tbuckley/cabot-search huggingface dataset:
Pilot Study of the Cytochrome P450-2D6 Genotype in a Psychiatric State Hospital
Authors: J de Leon, J Barnhill, T Rogers, J Boyle, W H Chou, P J Wedlund
Journal: American Journal of Psychiatry (1998)

The authors conducted a pilot study to develop preliminary data on the frequency of cytochrome P450-2D6 (CYP2D6) genotypes in state psychiatric hospital patients and to establish population sizes needed to determine potential clinical relevance in therapeutic outcome.One hundred consecutive inpatients at Eastern State Hospital in Kentucky who provided informed consent were genotyped at the CYP2D6 locus during their hospital stay.Twelve of the patients were CYP2D6 deficient, and four carried the *1Xn or *2Xn allele associated with ultrarapid metabolism; all of these patients were Caucasian (N=87). The rate of deficiency in CYP2D6 expression in these Caucasian state psychiatric hospital patients (14%) was twice that of the U.S. population (7%). The patients with CYP2D6 deficiency also appeared more likely to experience side effects in response to CYP2D6 medications.This study, limited by a small number of subjects, suggests that one-fifth of Caucasians admitted to a state hospital in Kentucky had genotypes associated with extremes in CYP2D6 activity that may have affected their response to CYP2D6 medications.
Towards an HBV cure: state-of-the-art and unresolved questions—report of the ANRS workshop on HBV cure
Authors: Mirjam B Zeisel, Julie Lucifora, William S Mason, Camille Sureau, Jürgen Beck, Massimo Levrero, Michael Kann, Percy A Knolle, Monsef Benkirane, David Durantel, Marie-Louise Michel, Brigitte Autran, François-Loïc Cosset, Hélène Strick-Marchand, Christian Trépo, Jia-Horng Kao, Fabrice Carrat, Karine Lacombe, Raymond F Schinazi, Françoise Barré-Sinoussi, Jean-François Delfraissy, Fabien Zoulim
Journal: Gut (2015)

HBV infection is a major cause of liver cirrhosis and hepatocellular carcinoma. Although HBV infection can be efficiently prevented by vaccination, and treatments are available, to date there is no reliable cure for the >240 million individuals that are chronically infected worldwide. Current treatments can only achieve viral suppression, and lifelong therapy is needed in the majority of infected persons. In the framework of the French National Agency for Research on AIDS and Viral Hepatitis 'HBV Cure' programme, a scientific workshop was held in Paris in June 2014 to define the state-of-the-art and unanswered questions regarding HBV pathobiology, and to develop a concerted strategy towards an HBV cure. This review summarises our current understanding of HBV host-interactions leading to viral persistence, as well as the roadblocks to be overcome to ultimately address unmet medical needs in the treatment of chronic HBV infection.
Differentiating tumor recurrence from treatment necrosis: a review of neuro-oncologic imaging strategies
Authors: Nishant Verma, Matthew C. Cowperthwaite, Mark G. Burnett, Mia K. Markey
Journal: Neuro-Oncology (2013)

Differentiating treatment-induced necrosis from tumor recurrence is a central challenge in neuro-oncology. These 2 very different outcomes after brain tumor treatment often appear similarly on routine follow-up imaging studies. They may even manifest with similar clinical symptoms, further confounding an already difficult process for physicians attempting to characterize a new contrast-enhancing lesion appearing on a patient's follow-up imaging. Distinguishing treatment necrosis from tumor recurrence is crucial for diagnosis and treatment planning, and therefore, much effort has been put forth to develop noninvasive methods to differentiate between these disparate outcomes. In this article, we review the latest developments and key findings from research studies exploring the efficacy of structural and functional imaging modalities for differentiating treatment necrosis from tumor recurrence. We discuss the possibility of computational approaches to investigate the usefulness of fine-grained imaging characteristics that are difficult to observe through visual inspection of images. We also propose a flexible treatment-planning algorithm that incorporates advanced functional imaging techniques when indicated by the patient's routine follow-up images and clinical condition.
Adiponectin protects against myocardial ischaemia-reperfusion injury via AMP-activated protein kinase, Akt, and nitric oxide
Authors: A. T. Gonon, U. Widegren, A. Bulhak, F. Salehzadeh, J. Persson, P.-O. Sjoquist, J. Pernow
Journal: Cardiovascular Research (2008)

Cardiovascular disease and type 2 diabetes mellitus are associated with low plasma concentration of adiponectin. The aim of this study was to investigate whether adiponectin exerts cardioprotective effects during myocardial ischaemia-reperfusion and whether this effect is related to the production of nitric oxide (NO).Isolated rat hearts were subjected to 30 min of either global or local ischaemia followed by 60 min of reperfusion. The hearts received vehicle, adiponectin (3 microg/mL), the NO-synthase inhibitor nitro-l-arginine (L-NNA) (0.1 mM), or a combination of adiponectin and L-NNA at the onset of ischaemia. Haemodynamics, infarct size, and expression of endothelial NO-synthase (eNOS), AMP-activated protein kinase (AMPK), and Akt were determined. Adiponectin significantly increased left ventricular function and coronary flow during reperfusion in comparison with the vehicle group. Co-administration of L-NNA abrogated the improvement in myocardial function induced by adiponectin. Infarct size following local ischaemia-reperfusion was 40 +/- 6% of the area at risk in the vehicle group. Adiponectin reduced infarct size to 19 +/- 2% (P < 0.01). L-NNA did not affect infarct size per se but abolished the protective effect of adiponectin (infarct size 40 +/- 5%). Phosphorylation of eNOS Ser1177, AMPK Thr172, and Akt Ser 473 was increased in the adiponectin group (P < 0.05).Adiponectin protects from myocardial contractile dysfunction and limits infarct size following ischaemia and reperfusion by a mechanism involving activation of AMPK and production of NO.
TIF1γ Suppresses Tumor Progression by Regulating Mitotic Checkpoints and Chromosomal Stability
Authors: Roxane M. Pommier, Johann Gout, David F. Vincent, Lindsay B. Alcaraz, Nicolas Chuvin, Vanessa Arfi, Sylvie Martel, Bastien Kaniewski, Guillaume Devailly, Geneviève Fourel, Pascal Bernard, Caroline Moyret-Lalle, Stéphane Ansieau, Alain Puisieux, Ulrich Valcourt, Stéphanie Sentis, Laurent Bartholin
Journal: Cancer Research (2015)

The transcription accessory factor TIF1γ/TRIM33/RFG7/PTC7/Ectodermin functions as a tumor suppressor that promotes development and cellular differentiation. However, its precise function in cancer has been elusive. In the present study, we report that TIF1γ inactivation causes cells to accumulate chromosomal defects, a hallmark of cancer, due to attenuations in the spindle assembly checkpoint and the post-mitotic checkpoint. TIF1γ deficiency also caused a loss of contact growth inhibition and increased anchorage-independent growth in vitro and in vivo. Clinically, reduced TIF1γ expression in human tumors correlated with an increased rate of genomic rearrangements. Overall, our work indicates that TIF1γ exerts its tumor-suppressive functions in part by promoting chromosomal stability.
In vivo effects of recombinant human DNase I on sputum in patients with cystic fibrosis.
Authors: P. L. Shah, S. F. Scott, R. A. Knight, C. Marriott, C. Ranasinha, M. E. Hodson
Journal: Thorax (1996)

BACKGROUND: Viscoelastic secretions in cystic fibrosis cause impaired mucus clearance and persistence of bacteria within the lung. The abnormal rheology is partly due to the presence of high molecular weight deoxyribonucleic acid (DNA). Recombinant human DNase I (rhDNase) has been shown to depolymerise DNA and thereby reduce the in vitro viscoelasticity of sputum in patients with cystic fibrosis. A phase II double blind placebo controlled study showed that rhDNase improved pulmonary function in patients with cystic fibrosis. The object of the present study was to evaluate the in vivo effects of rhDNase on sputum rheology and to determine whether these were correlated with changes in pulmonary function. METHODS: Patients were randomised to receive either placebo or rhDNase 2.5 mg twice daily for 10 days. Sputum samples were collected in sterile containers during screening and during treatment with the study drug. Pulmonary function and rheological analysis were the primary outcomes evaluated. Other parameters assessed were quantitative sputum bacteriology, sputum DNA concentration, and change in molecular mass of DNA polymers. RESULTS: The viscoelasticity of the sputum in untreated patients with cystic fibrosis was high and treatment with rhDNase reduced all the rheological parameters measured: dynamic storage modulus (a measure of elasticity), dynamic loss modulus (a measure of viscosity), and log complex modulus (a measure of mucus rigidity). The calculated cough clearance index was also improved following treatment with rhDNase. These rheological parameters showed a correlation with forced expiratory volume in one second (FEV1) which was improved by a mean (SE) of 13.3 (5.6)% on day 10 of treatment with rhDNase compared with a change of 0.2 (3.1)% in the placebo group. There was no change in bacterial colony counts or sputum DNA concentrations following treatment with rhDNase, but a small decrease in high molecular weight DNA was observed. CONCLUSIONS: Patients with cystic fibrosis treated with rhDNase show an improvement in rheological properties and pulmonary function, one of the mechanisms being a reduction in the proportion of high molecular weight DNA.
Comparison of complete nuclear receptor sets from the human, Caenorhabditis elegans and Drosophila genomes
Authors: Jodi M Maglich, Ann Sluder, Xiaojun Guan, Yunling Shi, David D McKee, Kevin Carrick, Kim Kamdar, Timothy M Willson, John T Moore
Journal: Genome biology (2001)

The availability of complete genome sequences enables all the members of a gene family to be identified without limitations imposed by temporal, spatial or quantitative aspects of mRNA expression. Using the nearly completed human genome sequence, we combined in silico and experimental approaches to define the complete human nuclear receptor (NR) set. This information was used to carry out a comparative genomic study of the NR superfamily. Our analysis of the human genome identified two novel NR sequences. Both these contained stop codons within the coding regions, indicating that both are pseudogenes. One (HNF4 γ-related) contained no introns and expressed no detectable mRNA, whereas the other (FXR-related) produced mRNA at relatively high levels in testis. If translated, the latter is predicted to encode a short, non-functional protein. Our analysis indicates that there are fewer than 50 functional human NRs, dramatically fewer than in Caenorhabditis elegans and about twice as many as in Drosophila. Using the complete human NR set we made comparisons with the NR sets of C. elegans and Drosophila. Searches for the >200 NRs unique to C. elegans revealed no human homologs. The comparative analysis also revealed a Drosophila member of NR subfamily NR3, confirming an ancient metazoan origin for this subfamily. This work provides the basis for new insights into the evolution and functional relationships of NR superfamily members.
The safety and tolerability of darbepoetin alfa in patients with anaemia and symptomatic heart failure
Authors: Marc Klapholz, William T. Abraham, Jalal K. Ghali, Piotr Ponikowski, Stefan D. Anker, Beat Knusel, Yan Sun, Scott M. Wasserman, Dirk J. van Veldhuisen
Journal: European Journal of Heart Failure (2009)
The Neurobiology of Language Beyond Single Words
Authors: Peter Hagoort, Peter Indefrey
Journal: Annual Review of Neuroscience (2014)

A hallmark of human language is that we combine lexical building blocks retrieved from memory in endless new ways. This combinatorial aspect of language is referred to as unification. Here we focus on the neurobiological infrastructure for syntactic and semantic unification. Unification is characterized by a high-speed temporal profile including both prediction and integration of retrieved lexical elements. A meta-analysis of numerous neuroimaging studies reveals a clear dorsal/ventral gradient in both left inferior frontal cortex and left posterior temporal cortex, with dorsal foci for syntactic processing and ventral foci for semantic processing. In addition to core areas for unification, further networks need to be recruited to realize language-driven communication to its full extent. One example is the theory of mind network, which allows listeners and readers to infer the intended message (speaker meaning) from the coded meaning of the linguistic utterance. This indicates that sensorimotor simulation cannot handle all of language processing.
High-Flow Oxygen through Nasal Cannula in Acute Hypoxemic Respiratory Failure
Authors: Jean-Pierre Frat, Arnaud W. Thille, Alain Mercat, Christophe Girault, Stéphanie Ragot, Sébastien Perbet, Gwénael Prat, Thierry Boulain, Elise Morawiec, Alice Cottereau, Jérôme Devaquet, Saad Nseir, Keyvan Razazi, Jean-Paul Mira, Laurent Argaud, Jean-Charles Chakarian, Jean-Damien Ricard, Xavier Wittebole, Stéphanie Chevalier, Alexandre Herbland, Muriel Fartoukh, Jean-Michel Constantin, Jean-Marie Tonnelier, Marc Pierrot, Armelle Mathonnet, Gaëtan Béduneau, Céline Delétage-Métreau, Jean-Christophe M. Richard, Laurent Brochard, René Robert
Journal: New England Journal of Medicine (2015)

Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia.
GLOMERULAR PERMEABILITY
Authors: M. A. Venkatachalam, Morris J. Karnovsky, Ramzi S. Cotran
Journal: The Journal of Experimental Medicine (1969)

Wistar/Furth rats were made nephrotic by daily administration of amino-nucleoside of puromycin, and the ultrastructural localization of horseradish peroxidase (mol wt 40,000) in the renal glomerulus was studied from 1 min to 20 hr after intravenous injection of the tracer. In control rats, peroxidase permeated the endothelial fenestrae, the basement membrane, and the epithelial slits, and was present in tubular lumina. Nephrotic glomeruli showed relatively normal basement membranes, extensive fusion of foot processes with formation of "close" intercellular junctions, and large vacuoles and pockets in epithelial cells. On serial sections some of the epithelial vacuoles communicated on one side with the extracellular space overlying basement membrane, and on the other side with the urinary space. In nephrotic animals, peroxidase permeated the basement membrane and the close junctions, and was present in many of the vacuoles and pockets as early as 1 min after injection. Only small numbers of peroxidase-positive vacuoles remained in. epithelial cells 1 hr or more after injection of the tracer. It is suggested that the epithelial pockets and vacuoles form pathways across which leaking proteins can be transferred across the epithelium into the urinary space. Epithelial vacuoles may also be absorption droplets designed to "conserve" leaking proteins, but this function was not prominent in our experiments with peroxidase.
Randomized, Placebo-Controlled, Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma
Authors: Eric Van Cutsem, Emilio Bajetta, Juan Valle, Claus-Henning Köhne, J. Randolph Hecht, Malcolm Moore, Colin Germond, William Berg, Bee-Lian Chen, Tarja Jalava, David Lebwohl, Gerold Meinhardt, Dirk Laurent, Edward Lin
Journal: Journal of Clinical Oncology (2011)

Purpose Treatment options for patients with previously treated metastatic colorectal cancer (mCRC) are limited, and treatments with differing mechanisms of action are needed. PTK787/ZK 222584 (PTK/ZK) is a novel oral angiogenesis inhibitor with therapeutic potential for the treatment of solid tumors. Methods Patients (N = 855) were randomly assigned to treatment with PTK/ZK or placebo once daily in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4). Stratification factors included WHO performance status (PS; 0 v 1 to 2) and lactate dehydrogenase ([LDH] ≤ 1.5× the upper limit of normal [ULN] v &gt; 1.5 × ULN). Treatment was given until disease progression or unacceptable toxicity. The primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), safety, tolerability, and pharmacokinetics of PTK/ZK. Results No statistically significant differences were seen between the treatment groups for the overall comparison of OS. With PTK/ZK and placebo, respectively, median OS was 13.1 and 11.9 months (hazard ratio [HR], 1.00; 95% CI, 0.87 to 1.16; P = .957). Median PFS was longer with PTK/ZK than with placebo (5.6 and 4.2 months, respectively; HR, 0.83; 95% CI, 0.71 to 0.96; P = .013). An exploratory, post hoc analysis demonstrated improved PFS in patients with high LDH, regardless of WHO PS (HR, 0.63; 95% CI, 0.48 to 0.83; P &lt; .001). Conclusion PTK/ZK in combination with FOLFOX4 did not improve OS of patients with pretreated mCRC but did improve PFS. The effect of PTK/ZK was more pronounced in patients with high LDH at baseline.
Quantitative MRI measures of cartilage predict knee replacement: a case–control study from the Osteoarthritis Initiative
Authors: Felix Eckstein, C Kent Kwoh, Robert M Boudreau, Zhijie Wang, Michael J Hannon, Sebastian Cotofana, Martin I Hudelmaier, Wolfgang Wirth, Ali Guermazi, Michael C Nevitt, Markus R John, David J Hunter
Journal: Annals of the Rheumatic Diseases (2012)

<h3>Objective</h3> Knee osteoarthritis commonly requires joint replacement, substantially reduces quality of life and increases healthcare utilisation and costs. This study aimed to identify whether quantitative measures of articular cartilage structure predict knee replacement, and to establish their utility as outcomes in clinical trials of disease-modifying therapy. <h3>Methods</h3> A nested case–control study was performed in Osteoarthritis Initiative participants, a multicentre observational cohort of 4796 participants with or at risk of knee osteoarthritis. 127 knees were replaced between baseline and 4 years follow-up, and one control knee per case matched for baseline radiographic disease stage (Kellgren–Lawrence grade; KLG), gender and age. Quantitative cartilage measures were obtained from 3 T magnetic resonance images at the exam before knee replacement, and longitudinal change during the previous 12 months when available (n=110). <h3>Results</h3> Cartilage thickness loss in the central and total medial femorotibial compartment (primary and secondary predictor variables) was significantly greater in case than control knees (AUC=0.59/0.58). Differences in cartilage loss were greater at earlier than later radiographic disease stages (p&lt;0.01 for interaction with KLG). Cartilage thickness loss in the central tibia was the most predictive longitudinal measure (AUC=0.64). Denuded bone areas in the medial femur were the most predictive and discriminatory cross-sectional measure between case and control knees (AUC=0.66). <h3>Conclusions</h3> This study demonstrates the predictive value of quantitative, MRI-based measures of cartilage for the clinically relevant endpoint of knee replacement, providing support for their utility in clinical trials to evaluate the effectiveness of structure-modifying intervention.
A Natural Killer T (NKT) Cell Developmental Pathway Involving a Thymus-dependent NK1.1−CD4+ CD1d-dependent Precursor Stage
Authors: Daniel G. Pellicci, Kirsten J.L. Hammond, Adam P. Uldrich, Alan G. Baxter, Mark J. Smyth, Dale I. Godfrey
Journal: The Journal of Experimental Medicine (2002)

The development of CD1d-dependent natural killer T (NKT) cells is poorly understood. We have used both CD1d/α-galactosylceramide (CD1d/αGC) tetramers and anti-NK1.1 to investigate NKT cell development in vitro and in vivo. Confirming the thymus-dependence of these cells, we show that CD1d/αGC tetramer-binding NKT cells, including NK1.1+ and NK1.1− subsets, develop in fetal thymus organ culture (FTOC) and are completely absent in nude mice. Ontogenically, CD1d/αGC tetramer-binding NKT cells first appear in the thymus, at day 5 after birth, as CD4+CD8−NK1.1−cells. NK1.1+ NKT cells, including CD4+ and CD4−CD8− subsets, appeared at days 7–8 but remained a minor subset until at least 3 wk of age. Using intrathymic transfer experiments, CD4+NK1.1− NKT cells gave rise to NK1.1+ NKT cells (including CD4+ and CD4− subsets), but not vice-versa. This maturation step was not required for NKT cells to migrate to other tissues, as NK1.1− NKT cells were detected in liver and spleen as early as day 8 after birth, and the majority of NKT cells among recent thymic emigrants (RTE) were NK1.1−. Further elucidation of this NKT cell developmental pathway should prove to be invaluable for studying the mechanisms that regulate the development of these cells.
PUMA Sensitizes Lung Cancer Cells to Chemotherapeutic Agents and Irradiation
Authors: Jian Yu, Wen Yue, Bin Wu, Lin Zhang
Journal: Clinical Cancer Research (2006)

Abstract Purpose: Lung cancer, the leading cause of cancer mortality worldwide, is often diagnosed at late stages and responds poorly to conventional therapies, including chemotherapy and irradiation. A great majority of lung tumors are defective in the p53 pathway, which plays an important role in regulating apoptotic response to anticancer agents. PUMA was recently identified as an essential mediator of DNA damage–induced and p53-dependent apoptosis. In this study, we investigated whether the regulation of PUMA by anticancer agents is abrogated in lung cancer cells and whether PUMA expression suppresses growth of lung cancer cells and/or sensitizes lung cancer cells to chemotherapeutic agents and irradiation through induction of apoptosis. Experimental Designs: The expression of PUMA was examined in lung cancer cells with different p53 status treated with chemotherapeutic agents. An adenovirus expressing PUMA (Ad-PUMA), alone or in combination with chemotherapeutic agents or γ-irradiation, was used to treat lung cancer cells. The growth inhibitory and apoptotic effects of PUMA in vitro and in vivo were examined. The mechanisms of PUMA-mediated growth suppression and apoptosis were investigated through analysis of caspase activation and release of mitochondrial apoptogenic proteins. The cytotoxicities of PUMA on cancer and normal/nontransformed cells were compared. The efficacy of PUMA and p53 in suppressing the growth of lung cancer cells was also compared. Results: We showed that the induction of PUMA by chemotherapeutic agents is abolished in p53-deficient lung cancer cells. PUMA expression resulted in potent growth suppression of lung cancer cells and suppressed xenograft tumor growth in vivo through induction of apoptosis. Low dose of Ad-PUMA significantly sensitized lung cancer cells to chemotherapeutic agents and γ-irradiation through induction of apoptosis. The effects of PUMA are mediated by enhanced caspase activation and release of cytochrome c and apoptosis-inducing factor into the cytosol. Furthermore, PUMA seems to be selectively toxic to cancer cells and more efficient than p53 in suppressing lung cancer cell growth. Conclusions: Our findings indicate that PUMA is an important modulator of therapeutic responses of lung cancer cells and is potentially useful as a sensitizer in lung cancer therapy.