tbuckley/cabot-search huggingface dataset:
Abstract 3912: The discovery of AZD4547: An orally bioavailable, potent and selective N-(5-Pyrazolyl)benzamide FGFR1-3 inhibitor
Authors: Andrew P. Thomas, Maria-Elena Theoclitou, David Buttar, Linette Ruston, Gail Wrigley, Mike Dennis, David A. Rudge, Tanya Coleman, Robin Smith, Paul R. Gavine, Teresa Klinowska, Lorraine Mooney, Nigel Brooks
Journal: Cancer Research (2012)

Abstract There is increasing evidence that FGFR signaling plays an important role within human cancer, with members of FGFR family acting as driving oncogenes in a significant number of human tumors. Deregulation of FGFR-signaling has been documented within clinical samples of breast multiple myeloma, bladder, endometrial, gastric, squamous NSCLC and prostate cancers. This dysregulation most frequently occurs through gene amplification, or through genetically altered forms of FGFR proteins. This increasing body of evidence implicating FGFR signaling in cancer has provided rationale for the identification and testing of selective inhibitors of FGFR signaling in the clinic. In this presentation, we describe the progress of our FGFR tyrosine kinase inhibitor programme and report the discovery of N-(5-pyrazolyl)benzamide FGFR inhibitors. Early compounds in this series suffered from poor in vivo pharmacokinetic (PK) properties. The key site of metabolism was identified to be at a basic N-methyl group. This group was shown to be located in the solvent channel of the ATP binding site on binding to FGFR1, and modification could be made without causing major changes to intrinsic binding affinity. However, the first compounds identified with low metabolic clearance also showed a significant reduction in oral bioavailability, due to apparent low permeability and increased efflux potential. The characterization of these PK issues and the discovery of compounds which overcame them, through modulation of pKa, lipophilicity and masking of the polar groups, will be described. Leading compounds showed significant anti-tumor activity in xenograft tumors grown in mice. Detailed characterization of these compounds led to the identification of AZD4547, a potent and selective FGFR tyrosine kinase inhibitor currently in Phase I clinical studies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3912. doi:1538-7445.AM2012-3912
Effect of acute anaesthesia on synthesis of contractile and non-contractile proteins of heart muscle and mixed proteins of types I and II fibre rich skeletal muscles of rat
Authors: T Siddiq, P J Richardson, I A Hashim, V R Preedy
Journal: Cardiovascular Research (1991)

Journal Article Effect of acute anaesthesia on synthesis of contractile and non-contractile proteins of heart muscle and mixed proteins of types I and II fibre rich skeletal muscles of rat Get access T Siddiq, T Siddiq Search for other works by this author on: Oxford Academic PubMed Google Scholar P J Richardson, P J Richardson Search for other works by this author on: Oxford Academic PubMed Google Scholar I A Hashim, I A Hashim Search for other works by this author on: Oxford Academic PubMed Google Scholar V R Preedy V R Preedy Search for other works by this author on: Oxford Academic PubMed Google Scholar Cardiovascular Research, Volume 25, Issue 4, April 1991, Pages 314–318, https://doi.org/10.1093/cvr/25.4.314 Published: 01 April 1991 Article history Received: 27 March 1990 Accepted: 26 November 1990 Published: 01 April 1991
Preparing for Medical Consequences of Terrorism
Authors: Marsha F. Goldsmith
Journal: JAMA (1996)

"THE USE OF violence or the threat of violence in furtherance of a political or social agenda" is the Federal Bureau of Investigation (FBI) definition of terrorism. Because such actions have increased in lethality if not in number in the United States, a group of concerned medical, military, and government experts led by Susan Briggs, MD, organized The First Harvard Symposium on Medical Consequences of Terrorism. Opening the conference in Boston, Mass, on April 24, the day President Bill Clinton signed into law a strong counterterrorism bill, Briggs, who is associate chief of the Trauma Service at Massachusetts General Hospital and national supervising medical officer of the National Disaster Medical System (NDMS) Medical Specialty Teams, said, "One impetus for this conference was to try to pull together those who are concerned with the threat of terrorism and those who are concerned with the consequences. Only by interacting in advance can
Vulvovaginal surgery is being carried out without evidence of safety or benefits, gynaecologists say
Authors: R. Dobson
Journal: BMJ (2008)

Aggressive marketing by private clinics in the United Kingdom and United States and media coverage have led to growing numbers of women asking for cosmetic genital procedures, a new report says.

But many such procedures are being carried out without adequate evidence of either safety or psychosocial benefits, say the authors ( Obstetrics, Gynaecology and Reproductive Medicine , doi:10.1016/j.ogrm.2008.07.008).

“There are very significant gaps in our understanding of these types of procedures. Given the political and ethical controversy, the onus remains on the surgeons who perform such surgery …
Clinical Impact of Routine Biopsies of the Gastric Antrum and Body
Authors: P. Sipponen, M. Stolte
Journal: Endoscopy (1997)

Biopsy sampling of gastric mucosa at diagnostic endoscopy provides information that cannot be obtained by other means. The most common indication for gastric biopsy is the need to know whether or not the patient is infected with Helicobacter pylori, and whether the stomach is gastritic or not. Microscopic examination of gastric biopsy specimens, in addition to H. pylori status, provides information about the grade, extent, and topography of gastritis-related and atrophy-related lesions in the stomach. This information provides further opportunities for assessing the risk and likelihood of various gastric disorders. These are: a) The predominance or restriction of the H. pylori-related gastritis in the antrum strongly correlates with an increased risk of peptic ulcer disease, and of duodenal ulcer in particular (the duodenal ulcer phenotype of gastritis), b) The presence of atrophic gastritis (loss of normal glands) in the area of the gastric body indicates a low risk of ulcer and also a reduction in the capacity of the patient to secrete acid, c) The occurrence of advanced atrophic gastritis and intestinal metaplasia multifocally in the stomach (advanced multifocal atrophic gastritis), and in the lesser curvature and angular notch in particular, are features suggestive of an increased risk of gastric neoplasias (the gastric cancer phenotype of gastritis), d) The presence of normal and healthy gastric mucosa indicates, on the other hand, an extremely low risk of both peptic ulcer disease and gastric cancer. In addition to diagnosis of H. pylori-related gastritic lesions, routine gastric biopsies may reveal findings that indicate special forms of gastritis, such as eosinophilic, lymphocytic, reactive, or granulomatous gastritis (e.g., Crohn's gastritis), or Helicobacter heilmannii gastritis. These types of gastritis can be found incidentally in a small percentage of patients who undergo diagnostic gastroscopy for abdominal complaints.
Effect of cycloheximide on intestinal secretion induced by hypertonic glucose
Authors: C. H. Halsted, D. I. Grayer, E. H. Luebbers, J. H. Yardley, T. R. Hendrix
Journal: Gut (1971)

Since intestinal fluid production in experimental cholera can be limited by cycloheximide, an inhibitor of protein synthesis, the same agent was used to determine whether there are similar mechanisms for fluid production in response to an osmotic gradient. Intestinal fluid production was measured by perfusion of paired rabbit jejunal loops (10 cm) <i>in vivo</i>, in controls, and in animals receiving 20 mg/kg intravenous cycloheximide one hour before perfusion. In each animal one loop was perfused with isotonic Ringer9s lactate and the other with a hypertonic glucose-Ringer9s lactate solution, 563 mOsm/litre. In control animals mean fluid production in the hypertonic loop was seven times that in the isotonic loop. Cycloheximide decreased the fluid response to the hypertonic stimulus by one half (p &lt; 0·001). In a separate measurement of bidirectional sodium fluxes, using sodium<sup>22</sup>, it was shown that the decreased net sodium movement into the lumen observed after cycloheximide was the result of decreased flux from blood to lumen. The major histological alteration after cycloheximide was on the crypt epithelial cells with sparing of villus crests. Glucose absorption was unaffected. These data parallel the observed effect of cycloheximide on cholera exotoxin induced secretion, suggesting that a process requiring continued protein synthesis is also necessary for the intestinal fluid response to an osmotic gradient.
The Fire of Life
Authors: F. T. Jung
Journal: JAMA (1962)

Lavoisier's important dictum that respiration is a kind of combustion is quoted at the outset in this book. It becomes the basis for a magnificent synthesis of scientific information. The book consists of 6 parts entitled "The Evolution of Bioenergetics," "Total Starvation," "The Physical Aspect of Metabolism," "The Metabolism of the Starving Animal," "Food as Fuel," and "Food and Population." These subjects are discussed with admirable clarity and an abundance of accurate detail. The author does not evade the essential complexities of his material, and when mathematical treatment is necessary it is set forth explicitly and correctly. Two features of the book that make for lively reading may be noted. One is the repeated mention, in connection with the subject of starvation, of Malthus and "writers with a hate complex." Malthus pointed out some bitter facts of life, but whether the cruel words ascribed to him on page 330 were
366 VIROLOGICAL HETEROGENEITY IN HEPATITIS B POSITIVE WOMEN; QUANTITATIVE HBeAg ESTIMATION DISTINGUISHES THOSE WITH SUBPOPULATIONS OF BASAL CORE PROMOTER MUTATIONS
Authors: S. Tattersall, S. Holden, M. Maley, R. Porritt, T. Nguyen, S. Locarnini, M. Levy
Journal: Journal of Hepatology (2009)
OBSERVATIONS ON INFANT FEEDING, WITH REPORT OF CASES.
Authors: FRANK SPOONER CHURCHILL
Journal: JAMA (1905)

The question of substitute infant feeding is an ever important one. Much progress has been made in the subject during the last decade, and certain principles laid down and insisted on by Rotch are now well known and accepted, e. g., good breast milk is the ideal food for infants during their first year; if breast milk is impossible, feed accurate percentages of fat, proteids and sugar, feed individuals, not groups, etc. These principles need no further comment. They are universally accepted. Their application, however, is often difficult, and in practice we are constantly meeting with infants, the management of whose diet is puzzling and unsatisfactory. The whole subject has now been crystallized into a study of the fats, sugars and proteids, and the effects of feeding definite amounts of these elements. Obviously, such study has been made possible only by the method of percentage feeding, which has been gradually
In older patients, rosiglitazone was associated with increased risk for stroke, heart failure, and mortality compared with pioglitazone
Authors: Amy T. Wang, Steven A. Smith
Journal: Annals of Internal Medicine (2010)

Source Citation Graham DJ, Ouellet-Hellstrom R, MaCurdy TE, et al. Risk of acute myocardial infarction, stroke, heart failure, and death in elderly medicare patients treated with rosiglitazone or pioglitazone. JAMA. 2010;304:411-8. 20584880
Gutter treatment for ingrowing toenails.
Authors: E P Abson
Journal: BMJ (1979)

August, p 308) as I have recently seen a patient who obtained the same dramatic rc-- mission of symptoms in rheumatoid arthritis after taking Chuei-Fong-Tou-Geu-Wan.The samples of these pills have not yet been analysed but it would seem from the speed of the remission that these also contain steroid drugs.It appears from discussion with my patient that quite a number of people in Britain are taking these pills, as the dramatic relief afforded by them caused the patient to recom- mend them to all his friends.As far as I can ascertain, all these pills have been obtained by individual patients from Hong Kong by post, therefore avoiding distributors and the need for a product licence.I feel that through your columns the widest possible publicity should be given to the dangers of these pills, and, indeed, perhaps attempts should be made through the Hong Kong authorities to ban their manufacture.
Organ donation from intensive care units.
Authors: J. Kwartz, A. E. Ridgway, A. B. Tullo
Journal: BMJ (1992)

ficulties of taking into account the comparative purchasing power of currencies -outside the Organisation for Economic Cooperation and Development,4 and the countries' large "black economy."But people in most types of occupation, both manual and non-manual, seem to work in the black economy.Relative deprivation was seen not necessarily in relation to direct income distribution but in relation to privileges such as the ability to travel abroad or access to Western goods, privileges that in the West are related to income.Eastern Europe will be a testing ground for Wilkinson's hypothesis in view of the introduction of market forces, which will widen income dif- ferentials appreciably.
People want to learn as much as possible from the PACE trial for chronic fatigue syndrome
Authors: T. Kindlon
Journal: BMJ (2013)

One reason that the minutes are sought for the PACE (Pacing, Graded Activity, and Cognitive Behaviour Therapy—a Randomised Evaluation) trial, which looked at the effectiveness of treatments for chronic fatigue syndrome, is to find out why outcome measures were changed.1 None of the three …
Ambulatory Peritoneal Dialysis
Authors: D. G. Oreopoulos, J. L. Funck-Brentano
Journal: Annals of Internal Medicine (1978)

Letters and Corrections1 December 1978Ambulatory Peritoneal DialysisD. G. OREOPOULOS, M.D., J. L. FUNCK-BRENTANO, M.D.D. G. OREOPOULOS, M.D.Search for more papers by this author, J. L. FUNCK-BRENTANO, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-89-6-1009_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: With data on inulin and vitamin B12 clearances during continuous ambulatory peritoneal dialysis, Popovich and colleagues (1) have shown that the weekly clearances of these substances and, by extrapolation, of middle molecules are three times higher than those of conventional intermittent peritoneal dialysis and two to six times higher than those of hemodialysis.We recently had the opportunity to measure middle-molecules plasma levels in four patients converted from intermittent peritoneal dialysis to continuous ambulatory peritoneal dialysis and in one patient converted from continuous ambulatory peritoneal dialysis to intermittent peritoneal dialysis (Figure 1). Measurement was by gel chromatography...References1. POPOVICHMONCRIEFNOLPHGHODSTWARDOWSKIPYLE RJKAZW: Continuous ambulatory peritoneal dialysis. Ann Intern Med 88:449-456, 1978 LinkGoogle Scholar2. FUNCK-BRENTANOMANSAUSSEZINGRAFFBOUDETBECKERCUEILLE JNAJJAG: Characterization of a 1100-1300 MW uremic neurotoxin. Trans Am Soc Artif Intern Organs 22:163-167, 1976 MedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByComplications of Peritoneal Dialysis Other Than PeritonitisContinuous Ambulatory Peritoneal Dialysis (CAPD) after Three Years: Still a Promising Treatment 1 December 1978Volume 89, Issue 6Page: 1009-1009KeywordsBlood plasmaChromatographyExtrapolationPeritoneal dialysis Issue Published: 1 December 1978 PDF DownloadLoading ...
Raloxifene (LY139481 HCI) prevents bone loss and reduces serum cholesterol without causing uterine hypertrophy in ovariectomized rats.
Authors: L J Black, M Sato, E R Rowley, D E Magee, A Bekele, D C Williams, G J Cullinan, R Bendele, R F Kauffman, W R Bensch
Journal: Journal of Clinical Investigation (1994)

There is a medical need for an agent with the positive effects of estrogen on bone and the cardiovascular system, but without the negative effects on reproductive tissue. Raloxifene (LY139481 HCI) is a benzothiophene derivative that binds to the estrogen receptor and inhibits the effects of estrogen on the uterus. In an ovariectomized (OVX) rat model we investigated the effects of raloxifene on bone loss (induced by estrogen deficiency), serum lipids, and uterine tissue. After oral administration of raloxifene for 5 wk (0.1-10 mg/kg per d) to OVX rats, bone mineral density in the distal femur and proximal tibia was significantly greater than that observed in OVX controls (ED50 of 0.03-0.3 mg/kg). Serum cholesterol was lower in the raloxifene-treated animals, which had a minimal effective dose of 0.1 mg/kg and an approximate oral ED50 of 0.2 mg/kg. The effects of raloxifene on bone and serum cholesterol were comparable to those of a 0.1-mg/kg per d oral dose of ethynyl estradiol. Raloxifene diverged dramatically from estrogen in its lack of significant estrogenic effects on uterine tissue. Ethynyl estradiol produced a marked elevation in a number of uterine histologic parameters (e.g., epithelial cell height, stromal eosinophilia). These data suggest that raloxifene has promise as an agent with beneficial bone and cardiovascular effects in the absence of significant uterine effects.
Age for starting cervical cancer screening in England will not be lowered
Authors: J. Wise
Journal: BMJ (2009)

The government has ruled that 25 should remain the age at which women start screening for cervical cancer in England, after a review by an independent advisory committee. But GPs will be given guidance to improve the management of young women with gynaecological symptoms.

The Advisory Committee on Cervical Screening agreed unanimously that the screening age should not be lowered, because evidence shows that earlier screening could do more harm than good. There has been a high profile campaign to reduce the screening age to 20 after the death of the reality television star …
Changes in the occurrence of and risk factors for hemophilia‐associated intracranial hemorrhage
Authors: Rachelle Nuss, J. Michael Soucie, Bruce Evatt
Journal: American Journal of Hematology (2001)

Recent studies suggest that rates of intracranial hemorrhage (ICH) increased concomitant with the HIV epidemic among the hemophilia population, but no studies have directly examined factors associated with ICH. To determine ICH rates and identify factors associated with ICH, we performed a nested case-control study of a cohort composed of all hemophilic males identified by a surveillance system. Data were obtained from medical records of care received during 1993-1997. Patients with ICH listed in hospital records or on death certificates during the 5-year period were compared to the remainder of the cohort to examine associations between ICH and patients' demographic and clinical factors including the presence of HIV infection. Among the 3,269 males in the cohort, 88 (2.7%) had an ICH during follow-up, an average incidence rate of 0.0054 case/year. Hemorrhage sites were intracerebral for 37.5%, subdural for 34.1%, unspecified for 19.3%, subarachnoid for 12.5%, and epidural for 8% of cases. For 22% of cases, the ICH was trauma-related, and, overall, 16 patients (18.2%) died. Several factors were independently associated with ICH (odds ratio, P value): severe disease (2.0, 0.05); age 51+ years compared to 6-10 year olds (3.7, 0.02); presence of an inhibitor (3.5, <0.001); and HIV infection among whites only (4.0, <0.001). ICH rates in our cohort were 2-fold higher compared to rates from previous reports. Much of the increase was attributed to HIV infection, which raised ICH risk primarily in whites and was frequently associated with spontaneous ICH among older individuals. Published 2001 Wiley-Liss, Inc.
Effects of Sample Selection on the Coincidence of Hypertension and Diabetes
Authors: Linda M. Gerber
Journal: JAMA (1982)

The occurrence of both hypertension and diabetes in patients at a general medical clinic at a university center and within a work-site community has been determined. In addition, the course of such patients for four years following presentation has been observed. The combination of hypertension and diabetes appeared more frequently, was expressed by greater severity, and coincided with a higher observed morbidity among the hospital clinic patients than among the work-site population. These findings regarding the prevalence and natural history of these coexistent diseases reaffirm that the source of a selected population can significantly affect the pattern of disease expression observed and, therefore, limit the capacity to extrapolate results from one population to another.
615 PROSPECTIVE EVALUATION OF LIVER STIFFNESS DYNAMICS DURING AND AFTER PEGINTERFERON ALPHA-RIBAVIRIN TREATMENT IN PATIENTS WITH CHRONIC HEPATITIS C
Authors: C. Hezode, L. Castera, F. Roudot-Thoraval, I. Rosa, D. Roulot, V. Leroy, M. Bouvier-Alias, A. Mallat, J.-M. Pawlotsky
Journal: Journal of Hepatology (2009)
Abstract 2419: Protective role of thioredoxin-1 in base excision repair under redox modulation
Authors: Hye Lim Kim, Preeyaporn Koedrith, Sang Min Lee, Yeo Jin Kim, Young Rok Seo
Journal: Cancer Research (2014)

Abstract Thioredoxin-1 (Trx1) is an antioxidant enzyme with a protective role in the removal of reactive oxygen species (ROS). We investigated the mechanism by which the redox modulator Trx1 affects base excision repair (BER) activity to understand the protective role of Trx1. We constructed a Trx1 knockdown system to demonstrate the specific mechanism of Trx1. DNA damage in terms of relative intensity of the DNA tail and γ-H2AX foci was markedly higher in the Trx1 shRNA cells compared with that in the wild type cells, leading to increased cellular susceptibility to a sublethal dose of BER-inducible toxicant, nitrosomethylurea (NMU). In addition, we observed a modulatory role of Trx1 in the BER pathway via the p53 downstream gene, growth arrest, and DNA-damage-inducible protein 45 α (Gadd45a). The protein level and function of p53, a Trx1 downstream gene, coincidently decreased in the Trx1 shRNA cells. Furthermore, Trx1 shRNA cells showed decreased Gadd45a expression and interaction of Gadd45a with apurynic/apyrimidinic endonuclease 1 (APE1) as well as APE1 activity. In conclusion, Trx1 might cooperate in the control of APE1 function by modulating the p53-mediated BER via the protein-protein interaction between Gadd45a and APE1, providing insight into the novel role of redox factor Trx1 in modulation of BER. Note: This abstract was not presented at the meeting. Citation Format: Hye Lim Kim, Preeyaporn Koedrith, Sang Min Lee, Yeo Jin Kim, Young Rok Seo. Protective role of thioredoxin-1 in base excision repair under redox modulation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2419. doi:10.1158/1538-7445.AM2014-2419