tbuckley/cabot-search huggingface dataset:
Abstract 4776: PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity
Authors: Arturo Orlacchio, Valeria Antico Arciuch, Antonio Di Cristofano
Journal: Cancer Research (2014)

Abstract The PI3K signaling cascade is frequently activated in human cancer, and AKT is commonly considered its major transforming conduit. Thus, PI3K and AKT represent relevant targets for therapeutic purposes. However, the many essential of roles played by this pathway in normal cells poses the problem of reaching therapeutic efficacy without harming healthy tissues. In principle, it would be ideal to target only molecules directly involved in the transformation process, thus reducing the toxicity associated with wide-range inhibitors. PDK1 plays a key role in the PI3K cascade, directly activating AKT. In addition, PDK1 possesses a substrate docking site named “PIF pocket” that is required to phosphorylate and activate members of the AGC kinase family, including S6K, PKC, SGK, and RSK. Mice in which the PI3K pathway is constitutively activated in the thyroid epithelium through loss of Pten are born with thyroid hyperplasia that progresses to invasive and metastatic follicular carcinoma, a process that is accelerated by the simultaneous loss of p27 or p53, and by Ras or Braf activation. Using in vivo as well as ex vivo and in vitro genetic and pharmacological approaches, we now show that although Akt activation is necessary, it is not sufficient to transform thyroid epithelial cells. Concomitant activation of Pdk1-dependent pathways is absolutely required to develop neoplastic lesions in vivo, and to induce cell proliferation ex vivo. Pten mutants develop adenomas and carcinomas by one year of age. Strikingly, complete rescue of this phenotype is observed in compound mutants in which, in addition to thyroid-specific Pten loss, the PIF-pocket of Pdk1 has been genetically disrupted, maintaining constitutive activation of Akt and mTor, but not of PIF-pocket dependent AGC kinases. We also show that the transcription factor STAT3 represents a key mediator of this essential Pdk1-dependent pathway: STAT3 phosphorylation is increased in Pten mutants, and abolished in compound mutants. Furthermore, genetic and pharmacological inhibition of STAT3 drastically impairs cell proliferation in vitro and rescues the hyperplastic phenotype of Pten mutant mice in vivo. Thus, we have identified an essential and druggable signaling cascade that critically cooperates with AKT activation to transform thyroid epithelial cells. Citation Format: Arturo Orlacchio, Valeria Antico Arciuch, Antonio Di Cristofano. PDK1-dependent activation of AGC kinases is an absolute requirement for AKT oncogenic activity. [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 4776. doi:10.1158/1538-7445.AM2014-4776
THE EFFECTS OF CHANGES IN HYDROGEN ION CONCENTRATION ON THE BLOOD FLOW OF MORPHINIZED DOGS
Authors: Tinsley Randolph Harrison, Charles P. Wilson, Alfred Blalock
Journal: Journal of Clinical Investigation (1925)

HYDROGEN ION CONCENTRATION AND BLOOD FLOWOne of the arterial samples was used for pH determination accord- ing to Hawkins' (1923) modification of Cullen's (1922) colorimetric method.In many of the experiments in which acid was injected slight laking of the blood occurred and accurate pH readings were difficult.Greater accuracy than --pH 0.03 is not assumed.However the changes found in H-ion concentration were much greater than the limits of error of the method.The oxygen and carbon dioxide content of the arterial and venous blood were determined.The circulatory minute volume was calcu- lated from the Fick formula:CC. 02 consumed per minute Number of cubic centimeters of blood Amount 02 taken up in lungs by 1 cc. of blood flowing through lungs per minute Acid and alkali were injected into the femoral vein.In some experi- ments N/5 HCI was used, in others N/5, N/2.5 or N/1 lactic acid, N/l and 2N Na2CO3 were used.The amount of acid or alkali given was varied in different experiments, according to the size of the animal and the degree of change in pH desired.Fifty to 100 cc.were injected in most instances.Some animals received acid alone, some alkali alone, while in a third group both acid and alkali were given.Five to ten
Epizootiology and distribution of transmissible sarcoma in Maryland softshell clams, Mya arenaria, 1984-1988.
Authors: C A Farley, D L Plutschak, R F Scott
Journal: Environmental Health Perspectives (1991)

Seasonal and geographic studies of transmissible sarcoma in Maryland softshell clams, Mya arenaria, were carried out from 1984 to 1988. Three major epizootics occurred in our sampling location during this time, resulting in prevalences as high as 90%, with comparable mortalities in other high prevalence areas. The disease invaded populations of large adult clams first, later spreading to the small juvenile clam populations. An apparent 2-year cycle was noted with varying seasonal effects. Affected sites tended to be in the main stem of Chesapeake Bay north of Tangier Sound, primarily in the areas where the major harvesting occurs. Several sites, mostly in upstream locations, were consistently free of disease. The epizootiological study supports the interpretation that the disease is infectious exclusively to this species. Regression analysis between sarcoma prevalence and contaminant levels in clam tissues showed a significant correlation (p = 0.0001) between chlordane levels and this disease. No correlations were found with other contaminants that were analyzed.
Pharmacokinetics of indium-111-labeled antimyosin monoclonal antibody in murine experimental viral myocarditis
Authors: Takehiko Yamada, Akira Matsumori, Yuji Watanabe, Nagara Tamaki, Yoshiharu Yonekura, Keigo Endo, Junji Konishi, Chuichi Kawai
Journal: Journal of the American College of Cardiology (1990)
E-cadherin Suppression Accelerates Squamous Cell Carcinoma Progression in Three-Dimensional, Human Tissue Constructs
Authors: Alexander Margulis, Weitian Zhang, Addy Alt-Holland, Howard C. Crawford, Norbert E. Fusenig, Jonathan A. Garlick
Journal: Cancer Research (2005)

Abstract We studied the link between loss of E-cadherin–mediated adhesion and acquisition of malignant properties in three-dimensional, human tissue constructs that mimicked the initial stages of squamous cell cancer progression. Suppression of E-cadherin expression in early-stage, skin-derived tumor cells (HaCaT-II-4) was induced by cytoplasmic sequestration of β-catenin upon stable expression of a dominant-negative E-cadherin fusion protein (H-2Kd-Ecad). In monolayer cultures, expression of H-2Kd-Ecad resulted in decreased levels of E-cadherin, redistribution of β-catenin to the cytoplasm, and complete loss of intercellular adhesion when compared with control II-4 cells. This was accompanied by a 7-fold decrease in β-catenin–mediated transcription and a 12-fold increase in cell migration. In three-dimensional constructs, E-cadherin–deficient tissues showed disruption of architecture, loss of adherens junctional proteins from cell contacts, and focal tumor cell invasion. Invasion was linked to activation of matrix metalloproteinase (MMP)–mediated degradation of basement membrane in H-2Kd-Ecad–expressing tissue constructs that was blocked by MMP inhibition (GM6001). Quantitative reverse transcription–PCR showed a 2.5-fold increase in MMP-2 and an 8-fold increase in MMP-9 in cells expressing the H-2Kd-Ecad fusion protein when compared with controls, and gel zymography showed increased MMP protein levels. Following surface transplantation of three-dimensional tissues, suppression of E-cadherin expression greatly accelerated tumorigenesis in vivo by inducing a switch to high-grade carcinomas that resulted in a 5-fold increase in tumor size after 4 weeks. Suppression of E-cadherin expression and loss of its function fundamentally modified squamous cell carcinoma progression by activating a highly invasive, aggressive tumor phenotype, whereas maintenance of E-cadherin prevented invasion in vitro and limited tumor progression in vivo.
In vivo effect of adhesion inhibitor heparin on Legionella pneumophila pathogenesis in a murine pneumonia model
Authors: Florence Ader, Rozenn Le Berre, Rémi Fackeure, Dominique Raze, Franco Dante Menozzi, Nathalie Viget, Karine Faure, Eric Kipnis, Benoît Guery, Sophie Jarraud, Jerome Etienne, Christian Chidiac
Journal: Intensive Care Medicine (2008)
General practitioners' role in commissioning
Authors: P James, S Ramaiah
Journal: BMJ (1994)

EDITOR, - Jonathan P Graffy and Juliet Williams are right to conclude that “health authorities must be prepared to share important decisions and offer representation at every level if a commissioning partnership is to be based on trust.”1 In Walsall this representation in the commissioning of services occurs at three levels.

Firstly, service review meetings with local providers take place regularly, at which one or often two general practitioners are part …
Large bowel obstruction due to a benign uterine leiomyoma
Authors: R P C Chaparala
Journal: Gut (2004)

Background: The prevalence of duodenal carcinoma is much higher in familial adenomatous polyposis (FAP) than in the background population, and duodenal adenomatosis is found in most polyposis patients.Aims: To describe the long term natural history of duodenal adenomatosis in FAP and evaluate if cancer prophylactic surveillance of the duodenum is indicated.Methods: A prospective five nation study was carried out in the Nordic countries and the Netherlands.Patients: A total of 368 patients were examined by gastroduodenoscopy at two year intervals during the period 1990-2001.Results: At the first endoscopy, 238 (65%) patients had duodenal adenomas at a median age of 38 years.Median follow up was 7.6 years.The cumulative incidence of adenomatosis at age 70 years was 90% (95% confidence interval (CI) 79-100%), and of Spigelman stage IV 52% (95% CI 28-76%).The probability of an advanced Spigelman score increased during the study period (p,0.0001)due to an increasing number and size of adenomas.Two patients had asymptomatic duodenal carcinoma at their first endoscopy while four developed carcinoma during the study at a median age of 52 years (range 26-58).The cumulative incidence rate of cancer was 4.5% at age 57 years (95% CI 0.1-8.9%)and the risk was higher in patients with Spigelman stage IV at their first endoscopy than in those with stages 0-III (p,0.01).Conclusions: The natural course of duodenal adenomatosis has now been described in detail.The high incidence and increasing severity of duodenal adenomatosis with age justifies prophylactic examination, and a programme is presented for upper gastrointestinal endoscopic surveillance.. . . . . .
The Concept of Airway Inflammation
Authors: GARY L. LARSEN, PATRICK G. HOLT
Journal: American Journal of Respiratory and Critical Care Medicine (2000)

The generation of an inflammatory response is a critical mechanism through which mammalian species respond to and protect themselves from infectious as well as noninfectious insults (1). In terms of the lung, both nonspecific and antigen-specific (immune) mechanisms may lead to an inflammatory response. While this response is usually protective and beneficial, inflammation also has the potential to injure tissue, including the airways, within the lung. This brief communication focuses in general terms on basic aspects of inflammation within airways. The issue of what we need to know if we are to better understand and more effectively treat children with respiratory disorders in which inflammation plays a role is addressed. Emphasis is placed on providing information and examples that are most relevant to childhood asthma. Although data from animal models cannot be reliably extrapolated to humans, animal studies that provide insight into the inflammatory process are included in this review.
CHEST INJURY AND CORONARY OCCLUSIONS
Authors: Harry D. Leinoff
Journal: JAMA (1942)

To the Editor:—  In the October 3 issue ofThe Journal, in a communication on chest injury and coronary occlusion (p. 392), Master suggested that the use of acute coronary thrombosis in the title of my paper (Leinoff, H. D.; Acute Coronary Thrombosis in Industry, Arch. Int. Med.  70 :33 [July] 1942) was misleading. This is untrue since I definitely have suggested that in all these cases a better diagnostic term would have been acute traumatic heart disease with myocardial and pericardial damage. The conclusion also stresses the importance of a differential diagnosis between acute occlusion and traumatic heart damage.  He has further confused this subject by attempting to discuss physical exertions and direct nonpenetrating chest injuries as one. I should like to take this opportunity of stressing the fact that these two types of injuries should be considered separately at all times, since the mechanisms and the end results
Chronic diarrhoea in AIDS
Authors: S. HICKS, A. D PHILLIPS
Journal: Gut (1997)

Editor,—We read with interest the article by Blanshard et al ( Gut 1996; 39: 824–32) where a cohort of adult AIDS patients with chronic diarrhoea was investigated for potential stool pathogens. An extensive array of diagnostic tools was used, including microbiological examination of stools, duodenal aspirates, and microscopic examination of biopsy specimens from the duodenum, jejunum, and rectum. However, despite investigation for at least 20 bacterial, viral, and …
Protection of bone marrow transplant recipients from lethal doses of methotrexate by the generation of methotrexate-resistant bone marrow.
Authors: D A Williams, K Hsieh, A DeSilva, R C Mulligan
Journal: The Journal of Experimental Medicine (1987)

To develop a highly efficient means for generating methotrexate resistant (MTXr) hematopoietic cells in vivo, a recombinant retroviral genome was constructed that encodes a MTXr dihydrofolate reductase (DHFRr). Cell lines producing high titers of virus capable of transmitting the DHFR gene were generated and used to infect mammalian cells in vitro. Analysis of infected fibroblasts indicated that the DHFRr gene was transmitted intact and conferred a high level of MTXr upon cells. Based on these findings, DHFRr-containing virus was used to infect murine bone marrow cells in vitro. Following infection, the transduced cells were introduced into lethally irradiated recipients via bone marrow transplantation techniques. The presence of the proviral sequences in cells of the spleen and bone marrow of engrafted recipients was associated with significantly increased survival of mice treated with otherwise lethal doses of MTX.
Brain, spine surgeons say yes to ultrasound
Authors: Chris Anne Raymond
Journal: JAMA (1986)

Intraoperative ultrasound appears to be gaining increasing acceptance in neurosurgery—in some areas of the United States, at least—but not as rapidly as some predicted when the first studies were reported early in this decade. Hospitals in cities such as Los Angeles, New Orleans, Philadelphia, and Palo Alto, Calif, have reported successful tumor location and resection guided by ultrasound (<i>Neurosurgery</i>1983;12:624-628;<i>Radiology</i>1983;148:513-517;<i>AJNR</i>1984;5:243-246;<i>J Ultrasound Med</i>1984;3:245-249). "This is becoming quite widely used in the United States. But it's still catching on elsewhere," says William F. Chandler, MD, associate professor of neurosurgery, University of Michigan Medical School. In fact, much of this acceptance appears to have come in just the last two or three years. The neurosurgical ultrasound technique has been in use since 1980. Jonathan M. Rubin, MD, PhD, associate professor of radiology, University of Michigan Medical School, Ann Arbor; George J. Dohrmann III, MD, PhD, University of
NOTES ON ARISTOL IN THE TREATMENT OF THE DISEASES OF THE NOSE AND THROAT.Read in the Section of Laryngology and Otology, at the Forty-second Annual Meeting of the American Medical Association, held at Washington, D. C., May 6, 1891.
Authors: WENDELL C. PHILLIPS
Journal: JAMA (1891)

Nearly every month a new antiseptic is presented to the medical profession, each claiming to outdo all its predecessors and to be perfect in all its attainments. But experiments have proved most of them to have one or more obnoxious qualities that greatly interfere with their usefulness in the sphere for which they have been recommended. One, if used in sufficient strength to become a true antiseptic, is found to be a local irritant. Another corrodes the instruments and unless great care is used will poison both the patient and the operator. A third is accompanied by an odor so pungent and disagreeable that few patients will submit to it, and the usefulness of still another is greatly lessened by the staining to hands and clothing that results from its use. All of the earlier antiseptics were handicapped by their poisonous qualities, and consequently oould only be used to a
In vitro replication and expression of hepatitis B virus from chronically infected primary chimpanzee hepatocytes
Authors: James R. Jacob, Jorg W. Eichberg, Robert E. Lanford
Journal: Hepatology (1989)

Primary chimpanzee hepatocytes were maintained in vitro utilizing a serum-free medium. Hepatocyte functions were sustained throughout the culture period as demonstrated by the synthesis and secretion of liver-specific plasma proteins characteristic for differentiated hepatocytes. Hepatocyte cultures established from a chimpanzee chronically infected with human hepatitis B virus exhibited the synthesis and secretion of hepatitis B virus proteins into the medium. In addition, the de novo replication of hepatitis B virus was documented by the recovery of virus, exhibiting an endogenous DNA polymerase activity, from the tissue culture medium. Therefore, both the long-term maintenance of differentiated hepatocytes and the expression of hepatitis B virus from these primary cultures were sustained in the serum-free medium.
Abstract 4738: The early response protein EGR-1 mediates vitamin E γ-tocotrienol-induced apoptosis in pancreatic cancer cells
Authors: Chen Wang, Jose M. Pimiento, Kazim Husain, Anying Zhang, Zhongsheng Tong, Mokenge P. Malafa
Journal: Cancer Research (2012)

Abstract Background: Vitamin E tocotrienols are bioactive components of cereal foods such as oats, barley, rice bran, and palm, that have demonstrated anticancer and chemopreventive activities in various types of cancer. Recently we have shown that γ-tocotrienol is the most bioactive tocotrienol against pancreatic cancer both in vitro as well as in vivo. However, the molecular mechanism of action of tocotrienols in pancreatic cancer has not been fully elucidated. In this work, we investigated the early genes associated with Vitamin E γ-tocotrienol induced apoptosis, and therefore identify novel pathways related with its anticancer effects. Methods: Human pancreatic cancer MiaPaca-2 cells were treated with γ-tocotrienol (50 µM) and vehicle (ethanol) for 3 h and were subjected to microarray analysis using costume Affymetrix for the identification of early regulatory genes. Early growth response protein-1 (EGR-1) was one of those early response genes induced by γ-tocotrienol. Then we evaluated the protein expression of EGR-1 by real-time PCR and western-blot in pancreatic cancer cell lines (MiaPaca-2 and Panc-1) after treatment with γ-tocotrienol. Mechanistic studies were conducted trough siRNA knockdown of EGR-1 and the rescue of Vitamin of γ-tocotrienol-induced apoptosis, anti-proliferative effects and signaling pathways. Results: We identified 8 genes that were induced and 8 genes that were suppressed early after treatment with γ-tocotrienol in MiaPaca-2 cells. Then we selected and focused on the EGR-1 for signaling pathway analysis. Induction of protein expression was noticed in both MiaPac-2 cells and Panc-1 (6 fold and 10 fold respectively;p&amp;lt;0.05) after 24 h γ-tocotrienol treatment. γ-tocotrienol-induced apoptosis in MiaPac-2 cells and Panc-1 cells (PARP1 cleavage and Annexin V) was associated with induction of p-JNK, p-C-JUN, and EGR-1. Knockdown of EGR-1 in this two cell lines partially rescued γ-tocotrienol-induced apoptosis. Conclusion: Our data identifies EGR-1 as an early gene which is induced by Vitamin E γ-tocotrienol in pancreatic cancer cells. Activation of the EGR-1 pathway, may constitute a novel potential strategy for inhibiting pancreatic tumor growth. 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 4738. doi:1538-7445.AM2012-4738
Do Targeted Bans of Insecticides to Prevent Deaths from Self-Poisoning Result in Reduced Agricultural Output?
Authors: Gamini Manuweera, Michael Eddleston, Samitha Egodage, Nick A. Buckley
Journal: Environmental Health Perspectives (2008)

The pesticides monocrotophos, methamidophos, and endosulfan were a very common cause of severe poisoning in Sri Lanka during the 1980s and early 1990s, before they were banned in 1995 and 1998. Now, the most commonly used insecticides are the less toxic World Health Organization Class II organophosphorus pesticides and carbamates. These bans were followed by a large reduction in both fatal poisonings and suicide in Sri Lanka.We aimed to see if these bans adversely affected agricultural production or costs.We used data from the World Resources Institute to compare the yields of the main crop groups in Sri Lanka with those from surrounding South Asian countries for 1980-2005. We also examined data from the Sri Lankan Department of Census and Statistics to examine the yields of 13 specific vegetable crops and rice for 1990-2003, along with the costs of rice production.We found no drop in productivity in the years after the main bans were instituted (1995, 1998). We observed substantial annual fluctuation in estimated yields in all data sources, but these did not coincide with the bans and were no larger than the fluctuations in other countries. Also, there was no sudden change in costs of rice production coinciding with bans.Countries aiming to apply restrictions to reduce deaths from pesticide poisoning should evaluate agricultural needs and develop a plan that encourages substitution of less toxic pesticides. If farmers have an affordable alternative for pest control for each crop, there is no obvious adverse effect on agricultural output.
STUDIES OF I131-ALBUMIN CATABOLISM AND DISTRIBUTION IN NORMAL YOUNG MALE ADULTS*
Authors: Warren L. Beeken, Wade Volwiler, Patrick D. Goldsworthy, Lars E. Garby, William E. Reynolds, Rose Stogsdill, Richard S. Stemler
Journal: Journal of Clinical Investigation (1962)

Studies of I13'-albumin catabolism and distribution are appearing in rapidly increasing numbers in current literature.The data for normal human subjects reported from various laboratories differ considerably in mode of analysis and in results ob- tained.In normal subjects the observed "half-life" of I'31-albumin has ranged from below 10 to above 20 days (1-15), and the ratio of the amount of albumin contained extravascularly to that present in the plasma has been calculated as ranging from 1 to 4.5 (6,7,(15)(16)(17).Although these wide vari- ations are due to many factors, the major causes appear to be these: 1) variable degrees of denaturation incurred during the preparation of the protein and its radioisotopic labeling, perhaps de- tectable only through biological testing; 2) vari- able lengths of study periods, many being too short to allow metabolic trends to be fully realized; and 3) differing mathematical approaches to the analysis of data, each requiring assumptions of variable validity.With the availability of im- proved I131-albumin preparations, it can be antici- pated that greater efforts will be directed toward the investigation of albumin catabolism and distri-