tbuckley/cabot-search huggingface dataset:
Handicapping the Race to Develop Inhibitors of the Phosphoinositide 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway
Authors: Courtney A. Granville, Regan M. Memmott, Joell J. Gills, Phillip A. Dennis
Journal: Clinical Cancer Research (2006)

Abstract The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway controls many cellular processes that are important for the formation and progression of cancer, including apoptosis, transcription, translation, metabolism, angiogenesis, and cell cycle progression. Genetic alterations and biochemical activation of the pathway are frequent events in preneoplastic lesions and advanced cancers and often portend a poor prognosis. Thus, inhibition of the PI3K/Akt/mTOR pathway is an attractive concept for cancer prevention and/or therapy. Inhibitors of individual components, such as PI3K, PDK-1, Akt, and mTOR, are being developed at a rapid pace and have promise for improving the care of cancer patients. Here, we review the published data on inhibitors of the pathway and discuss relevant issues, such as the complex regulation of the pathway, the design of clinical trials, and the likelihood of finding a therapeutic index when targeting such a critical signaling pathway.
Is There a Role for Tamsulosin in the Treatment of Distal Ureteral Stones of 7mm or Less? Results of a Randomised, Double-Blind, Placebo-Controlled Trial
Authors: Thomas Hermanns, Peter Sauermann, Kaspar Rufibach, Thomas Frauenfelder, Tullio Sulser, Räto T. Strebel
Journal: European Urology (2009)
Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade
Authors: T Cantaert, L De Rycke, C P Mavragani, C A Wijbrandts, T B Niewold, T Niers, B Vandooren, E M Veys, D Richel, P P Tak, M K Crow, D Baeten
Journal: Annals of the Rheumatic Diseases (2008)

<h3>Objective:</h3> Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis. <h3>Methods:</h3> 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry. <h3>Results:</h3> Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment. <h3>Conclusion:</h3> Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.
Voltage-Gated Sodium Channels Are Required for Heart Development in Zebrafish
Authors: Sameer S. Chopra, Dina Myers Stroud, Hiroshi Watanabe, Jeffrey S. Bennett, C. Geoffrey Burns, K. Sam Wells, Tao Yang, Tao P. Zhong, Dan M. Roden
Journal: Circulation Research (2010)

Voltage-gated sodium channels initiate action potentials in excitable tissues. Mice in which Scn5A (the predominant sodium channel gene in heart) has been knocked out die early in development with cardiac malformations by mechanisms which have yet to be determined.Here we addressed this question by investigating the role of cardiac sodium channels in zebrafish heart development.Transcripts of the functionally-conserved Scn5a homologs scn5Laa and scn5Lab were detected in the gastrulating zebrafish embryo and subsequently in the embryonic myocardium. Antisense knockdown of either channel resulted in marked cardiac chamber dysmorphogenesis and perturbed looping. These abnormalities were associated with decreased expression of the myocardial precursor genes nkx2.5, gata4, and hand2 in anterior lateral mesoderm and significant deficits in the production of cardiomyocyte progenitors. These early defects did not appear to result from altered membrane electrophysiology, as prolonged pharmacological blockade of sodium current failed to phenocopy channel knockdown. Moreover, embryos grown in calcium channel blocker-containing medium had hearts that did not beat but developed normally.These findings identify a novel and possibly nonelectrogenic role for cardiac sodium channels in heart development.
Artemisinin-Resistant Malaria
Authors: M. J. Friedrich
Journal: JAMA (2012)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Angiotensin II Type 2 Receptor Deficiency Exacerbates Heart Failure and Reduces Survival After Acute Myocardial Infarction in Mice
Authors: Yuichiro Adachi, Yoshihiko Saito, Ichiro Kishimoto, Masaki Harada, Koichiro Kuwahara, Nobuki Takahashi, Rika Kawakami, Michio Nakanishi, Yasuaki Nakagawa, Keiji Tanimoto, Yoshitomo Saitoh, Shinji Yasuno, Satoru Usami, Masaru Iwai, Masatsugu Horiuchi, Kazuwa Nakao
Journal: Circulation (2003)

Angiotensin II plays a prominent role in the progression of heart failure after acute myocardial infarction (AMI). Although both angiotensin type 1 (AT1) and type 2 (AT2) receptors are known to be present in the heart, comparatively little is known about the latter. We therefore examined the role played by AT2 receptors in post-AMI heart failure.In wild-type mice subjected to AMI by coronary artery ligation, AT2 receptor immunoreactivity is upregulated in the infarct and border areas. Among AT2 receptor-null (-/-) mice, the 7-day survival rate after AMI was significantly lower than among wild-type mice (43% versus 67%; P<0.05). All sham-operated animals of both genotypes survived through the study. Ventricular mRNA levels for brain natriuretic peptide were elevated in both genotypes 24 hours after coronary occlusion, with levels in AT2-/- significantly higher than in wild-type mice, as were their lung weights, and histological examination revealed marked pulmonary congestion in the AT2-/- mice. Cardiac function was significantly decreased in AT2-/- mice 2 days after AMI.AT2 receptor deficiency exacerbates short-term death rates and heart failure after experimental AMI in mice. The AT2 receptor may thus exert a protective effect on the heart after AMI.
DESENSITIZATION OF G PROTEIN–COUPLED RECEPTORS AND NEURONAL FUNCTIONS
Authors: Raul R. Gainetdinov, Richard T. Premont, Laura M. Bohn, Robert J. Lefkowitz, Marc G. Caron
Journal: Annual Review of Neuroscience (2004)

G protein-coupled receptors (GPCRs) have proven to be the most highly favorable class of drug targets in modern pharmacology. Over 90% of nonsensory GPCRs are expressed in the brain, where they play important roles in numerous neuronal functions. GPCRs can be desensitized following activation by agonists by becoming phosphorylated by members of the family of G protein-coupled receptor kinases (GRKs). Phosphorylated receptors are then bound by arrestins, which prevent further stimulation of G proteins and downstream signaling pathways. Discussed in this review are recent progress in understanding basics of GPCR desensitization, novel functional roles, patterns of brain expression, and receptor specificity of GRKs and beta arrestins in major brain functions. In particular, screening of genetically modified mice lacking individual GRKs or beta arrestins for alterations in behavioral and biochemical responses to cocaine and morphine has revealed a functional specificity in dopamine and mu-opioid receptor regulation of locomotion and analgesia. An important and specific role of GRKs and beta arrestins in regulating physiological responsiveness to psychostimulants and morphine suggests potential involvement of these molecules in certain brain disorders, such as addiction, Parkinson's disease, mood disorders, and schizophrenia. Furthermore, the utility of a pharmacological strategy aimed at targeting this GPCR desensitization machinery to regulate brain functions can be envisaged.
GENOMIC IMPRINTING: Nature and Clinical Relevance
Authors: J. G. Hall, MD
Journal: Annual Review of Medicine (1997)

▪ Abstract Molecular genetic techniques allow investigators to trace chromosomes and genes from parent to child and, in a single individual, from tissue to tissue. These techniques have uncovered a new type of gene control in which the allele from one parent is expressed and the allele from the other parent is not. This differential expression is called genomic imprinting. It may lead to phenotypic differences when inheritance is from the mother versus the father. Genomic imprinting has been observed in a number of disorders having to do with growth, behavior, and abnormal cell growth. It is important to be aware that such a phenomenon exists and to consider it when making diagnoses and determining therapy.
Managing wheeze in preschool children
Authors: A. Bush, J. Grigg, S. Saglani
Journal: BMJ (2014)

<h3>Abstract</h3> Background/Aim: The regeneration of a completely damaged spinal cord is still a challenge in modern medicine. A promising treatment method is autologous transplantation of olfactory ensheathing cells (OECs). This study aimed primarily to test methods of culturing OECs with the use of materials and reagents that are certified for pharmaceutical use in the production of an advanced cell therapy product intended for humans. Materials and Methods: The culture of OECs was performed using various modifications of the surface of the culture vessels (with fibronectin and poly-D-lysine). The number of cells was assessed after immunofluorescence staining using anti-fibronectin and anti-p75 NGF receptor antibodies. The study compared, in terms of surgical manipulations, scaffolds with OECs prepared based on 3 types of collagen: Acid Solubilized Telo Collagen and Pepsin Solubilized Atelocollagen, and the popular Corning collagen. Results: We have shown that when suspending OECs in collagen gel, it is much better to use acid-solubilized collagen (ASC) than pepsin-solubilized collagen (PSC) because the 3D collagen scaffold from ASC provides much easier handling of the product during a surgical procedure. We also found that the OEC cultures should be grown on the surface modified with fibronectin. Furthermore, we have also shown that the optimal concentration of fetal bovine serum (FBS) for culturing these cells should be around 10%. Conclusion: The culture of OECs based on reagents intended for human use can be successfully carried out, obtaining sufficient OECs content in the heterogeneous cell culture to produce a functional advanced therapy medicinal product.
Genotype–phenotype correlation in Italian children with Wilson’s disease
Authors: Emanuele Nicastro, Georgios Loudianos, Lucia Zancan, Lorenzo D’Antiga, Giuseppe Maggiore, Matilde Marcellini, Cristiana Barbera, Maria Grazia Marazzi, Ruggiero Francavilla, Maria Pastore, Pietro Vajro, Mariangela D’Ambrosi, Angela Vegnente, Giusy Ranucci, Raffaele Iorio
Journal: Journal of Hepatology (2008)
Diagnostic and therapeutic utility of spyglass peroral cholangioscopy for indeterminate biliary lesions and bile duct stones
Authors: E. Kalaitzakis, G. Webster, P. Vlavianos, R. Burnham, Y. Kallis, A. Hatfield, R. Aljabiri, D. Westaby, R. Sturgess
Journal: Gut (2011)

<h3>Introduction</h3> Peroral cholangioscopy (POC) enables direct visual examination of bile ducts, tissue sampling and therapeutic interventions. The authors aimed to evaluate the diagnostic utility of Spyglass POC for indeterminate biliary lesions and its usefulness in electrohydraulic lithotripsy (EHL) of bile duct stones not amenable to conventional endoscopic therapy. <h3>Methods</h3> A total of 141 consecutive patients (mean age 61 years (SD15); 62F), undergoing 149 attempted Spyglass procedures, in 3 UK tertiary referral centres between 2008 and 2010 were retrospectively enrolled. The authors estimate that &gt;80% of all Spyglass procedures performed for indeterminate biliary lesions or EHL of stones in the UK are included. Brush cytology or POC-directed biopsies were obtained as clinically indicated. Patients were followed up for a mean of 9 months (7). The operating characteristics of POC for detecting malignant biliary lesions were calculated using a composite reference standard that included surgery, tissue sampling and follow-up. Bile duct clearance after POC-EHL was also determined using stone recurrence at follow-up as a reference standard. <h3>Results</h3> Indications for Spyglass procedures included 108/149 (72%) stricture assessment, 16/149 (11%) intraluminal mass assessment and 25/149 (17%) EHL for stones. The Spyglass cholangioscope could be inserted in the bile duct in 140/149 (94%) and adequate mucosal visualisation was achieved in 121/149 (81%). A diagnosis of cancer was made in 36/149 (24%). Brush cytology sampling was performed in 60/149 (40%) with 50/60 (83%) yielding sufficient samples. POC-directed biopsies were performed in 67/149 (45%) with 52/67 (78%) yielding sufficient samples. The sensitivity, specificity, positive and negative predictive values and accuracy of POC for the diagnosis of malignant lesions were 72%, 97%, 93%, 86% and 88%, respectively. 17 out of 36 (42%) malignant lesions were correctly identified at Spyglass POC (with/without tissue confirmation). In all 27 EHL procedures were performed in 25 patients. Bile duct clearance was achieved in 17/25 (68%) with a further 2/25 (8%) awaiting further procedures. There were 11/149 (7%) adverse events (8 cholangitis/sepsis, 1 postsphincterotomy bleed, 1 hypotension, 1 pancreatitis). Two adverse events were severe (1 death and 1 ITU admission both with sepsis) and one was moderate (sepsis). <h3>Conclusion</h3> In experienced hands, Spyglass POC is very accurate in the diagnosis of malignant biliary lesions and effective for the treatment of bile duct stones not amenable to conventional endoscopic therapy. The complication rate is comparable to that of conventional ERCP with sepsis being the most common adverse event.
Antigen presentation by tumor infiltrating B cells influences CD4 T cell phenotype and function in primary lung cancer patient tumors
Authors: Tullia Bruno, Peggy Ebner, Brandon Moore, Daniel Munson, John Mitchell, Jeffrey Kern, Dario AA Vignali, Jill Slansky
Journal: Journal for ImmunoTherapy of Cancer (2015)

Meeting abstracts Despite improvements in surgical techniques and combined chemotherapies, the 5-year survival rate for all stages of non-small cell lung cancer (NSCLC) is only 18%. Understanding the function of tumor infiltrating lymphocytes (TILs) in NSCLC patient tumors will contribute to the
HOMOLOGOUS DISEASE IN THE ADULT RAT, A MODEL FOR AUTOIMMUNE DISEASE
Authors: Peter Stastny, Vernie A. Stembridge, Thomas Vischer, Morris Ziff
Journal: The Journal of Experimental Medicine (1965)

Polyarthritis and cardiac lesions have been observed in the adult rat with homologous disease. Changes in the lymphoid tissue and kidney have also been noted. A migratory polyarthritis occurred in over half of the affected animals, and cardiac involvement of varying intensity was present in all. Histologically, the arthritis was characterized by a mononuclear synovial inflammatory reaction. In the heart, the valves and myocardium demonstrated a similar type of response. Cultures of involved joints and hearts for pyogens and pleuropneumonia-like organisms were negative. The lymphoid tissues showed progressive changes in three stages: (a) disappearance of follicles; (b) increase in plasma-like cells and histiocytes; and (c) fibrosis. The second stage tended to coincide with the development of the polyarthritis. The kidney showed mild interstitial mononuclear infiltration. The pathologic changes described appear to be a consequence of reaction between foreign immunologically competent cells and host antigens, but the possibility that these lesions represent a response to antigens derived from unknown infectious agents is, however, not ruled out.
The equivalent strap muscle of the left ventricle. A model for describing myocardial force and length, and mean endocardial fiber-shortening rate in man.
Authors: C Grant
Journal: Circulation Research (1978)

The force exerted by cardiac muscle usually has been estimated as wall stress, i.e., force per unit area of cross-section.This calculation fails to allow for the decrease in number of muscle fibers per square centimeter as the fibers shorten and become thicker during systole.To describe better the behavior of actual muscle fibers, a model composed of fibers has been identified and examined.It permits the fibers forming a left ventricle to be uncurled into a straight or strap-shaped muscle equivalent to the actual ventricular muscle mass.This transform allows quantitative conversion of volumetric and pressure data into linear data of force, velocity, and length (more exactly: equivalent myocardial force, mean endocardial velocity of fiber-shortening, and equivalent endocardial fiber-length).Data from 17 subjects (fifteen with coronary disease) show the left ventricles equivalent to strap muscles exerting a maximum force of 2.1 to 4.8 kg and having end-diastolic lengths of 18 to 24.5 cm.Corresponding end-systolic lengths range from 11 to 22 cm and fiber shortening rates from 0.52 to 1.69 lengths/sec.Algebraic analysis, for spherical and elongated (cylindrical) shapes, suggests that different fiber arrangements in the walls may be equivalent to each other.The inward force exerted by each circular loop of fiber is the same, regardless of diameter, so it is possible that the outer and inner fibers of a thick-walled model may make equal contributions to myocardial force (although, of course, the outer fibers will be longer).
Prognostic value of p53 molecular status in high-risk primary breast cancer
Authors: P. Marchetti, K. Cannita, E. Ricevuto, F. De Galitiis, Z.C. Di Rocco, A. Tessitore, R. Bisegna, G. Porzio, G.P. De Rubeis, T. Ventura, S. Martinotti, C. Ficorella
Journal: Annals of Oncology (2003)
α<sub>ν</sub>β<sub>3</sub>-targeted Copper Nanoparticles Incorporating an Sn 2 Lipase-Labile Fumagillin Prodrug for Photoacoustic Neovascular Imaging and Treatment
Authors: Ruiying Zhang, Dipanjan Pan, Xin Cai, Xiaoxia Yang, Angana Senpan, John S. Allen, Gregory M. Lanza, Lihong V. Wang
Journal: Theranostics (2014)

Photoacoustic (PA) tomography enables multiscale, multicontrast and high-resolution imaging of biological structures. In particular, contrast-enhanced PA imaging offers high-sensitivity noninvasive imaging of neovessel sprout formation and nascent tubules, which are important biomarkers of malignant tumors and progressive atherosclerotic disease. While gold nanoparticles or nanorods have been used as PA contrast agents, we utilized high-density copper oleate small molecules encapsulated within a phospholipid surfactant (CuNPs) to generate a soft nanoparticle with PA contrast comparable to that from gold. Within the NIR window, the copper nanoparticles provided a 4-fold higher signal than that of blood. ανβ3-integrin targeting of CuNPs in a Matrigel(TM) angiogenesis mouse model demonstrated prominent (p<0.05) PA contrast enhancement of the neovasculature compared with mice given nontargeted or competitively inhibited CuNPs. Furthermore, incorporation of a Sn 2 lipase-labile fumagillin prodrug into the CuNP outer lipid membrane produced marked antiangiogenesis in the same model when targeted to the ανβ3-integrin, providing proof of concept in vivo for the first targeted PA - drug delivery agent.
T Cells and the Regulation of Herpes Simplex Virus Latency and Reactivation
Authors: Anthony A. Nash
Journal: The Journal of Experimental Medicine (2000)

Herpes simplex virus (HSV), like all herpesviruses, is a formidable adversary with numerous strategies to evade the immune system. The fact that the virus is able to persist indefinitely in the host suggests that for most of the time the immune system is powerless to act. The anatomy of infection is
Expression Profiling of Archival Tumors for Long-term Health Studies
Authors: Levi Waldron, Shuji Ogino, Yujin Hoshida, Kaori Shima, Amy E. McCart Reed, Peter T. Simpson, Yoshifumi Baba, Katsuhiko Nosho, Nicola Segata, Ana Cristina Vargas, Margaret C. Cummings, Sunil R. Lakhani, Gregory J. Kirkner, Edward Giovannucci, John Quackenbush, Todd R. Golub, Charles S. Fuchs, Giovanni Parmigiani, Curtis Huttenhower
Journal: Clinical Cancer Research (2012)

More than 20 million archival tissue samples are stored annually in the United States as formalin-fixed, paraffin-embedded (FFPE) blocks, but RNA degradation during fixation and storage has prevented their use for transcriptional profiling. New and highly sensitive assays for whole-transcriptome microarray analysis of FFPE tissues are now available, but resulting data include noise and variability for which previous expression array methods are inadequate.We present the two largest whole-genome expression studies from FFPE tissues to date, comprising 1,003 colorectal cancer (CRC) and 168 breast cancer samples, combined with a meta-analysis of 14 new and published FFPE microarray datasets. We develop and validate quality control (QC) methods through technical replication, independent samples, comparison to results from fresh-frozen tissue, and recovery of expected associations between gene expression and protein abundance.Archival tissues from large, multicenter studies showed a much wider range of transcriptional data quality relative to smaller or frozen tissue studies and required stringent QC for subsequent analysis. We developed novel methods for such QC of archival tissue expression profiles based on sample dynamic range and per-study median profile. This enabled validated identification of gene signatures of microsatellite instability and additional features of CRC, and improved recovery of associations between gene expression and protein abundance of MLH1, FASN, CDX2, MGMT, and SIRT1 in CRC tumors.These methods for large-scale QC of FFPE expression profiles enable study of the cancer transcriptome in relation to extensive clinicopathological information, tumor molecular biomarkers, and long-term lifestyle and outcome data.