in E6-negative cells and the reduction of both genes was caused by promoter hypermethylation. Collectively, the promoter hypermethylation of XRCC3 and XRCC5 induced by E6 may increase B[a]P-induced CIN and contribute to lung tumorigenesis in nonsmokers. Citation Format: Yawen Cheng, Nan-Yung Hsu, Huei Lee. Interaction between environmental exposure and HPV infection on developing lung cancer among Taiwanese nonsmokers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4787. doi:10.1158/1538-7445.AM2013-4787
Gremlin-mediated Decrease in Bone Morphogenetic Protein Signaling Promotes Pulmonary Fibrosis
Authors: Marjukka Myllärniemi, Pamela Lindholm, Merja J. Ryynänen, Corrine R. Kliment, Kaisa Salmenkivi, Jorma Keski-Oja, Vuokko L. Kinnula, Tim D. Oury, Katri Koli
Journal: American Journal of Respiratory and Critical Care Medicine (2007)

Rationale: Members of the transforming growth factor (TGF)-β superfamily, including TGF-βs and bone morphogenetic proteins (BMPs), are essential for the maintenance of tissue homeostasis and regeneration after injury. We have observed that the BMP antagonist, gremlin, is highly up-regulated in idiopathic pulmonary fibrosis (IPF).Objectives: To investigate the role of gremlin in the regulation of BMP signaling in pulmonary fibrosis.Methods: Progressive asbestos-induced fibrosis in the mouse was used as a model of human IPF. TGF-β and BMP expression and signaling activities were measured from murine and human fibrotic lungs. The mechanism of gremlin induction was analyzed in cultured lung epithelial cells. In addition, the possible therapeutic role of gremlin inhibition was tested by administration of BMP-7 to mice after asbestos exposure.Measurements and Main Results: Gremlin mRNA levels were up-regulated in the asbestos-exposed mouse lungs, which is in agreement with the human IPF biopsy data. Down-regulation of BMP signaling was demonstrated by reduced levels of Smad1/5/8 and enhanced Smad2 phosphorylation in asbestos-treated lungs. Accordingly, analyses of cultured human bronchial epithelial cells indicated that asbestos-induced gremlin expression could be prevented by inhibitors of the TGF-β receptor and also by inhibitors of the mitogen-activated protein kinase kinase/extracellular signal-regulated protein kinase pathways. BMP-7 treatment significantly reduced hydroxyproline contents in the asbestos-treated mice.Conclusions: The TGF-β and BMP signaling balance is important for lung regenerative events and is significantly perturbed in pulmonary fibrosis. Rescue of BMP signaling activity may represent a potential beneficial strategy for treating human pulmonary fibrosis.
Utility of peanut-specific IgE levels in predicting the outcome of double-blind, placebo-controlled food challenges
Authors: Nancy H.G. van Nieuwaal, Wafae Lasfar, Yolanda Meijer, Petra A. Kentie, Annebeth E. Flinterman, Suzanne G.A.M. Pasmans, André C. Knulst, Maarten O. Hoekstra
Journal: Journal of Allergy and Clinical Immunology (2010)
DDR2 receptor promotes MMP-2–mediated proliferation and invasion by hepatic stellate cells
Authors: Elvira Olaso, Kazuo Ikeda, Francis J. Eng, Lieming Xu, Li-Hsien Wang, Hsin Chieh Lin, Scott L. Friedman
Journal: Journal of Clinical Investigation (2001)

Type I collagen provokes activation of hepatic stellate cells during liver injury through mechanisms that have been unclear. Here, we tested the role of the discoidin domain tyrosine kinase receptor 2 (DDR2), which signals in response to type I collagen, in this pathway. DDR2 mRNA and protein are induced in stellate cells activated by primary culture or in vivo during liver injury. The receptor becomes tyrosine phosphorylated in response to either endogenous or exogenous type I collagen, whereas its expression is downregulated during cellular quiescence induced by growth on Matrigel. We developed stellate cell lines stably overexpressing either wild-type DDR2, a constitutively active chimeric DDR2 receptor (Fc-DDR2), a truncated receptor expressing the extracellular domain, or a kinase-dead DDR2 Cells overexpressing DDR2 showed enhanced proliferation and invasion through Matrigel, activities that were directly related to increased expression of active matrix metalloproteinase 2 (MMP-2). These data show that DDR2 is induced during stellate cell activation and implicate the phosphorylated receptor as a mediator of MMP-2 release and growth stimulation in response to type I collagen. Moreover, type I collagen-dependent upregulation of DDR2 expression establishes a positive feedback loop in activated stellate cells, leading to further proliferation and enhanced invasive activity.
Dopamine enhances the phosphaturic response to parathyroid hormone in phosphate-deprived rats.
Authors: J Isaac, T J Berndt, S L Chinnow, G M Tyce, T P Dousa, F G Knox
Journal: Journal of the American Society of Nephrology (1992)

Phosphate deprivation results in a resistance to the phosphaturic effect of parathyroid hormone. Dopamine is phosphaturic and is synthesized by kidney proximal tubule, the nephron subsegment where parathyroid hormone inhibits phosphate transport. Thus, to test the hypothesis that phosphate deprivation is associated with low intrarenal dopamine synthesis and that dopamine infusion will overcome the resistance to the phosphaturic response to parathyroid hormone, the following study was performed. The effect of dietary phosphate intake on intrarenal dopamine synthesis, as reflected by urinary dopamine excretion, was determined. Rats were placed in metabolic cages (N = 5) and were fed a low-phosphate diet (0.07% Pi) for 4 days and then a high-phosphate diet (1.8% Pi) for 4 days. Twenty-four-hour urinary dopamine excretion was significantly lower in rats fed a low-phosphate diet (2.53 +/- 0.06 versus 4.10 +/- 0.30 micrograms/day). Further, the effect of dopamine infusion on the blunted phosphaturic response to parathyroid hormone was studied in rats fed a low-phosphate diet for 1, 2, and 3 days. Control clearances were taken 2 h after thyroparathyroidectomy; then, parathyroid hormone (33 U/kg plus 1 U/kg/min), dopamine (25 micrograms/kg/min), or parathyroid hormone plus dopamine were infused for 60 min. Changes in the fractional excretion of phosphate were significantly greater in rats fed a low-phosphate diet infused with parathyroid hormone plus dopamine than in rats fed a low-phosphate diet infused with parathyroid hormone alone (delta 27.9 +/- 5.8 versus 11.2 +/- 2.6% for day 1; 28.4 +/- 1.4 versus 7.1 +/- 3.6% for day 2; and 10.7 +/- 2.8 versus -0.2 +/- 0.2% for day 3; N = 5 for all groups).(ABSTRACT TRUNCATED AT 250 WORDS)