tbuckley/cabot-search huggingface dataset:
Molecular cloning and characterization of retinal photoreceptor guanylyl cyclase-activating protein
Authors: Krzysztof Palczewski, Iswari Subbaraya, Wojciech A. Gorczyca, Bharati S. Helekar, Claudia C. Ruiz, Hiroshi Ohguro, Jing Huang, Xinyu Zhao, John W. Crabb, Richard S. Johnson, Kenneth A. Walsh, Mark P. Gray-Keller, Peter B. Detwiler, Wolfgang Baehr
Journal: Neuron (1994)
Rational monitoring of COPD: where do current clinical guidelines stand?
Authors: L. van den Bemt, T. Schermer, C. van Weel
Journal: European Respiratory Journal (2007)

he Global Initiative for Chronic Obstructive Lung Disease (GOLD) guideline serves as an international reference for evidence-based management of patients with chronic obstructive pulmonary disease (COPD) [1].Based on the available scientific evidence, recommendations for diagnosis and treatment are presented.An important goal of the GOLD initiative is to counter the nihilistic attitude and to promote a proactive engagement of physicians and allied healthcare professionals with COPD patients over time [2].In addition, GOLD, and also other guidelines, recommend regular surveillance of patients' respiratory health status [1,[3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].The rationale behind the regular follow-up of patients with chronic conditions, also referred to as ''monitoring'', is that it facilitates optimal outcome of patient care [20,21].However, care of COPD implicates large numbers of patients and, consequently, monitoring their health status would result in substantial use of healthcare resources.In the present paper, the authors reflect on monitoring, as currently recommended in COPD guidelines, and discuss the rationale behind it, including some pros and cons of the procedures involved.
Cancer-Associated Fibroblasts Expressing CXCL14 Rely upon NOS1-Derived Nitric Oxide Signaling for Their Tumor-Supporting Properties
Authors: Martin Augsten, Elin Sjöberg, Oliver Frings, Sabine U. Vorrink, Jeroen Frijhoff, Eleonor Olsson, Åke Borg, Arne Östman
Journal: Cancer Research (2014)

Abstract Cancer-associated fibroblasts (CAF) stimulate tumor growth and metastasis. Signals supporting CAF function are thus emerging as candidate therapeutic targets in the tumor microenvironment. The chemokine CXCL14 is a potent inducer of CAF protumorigenic functions. This study is aimed at learning how the protumoral functions of CXCL14-expressing CAF are maintained. We found that the nitric oxide synthase NOS1 is upregulated in CXCL14-expressing CAF and in fibroblasts stimulated with CXCL14. Induction of Nos1 was associated with oxidative stress and occurred together with activation of NRF2 and HIF1α signaling in CXCL14-expressing CAF. Genetic or pharmacologic inhibition of NOS1 reduced the growth of CXCL14-expressing fibroblasts along with their ability to promote tumor formation following coinjection with prostate or breast cancer cells. Tumor analysis revealed reduced macrophage infiltration, with NOS1 downregulation in CXCL14-expressing CAF and lymphangiogenesis as a novel component of CXCL14-promoted tumor growth. Collectively, our findings defined key components of a signaling network that maintains the protumoral functions of CXCL14-stimulated CAF, and they identified NOS1 as intervention target for CAF-directed cancer therapy. Cancer Res; 74(11); 2999–3010. ©2014 AACR.
Cholangiocyte senescence by way of N-ras activation is a characteristic of primary sclerosing cholangitis
Authors: James H. Tabibian, Steven P. O'Hara, Patrick L. Splinter, Christy E. Trussoni, Nicholas F. LaRusso
Journal: Hepatology (2014)

Primary sclerosing cholangitis (PSC) is an incurable cholangiopathy of unknown etiopathogenesis. Here we tested the hypothesis that cholangiocyte senescence is a pathophysiologically important phenotype in PSC. We assessed markers of cellular senescence and senescence-associated secretory phenotype (SASP) in livers of patients with PSC, primary biliary cirrhosis, hepatitis C, and in normals by fluorescent in situ hybridization (FISH) and immunofluorescence microscopy (IFM). We tested whether endogenous and exogenous biliary constituents affect senescence and SASP in cultured human cholangiocytes. We determined in coculture whether senescent cholangiocytes induce senescence in bystander cholangiocytes. Finally, we explored signaling mechanisms involved in cholangiocyte senescence and SASP. In vivo, PSC cholangiocytes expressed significantly more senescence-associated p16(INK4a) and γH2A.x compared to the other three conditions; expression of profibroinflammatory SASP components (i.e., IL-6, IL-8, CCL2, PAI-1) was also highest in PSC cholangiocytes. In vitro, several biologically relevant endogenous (e.g., cholestane 3,5,6 oxysterol) and exogenous (e.g., lipopolysaccharide) molecules normally present in bile induced cholangiocyte senescence and SASP. Furthermore, experimentally induced senescent human cholangiocytes caused senescence in bystander cholangiocytes. N-Ras, a known inducer of senescence, was increased in PSC cholangiocytes and in experimentally induced senescent cultured cholangiocytes; inhibition of Ras abrogated experimentally induced senescence and SASP. Cholangiocyte senescence induced by biliary constituents by way of N-Ras activation is an important pathogenic mechanism in PSC. Pharmacologic inhibition of N-Ras with a resultant reduction in cholangiocyte senescence and SASP is a new therapeutic approach for PSC.
Cell Proliferation, Cell Cycle Abnormalities, and Cancer Outcome in Patients with Barrett's Esophagus: A Long-term Prospective Study
Authors: Dennis L. Chao, Carissa A. Sanchez, Patricia C. Galipeau, Patricia L. Blount, Thomas G. Paulson, David S. Cowan, Kamran Ayub, Robert D. Odze, Peter S. Rabinovitch, Brian J. Reid
Journal: Clinical Cancer Research (2008)

Abstract Purpose: Elevated cellular proliferation and cell cycle abnormalities, which have been associated with premalignant lesions, may be caused by inactivation of tumor suppressor genes. We measured proliferative and cell cycle fractions of biopsies from a cohort of patients with Barrett's esophagus to better understand the role of proliferation in early neoplastic progression and the association between cell cycle dysregulation and tumor suppressor gene inactivation. Experimental Design: Cell proliferative fractions (determined by Ki67/DNA multiparameter flow cytometry) and cell cycle fractions (DNA content flow cytometry) were measured in 853 diploid biopsies from 362 patients with Barrett's esophagus. The inactivation status of CDKN2A and TP53 was assessed in a subset of these biopsies in a cross-sectional study. A prospective study followed 276 of the patients without detectable aneuploidy for an average of 6.3 years with esophageal adenocarcinoma as an end point. Results: Diploid S and 4N (G2/tetraploid) fractions were significantly higher in biopsies with TP53 mutation and loss of heterozygosity. CDKN2A inactivation was not associated with higher Ki67-positive, diploid S, G1, or 4N fractions. High Ki67-positive and G1-phase fractions were not associated with the future development of esophageal adenocarcinoma (P = 0.13 and P = 0.15, respectively), whereas high diploid S-phase and 4N fractions were (P = 0.03 and P &amp;lt; 0.0001, respectively). Conclusions: High Ki67-positive proliferative fractions were not associated with inactivation of CDKN2A and TP53 or future development of cancer in our cohort of patients with Barrett's esophagus. Biallelic inactivation of TP53 was associated with elevated 4N fractions, which have been associated with the future development of esophageal adenocarcinoma.
ABC of transfusion. Human albumin solutions.
Authors: D B McClelland
Journal: BMJ (1990)

Production of albumin and solutions availableHuman albumin solutions for clinical use Plasma protein Human Human fraction (stable albumin albumin plasma protein (4 5 or 5%) (20%) solution) Concentration of human albumin (g/l) 40-50 200 50 Albumin (as % total protein) >96 >96 >85 Colloid osmotic pressure (mm Hg) 26-30 100-120 26-30 Sodium (mmol/l)
The Ethics of Early Stopping Rules: Who Is Protecting Whom?
Authors: Stephen A. Cannistra
Journal: Journal of Clinical Oncology (2004)

Well-conducted clinical investigation, in concert with basic laboratory research, is the cornerstone for progress in medicine. Without it, we are forced to depend solely on experience and bias in the choice of proper treatment, which can sometimes be misleading. Our well-intended predecessors from the time of Hippocrates would envy our analytic approach to clinical investigation, releasing them from the limitations of leeches, bad humors, and evil spirits inthemanagementofpatientswithlife-threateningdisease. Giventheimportanceoftheclinicaltrialprocess,ourgreatest challenge as clinical investigators is to ensure that trials yield interpretable results while preserving the safety of study participants. For phase III randomized trials, these issues are typically under the purview of an independent Data and Safety Monitoring Board (DSMB), composed of statisticians and clinical investigators not directly involved with the study. The DSMB is responsible for reviewing the data, performing interim analyses when the study reaches its specified number of events, and deciding whether or not to close the study on the basis of predetermined early stopping rules that relate to toxicity or outcome. If excess harm is observed, or if a statistically significant benefit is observed, the study is stopped early and the patient is informed of the results. If treatment is ongoing, the patient is
Mathematical and Experimental Approaches to Identify and Predict the Effects of Chemotherapy on Neuroglial Precursors
Authors: Ollivier Hyrien, Jörg Dietrich, Mark Noble
Journal: Cancer Research (2010)

The adverse effects of chemotherapy on normal cells of the body create substantial clinical problems for many cancer patients. However, relatively little is known about the effects, other than promotion of cell death, of such agents on the function of normal precursor cells critical in tissue homeostasis and repair. We have combined mathematical and experimental analyses to identify the effects of sublethal doses of chemotherapy on glial precursor cells of the central nervous system. We modeled the temporal development of a population of precursor and terminally differentiated cells exposed to sublethal doses of carmustine (BCNU), a classic alkylating chemotherapeutic agent used in treatment of gliomas and non-Hodgkin's lymphomas, as a multitype age-dependent branching process. We fitted our model to data from in vitro clonal experiments using the method of pseudo-likelihood. This approach identifies several novel drug effects, including modification of the cell cycle length, the time between division and differentiation, and alteration in the probability of undergoing self-renewal division in precursor cells. These changes of precursor cell function in the chemotherapy-exposed brain may have profound clinic implications.We applied our computational approach to analyze the effects of BCNU on clonal cultures of oligodendrocyte progenitor cells-one of the best-characterized neural progenitor cells in the mammalian brain. Our analysis reveals that transient exposures to BCNU increased the cell cycle length of progenitor cells and decreased their time to differentiation, while also decreasing the likelihood that they will undergo self-renewing divisions. By investigating the behavior of our mathematical model, we demonstrate that precursor cell populations should recover spontaneously from transient modifications of the timing of division and of differentiation, but such recovery will not happen after alteration of cell fate. These studies identify means by which precursor cell function can be critically compromised by transient exposure to chemotherapy with long-term consequences on the progenitor cell pool even in the absence of drug-induced apoptosis. These analyses also provide novel tools that apply broadly to identify effects of chemotherapeutic agents and other physiological stressors.
Tamoxifen Versus Control After Adjuvant, Risk-Adapted Chemotherapy in Postmenopausal, Receptor-Negative Patients With Breast Cancer: A Randomized Trial (GABG-IV D-93)—The German Adjuvant Breast Cancer Group
Authors: Manfred Kaufmann, Erika Graf, Walter Jonat, Wolfgang Eiermann, Matthias Geberth, Ute-Susann Albert, Günther Gademann, Bettina Conrad, Karin Stahl, Gunter von Minckwitz, Martin Schumacher
Journal: Journal of Clinical Oncology (2005)

To investigate the effect of adjuvant sequential tamoxifen after chemotherapy in postmenopausal patients with hormone receptor-negative breast cancer.Patients were randomly assigned to oral tamoxifen (30 mg daily for 5 years; n = 421) or no additional treatment (n = 408) after risk-adapted polychemotherapy consisting of three 28-day cycles of CMF (cyclophosphamide, 500 mg/m(2), methotrexate, 40 mg/m(2), and fluorouracil, 600 mg/m(2)) in patients with negative or one to three positive lymph nodes and four 21-day cycles of epirubicin 90 mg/m(2), cyclophosphamide 600 mg/m(2) followed by three cycles of CMF in patients with four to nine positive lymph nodes.Thirty-six percent of the patients included were older than 60 years, 63% were node negative, 13% had four to nine positive nodes, 55% had tumor grade 3, and 41% received breast-preserving surgery. At 5.3 years' median follow-up, the first event of failure (recurrence, secondary tumor, or death) had occurred in 123 patients in the tamoxifen group and 107 patients of the control group. Event-free survival rates after 5 years were 70.3% (95% CI, 65.5% to 75.0%) and 72.8% (95% CI, 68.2% to 77.5%) for the tamoxifen and control groups, respectively. The estimated hazard ratio of tamoxifen versus control was 1.13 (95% CI, 0.87 to 1.48; P = .34), which gives no indication of an additional benefit of tamoxifen in these patients.This study contributes substantially to finalization of the presently emerging evidence that tamoxifen does not benefit women with receptor-negative breast cancer after chemotherapy.
Cell-Based Assays for Identification of Novel Double-Strand Break-Inducing Agents
Authors: H. M. Dunstan, C. Ludlow, S. Goehle, M. Cronk, P. Szankasi, D. R. H. Evans, J. A. Simon, J. R. Lamb
Journal: JNCI Journal of the National Cancer Institute (2002)

Background:We are developing cell-based assays to identify anticancer agents that are selectively toxic to cells with defined mutations. As a test, we used a three-stage strategy to screen compounds from the National Cancer Institute's repository for agents that are selectively toxic to double-strand break repair-deficient yeast cells. Methods:Compounds identified in the screen were further analyzed by use of yeast and vertebrate cell-based and in vitroassays to distinguish between topoisomerase I and II poisons. Results:Of the more than 85 000 compounds screened, 126 were selectively toxic to yeast deficient in DNA double-strand break repair. Eighty-seven of these 126 compounds were structurally related to known topoisomerase poisons, and 39 were not. Twenty-eight of the 39 were characterized, and we present data for eight of the compounds. Among these eight compounds, we identified two novel topoisomerase II poisons (NSC 327929 and NSC 638432) that were equipotent to etoposide in biochemical tests and in cells, five (NSC 63599, NSC 65601, NSC 380271, NSC 651646, and NSC 668370) with topoisomerase I-dependent toxicity in yeast that induced DNA damage and toxicity in mammalian cells, and one (NSC 610898) that directly bound to DNA and induced strand breaks. Conclusions:Cell-based assays can be used to identify molecules that are selectively toxic to cells with a predetermined genetic background, including mutations in genes involved in the cell cycle and its checkpoints, for which there are currently no selectively toxic compounds.
Coronary Hemodynamics in Endothelial NO Synthase Knockout Mice
Authors: Axel Gödecke, Ulrich K. M. Decking, Zhaoping Ding, Jens Hirchenhain, Hans-Jürgen Bidmon, Stefanie Gödecke, Jürgen Schrader
Journal: Circulation Research (1998)

Abstract —For the specific analysis of endothelial NO synthase (eNOS) function in the coronary vasculature, we generated a mouse homozygous for a defective eNOS gene (eNOS−/−). Western blot as well as immunohistochemical staining revealed the absence of eNOS protein in eNOS−/− mice. Aortic endothelial cells derived from eNOS−/− mice displayed only background levels of NO x formation compared with wild-type (WT) cells (88 versus 1990 pmol NO x · h −1 /mg protein −1 ). eNOS−/− mice were hypertensive (mean arterial pressure, 135±15 versus 107±8 mm Hg in WT) without the development of cardiac hypertrophy. Coronary hemodynamics, analyzed in Langendorff-perfused hearts, showed no differences either in basal coronary flow or in maximal and repayment flow of reactive hyperemia. Acute NOS inhibition with N ω -nitro- l -arginine methyl ester (L-NAME) in WT hearts substantially reduced basal flow and reactive hyperemia. The coronary response to acetylcholine (ACh) (500 nmol/L) was biphasic: An initial vasoconstriction (flow, −35%) in WT hearts was followed by sustained vasodilation (+190%). L-NAME significantly reduced vasodilation in WT hearts (+125%) but did not alter the initial vasoconstriction. In eNOS−/− hearts, the initial vasoconstriction was augmented (−70%), whereas the ACh-induced vasodilation was not affected. Inhibition of cyclooxygenase with diclofenac converted the ACh-induced vasodilation into vasoconstriction (−49% decrease of basal flow). This effect was even more pronounced in eNOS−/− hearts (−71%). Our results demonstrate that (1) acute inhibition of eNOS reveals a role for NO in setting the basal coronary vascular tone as well as participation in reactive hyperemia and the response to ACh; (2) chronic inhibition of NO formation in eNOS−/− mutant mice induces no changes in basal coronary flow and reactive hyperemia, suggesting the activation of important compensatory mechanisms; and (3) prostaglandins are the main mediators of the ACh-induced vasodilation in both WT and eNOS−/− mice.
Passive sensitization of human airways increases responsiveness to leukotriene C4
Authors: D. Schmidt, E. Ruehlmann, D Branscheid, H Magnussen, K.F. Rabe
Journal: European Respiratory Journal (1999)

Passive sensitization of human airways in vitro causes increased responsiveness to histamine and induces specific immunoglobulin (Ig)E-dependent contractile responsiveness to allergen. Leukotrienes (LTs) and, to a lesser extent, histamine are the major mediators of allergen-induced contraction. Since it is unclear whether passively sensitized airways are also hyperresponsive to cysteinyl leukotrienes, this study investigated the effect of passive sensitization on LTC4-, in addition to histamine- and allergen-induced contractions in vitro. Bronchial rings from nine nonatopic patients were sensitized overnight with serum containing high levels of total IgE (>250 U x mL(-1)) and allergen-specific IgE against Dermatophagoides farinae (fluorescence allergosorbent test) (FAST class > or =3). The potency (-log10 of the mediator concentration causing a half maximal response (pEC50) of histamine was significantly increased in serum-sensitized tissues compared to nonsensitized controls ((mean+/-SEM) pEC50 5.20+/-0.27 versus 5.64+/-0.18; p=0.02) and maximal contractions were enhanced (877+/-47 versus 543+/-51 mg; p<0.0001). Similarly, the potency of LTC4 was significantly increased in sensitized compared to nonsensitized bronchial rings (pEC50 9.37+/-0.20 versus 8.66+/-0.26; p=0.004); maximal contractions were also enhanced (811+/-57 versus 361+/-86 mg; p<0.0001). These data demonstrate that passive sensitization of human airways induces an increase not only in histamine but also in leukotriene responsiveness. Therefore, it might be speculated that allergen responses in sensitized airways are effected through a combination of increased mediator release from inflammatory cells and increased responsiveness of airway smooth muscle.
The Association Between Maternal Glucose Concentration and Child BMI at Age 3 Years
Authors: Andrea L. Deierlein, Anna Maria Siega-Riz, Kim Chantala, Amy H. Herring
Journal: Diabetes Care (2011)

The objective of the study was to determine the association between child BMI at age 3 years and maternal glucose concentration among women without pre-existing diabetes or a gestational diabetes mellitus (GDM) diagnosis.Data are from the Pregnancy Infection and Nutrition and Postpartum studies and include 263 mother-child pairs. Measured weights and heights at 3 years were used to calculate age- and sex-specific BMI z scores and percentiles. Multivariable linear regression models were used to examine associations of continuous BMI z scores with maternal glucose concentration. Modified Poisson regression estimated risk ratios of child overweight/obesity (BMI ≥ 85th percentile).The mean (SD) maternal glucose concentration and prepregnancy BMI were 103.8 (23.7) mg/dL and 24.3 (5.9) kg/m(2), respectively. At 3 years, the mean (SD) child BMI z score was 0.29 (0.99), 20.9% were overweight/obese and 5.3% were obese. In the adjusted model, when compared with glucose concentration <100 mg/dL, a concentration ≥ 130 mg/dL was associated with significantly higher child BMI z score at 3 years (estimated z score difference of 0.39 [95% CI: 0.03-0.75]). With the use of the same reference category, a concentration ≥ 130 mg/dL was associated with an approximate twofold greater risk of child overweight/obesity (adjusted risk ratio 2.34 [95% CI: 1.25-4.38]).Fetal exposure to high maternal glucose concentration in the absence of pre-existing diabetes or GDM may contribute to the development of overweight/obesity in the offspring, independent of maternal prepregnancy BMI.
Transient pharmacologic lowering of Aβ production prior to deposition results in sustained reduction of amyloid plaque pathology
Authors: Pritam Das, Christophe Verbeeck, Lisa Minter, Paramita Chakrabarty, Kevin Felsenstein, Thomas Kukar, Ghulam Maharvi, Abdul Fauq, Barbara A Osborne, Todd E Golde
Journal: Molecular Neurodegeneration (2012)

Alzheimer's disease (AD) is the leading cause of dementia among the elderly. Disease modifying therapies targeting Aβ that are in development have been proposed to be more effective if treatment was initiated prior to significant accumulation of Aβ in the brain, but optimal timing of treatment initiation has not been clearly established in the clinic. We compared the efficacy of transient pharmacologic reduction of brain Aβ with a γ-secretase inhibitor (GSI ) for 1-3 months (M) treatment windows in APP Tg2576 mice and subsequent aging of the mice to either 15M or 18M.These data show that reducing Aβ production in a 2-3M windows both initiated and discontinued before detectable Aβ deposition has the most significant impact on Aβ loads up to 11M after treatment discontinuation. In contrast, initiation of treatment for 3M windows from 7-10M or 12-15M shows progressively decreasing efficacy.These data have major implications for clinical testing of therapeutics aimed at lowering Aβ production, indicating that; i) these therapies may have little efficacy unless tested as prophylactics or in the earliest preclinical stage of AD where there is no or minimal Aβ accumulation and ii) lowering Aβ production transiently during a critical pre-deposition window potentially provides long-lasting efficacy after discontinuation of the treatment.