tbuckley/cabot-search huggingface dataset:
Activation of Double-Stranded RNA–Dependent Protein Kinase, A New Pathway by Which Human Polynucleotide Phosphorylase (<i>hPNPaseold-35</i>) Induces Apoptosis
Authors: Devanand Sarkar, Eun Sook Park, Glen N. Barber, Paul B. Fisher
Journal: Cancer Research (2007)

Abstract Human polynucleotide phosphorylase (hPNPaseold-35) is a type I IFN-inducible 3′,5′ exoribonuclease that mediates mRNA degradation. In melanoma cells, slow and sustained overexpression of hPNPaseold-35 induces G1 cell cycle arrest ultimately culminating in apoptosis, whereas rapid overexpression of hPNPaseold-35 directly promotes apoptosis without cell cycle changes. These observations imply that inhibition of cell cycle progression and induction of apoptosis by hPNPaseold-35 involve multiple intracellular targets and signaling pathways. We now provide evidence that the apoptosis-inducing activity of hPNPaseold-35 is mediated by activation of double-stranded RNA–dependent protein kinase (PKR). Activation of PKR by hPNPaseold-35 precedes phosphorylation of eukaryotic initiation factor-2α and induction of growth arrest and DNA damage-inducible gene 153 (GADD153) that culminates in the shutdown of protein synthesis and apoptosis. Activation of PKR by hPNPaseold-35 also instigates down-regulation of the antiapoptotic protein Bcl-xL. A dominant-negative inhibitor of PKR, as well as GADD153 antisense or bcl-xL overexpression, effectively inhibits apoptosis induction by hPNPaseold-35. These studies elucidate a novel pathway by which an evolutionary conserved RNA-metabolizing enzyme, hPNPaseold-35, regulates cell growth and viability. [Cancer Res 2007;67(17):7948–53]
EPIC: Phase III Trial of Cetuximab Plus Irinotecan After Fluoropyrimidine and Oxaliplatin Failure in Patients With Metastatic Colorectal Cancer
Authors: Alberto F. Sobrero, Joan Maurel, Louis Fehrenbacher, Werner Scheithauer, Yousif A. Abubakr, Manfred P. Lutz, M. Eugenia Vega-Villegas, Cathy Eng, Ernst U. Steinhauer, Jana Prausova, Heinz-Josef Lenz, Christophe Borg, Gary Middleton, Hendrik Kröning, Gabriele Luppi, Oliver Kisker, Angela Zubel, Christiane Langer, Justin Kopit, Howard A. Burris
Journal: Journal of Clinical Oncology (2008)

To determine whether adding cetuximab to irinotecan prolongs survival in patients with metastatic colorectal cancer (mCRC) previously treated with fluoropyrimidine and oxaliplatin.This multicenter, open-label, phase III study randomly assigned 1,298 patients with epidermal growth factor receptor-expressing mCRC who had experienced first-line fluoropyrimidine and oxaliplatin treatment failure to cetuximab (400 mg/m(2) day 1 followed by 250 mg/m(2) weekly) plus irinotecan (350 mg/m(2) every 3 weeks) or irinotecan alone. Primary end point was overall survival (OS); secondary end points included progression-free survival (PFS), response rate (RR), and quality of life (QOL).Median OS was comparable between treatments: 10.7 months (95% CI, 9.6 to 11.3) with cetuximab/irinotecan and 10.0 months (95% CI, 9.1 to 11.3) with irinotecan alone (hazard ratio [HR], 0.975; 95% CI, 0.854 to 1.114; P = .71). This lack of difference may have been due to post-trial therapy: 46.9% of patients assigned to irinotecan eventually received cetuximab (87.2% of those who did, received it with irinotecan). Cetuximab added to irinotecan significantly improved PFS (median, 4.0 v 2.6 months; HR, 0.692; 95% CI, 0.617 to 0.776; P <or= .0001) and RR (16.4% v 4.2%; P < .0001), and resulted in significantly better scores in the QOL analysis of global health status (P = .047). Cetuximab did not exacerbate toxicity, except for acneform rash, diarrhea, hypomagnesemia, and associated electrolyte imbalances. Neutropenia was the most common severe toxicity across treatment arms.Cetuximab and irinotecan improved PFS and RR, and resulted in better QOL versus irinotecan alone. OS was similar between study groups, possibly influenced by the large number of patients in the irinotecan arm who received cetuximab and irinotecan poststudy.
Characterisation of liver pathogenesis, human immune responses and drug testing in a humanised mouse model of HCV infection
Authors: Choong Tat Keng, Ching Wooen Sze, Dahai Zheng, Zhiqiang Zheng, Kylie Su Mei Yong, Shu Qi Tan, Jessica Jie Ying Ong, Sue Yee Tan, Eva Loh, Megha Haridas Upadya, Chik Hong Kuick, Hak Hotta, Seng Gee Lim, Thiam Chye Tan, Kenneth T E Chang, Wanjin Hong, Jianzhu Chen, Yee-Joo Tan, Qingfeng Chen
Journal: Gut (2015)

HCV infection affects millions of people worldwide, and many patients develop chronic infection leading to liver cancers. For decades, the lack of a small animal model that can recapitulate HCV infection, its immunopathogenesis and disease progression has impeded the development of an effective vaccine and therapeutics. We aim to provide a humanised mouse model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies.Recently, we have established human liver cells with a matched human immune system in NOD-scid Il2rg(-/-) (NSG) mice (HIL mice). These mice are infected with HCV by intravenous injection, and the pathologies are investigated.In this study, we demonstrate that HIL mouse is capable of supporting HCV infection and can present some of the clinical symptoms found in HCV-infected patients including hepatitis, robust virus-specific human immune cell and cytokine responses as well as liver fibrosis and cirrhosis. Similar to results obtained from the analysis of patient samples, the human immune cells, particularly T cells and macrophages, play critical roles during the HCV-associated liver disease development in the HIL mice. Furthermore, our model is demonstrated to be able to reproduce the therapeutic effects of human interferon alpha 2a antiviral treatment.The HIL mouse provides a model for the understanding of HCV-specific human immune responses and HCV-associated disease pathologies. It could also serve as a platform for antifibrosis and immune-modulatory drug testing.
Molecular characterization of receptor binding proteins and immunogens of virulent Treponema pallidum.
Authors: J B Baseman, E C Hayes
Journal: The Journal of Experimental Medicine (1980)

Receptor binding proteins of Treponema pallidum were identified by incubation of [35S]methionine-labeled, soluble T. pallidum preparations with formaldehyde-fixed HEp-2 cells. Three major treponemal proteins (bands 1--3) that avidly bound to the eucaryotic cell surface were detected by sodium dodecylsulfate-polyacrylamide gel electrophoresis and fluorography. Brief trypsin treatment of HEp-2 cells before formaldehyde fixation reduced the extent of the interaction of these treponemal macromolecules, which implicated receptor-mediated attachment mechanisms. The presence of unlabeled T. pallidum preparations directly competed with radiolabeled T. pallidum samples for the available HEp-2 cells, which suggested a limiting number of membrane binding sites. Samples of unlabeled avirulent Reiter treponeme did not compete. T. Pallidum immunogens were examined by radioimmunoprecipitation with human and rabbit syphilitic sera. Of interest were the similarities and extent of the humoral response represented by the detection of antigen-antibody complexes against numberous treponemal proteins, including bands 1--3. T. pallidum portein band 1 appeared to be the major antigenic stimulus. Formation of antigen-antibody complexes between 35S-labeled T. pallidum proteins and human syphilitic sera was prevented by unlabeled T. pallidum but not by T. phagedenis preparations, which demonstrated specificity of the reaction. Gel profiles of radioimmunoprecipitation assays using radiolabeled T. pallidum antigens and human syphilitic and yaws sera delineated both the similarities and differences in the humoral response to these two spirochetes. The latter suggested both overlapping and distinguishing antigenic properties between T. pallidum and T. pertenue. Detection in yaws sera of specific antibody against T. pallidum protein bands 1--3 further incriminates the role of these three treponemal proteins as virulence determinants.
Resistance to Targeted Therapies: Refining Anticancer Therapy in the Era of Molecular Oncology
Authors: Lee M. Ellis, Daniel J. Hicklin
Journal: Clinical Cancer Research (2009)

The advent of targeted therapy for treatment of human cancers has added significantly to our armamentarium as we strive to prolong patient survival while minimizing toxicity. In cancers driven by a dominant oncogene, targeted therapies have led to remarkable improvements in response and survival, whereas in others the outcome has been more modest. One key aspect toward realizing the potential of targeted therapies is a better understanding of the intrinsic or acquired resistance mechanisms that limit their efficacy. The articles in this CCR Focus provide insights into molecular mechanisms of resistance to targeted therapy. Recent discoveries of the molecular pathways that mediate intrinsic resistance to targeted therapy have led to the identification of predictive biomarkers that allow for better patient selection for front line treatment. Equally important, the identification of mechanisms of acquired resistance following front line therapy has led to the discovery of novel agents that overcome these resistance mechanisms. Improving the efficacy of targeted therapies in the future will require expanding our understanding of resistance mechanisms, the development of new generations of rationally designed targeted agents, and translating this information to the clinic to select patients for appropriate therapy. (Clin Cancer Res 2009;15(24):7471-8).
Carotid sinus baroreceptor reflex in dogs with experimental heart failure.
Authors: W Wang, J S Chen, I H Zucker
Journal: Circulation Research (1991)

We have previously demonstrated a decrease in baroreceptor discharge sensitivity in dogs with experimental heart failure. In the present study, we determined the sensitivity of the carotid sinus baroreceptor reflex in dogs with pacing-induced heart failure. The carotid sinus baroreceptor reflex sensitivity was determined by pressurizing one carotid sinus with all other baroreceptor and cardiopulmonary receptor inputs removed. The data were analyzed by plotting carotid sinus pressure-mean arterial pressure curves and carotid sinus pressure-renal sympathetic nerve activity curves in the two groups of dogs. The peak arterial pressure during carotid hypotension was significantly depressed in dogs with heart failure compared with normal dogs (107.1 +/- 5.7 versus 139.8 +/- 7.0 mm Hg, p less than 0.001). Mean arterial pressure range, renal sympathetic nerve activity range, and peak slope were significantly decreased in the heart-failure group. To determine if this depression was completely due to depression of baroreceptor discharge per se, or to alterations in central or end-organ responsiveness, similar experiments were performed by stimulating the carotid sinus nerve and evaluating frequency, voltage, and duration of stimulation on the resultant mean arterial pressure and renal sympathetic nerve activity. As was the case with carotid sinus pressurization, electrical stimulation caused a significantly smaller change in mean arterial pressure in heart-failure dogs compared with the normal dogs. However, there was no significant difference between normal and heart-failure dogs for the renal sympathetic nerve activity-electrical stimulation curves. These data strongly suggest that the depressed carotid sinus baroreceptor reflex in heart failure is not solely the result of depressed baroreceptor responsiveness but may be related to poor end-organ responses and normal central control of renal sympathetic outflow.
Core Safeguards for Clinical Research with Adults Who Are Unable To Consent
Authors: Dave Wendler, Kiran Prasad
Journal: Annals of Internal Medicine (2001)

The National Bioethics Advisory Commission has proposed new safeguards for clinical research with adults who are unable to consent. Three other major U.S. groups have also proposed additional safeguards for this population, and existing Canadian and European guidelines already include such safeguards. While these six guidelines agree on some safeguards, they disagree on others. To allow important research to proceed while protecting adults who are unable to consent, it will be crucial to resolve these differences. This paper uses a side-by-side comparison of these six guidelines to highlight their major points of consensus, analyze their significant differences, and distill six core safeguards.
Frameshift mutation near the 3' end of the COL1A1 gene of type I collagen predicts an elongated Pro alpha 1(I) chain and results in osteogenesis imperfecta type I.
Authors: M C Willing, D H Cohn, P H Byers
Journal: Journal of Clinical Investigation (1990)

Osteogenesis imperfecta (OI) is a heterogeneous disorder of type I collagen of which OI type I, an autosomal dominant condition, is the mildest and most common form. Affected individuals have blue sclerae, normal stature, bone fragility without significant deformity and osteopenia. Fibroblasts from most affected individuals produce about half the expected amount of structurally normal type I collagen as a result of decreased synthesis of one of its constituent chains, pro alpha 1(I), but the nature of the mutations which result in OI type I are unknown. We describe a three generation family with OI type I in which all affected members have one normal COL1A1 allele and another from which the intragenic Eco RI restriction site near the 3' end of the gene is missing. Amplification by polymerase chain reaction and sequence determination of the normal allele and of the mutant allele in the domain that normally contains the Eco RI site demonstrated a 5-bp deletion from the mutant allele. The deletion changes the translational reading-frame beginning at the Eco RI site and predicts the synthesis of a pro alpha 1(I) chain that extends 84 amino acids beyond the normal termination. Although the mutant pro alpha 1(I) chain is synthesized in an in vitro translation system, we are unable to detect its presence in intact cells, suggesting that it is unstable and rapidly destroyed in one of the cell's degradative pathways. Our analysis of individuals with OI type I from 20 families indicates that this is a unique mutation and suggests that the phenotype can result from multiple mechanisms that decrease the synthesis of normal type I procollagen molecules, including those that alter protein stability.
Outcome of patients with sarcoma and other mesenchymal tumours participating in phase I trials: a subset analysis of a European Phase I database
Authors: P.A. Cassier, V. Polivka, I. Judson, J.-C. Soria, N. Penel, S. Marsoni, J. Verweij, J.H. Schellens, R. Morales-Barrera, P. Schöffski, E.E. Voest, C. Gomez-Roca, T.R.J. Evans, R. Plummer, E. Gallerani, S.B. Kaye, D. Olmos
Journal: Annals of Oncology (2014)
Transpleural Cardioplasty in Achalasia: Operation Results and Sequelae
Authors: H. B. Wulff, A. Malm
Journal: Thorax (1949)

The clinical syndrome characterized by dysphagia, retrosternal or epigastric pain, and, in advanced stages, by regurgitation of undigested food and total obstruction of the oesophagus, has long been known and has been called by many different names.The Englishman, Thomas Willis, gave a detailed description in 1672, and after 1882, when v. Mikulicz, who believed it to be caused by a spasm in the region of the cardia, published his studies on the subject the syndrome was known as "cardio- spasm"; this name is still in current use in many countries.When later investigations disproved the occurrence of a spasm in the cardiac region Hurst (1914) introduced the name " achalasia," or lack of relaxation of the cardiac sphincter.But in the light of our experience and knowledge to-day it seems that the condition is due to a combination of factors and not solely to failure of relaxation, so that Hurst's suggestion is no longer satisfactory.Imbalance in the nerve supply to the cardiac sphincter may be responsible for the onset; if so, the sphincter does not respond by relaxing to waves of peristalsis from the oesophagus but remains closed and thereby arrests the descent of the food to the stomach until the cardiac orifice has been opened by dilatation or surgical intervention or until later on it spontaneously relaxes.Our knowledge of the aetiology is still obscure, but causal factors do not seem to be uniform.Some authors ascribe the disease to a disorder in Auerbach's plexus (Rake, 1927; Cameron, 1927; Mosher and McGregor, 1928) or to lesions of the central nervous system.Others envisage the possibility of vagotonia (Held and Gross, 1916), degenerative changes in the vagus (Kraus, 1902;Heyrovsky, 1913;Pollitzer, 1913) or a sympathetic nerve derangement (Carlson and Luckhardt, 1921 ; Kurd, 1929; Knight, 1934, and others).Sauerbruch and v. Haecker (1906) suggested that the diaphragm was concerned, and Jackson, who shared this view, proposed the name of " phrenospasm " for the syndrome.*Several surgeons in Great Britain have had isolated cases in which vagotomy has been followed by the typicar radiological and clinical manifes:ations of achalasia.These symptoms have been of temporary duration.-EmToR.
Use of continuous positive airway pressure in the management of community acquired pneumonia.
Authors: A Brett, D G Sinclair
Journal: Thorax (1993)

Three cases of severe community acquired pneumonia requiring ventilatory support are presented. Continuous positive airway pressure (CPAP) applied via a tightly fitting face mask was used and was successful in two cases; the third required intermittent positive pressure ventilation. More extensive use of CPAP in these circumstances should be considered.
Regulatory and Reimbursement Innovation
Authors: Rachel A. Lindor, Scott J. Allocco, Lee Cheatham, Denis A. Cortese, Ralph F. Hall, William J. Mangold, Vincent Pizziconi, George Poste, Bruce Quinn, Mollie Roth, Michael J. Saks, E. Robert Wassman, Raymond L. Woosley, Gary E. Marchant
Journal: Science Translational Medicine (2013)

Coverage with evidence development and parallel review for molecular diagnostics aid regulation and reimbursement.
Declaration of conflicts of interest
Authors: R. O'Driscoll
Journal: European Respiratory Journal (2004)

To the Editor: 

I am increasingly concerned by the failure of the European Respiratory Journal to require authors to declare competing interests. The most recent example was an editorial by one of the co-editors of the journal, which implied that long-acting bronchodilators and inhaled steroids are more beneficial if given in a combined inhaler device than as separate inhalers 1. This statement was …
Psychological predictors of injury among elite athletes
Authors: S A Galambos, P C Terry, G M Moyle, S A Locke
Journal: British Journal of Sports Medicine (2005)

To establish injury rates among a population of elite athletes, to provide normative data for psychological variables hypothesised to be predictive of sport injuries, and to establish relations between measures of mood, perceived life stress, and injury characteristics as a precursor to introducing a psychological intervention to ameliorate the injury problem.As part of annual screening procedures, athletes at the Queensland Academy of Sport report medical and psychological status. Data from 845 screenings (433 female and 412 male athletes) were reviewed. Population specific tables of normative data were established for the Brunel mood scale and the perceived stress scale.About 67% of athletes were injured each year, and about 18% were injured at the time of screening. Fifty percent of variance in stress scores could be predicted from mood scores, especially for vigour, depression, and tension. Mood and stress scores collectively had significant utility in predicting injury characteristics. Injury status (current, healed, no injury) was correctly classified with 39% accuracy, and back pain with 48% accuracy. Among a subset of 233 uninjured athletes (116 female and 117 male), five mood dimensions (anger, confusion, fatigue, tension, depression) were significantly related to orthopaedic incidents over the preceding 12 months, with each mood dimension explaining 6-7% of the variance. No sex differences in these relations were found.The findings support suggestions that psychological measures have utility in predicting athletic injury, although the relatively modest explained variance highlights the need to also include underlying physiological indicators of allostatic load, such as stress hormones, in predictive models.
Activation of Clotting Factor XI Without Detectable Contact Activation in Experimental Human Endotoxemia
Authors: M.C. Minnema, D. Pajkrt, W.A. Wuillemin, D. Roem, W.K. Bleeker, M. Levi, S.J.H. van Deventer, C.E. Hack, H. ten Cate
Journal: Blood (1998)
Post-bronchoscopy sputum in the current bronchoscopy technique dose not improve the diagnostic yield in thoracic malignancies
Authors: Atsushi Kitamura, Yasuhiko Yamano, Genta Ishikawa, Yutaka Tomishima, Torahiko Jinta, Naoki Nishimura, Naohiko Chohnabayashi
Journal: European Respiratory Journal (2013)

[Introduction]The utility of post-bronchoscopy sputum (PBS) for the diagnosis of thoracic malignancies (primary or metastatic lung cancer) was reported in the previous study. Recently, the diagnostic yield in thoracic malignancies has been improved by endobronchial ultrasound bronchoscopy and thin section computed tomography (CT). It is not clear whether PBS is useful for the diagnosis of thoracic malignancies in the current bronchoscopy technique. Therefore, we examined the diagnostic value of PBS in thoracic malignancies.  [Patinets and Methods]In this prospective observational study, patients who were suspected thoracic malignancies and underwent bronchoscopy in our hospital between July 2012 and January 2013 were eligible. We used endobronchial ultrasound bronchoscopy and five respiratory specialists identified the bronchus to the lesion in thin section CT before the procedure. Sampling PBS for cytology was performed within 1 day after bronchoscopy.  [Results]The overall diagnostic rate was 66.7%(36/54), (Adenocarcinoma: 25, Squamous cell carcinoma: 5, Small cell carcinoma: 2, other malignancy: 4). The rate of sampling PBS was 75.9%(41/54). The diagnostic rate with the PBS was 26.8%(11/41), (Adenocarcinoma: 11), and no patient was able to be diagnosed only with PBS.  [Conclusion]PBS in the current bronchoscopy technique dose not improve the diagnostic yield in thoracic malignancies. PBS might not be necessary for the diagnosis of thoracic malignancies.
Absence of the Full-Length Breast Cancer–Associated Gene-1 Leads to Increased Expression of Insulin-Like Growth Factor Signaling Axis Members
Authors: Vivek Shukla, Xavier Coumoul, Liu Cao, Rui-Hong Wang, Cuiying Xiao, Xiaoling Xu, Sebastiano Andò, Shoshana Yakar, Derek LeRoith, Chuxia Deng
Journal: Cancer Research (2006)

Abstract The breast cancer–associated gene-1 (BRCA1) plays many important functions in multiple biological processes/pathways. Mice homozygous for a targeted deletion of full-length BRCA1 (Brca1Δ11/Δ11) display both increased tumorigenesis and premature aging, yet molecular mechanisms underlying these defects remain elusive. Here, we show that Brca1 deficiency leads to increased expression of several insulin-like growth factor (IGF) signaling axis members in multiple experimental systems, including BRCA1-deficient mice, primary mammary tumors, and cultured human cells. Furthermore, we provide evidence that activation of IGF signaling by BRCA1 deficiency can also occur in a p53-independent fashion. Our data indicate that BRCA1 interacts with the IRS-1 promoter and inhibits its activity that is associated with epigenetic modification of histone H3 and histone H4 to a transcriptional repression chromatin configuration. We further show that BRCA1-deficient mammary tumor cells exhibit high levels of IRS-1, and acute suppression of Irs-1 using RNA interference significantly inhibits growth of these cells. Those observations provide a molecular insight in understanding both fundamental and therapeutic BRCA1-associated tumorigenesis and aging. (Cancer Res 2006; 66(14): 7151-7)