tbuckley/cabot-search huggingface dataset:
Molecular Identification of GD3 as a Suppressor of the Innate Immune Response in Ovarian Cancer
Authors: Tonya J. Webb, Xiangming Li, Robert L. Giuntoli, Pablo H.H. Lopez, Christoph Heuser, Ronald L. Schnaar, Moriya Tsuji, Christian Kurts, Mathias Oelke, Jonathan P. Schneck
Journal: Cancer Research (2012)

Abstract Tumors often display mechanisms to avoid or suppress immune recognition. One such mechanism is the shedding of gangliosides into the local tumor microenvironment, and a high concentration of circulating gangliosides is associated with poor prognosis. In this study, we identify ganglioside GD3, which was isolated from the polar lipid fraction of ovarian cancer–associated ascites, as an inhibitory factor that prevents innate immune activation of natural killer T (NKT) cells. Purified GD3 displayed a high affinity for both human and mouse CD1d, a molecule involved in the presentation of lipid antigens to T cells. Purified GD3, as well as substances within the ascites, bound to the CD1d antigenic-binding site and did not require additional processing for its inhibitory effect on NKT cells. Importantly, in vivo administration of GD3 inhibited α-galactosylceramide (α-GalCer)-induced NKT cell activation in a dose-dependent manner. These data therefore indicate that ovarian cancer tumors may use GD3 to inhibit the antitumor NKT cell response as an early mechanism of tumor immune evasion. Cancer Res; 72(15); 3744–52. ©2012 AACR.
Safety and efficacy of quinacrine in human prion disease (PRION-1 study): a patient-preference trial
Authors: John Collinge, Michele Gorham, Fleur Hudson, Angus Kennedy, Geraldine Keogh, Suvankar Pal, Martin Rossor, Peter Rudge, Durre Siddique, Moira Spyer, Dafydd Thomas, Sarah Walker, Tom Webb, Steve Wroe, Janet Darbyshire
Journal: The Lancet Neurology (2009)

The propagation of prions, the causative agents of Creutzfeldt-Jakob disease and other human prion diseases, requires post-translational conversion of normal cellular prion protein to disease-associated forms. The antimalarial drug quinacrine (mepacrine) prevents this conversion in vitro, and was given to patients with various prion diseases to assess its safety and efficacy in changing the course of these invariably fatal and untreatable diseases.Patients with prion disease were recruited via the UK national referral system and were offered a choice between quinacrine (300 mg daily), no quinacrine, or randomisation to immediate quinacrine or deferred quinacrine in an open-label, patient-preference trial. The primary endpoints were death and serious adverse events possibly or probably related to the study drug. This study is registered, ISRCTN 06722585.107 patients with prion disease (45 sporadic, two iatrogenic, 18 variant, and 42 inherited) were enrolled, 23 in a pilot study and 84 in the main study. Only two patients chose randomisation; 40 took quinacrine during follow-up (37 who chose it at enrollment). Choice of treatment was associated with disease severity, with those least and most severely affected more likely to choose not to receive quinacrine. 78 (73%) patients died: one randomly assigned to deferred treatment, 26 of 38 who chose immediate quinacrine, and 51 of 68 who chose no quinacrine. Although adjusted mortality was lower in those who chose to take quinacrine than in those who did not, this was due to confounding with disease severity, and there was no difference in mortality between groups after adjustment. Four of 40 patients who took quinacrine had a transient response on neurological rating scales. Only two of 14 reported serious adverse events were judged quinacrine-related.Quinacrine at a dose of 300 mg per day was reasonably tolerated but did not significantly affect the clinical course of prion diseases in this observational study.
Abstract 4499: HM5016699, a novel and selective PI3K/mTOR dual inhibitor
Authors: Yongxin Ren, Weihan Zhang, Yumin Cui, Mingchuan Guo, Jingwen Long, Yang Sai, Jian Wang, James Yan, Jia Li, Weiguo Qing, Weiguo Su
Journal: Cancer Research (2011)

Abstract PI3KCA gene amplification and mutations have been identified in many types of tumors, suggesting the dysregulation of PI3K/AKT/mTOR axis plays pivotal roles in tumorigenesis and development. Reported here is the discovery of HM5016699 as a potent, reversible ATP-competitive PI3K/mTOR dual inhibitor for treatment of cancer. HM5016699 showed potent kinase inhibition with IC50 of 0.01, 0.206, 0.052, 0.051 and 0.059 µM on PI3Kα, β, γ, Δ and mTOR, respectively. It demonstrated high selectivity on PI3K family and mTOR over a panel of 274 kinases. Of the 67 tumor cell lines screened from lung, colon, breast, ovarian, and other tumor types, we found that the tumor cells with HER2 gene amplification or PTEN loss tended to be sensitive to HM5016699, while the tumor cells harboring PI3KCA mutations and wild type Ras/Raf were mostly sensitive to the compound. HM5016699 could also show p-Erk inhibition and apoptotic induction at higher concentrations in the tumor cells harboring Ras/Raf mutations, suggesting it might bring benefits to patients carrying Ras/Raf mutations in the clinic. Consistent with in vitro studies, HM5016699 exhibited dose dependent tumor growth inhibition on multiple human xenografts models. It was found that the tumors with PIK3CA mutation or PTEN deletion were highly sensitive to HM5016699 with ED50s ranging from 0.6 to 1.8 mg/kg in U87MG (pTEN null), SKOV3 (H1047) and H1975 (G118D), whereas in tumors with Ras/Raf mutations, such as DLD-1(G13D), A549 (G12S) and HT-29(V600E), its ED50s were from 3.0 to 15.0 mg/kg. The decreased phosphorylation of AKT and S6 was observed in the tumor xenograft tissues treated with HM5016699, which was well-correlated with compound exposure. Therefore, we concluded that HM5016699 demonstrated both in vitro and in vivo activity through acting on PI3K/mTOR pathway. HM5016699 exhibited a favorable pharmacokinetic profile and acceptable safety window in rats. The pre-clinical study results suggest that HM5016699 could be a promising anti-cancer agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4499. doi:10.1158/1538-7445.AM2011-4499
The Organotypic Multicellular Spheroid Is a Relevant Three-Dimensional Model to Study Adenovirus Replication and Penetration in Human Tumors in Vitro
Authors: Jacques Grill, Martine L.M. Lamfers, Victor W. van Beusechem, Clemens M. Dirven, D.Shareen Pherai, Mathijs Kater, Paul Van der Valk, Ronald Vogels, W.Peter Vandertop, Herbert M. Pinedo, David T. Curiel, Winald R. Gerritsen
Journal: Molecular Therapy (2002)

The use of adenoviruses for gene transfer and as oncolytic agents is currently receiving widespread attention. As specific constraints to adenovirus distribution and spread cannot be studied in cell cultures, there is a need for an in vitro three-dimensional (3D) model mimicking the in vivo biology of tumors. We studied the interactions between tumor and adenoviruses using multicellular spheroids grown from primary brain tumor material. Using beta-galactosidase and luciferase reporter genes expressed by replication-defective adenoviruses, we showed that infection was restricted to the first layer of cells. Using a replication-competent adenovirus expressing the luciferase gene, we showed that transgene expression in the spheroid was considerably enhanced and that viral spreading deep into the 3D structure took place. In addition, a tetrazolium salt-based metabolic assay could be used to compare the oncolytic activity of different concentrations of replication-competent adenoviruses. We can conclude that organotypic spheroids offer a versatile in vitro system for studying distribution, spread, and oncolysis by adenoviruses in a clinically relevant model.
Book Review Textbook of Benign Prostatic Hyperplasia Edited by Roger Kirby, John McConnell, John Fitzpatrick, Claus Roehrborn, and Peter Boyle. 566 pp., illustrated. Oxford, England, Isis Medical Media, 1996. (Distributed by Mosby, St. Louis.) $160. 1-899066-24-1
Authors: Barbara Bassil
Journal: New England Journal of Medicine (1997)
Impaired Response of Left Ventricular Relaxation to Exercise-Induced Adrenergic Stimulation in Patients With Hypertrophic Cardiomyopathy
Authors: Hideo Izawa, Mitsuhiro Yokota, Kohzo Nagata, Mitsunori Iwase, Toshikazu Sobue
Journal: Journal of the American College of Cardiology (1996)
Bacteremia and Fungemia in Patients with the Acquired Immunodeficiency Syndrome
Authors: ESTELLA WHIMBEY
Journal: Annals of Internal Medicine (1986)

Forty-nine episodes of bacteremia and fungemia occurred in 38 of 336 patients with the acquired immunodeficiency syndrome seen at our institution since 1980. There were five types of infections. Infections commonly associated with a T-cell immunodeficiency disorder comprised 16 episodes and included those with Salmonella species, Listeria monocytogenes, Cryptococcus neoformans, and Histoplasma capsulatum. Infections commonly associated with a B-cell immunodeficiency disorder included those with Streptococcus pneumoniae and Haemophilus influenzae. Infections occurring with neutropenia were caused by Pseudomonas aeruginosa, Staphylococcus epidermidis, and Streptococcus faecalis. Other infections occurring in the hospital were caused by Candida albicans, Staphylococcus epidermidis, enteric gram-negative rods, Staphylococcus aureus, and mixed S. aureus and group G streptococcus. Other infections occurring out of the hospital included those with S. aureus, Clostridium perfringens, Shigella sonnei, Pseudomonas aeruginosa, and group B streptococcus. Because two thirds of the septicemias were caused by organisms other than T-cell opportunists, these pathogens should be anticipated during diagnostic evaluation and when formulating empiric therapy.
Weight and consequences of post-marketing (-approval) experience
Authors: G Kreutz
Journal: Annals of the Rheumatic Diseases (2002)

In the European Union the term pharmacovigilance is normally used to describe post-marketing or, more precisely, post-approval experience after the regulatory approval of drugs and their introduction to the market under defined conditions. The term describes activities used to gather information on the effects of medicinal products, with emphasis on those aspects which have not, or could not have been, detected in the pre-approval phase of the development of the product.

The term was first introduced in France more than two decades ago when authorities there set up and developed a national system to determine possible adverse reactions caused by medicinal products and to confirm or reject these reactions. In addition to this pharmacovigilance system, nationally agreed and implemented methods for collecting, reporting, and imputing suspected adverse drug reactions have been used.

When the term was included in the European regulations for medicines its meaning was extended to include all regulatory aspects of the evaluation of proprietary medicinal products resulting from, and relevant to, the description of the regulatory status and use of medicinal products after post-marketing authorisation of the product in the Union or in any of its member states.

Pharmacovigilance …
Cloning of the rat alpha 1C-adrenergic receptor from cardiac myocytes. alpha 1C, alpha 1B, and alpha 1D mRNAs are present in cardiac myocytes but not in cardiac fibroblasts.
Authors: A F Stewart, D G Rokosh, B A Bailey, L R Karns, K C Chang, C S Long, K Kariya, P C Simpson
Journal: Circulation Research (1994)

alpha 1-Adrenergic receptor (AR) activation in cardiac muscle has several different physiological effects that might be mediated through different alpha 1-AR subtypes. Two alpha 1-AR subtypes have been cloned from the rat, the alpha 1B and the alpha 1D; both are present in adult rat heart. A third subtype, the alpha 1C, cloned from the cow and human, was reported to be absent in the rat. However, we recently found alpha 1C mRNA in adult rat heart by using a partial alpha 1C cDNA. Thus, all three cloned alpha 1-AR subtypes are present in the heart, but it is unknown whether each is expressed in cardiac myocytes or in cardiac fibroblasts. In the present study, the full-length rat alpha 1C-AR was cloned from cultured neonatal cardiac myocytes. alpha 1C mRNA transcripts of 3, 9.5, and 11 kb were present in adult rat heart by Northern blot analysis. alpha 1B-, alpha 1C-, and alpha 1D-subtype mRNAs were each present in isolated adult and neonatal cardiac myocytes by RNase protection assay. In addition, cultured neonatal cardiac myocytes expressed the three alpha 1-AR subtype mRNAs. In contrast, none of the alpha 1-AR mRNAs was detected in cultured neonatal cardiac fibroblasts. In addition, alpha 1-ARs were absent in fibroblasts by [3H]prazosin binding and norepinephrine-stimulated [3H]inositol phosphate production. The absence of alpha 1-ARs in cardiac fibroblasts differs from beta-adrenergic and angiotensin II receptors, which are present in both cardiac fibroblasts and cardiac myocytes.(ABSTRACT TRUNCATED AT 250 WORDS)
DETERMINATION OF RADIOACTIVELY LABELED GLOBULIN TURNOVER BY THE DIRECT WHOLE-BODY COUNTING TECHNIQUE*
Authors: Stuart W. Lippincott, Stanton H. Cohn, Helen Hamel, Samuel Fine, Samuel Korman
Journal: Journal of Clinical Investigation (1961)

The turnover rates of I131 labeled beta and gamma globulins in a hypergammaglobulinemic multiple myeloma patient were compared by the conventional serum and urinary excretion methods with those found using the in vivo whole-body gamma spectrometer counting method. The fractionated radioactively labeled globulins used in these studies were considered by free (Tiselius) electrophoresis and ultracentrifugal patterns to have an acceptable degree of homogeneity. The half-life for the beta globulin was 9.9 days by the serum concentration method, 8.7 days by the urinary excretion method, and in two different studies by the in vivo whole-body counter method, 10.3 and 9.8 days, respectively. The half-life for the gamma globulin utilizing urinary data was 6.5 days as compared to 6.3 days for the whole-body counter method. Finally, by the latter technique, with a different gamma globulin preparation, the half-life was 7.1 days.
A Second Portfolio of Chest Radiographs for Undergraduate and Postgraduate Students
Authors: Joseph E. Whitley
Journal: JAMA (1968)

The book is a sequel to<i>A Portfolio of Chest Radiographs</i>, and both books attempt to fuse the clinical and radiologic approaches to chest disease. An interesting collection of roentgenographic reproductions, organized by a British thoracic surgeon and a British radiographer, is presented to illustrate a text written with sound conservative surgical philosophy. The authors stress basic diagnostic procedures such as routine chest roentgenography, bronchoscopy, and bronchography. The illustrations center on plain films of the chest supplemented with only a few bronchographs, three aortograms, and two pulmonary arteriograms. In this volume we find described and illustrated some usually unsaid truths, such as the lack of diagnostic value of many isolated routine chest roentgenograms as well as the lack of specificity of some roentgenographic signs. The ambitious undertaking of a description of the pulmonary vasculature in congenital heart disease falls flat, due to a lack of proper angiographic illustrations. A few
Clinical Lecture on some Exceptional Cases of Gastric Surgery: Delivered at the Westminster Hospital on October 15th, 1900
Authors: W. Spencer
Journal: BMJ (1900)

GENTLEMEN,-There has been of late in my wards a series, especially among the females, of cases suffering from the effects of chronic gastric ulceration, most of whom have been passed on to me by my medical colleagues as being no longer amenable to medical treatment.Some of these cases have presented exceptional features, which I will make the subject of to-day's lecture.Pyloric Obstruction caused by an Impacted Fishbone.A married woman, aged 48, was transferred to me by Dr. Murrell with the following history.She had been in very
Which Arterial and Cardiac Parameters Best Predict Left Ventricular Mass?
Authors: Chen-Huan Chen, Chih-Tai Ting, Shing-Jong Lin, Tsui-Lieh Hsu, Shuenn-Jiin Ho, Pesus Chou, Mau-Song Chang, Frances O’Connor, Harold Spurgeon, Edward Lakatta, Frank C. P. Yin
Journal: Circulation (1998)

Background —Many cardiovascular and noncardiovascular parameters are thought to be determinants of left ventricular mass (LVM). Complicated interactions necessitate the simultaneous measurement and consideration of each to determine their individual and collective impact on LVM. We undertook such a comprehensive study. Methods and Results —The influence of anthropometry, cardiac size and contractility, arterial structure and function, as well as indices of lifestyle, physical activity, and dietary salt intake on LVM (by two-dimensionally guided M-mode echocardiography) was analyzed in 1315 Chinese subjects who were either normotensive or had untreated hypertension. Effects of many cardiac and arterial factors were assessed. In univariate analysis, almost all measured noncardiovascular, cardiac, and arterial variables were significantly correlated with LVM. In multivariate linear regression analyses, when age, sex, body habitus, fasting serum C-peptide level, dietary salt, physical activity, and lifestyle were accounted for, the optimum multivariate linear regression main effects model had an adjusted model r 2 of 0.740, with 98% of the model variance accounted for by the 5 independent determinants of LVM: stroke volume (49.6%), systolic blood pressure (30.7%), contractility (14.7%), body mass index (1.8%), and aortic root diameter (1.6%). Other proposed arterial indices were significant independent determinants of LVM only when blood pressure was removed from the model and, even then, these indices not only resulted in less powerful prediction but also accounted for only a very small percentage of the total variance of LVM. Conclusions —In a large population, we (1) confirmed that age, body habitus, and some indexes of arterial structure and function are independent determinants of LVM; (2) found aortic diameter to be an independent structural determinant of LVM; (3) demonstrated that the effects of the derived measures of arterial function were small and provided no better predictive power than blood pressure alone; and (4) showed that when the best measures of cardiac and vascular load were included, the single most potent predictor was an index of left ventricular size.
Gastric ulcer penetrating into the heart
Authors: Kuang-I Fu, H. Fukui, K. Tominaga, Y. Kaji, H. Hiraishi, T. Fujimori
Journal: Endoscopy (2006)

A 57-year-old man developed hematemesis and was referred to our institution. Esophagogastroduodenoscopy showed that he had an active gastric ulcer, 15 mm in diameter, on the lesser curvature in the upper third of the corpus (Figure [1]). The ulcer was generally elevated, as if it was being pushed up by an extragastric mass, and it had a pulse that was synchronous with the heartbeat. As the endoscopic findings suggested either the presence of a large artery at the ulcer base or penetration to the heart, emergency surgery rather than endoscopic therapy was planned for hemostasis. However, the patient suffered repeated massive hematemesis before surgery and went into hypovolemic shock. Unfortunately, he died despite vigorous attempts at cardiopulmonary resuscitation. At autopsy, a benign peptic ulcer, 15 mm × 15 mm in size, was found on the lesser curvature in the upper third of the corpus, and this had penetrated through the pericardium and myocardium into the cardiac lumen at the apex of the heart (Figure [2]). Histological examination revealed no evidence of malignancy and Helicobacter pylori was not detected.
Perirenal contrast medium. A new roentgenographic sign of neonatal urinary ascites
Authors: K. T. Dockray
Journal: JAMA (1965)

IF, DURING excretory urography, a halo of opaque contrast medium is seen about the kidney of an ascitic infant, the physician may possess a diagnostic key to that catastrophic disorder, neonatal ascites. This rare disease, marked by a 95% death rate, is characterized by massive quantities of fluid in the peritoneal cavity, quantities which accumulate in the perinatal period.<sup>1</sup>This ascites is said to be the result of obstructive malformations in the gastrointestinal and genitourinary tracts.<sup>2,3</sup>The subject of this communication was affected by neonatal urinary ascites and, fortunately, survived. The successful therapeutic regimen was based on urographic findings and proves the value of this distinctive roentgenographic halo sign. It is the purpose of this communication to call attention to this form of uropathy and its diagnosis. <h3>Report of a Case</h3> A 10-day-old moribund boy with severe respiratory distress was discovered to have ascites as demonstrated by an
The Association Between Hospital Volume and Processes, Outcomes, and Costs of Care for Congestive Heart Failure
Authors: Karen E. Joynt, E. John Orav, Ashish K. Jha
Journal: Annals of Internal Medicine (2011)

Background: Congestive heart failure (CHF) is common and costly, and outcomes remain suboptimal despite pharmacologic and technical advances. Objective: To examine whether hospitals with more experience in caring for patients with CHF provide better, more efficient care. Design: Retrospective cohort study. Setting: 4095 hospitals in the United States. Patients: Medicare fee-for-service patients with a primary discharge diagnosis of CHF. Measurements: Hospital Quality Alliance CHF process measures; 30-day, risk-adjusted mortality rates; 30-day, risk-adjusted readmission rates; and costs per discharge. National Medicare claims data from 2006 to 2007 were used to examine the relationship between hospital case volume and quality, outcomes, and costs for patients with CHF. Results: Hospitals in the low-volume group had lower performance on the process measures (80.2%) than did medium-volume (87.0%) or high-volume (89.1%) hospitals (P < 0.001). In the low-volume group, being admitted to a hospital with a higher case volume was associated with lower mortality, lower readmission, and higher costs. Similar, though smaller, relationships were found between case volume and both mortality and costs in the medium- and high-volume hospital groups. Limitations: Analysis was limited to Medicare patients 65 years or older. Risk adjustment was performed by using administrative data. Conclusion: Experience with managing CHF, as measured by an institution's volume, is associated with higher quality of care and better outcomes for patients but a higher cost. Understanding which practices employed by high-volume institutions account for these advantages can help improve quality of care and clinical outcomes for all patients with CHF. Primary Funding Source: American Heart Association.
Giant Infantile Hemangioendothelioma of the Liver Scintigraphic Diagnosis
Authors: CHAN H. PARK, HEE S. HWANG, JEONG HONG, MOON S. PAK
Journal: Clinical Nuclear Medicine (1996)

Infantile hemangioendothelloma of the liver is a benign mesenchymal tumor composed of anastomosing vascular channels lined with plump endothelial cells. It is a congenital lesion noted at birth or during the first 6 months of life. The authors report a large infantile hemangioendothelioma that was imaged with anatomical modalities and Tc-99m RBC scintigraphy. An early"blush" on Tc-99m RBC hepatic scintigraphy is a diagnostic feature of infantile hemangioendothelioma.