tbuckley/cabot-search huggingface dataset:
Vitamin D3 attenuates Th2 responses to Aspergillus fumigatus mounted by CD4+ T cells from cystic fibrosis patients with allergic bronchopulmonary aspergillosis
Authors: James L. Kreindler, Chad Steele, Nikki Nguyen, Yvonne R. Chan, Joseph M. Pilewski, John F. Alcorn, Yatin M. Vyas, Shean J. Aujla, Peter Finelli, Megan Blanchard, Steven F. Zeigler, Alison Logar, Elizabeth Hartigan, Marcia Kurs-Lasky, Howard Rockette, Anuradha Ray, Jay K. Kolls
Journal: Journal of Clinical Investigation (2010)

Allergic bronchopulmonary aspergillosis (ABPA) is caused by a dominant Th2 immune response to antigens derived from the opportunistic mold Aspergillus, most commonly Aspergillus fumigatus. It occurs in 4%-15% of patients with cystic fibrosis (CF); however, not all patients with CF infected with A. fumigatus develop ABPA. Therefore, we compared cohorts of A. fumigatus-colonized CF patients with and without ABPA to identify factors mediating tolerance versus sensitization. We found that the costimulatory molecule OX40 ligand (OX40L) was critical in driving Th2 responses to A. fumigatus in peripheral CD4+ T cells isolated from patients with ABPA. In contrast, CD4+ T cells from the non-ABPA cohort did not mount enhanced Th2 responses in vitro and contained a higher frequency of TGF-beta-expressing regulatory T cells. Heightened Th2 reactivity in the ABPA cohort correlated with lower mean serum vitamin D levels. Further, in vitro addition of 1,25 OH-vitamin D3 substantially reduced DC expression of OX40L and increased DC expression of TGF-beta. This in vitro treatment also resulted in increased Treg TGF-beta expression and reduced Th2 responses by CD4+ T cells from patients with ABPA. These data provide rationale for a therapeutic trial of vitamin D to prevent or treat ABPA in patients with CF.
A Phylogenomic Analysis of the Shikimate Dehydrogenases Reveals Broadscale Functional Diversification and Identifies One Functionally Distinct Subclass
Authors: S. Singh, J. Stavrinides, D. Christendat, D. S. Guttman
Journal: Molecular Biology and Evolution (2008)

The shikimate dehydrogenases (SDH) represent a widely distributed enzyme family with an essential role in secondary metabolism. This superfamily had been previously subdivided into 4 enzyme groups (AroE, YdiB, SdhL, and RifI), which show clear biochemical and functional differences ranging from amino acid biosynthesis to antibiotic production. Despite the importance of this group, little is known about how such essential enzymatic functions can evolve and diversify. We dissected the enzyme superfamily with a phylogenomic analysis of ∼250 fully sequenced genomes, making use of previously characterized representatives from each enzyme class, and the key substrate-binding residues known to distinguish substrate specificity. We identified 5 major evolutionary and functional SDH subgroups and several other potentially unique functional classes within this complex enzyme family and then validated the functional distinctiveness of each group by characterizing the 5 SDH homologs found in Pseudomonas putida KT2440 biochemically. We identified an entirely novel functionally distinct subgroup, which we designated Ael1 (AroE-like1) and also delineated a new group of shikimate/quinate dehydrogenases (YdiB2), which is phylogenetically distinct from the previously described Escherichia coli YdiB. The combination of biochemical, phylogenetic, and genomic approaches has revealed the broad extent to which the SDH enzyme superfamily has diversified. Five functional groups were validated with the potential for at least 5 additional subgroups. Our analysis also identified a new SDH functional group, which appears to have evolved recently from an ancestral AroE, illustrating a very prominent role of horizontal transmission and neofunctionalizaton in the evolutionary and functional diversification of this enzyme family.
Fasting in vivo delays myocardial cell damage after brief periods of ischemia in the isolated working rat heart.
Authors: C A Schneider, H Taegtmeyer
Journal: Circulation Research (1991)

To assess the effects of fasting on recovery of function and exogenous glucose metabolism after 15 minutes of total ischemia, we perfused isolated working rat hearts from fed and fasted animals. Hearts were perfused in a recirculating system with bicarbonate buffer containing glucose (10 mM). Mechanical performance, release of marker proteins for ischemic membrane damage (lactate dehydrogenase, myoglobin, citrate synthase), and the concentrations of lactate and glucose in the perfusion medium were measured serially. Tissue metabolites were also measured. Fasting raised the myocardial glycogen content by 25%. Cardiac performance of perfused hearts from fed and fasted animals was the same during the preischemic and the post-ischemic period. The time of return of function to preischemic values was significantly less in hearts from fasted rats (2.3 versus 7.8 minutes, p less than 0.025). The release of cytosolic and mitochondrial marker proteins was significantly lower in hearts from fasted rats than in hearts from fed rats. Glucose metabolic rates during control and reperfusion were unchanged for hearts from fasted rats, but decreased for hearts from fed rats during reperfusion. The adenine nucleotide content at the end of ischemia was higher in hearts from fasted animals than in hearts from fed animals. We conclude that increasing glycogen levels prior to ischemia improves recovery of function, lessens membrane damage, and prevents loss of adenine nucleotides.
Multidrug resistance 1 gene (P-glycoprotein 170): an important determinant in gastrointestinal disease?
Authors: G-T Ho
Journal: Gut (2003)

The interface between luminal contents and intestinal epithelium constitutes the largest area of interaction between the host and the environment. There is now strong evidence that the gene product of the multidrug resistant pump (MDR) plays a critical role in host-bacterial interactions in the gastrointestinal tract and maintenance of intestinal homeostasis. This review highlights the efflux mechanism in the intestinal epithelium which is mediated by the multidrug resistant pump, also known as P-glycoprotein 170. Current studies promise to provide further insights into the contribution of the MDR1 gene in the pathogenesis of inflammatory and malignant disorders of the gastrointestinal tract.
Real-time Liquid Biopsy in Cancer Patients: Fact or Fiction?
Authors: Klaus Pantel, Catherine Alix-Panabières
Journal: Cancer Research (2013)

Abstract Distant metastases harbor unique genomic characteristics not detectable in the corresponding primary tumor of the same patient and metastases located at different sites show a considerable intrapatient heterogeneity. Thus, the mere analysis of the resected primary tumor alone (current standard practice in oncology) or, if possible, even reevaluation of tumor characteristics based on the biopsy of the most accessible metastasis may not reveal sufficient information for treatment decisions. Here, we propose that this dilemma can be solved by a new diagnostic concept: liquid biopsy, that is, analysis of therapeutic targets and drug resistance–conferring gene mutations on circulating tumor cells (CTC) and cell-free circulating tumor DNA (ctDNA) released into the peripheral blood from metastatic deposits. We discuss the current challenges and future perspectives of CTCs and ctDNA as biomarkers in clinical oncology. Both CTCs and ctDNA are interesting complementary technologies that can be used in parallel in future trials assessing new drugs or drug combinations. We postulate that the liquid biopsy concept will contribute to a better understanding and clinical management of drug resistance in patients with cancer. Cancer Res; 73(21); 6384–8. ©2013 AACR.
Renal vasoconstriction by the endothelial cell-derived peptide endothelin in spontaneously hypertensive rats.
Authors: Y Hirata, H Matsuoka, K Kimura, K Fukui, H Hayakawa, E Suzuki, T Sugimoto, T Sugimoto, M Yanagisawa, T Masaki
Journal: Circulation Research (1989)

The effects of endothelin on systemic and renal hemodynamics in anesthetized spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats were examined. Endothelin (500 ng i.v. +1,000 ng/hr per 300-g rat) elevated mean blood pressure by 13% (p less than 0.02) and decreased renal blood flow by 71% and glomerular filtration rate by 66% (both p less than 0.01), resulting in a 430% (p less than 0.05) increase in renal vascular resistance (RVR) in SHR. This rise in blood pressure was associated with a significant increase in hematocrit (+8%), but a decrease in urinary sodium excretion (-51%). This dose of endothelin reduced cardiac output by 40% (p less than 0.001) and brought about a 96% (p less than 0.01) rise in systemic vascular resistance (SVR). However, the SVR increase was significantly smaller than the RVR increase. These changes in systemic and renal hemodynamics were observed in a dose-dependent manner, and the degrees of change did not differ between the two strains. Additional infusion of atrial natriuretic peptide (0.33 microgram/kg/min) into SHR completely reversed the changes in blood pressure and renal hemodynamics caused by endothelin, resulting in pronounced natriuresis (+760%). The renal vascular casting study revealed that endothelin mainly constricted the arcuate and interlobular arteries, as well as afferent arterioles. These results suggest that endothelin may be involved in blood pressure and body fluid volume regulation through systemic and renal vasoconstriction.
Phase I Study of Intermittent Oral Dosing of the Insulin-like Growth Factor-1 and Insulin Receptors Inhibitor OSI-906 in Patients With Advanced Solid Tumors
Authors: Robin L. Jones, Edward S. Kim, Pilar Nava-Parada, Salma Alam, Faye M. Johnson, Andrew W. Stephens, Ronit Simantov, Srinivasu Poondru, Rich Gedrich, Scott M. Lippman, Stan B. Kaye, Craig P. Carden
Journal: Clinical Cancer Research (2014)

We determined the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, and preliminary activity of OSI-906, a potent, oral, dual inhibitor of insulin-like growth factor-1 receptor (IGF1R) and insulin receptor (IR), in patients with advanced solid tumors.This was a multicenter, open-label, dose escalation phase I study evaluating three intermittent dosing schedules of once-daily OSI-906 [schedule (S) 1, days 1-3 every 14 days; S2, days 1-5 every 14 days; S3, days 1-7 every 14 days]. A fed-fasting expansion cohort was included in the study.Seventy-nine patients were enrolled: 62 in S1, 4 in S2, and 13 in S3. S2 was discontinued. Dose-limiting toxicity comprised grade 3-4 hyperglycemia, vomiting, fatigue, and prolonged QTc interval. The MTD and recommended phase II dose of OSI-906 was 600 mg for both S1 and S3 schedules. Other common adverse events were grade 1-2 nausea, vomiting, fatigue, and diarrhea. The pharmacokinetics of OSI-906 was dose linear, and the terminal half-life ranged between 2 and 6 hours. High-fat meals had a moderate effect on the pharmacokinetics of OSI-906. At the MTD, inhibition of IGF1R and IR was observed in peripheral blood mononuclear cells. An increase in plasma IGF1 concentrations, an indirect measure of IGF1R signaling inhibition, was seen at doses ≥ 450 mg. Two patients with adrenocortical carcinoma achieved partial responses.The MTD of 600 mg was well tolerated and associated with preliminary antitumor activity. These data support further evaluation of OSI-906 in solid tumors.
Treatment of Resistant Depression in Adolescents (TORDIA): Week 24 Outcomes
Authors: Graham J. Emslie, Taryn Mayes, Giovanna Porta, Benedetto Vitiello, Greg Clarke, Karen Dineen Wagner, Joan Rosenbaum Asarnow, Anthony Spirito, Boris Birmaher, Neal Ryan, Betsy Kennard, Lynn DeBar, James McCracken, Michael Strober, Matthew Onorato, Jamie Zelazny, Marty Keller, Satish Iyengar, David Brent
Journal: American Journal of Psychiatry (2010)

Objective The purpose of this study was to report on the outcome of participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial after 24 weeks of treatment, including remission and relapse rates and predictors of treatment outcome. Method Adolescents (ages 12–18 years) with selective serotonin reuptake inhibitor (SSRI)-resistant depression were randomly assigned to either a medication switch alone (alternate SSRI or venlafaxine) or a medication switch plus cognitive-behavioral therapy (CBT). At week 12, responders could continue in their assigned treatment arm and nonresponders received open treatment (medication and/or CBT) for 12 more weeks (24 weeks total). The primary outcomes were remission and relapse, defined by the Adolescent Longitudinal Interval Follow-Up Evaluation as rated by an independent evaluator. Results Of 334 adolescents enrolled in the study, 38.9% achieved remission by 24 weeks, and initial treatment assignment did not affect rates of remission. Likelihood of remission was much higher (61.6% versus 18.3%) and time to remission was much faster among those who had already demonstrated clinical response by week 12. Remission was also higher among those with lower baseline depression, hopelessness, and self-reported anxiety. At week 12, lower depression, hopelessness, anxiety, suicidal ideation, family conflict, and absence of comorbid dysthymia, anxiety, and drug/alcohol use and impairment also predicted remission. Of those who responded by week 12, 19.6% had a relapse of depression by week 24. Conclusions Continued treatment for depression among treatment-resistant adolescents results in remission in approximately one-third of patients, similar to adults. Eventual remission is evident within the first 6 weeks in many, suggesting that earlier intervention among nonresponders could be important.
Autoimmune skin inflammation is dependent on plasmacytoid dendritic cell activation by nucleic acids via TLR7 and TLR9
Authors: Cristiana Guiducci, Claudio Tripodo, Mei Gong, Sabina Sangaletti, Mario P. Colombo, Robert L. Coffman, Franck J. Barrat
Journal: The Journal of Experimental Medicine (2010)

Recognition of endogenous DNA and RNA by cells expressing TLR7 and TLR9 is an important contributor to the pathogenesis of systemic lupus erythematosus and has been suggested to contribute to cutaneous lupus and to a group of related inflammatory skin diseases termed interface dermatitis. We have developed a mouse model of TLR7- and TLR9-dependent skin inflammation using tape stripping. In normal mice, this resulted in a rapid but transient inflammatory cell infiltration accompanied by induction of type I IFN production by plasmacytoid dendritic cells (PDCs) and release of extracellular traps and proinflammatory cytokines by neutrophils. These responses were strongly reduced in MyD88-deficient mice and in mice treated with a bifunctional inhibitor of TLR7 and TLR9. In contrast, in lupus-prone (NZBxNZW)F1 mice, tape stripping induced the development of chronic lesions characterized by a persistent type I IFN gene signature and many clinical and histological features of cutaneous lupus. Depletion of PDCs before injury prevented the development of skin lesions, whereas treatment with a bifunctional TLR7/9 inhibitor before tape stripping or after the initial lesion was established led to a significant reduction of the disease. These data suggest that inhibitors of TLR7 and TLR9 signaling have potential therapeutic application for the treatment of interface dermatitis.
Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST)
Authors: J.B.A. Crusius, F. Canzian, G. Capellá, A.S. Peña, G. Pera, N. Sala, A. Agudo, F. Rico, G. Del Giudice, D. Palli, M. Plebani, H. Boeing, H.B. Bueno-de-Mesquita, F. Carneiro, V. Pala, V.E. Save, P. Vineis, R. Tumino, S. Panico, G. Berglund, J. Manjer, R. Stenling, G. Hallmans, C. Martínez, M. Dorronsoro, A. Barricarte, C. Navarro, J.R. Quirós, N. Allen, T.J. Key, S. Binghan, C. Caldas, J. Linseisen, R. Kaaks, K. Overvad, A. Tjønneland, F.C. Büchner, P.H.M. Peeters, M.E. Numans, F. Clavel-Chapelon, A. Trichopoulou, E. Lund, M. Jenab, S. Rinaldi, P. Ferrari, E. Riboli, C.A. González
Journal: Annals of Oncology (2008)
Variation in natriuretic peptides and mitral flow indexes during successful ventilatory weaning: a preliminary study
Authors: Hafid Ait-Oufella, Pierre-Louis Tharaux, Jean-Luc Baudel, Sophie Vandermeersch, Pascal Meyer, Marc Tonnellier, Jean-Claude Dussaule, Bertrand Guidet, Georges Offenstadt, Eric Maury
Journal: Intensive Care Medicine (2007)
Pharmacology for the Treatment of Premature Ejaculation
Authors: François Giuliano, Pierre Clèment
Journal: Pharmacological Reviews (2012)

Male sexual response comprises four phases: excitement, including erection; plateau; ejaculation, usually accompanied by orgasm; and resolution. Ejaculation is a complex sexual response involving a sequential process consisting of two phases: emission and expulsion. Ejaculation, which is basically a spinal reflex, requires a tight coordination between sympathetic, parasympathetic, and somatic efferent pathways originating from different segments and area in the spinal cord and innervating pelvi-perineal anatomical structures. A major relaying and synchronizing role is played by a group of lumbar neurons described as the spinal generator of ejaculation. Excitatory and inhibitory influences from sensory genital and cerebral stimuli are integrated and processed in the spinal cord. Premature ejaculation (PE) can be defined by ≤1-min ejaculatory latency, an inability to delay ejaculation, and negative personal consequences. Because there is no physiological impairment in PE, any pharmacological agent with central or peripheral mechanism of action that is delaying the ejaculation is a drug candidate for the treatment of PE. Ejaculation is centrally mediated by a variety of neurotransmitter systems, involving especially serotonin and serotonergic pathways but also dopaminergic and oxytocinergic systems. Pharmacological delay of ejaculation can be achieved either by inhibiting excitatory or reinforcing inhibitory pathways from the brain or the periphery to the spinal cord. PE can be treated with long-term use of selective serotonin-reuptake inhibitors (SSRIs) or tricyclic antidepressants. Dapoxetine, a short-acting SSRI, is the first treatment registered for the on-demand treatment of PE. Anesthetics applied on the glans penis have the ability to lengthen the time to ejaculation. Targeting oxytocinergic, neurokinin-1, dopaminergic, and opioid receptors represent future avenues to delaying ejaculation.
PDF Receptor Signaling in Drosophila Contributes to Both Circadian and Geotactic Behaviors
Authors: Inge Mertens, Anick Vandingenen, Erik C. Johnson, Orie T. Shafer, W. Li, J.S. Trigg, Arnold De Loof, Liliane Schoofs, Paul H. Taghert
Journal: Neuron (2005)
Protective Plasmodium knowlesi Mr 74,000 antigen in membranes of schizont-infected rhesus erythrocytes.
Authors: R Schmidt-Ullrich, J Lightholder, M T Monroe
Journal: The Journal of Experimental Medicine (1983)

The immunogenic Plasmodium knowlesi (H strain) Mr 74,000 protein in membranes of schizont-infected rhesus erythrocytes was purified on a large scale, free of other polypeptides as monitored by dodecyl sulfate polyacrylamide gel electrophoresis and isoelectric focusing. In a limited vaccination trial, four rhesus monkeys were immunized four consecutive times with the Mr 74,000 protein and Freund's complete and incomplete adjuvants. Two monkeys were injected with adjuvant only. Upon challenge with 10(4) viable P. knowlesi schizonts of the heterologous W strain, the control monkeys developed fatal parasitemias after 7 d. In contrast, the vaccinated monkeys exhibited a delayed onset of patent parasitemias and underwent self-cure on days 14 to 16 after peak parasitemias of between 7 and 11%. The protective immunity that was induced crossed different strains of P. knowlesi. Blood smears at the time of cure demonstrated limited reinfection, as indicated by the presence of normally appearing ring and trophozoite stages. The absence of schizont stages in the peripheral blood suggested a specific interruption of the erythrocytic schizogony at that stage. Immunochemical analyses of the rhesus sera revealed antibody only against the Mr 74,000 protein after the first two immunizations. Upon repeated antigen injection, antibodies reacted with components of Mr of approximately 102,000, 140,000, and 230,000 in addition to the Mr 74,000 protein. Besides immunological cross-reactivity, relatedness between all four immune-precipitated proteins was indicated by a greater than 50% tryptic peptide homology, suggesting that the Mr 230,000 component represents a precursor protein that is cleaved within the infected erythrocyte into proteins with Mr of approximately 140,000, 102,000, and 74,000.
Ticagrelor versus Clopidogrel in Patients with Acute Coronary Syndromes
Authors: Lars Wallentin, Richard C. Becker, Andrzej Budaj, Christopher P. Cannon, Håkan Emanuelsson, Claes Held, Jay Horrow, Steen Husted, Stefan James, Hugo Katus, Kenneth W. Mahaffey, Benjamin M. Scirica, Allan Skene, Philippe Gabriel Steg, Robert F. Storey, Robert A. Harrington
Journal: New England Journal of Medicine (2009)

Ticagrelor is an oral, reversible, direct-acting inhibitor of the adenosine diphosphate receptor P2Y12 that has a more rapid onset and more pronounced platelet inhibition than clopidogrel.In this multicenter, double-blind, randomized trial, we compared ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) and clopidogrel (300-to-600-mg loading dose, 75 mg daily thereafter) for the prevention of cardiovascular events in 18,624 patients admitted to the hospital with an acute coronary syndrome, with or without ST-segment elevation.At 12 months, the primary end point--a composite of death from vascular causes, myocardial infarction, or stroke--had occurred in 9.8% of patients receiving ticagrelor as compared with 11.7% of those receiving clopidogrel (hazard ratio, 0.84; 95% confidence interval [CI], 0.77 to 0.92; P<0.001). Predefined hierarchical testing of secondary end points showed significant differences in the rates of other composite end points, as well as myocardial infarction alone (5.8% in the ticagrelor group vs. 6.9% in the clopidogrel group, P=0.005) and death from vascular causes (4.0% vs. 5.1%, P=0.001) but not stroke alone (1.5% vs. 1.3%, P=0.22). The rate of death from any cause was also reduced with ticagrelor (4.5%, vs. 5.9% with clopidogrel; P<0.001). No significant difference in the rates of major bleeding was found between the ticagrelor and clopidogrel groups (11.6% and 11.2%, respectively; P=0.43), but ticagrelor was associated with a higher rate of major bleeding not related to coronary-artery bypass grafting (4.5% vs. 3.8%, P=0.03), including more instances of fatal intracranial bleeding and fewer of fatal bleeding of other types.In patients who have an acute coronary syndrome with or without ST-segment elevation, treatment with ticagrelor as compared with clopidogrel significantly reduced the rate of death from vascular causes, myocardial infarction, or stroke without an increase in the rate of overall major bleeding but with an increase in the rate of non-procedure-related bleeding. (ClinicalTrials.gov number, NCT00391872.)
Paclitaxel-loaded PEGylated PLGA-based nanoparticles: In vitro and in vivo evaluation
Authors: Fabienne Danhier, Nathalie Lecouturier, Benoît Vroman, Christine Jérôme, Jacqueline Marchand-Brynaert, Olivier Feron, Véronique Préat
Journal: Journal of Controlled Release (2008)