tbuckley/cabot-search huggingface dataset:
Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension
Authors: Hossein-Ardeschir Ghofrani, Andrea M. D'Armini, Friedrich Grimminger, Marius M. Hoeper, Pavel Jansa, Nick H. Kim, Eckhard Mayer, Gerald Simonneau, Martin R. Wilkins, Arno Fritsch, Dieter Neuser, Gerrit Weimann, Chen Wang
Journal: New England Journal of Medicine (2013)

Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)
Vectorcardiographic Differentiation Between Right Ventricular Hypertrophy and Posterobasal Myocardial Infarction
Authors: VIRENDRA S. MATHUR, HAROLD D. LEVINE
Journal: Circulation (1970)

Vectorcardiograms were recorded by the Frank lead system in 203 cases of right ventricular hypertrophy (RVH) and 85 cases of posterobasal myocardial infarction (PBMI). Of the RVH cases, 33 were confirmed by autopsy and 135 by cardiac catheterization or surgery. Of the cases of PBMI, 12 were confirmed by autopsy and 48 had definite clinical episodes associated with enzymatic or serial electrocardiographic changes or both. Of several measurements made, the following proved most helpful: (1) location of mean frontal plane QRS axis between 75° and 220° in 64% of the cases of RVH and between 350° and 74° in 78% of the cases of PBMI; (2) location of mean horizontal plane QRS axis between 350° and 90° in 85% of the cases of PBMI but in only 11% of the cases of RVH; (3) location of the 0.04-sec instantaneous vector in the horizontal plane between 350° and 60° in 76% of the cases of PBMI but in only 22% of the cases of RVH; (4) magnitude of terminal rightward voltage of less than 1.0 mv in 88% of the cases of PBMI and equal to or greater than 1.0 mv in 80% of the cases of RVH; and (5) clockwise inscription of the horizontal plane loop favored RVH, but counterclockwise rotation in the horizontal plane was not helpful. Synthesis of criteria 2 and 4 provided the best combination for the separation of RVH from PBMI. If both these criteria were fulfilled, a correct diagnosis could be made with 95% certainty.
Cost-effectiveness of Human Papillomavirus DNA Testing in the United Kingdom, The Netherlands, France, and Italy
Authors: Jane J. Kim, Thomas C. Wright, Sue J. Goldie
Journal: JNCI Journal of the National Cancer Institute (2005)

European countries with established cytology-based screening programs for cervical cancer will soon face decisions about whether to incorporate human papillomavirus (HPV) DNA testing and what strategies will be most cost-effective. We assessed the cost-effectiveness of incorporating HPV DNA testing into existing cervical cancer screening programs in the United Kingdom, The Netherlands, France, and Italy.We created a computer-based model of the natural history of cervical carcinogenesis for each using country-specific data on cervical cancer risk and compared each country's current screening policy with two new strategies: 1) cytology throughout a woman's lifetime, using HPV DNA testing as a triage strategy for equivocal cytology results ("HPV triage"), as well as 2) cytology until age 30 years and HPV DNA testing in combination with cytology in women more than 30 years of age ("combination testing"). Outcomes included reduction in lifetime cervical cancer risk, increase in life expectancy, lifetime costs, and incremental cost-effectiveness ratios, expressed as cost per year of life saved. We explored alternative protocols and conducted sensitivity analysis on key parameters of the model over a relevant range of values to identify the most cost-effective options for each country.Both HPV DNA testing strategies, HPV triage and combination testing, were more effective than each country's status quo screening policy. Incremental cost-effectiveness ratios for HPV triage were less than $13,000 per year of life saved, whereas those for combination testing ranged from $9800 to $75,900 per year of life saved, depending on screening interval. We identified options that would be very cost-effective (i.e., cost-effectiveness ratio less than the gross domestic product per capita) in each of the four countries.HPV DNA testing has the potential to improve health benefits at a reasonable cost compared with current screening policies in four European countries.
Human Amnion Epithelial Cell Transplantation Abrogates Lung Fibrosis and Augments Repair
Authors: Yuben Moodley, Sivagami Ilancheran, Chrishan Samuel, Vijesh Vaghjiani, Daniel Atienza, Elizabeth D. Williams, Graham Jenkin, Euan Wallace, Alan Trounson, Ursula Manuelpillai
Journal: American Journal of Respiratory and Critical Care Medicine (2010)

Section:ChooseTop of pageAbstract <<MATERIALS AND METHODSRESULTSDISCUSSIONReferencesCITING ARTICLES
Categorizing Asthma Severity
Authors: GENE L. COLICE, JENNIFER VANDEN BURGT, JESSIE SONG, PATTI STAMPONE, PHILIP J. THOMPSON
Journal: American Journal of Respiratory and Critical Care Medicine (1999)

The National Asthma Education and Prevention Program (NAEPP) Expert Panel II recommended a stepped care pharmacotherapy approach to asthma treatment based on an objective assessment of asthma severity using daytime symptoms, nocturnal symptoms, and physiologic lung function. The worst grade of the individual variables determines overall asthma severity. With this approach, patterns of asthma severity categorization might vary among individual variables; one variable might have a predominant effect on overall categorization. During the run-in, pretreatment phase of five controlled clinical trials, data from 744 inhaled steroid nonusers and 685 inhaled steroid users on asthma control were collected and asthma severity categorized. In inhaled steroid nonusers nocturnal symptoms classified the majority of patients as severe, persistent, but wheeze classified 27.3% of patients as mild, intermittent and 25.7% as mild, persistent. If the worst grade from the four asthma symptoms was used for severity grading, most patients were categorized as severe, persistent. β -Agonist use and FEV1 classified most as moderate, persistent. There was poor correlation between variables in severity categorization. Severity grading for European patients was similar to that for U.S. patients. Applying the Expert Panel II recommended method for asthma severity categorization to a large data set illustrates that a single variable, nocturnal symptoms, determined to a large extent overall categorization. Development of a validated method for asthma severity categorization is essential for using a stepped care approach to asthma pharmacotherapy. Colice GL, Vanden Burgt J, Song J, Stampone P, Thompson PJ. Categorizing asthma severity.
Uncovering the Hidden Risk Architecture of the Schizophrenias: Confirmation in Three Independent Genome-Wide Association Studies
Authors: Javier Arnedo, Dragan M. Svrakic, Coral del Val, Rocío Romero-Zaliz, Helena Hernández-Cuervo, Ayman H. Fanous, Michele T. Pato, Carlos N. Pato, Gabriel A. de Erausquin, C. Robert Cloninger, Igor Zwir
Journal: American Journal of Psychiatry (2014)

The authors sought to demonstrate that schizophrenia is a heterogeneous group of heritable disorders caused by different genotypic networks that cause distinct clinical syndromes.In a large genome-wide association study of cases with schizophrenia and controls, the authors first identified sets of interacting single-nucleotide polymorphisms (SNPs) that cluster within particular individuals (SNP sets) regardless of clinical status. Second, they examined the risk of schizophrenia for each SNP set and tested replicability in two independent samples. Third, they identified genotypic networks composed of SNP sets sharing SNPs or subjects. Fourth, they identified sets of distinct clinical features that cluster in particular cases (phenotypic sets or clinical syndromes) without regard for their genetic background. Fifth, they tested whether SNP sets were associated with distinct phenotypic sets in a replicable manner across the three studies.The authors identified 42 SNP sets associated with a 70% or greater risk of schizophrenia, and confirmed 34 (81%) or more with similar high risk of schizophrenia in two independent samples. Seventeen networks of SNP sets did not share any SNP or subject. These disjoint genotypic networks were associated with distinct gene products and clinical syndromes (i.e., the schizophrenias) varying in symptoms and severity. Associations between genotypic networks and clinical syndromes were complex, showing multifinality and equifinality. The interactive networks explained the risk of schizophrenia more than the average effects of all SNPs (24%).Schizophrenia is a group of heritable disorders caused by a moderate number of separate genotypic networks associated with several distinct clinical syndromes.
Loss of PPP2R2A Inhibits Homologous Recombination DNA Repair and Predicts Tumor Sensitivity to PARP Inhibition
Authors: Peter Kalev, Michal Simicek, Iria Vazquez, Sebastian Munck, Liping Chen, Thomas Soin, Natasha Danda, Wen Chen, Anna Sablina
Journal: Cancer Research (2012)

Abstract Reversible phosphorylation plays a critical role in DNA repair. Here, we report the results of a loss-of-function screen that identifies the PP2A heterotrimeric serine/threonine phosphatases PPP2R2A, PPP2R2D, PPP2R5A, and PPP2R3C in double-strand break (DSB) repair. In particular, we found that PPP2R2A-containing complexes directly dephosphorylated ATM at S367, S1893, and S1981 to regulate its retention at DSB sites. Increased ATM phosphorylation triggered by PPP2R2A attenuation dramatically upregulated the activity of the downstream effector kinase CHK2, resulting in G1 to S-phase cell-cycle arrest and downregulation of BRCA1 and RAD51. In tumor cells, blocking PPP2R2A thereby impaired the high-fidelity homologous recombination repair pathway and sensitized cells to small-molecule inhibitors of PARP. We found that PPP2R2A was commonly downregulated in non–small cell lung carcinomas, suggesting that PPP2R2A status may serve as a marker to predict therapeutic efficacy to PARP inhibition. In summary, our results deepen understanding of the role of PP2A family phosphatases in DNA repair and suggest PPP2R2A as a marker for PARP inhibitor responses in clinic. Cancer Res; 72(24); 6414–24. ©2012 AACR.
Cyclin E–Associated Kinase Activity Predicts Response to Platinum-Based Chemotherapy
Authors: Isabelle Bedrosian, Christine Lee, Susan L. Tucker, Shana L. Palla, Karen Lu, Khandan Keyomarsi
Journal: Clinical Cancer Research (2007)

Abstract Purpose: The role of cyclin E as a predictive marker of response to chemotherapy remains unknown. We have previously shown that deregulation of cyclin E in an ovarian tumor cell line model enhances cyclin E–associated kinase activity and sensitizes tumor cells to cisplatinum. We hypothesized that cyclin E deregulation would predict for responsiveness to platinum-based regimens in ovarian cancer patients. Experimental Design: Patients who met the following criteria were retrospectively identified from the institutional tumor bank records: (a) high-grade ovarian epithelial malignancy, (b) stage III/stage IV disease, (c) optimally debulked, (d) completed platinum-based therapy. Tumor samples were analyzed for cyclin E, p21, and p27 by Western blot analysis and assessed for cyclin E–associated kinase activity. Results: Seventy-five patients, who met the study criteria, were identified. Cyclin E protein levels did not correlate with cyclin E–cdk2 kinase activity (Spearman's rho, 0.07; P = 0.58). Cyclin E–associated kinase activity was the only significant predictive marker for response to platinum-based therapy, with higher response rates seen in patients with higher levels of activity (P = 0.045). Cyclin E protein levels did not predict for platinum sensitivity (P = 0.20). In contrast, cyclin E protein levels, but not cyclin E–associated kinase activity, was a significant predictor for freedom from recurrence (P = 0.01 and P = 0.25, respectively). Conclusions: Cyclin E overexpression and cyclin E–associated kinase activity have distinct roles in predicting for response to chemotherapy and outcome in ovarian cancer patients. These results suggest a compartmentalization of cyclin E functions in the oncogenic process.
5-Year Clinical Outcomes of the ARTS II (Arterial Revascularization Therapies Study II) of the Sirolimus-Eluting Stent in the Treatment of Patients With Multivessel De Novo Coronary Artery Lesions
Authors: Patrick W. Serruys, Yoshinobu Onuma, Scot Garg, Pascal Vranckx, Bernard De Bruyne, Marie-Claude Morice, Antonio Colombo, Carlos Macaya, Gert Richardt, Jean Fajadet, Christian Hamm, Monique Schuijer, Tessa Rademaker, Kristel Wittebols, Hans Peter Stoll
Journal: Journal of the American College of Cardiology (2010)
Cell-derived anaphylatoxins as key mediators of antibody-dependent type II autoimmunity in mice
Authors: V. Kumar
Journal: Journal of Clinical Investigation (2006)

Complement C5a, a potent anaphylatoxin, is a candidate target molecule for the treatment of inflammatory diseases, such as myocardial ischemia/reperfusion injury, RA, and the antiphospholipid syndrome. In contrast, up until now, no specific contribution of C5a and its receptor, C5aR, was recognized in diseases of antibody-dependent type II autoimmunity. Here we identify C5a as a novel key mediator of autoimmune hemolytic anemia (AIHA) and show that mice lacking C5aR are partially resistant to this IgG autoantibody–induced disease model. Upon administration of anti-erythrocyte antibodies, upregulation of activating Fcγ receptors (FcγRs) on Kupffer cells, as observed in WT mice, was absent in C5aR-deficient mice, and FcγR-mediated in vivo erythrophagocytosis was impaired. Surprisingly, in mice deficient in FcγRI and FcγRIII, anti-erythrocyte antibody–induced C5 and C5a production was abolished, demonstrating the existence of a previously unidentified FcγR-mediated C5a-generating pathway. These results show that the development of a full-blown antibody-dependent autoimmune disease requires C5a — produced by and acting on FcγR — and may suggest therapeutic benefits of C5 and/or C5a/C5aR blockade in AIHA and other diseases closely related to type II autoimmune injury.
Induction of pancreatic tumours by longterm duodenogastric reflux.
Authors: P R Taylor, R H Dowling, T J Palmer, D C Hanley, G M Murphy, R C Mason, I McColl
Journal: Gut (1989)

The incidence of pancreatic cancer is increased in patients who have undergone gastric surgery. An animal model is described in which pancreatic hyperplasia and adenoma formation developed within 56 weeks. The effects of a simple gastrojejunostomy were compared with those after a split gastrojejunostomy, in which the jejunum was transected and the two limbs implanted separately into the greater curvature of the glandular stomach 1 cm apart. After 56 weeks no animals in the simple gastrojejunostomy group had pancreatic hyperplasia whereas all 10 animals in the split gastrojejunostomy group had generalised pancreatic hyperplasia with macroscopic nodules. Microscopy of the nodules showed that in nine animals hyperplastic nodules had developed, and four of these also had adenomatous nodules. The remaining animal had enlarged lymph nodes. Pancreatic hyperplasia was associated with jejunal hyperplasia. Jejunal morphometry showed that the villus height was doubled and the villus height:crypt depth ratio was higher in the split gastrojejunostomy group compared with those animals with a simple gastrojejunostomy. This finding represents a new model for the investigation of pancreatic neoplastic change.
Transforming Properties of 8p11-12 Amplified Genes in Human Breast Cancer
Authors: Zeng-Quan Yang, Gang Liu, Aliccia Bollig-Fischer, Craig N. Giroux, Stephen P. Ethier
Journal: Cancer Research (2010)

Amplification of the 8p11-12 region has been found in about 15% of human breast cancers and is associated with poor prognosis. Earlier, we used genomic analysis of copy number and gene expression to perform a detailed analysis of the 8p11-12 amplicon to identify candidate oncogenes in breast cancer. We identified 21 candidate genes and provided evidence that three genes, namely, LSM-1, TC-1, and BAG4, have transforming properties when overexpressed. In the present study, we systematically investigated the transforming properties of 13 newly identified 8p11-12 candidate oncogenes in vitro. WHSC1L1, DDHD2, and ERLIN2 were most potently transforming oncogenes based on the number of altered phenotypes expressed by the cells. WHSC1L1 contains a PWWP-domain that is a methyl-lysine recognition motif involved in histone code modification and epigenetic regulation of gene expression. Knockdown of WHSC1L1 in 8p11-12-amplified breast cancer cells resulted in profound loss of growth and survival of these cells. Further, we identified several WHSC1L1 target genes, one of which is iroquois homeobox 3 gene (IRX3), a member of the Iroquois homeobox transcription factor family.
Interleukin-6 antisense oligonucleotides inhibit the growth of human myeloma cell lines.
Authors: Y Levy, A Tsapis, J C Brouet
Journal: Journal of Clinical Investigation (1991)

IL-6 has been shown to be a plasmacytoma growth factor in mice and is believed to play a key role in the development of human multiple myeloma. We investigated the IL-6 requirements for the growth of two human myeloma cell lines, U 266 and RPMI 8226. These cell lines secreted minute amounts of IL-6 (20 U/ml) and featured IL-6 mRNA. IL-6 receptors were detectable at the surface of malignant cells by immunofluorescence. Antibodies to IL-6 did not alter the proliferation of these myeloma cells. There was a dose-dependent decrease, however, in [3H]-thymidine uptake in the presence of IL-6 antisense (and not sense) oligodeoxynucleotides; in the presence of 20 microM IL-6 antisense, an 80 and 95% inhibition of the proliferation of U 266 and RPMI 8226 cells was observed, respectively. These results provide strong evidence for an IL-6 autocrine proliferation of myeloma cells which may occur via internal interaction between IL-6 and the IL-6 receptor.
Biomechanical factors in 100 m freestyle swimming and their relationships with anthropometric characteristics
Authors: Mohsen Barghamadi, Zohreh Behboodi
Journal: British Journal of Sports Medicine (2010)

The purpose of this study was to determine the relationships between stroke rate, stroke length and velocity in each 10 m distance in 100-m freestyle competitive in order to compare male and female swimmers' results and assess their relationships with anthropometric characteristics. Sixteen male and six female of Chandigarh's elite swimmers were tested during competition. Each of the 22 subjects swam and biomechanical factors were recorded with video camera and stopwatch at 10 m distances. Correlations showed that there was significant relation between SR (stroke rate), SL (stroke length) and V (velocity) in each 10 m distance. Correlations existed between SR, SL, V and any anthropometric characteristics between males and females in each 10 m distance. There were no significant correlations in SR and SL between males and females but velocity showed significant correlation in each 10 m distance.
Lung Microbiota and Bacterial Abundance in Patients with Bronchiectasis when Clinically Stable and during Exacerbation
Authors: Michael M. Tunney, Gisli G. Einarsson, Lan Wei, Maire Drain, Erich R. Klem, Chris Cardwell, Madeleine Ennis, Richard C. Boucher, Matthew C. Wolfgang, J. Stuart Elborn
Journal: American Journal of Respiratory and Critical Care Medicine (2013)

Rationale: Characterization of bacterial populations in infectious respiratory diseases will provide improved understanding of the relationship between the lung microbiota, disease pathogenesis, and treatment outcomes.Objectives: To comprehensively define lung microbiota composition during stable disease and exacerbation in patients with bronchiectasis.Methods: Sputum was collected from patients when clinically stable and before and after completion of antibiotic treatment of exacerbations. Bacterial abundance and community composition were analyzed using anaerobic culture and 16S rDNA pyrosequencing.Measurements and Main Results: In clinically stable patients, aerobic and anaerobic bacteria were detected in 40 of 40 (100%) and 33 of 40 (83%) sputum samples, respectively. The dominant organisms cultured were Pseudomonas aeruginosa (n = 10 patients), Haemophilus influenzae (n = 12), Prevotella (n = 18), and Veillonella (n = 13). Pyrosequencing generated more than 150,000 sequences, representing 113 distinct microbial taxa; the majority of observed community richness resulted from taxa present in low abundance with similar patterns of phyla distribution in clinically stable patients and patients at the onset of exacerbation. After treatment of exacerbation, there was no change in total (P = 0.925), aerobic (P = 0.917), or anaerobic (P = 0.683) load and only a limited shift in community composition. Agreement for detection of bacteria by culture and pyrosequencing was good for aerobic bacteria such as P. aeruginosa (κ = 0.84) but poorer for other genera including anaerobes. Lack of agreement was largely due to bacteria being detected by pyrosequencing but not by culture.Conclusions: A complex microbiota is present in the lungs of patients with bronchiectasis and remains stable through treatment of exacerbations, suggesting that changes in microbiota composition do not account for exacerbations.
Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C
Authors: Sarah C Darby, David W Ewart, Paul LF Giangrande, Rosemary JD Spooner, Charles R Rizza, Geoffrey M Dusheiko, Christine A Lee, Christopher A Ludlam, F Eric Preston
Journal: The Lancet (1997)
Courts, State Hospitals, and the Right to Treatment
Authors: JONAS ROBITSCHER
Journal: American Journal of Psychiatry (1972)

The author discusses the court decisions revolving around the right to treatment that have culminated in a new legal doctrine holding courts responsible for maintaining state hospital standards. To deal with the resulting dilemma, psychiatry must develop objective standards that the court can apply in measuring psychiatric care and thus prevent the legal determination of treatment adequacy from usurping psychiatric authority and determining hospital policy.