tbuckley/cabot-search huggingface dataset:
Targeting RAS: The Elusive Prize
Authors: Susan E. Bates
Journal: Clinical Cancer Research (2015)

This CCR Focus examines a prized target in oncology—inhibition of RAS, the GTPase signaling protein known as a molecular signaling switch and found to be mutated in many common cancers. These mutations, typically in one of three key hotspots, keep the protein always on, signaling proliferation and survival. This CCR Focus examines the intense quest under way to develop a molecule or therapeutic strategy that will inhibit RAS. The articles, guided by Guest Editor Frank McCormick, discuss various aspects of targeting RAS:Together, these articles demonstrate a multipronged effort to block RAS, known for over 30 years to be mutated in cancer, and express cautious optimism that it is just a matter of time before we can affect RAS activity in human cancer.After reading this CCR Focus, we no longer ask whether we “will ever have” an agent to inhibit aberrant RAS function in the clinic. Rather, we now may ask “how much benefit” we can expect to achieve. That is a complex question and, as discussed by McCormick, depends in large part on whether cancer cells remain dependent on RAS. The discovery of imatinib for chronic myelogenous leukemia (CML) created a paradigm shift in cancer research that sent the community on a search for solitary molecular targets that could fundamentally alter cancer biology. Over time, the uniqueness of the CML story has become apparent: For most other mutated oncogenic targets, long-term disease control has not been achievable, despite the availability of effective inhibitors. We expect that RAS inhibitors will shrink tumors in some cell types bearing RAS mutations, but not in all. But in 2015 we recognize that there will likely not be a “one-size-fits-all” anti-RAS drug for all RAS-driven cancers. Given all we have learned as a community, summarized in Text Box 1, this class of drugs should be one that we develop rationally with appropriate trial designs, patient selection, and confirmation of effective RAS inhibition, so that even if only a subset of patients is to derive meaningful benefit, we will be able to identify and treat that subset. And, in so doing, we will have a clear return on a 35-year investment in basic science.Susan E. BatesDeputy Editor, CCR FocusNational Cancer InstituteSee all articles in this CCR Focus section, “Targeting RAS-Driven Cancers.”
TCT-279 Comparison Of Two Paclitaxel-Coated Balloons In The Treatment Of Coronary In-Stent Restenosis: A Single Center Experience
Authors: Javier Benezet, Santiago Camacho-Freire, Antonio Agarrado, Alejandro Gutierrez-Barrios, Jesus Oneto
Journal: Journal of the American College of Cardiology (2014)
Experimental studies on arsenic absorption routes in rats
Authors: Tadeusz Dutkiewicz
Journal: Environmental Health Perspectives (1977)

Pentavalent inorganic arsenic was introduced by intravenous, intratracheal, gastrointestinal, and skin application in doses 0.1 to 4.0 mg/kg in rats. Isotopic technics were applied by use of As(74). It was found that the dynamics of arsenic distribution in the body as well as the kinetics of its elimination in urine and feces varies very substantially, depending on the mode of administration. Intravenous administration of As causes immediate appearance of arsenic in most tissues and a slow decrease of its concentrations in time. Similar situations could be observed with intratracheal dosing, because arsenic is very rapidly absorbed from the site of administration. Concentration in tissues increases more slowly after gastrointestinal resorption. Skin application causes first the accumulation of arsenic in the skin and next continuous, slow transport from the skin into the blood stream. The rate of skin resorption was 1.14-33.1 mug/cm(2)-hr for 0.01-0.2M concentrations. The red blood cell level of arsenic is very substantial and does not change with time, which indicates the accumulation of arsenic in this tissue. The elimination of arsenic occurred chiefly in urine and feces, but the urine/feces ratio changed very substantially, depending on the route of administration. The kinetics of arsenic elimination in urine was multiphasic, being three-phase in case of intravenous and intratracheal administration and two-phase after gavage and skin resorption. After intravenous administration of As, the half-times of elimination were 2.5, 10, and 690 hr, respectively. Administration of selenium salts during the slow phase increased the rate of arsenic elimination. The straight-line relations found between the absorbed dose of arsenic and its blood or urine concentrations could serve as baselines for exposure tests for humans.
Removal of the endothelium potentiates canine large coronary artery constrictor responses to 5-hydroxytryptamine in vivo.
Authors: K G Lamping, M L Marcus, W P Dole
Journal: Circulation Research (1985)

Recent studies in isolated epicardial coronary artery rings have shown that the endothelium modulates vasomotor responses to certain endogenous neurohumoral agents. It is not known whether the endothelium plays a role in large coronary vasoregulation in the intact coronary circulation. Accordingly, we examined effects of endothelial removal on vasoconstrictor responses of the proximal coronary artery in anesthetized adult mongrel dogs. The left anterior descending artery was perfused at 100 mm Hg with arterial blood from a pressurized reservoir. Coronary diameter was measured continuously with 7-MHz sonomicrometer crystals attached to the adventitia of the artery. Fifteen minutes after mechanical disruption of the endothelium with a balloon-tipped catheter, baseline diameter was unchanged from a control value of 2.60 +/- 0.13 mm (mean +/- SE, n = 17). Endothelial denudation resulted in a dose-dependent potentiation of the constrictor response to intracoronary 5-hydroxytryptamine (1-50 micrograms/min, n = 8). With the endothelium intact, a 5 micrograms/min infusion of 5-hydroxytryptamine reduced diameter by 24 +/- 14 micron, while a 50 micrograms/min dose reduced diameter by 54 +/- 25 micron. After endothelial removal, the decrease in diameter averaged 74 +/- 18 microns at 5 micrograms/min and 132 +/- 29 micron at 50 micrograms/min, indicating a 10-fold increase in the sensitivity to 5-hydroxytryptamine. The constrictor responses to angiotensin II (1 and 5 micrograms/min, n = 7) and phenylephrine (1-5 micrograms/min, n = 7) were not altered by endothelial removal. Thus, endothelial removal selectively potentiates the constrictor responses to 5-hydroxytryptamine in the intact coronary circulation of the dog.
Blood lead slope factor models for adults: comparisons of observations and predictions.
Authors: T S Bowers, J T Cohen
Journal: Environmental Health Perspectives (1998)

Here we explore the appropriateness of various parameter values for the Bowers et al. model [Risk Anal 14:183-189, 1994] in the context of predicting the influence of site-related exposure to lead in soil on the blood lead (PbB) levels of women of childbearing age. We outline the parameters prescribed by Bowers et al. as well as those prescribed by the U.S. Environmental Protection Agency (U.S. EPA). Comparison of the PbB levels predicted by the Bowers et al. model to those predicted by the validated O'Flaherty pharmacokinetic model indicates that the Bowers et al. model performs favorably when parameter values prescribed here are used. Use of the U.S. EPA-prescribed parameters yields predicted PbB levels that substantially exceed the validated O'Flaherty model predictions. Finally, both the U.S. EPA-prescribed parameter values and the parameter values recommended herein are used to predict PbB levels among adults living in four Superfund communities. Comparison of predicted PbB levels for these communities indicates that the U.S. EPA parameters overstate the incremental influence of lead in soil on PbB levels. Differences between the parameter values prescribed here and the U.S. EPA-prescribed parameters yield substantially different cleanup criteria for lead in soil, although conservative parameter values may still be appropriate for screening purposes.
P6 Work-related respiratory symptoms in the UK; Do primary care physicians miss diagnostic opportunities in occupational asthma?
Authors: J. Hoyle, L. Hussey, R. Barraclough, R. Agius
Journal: Thorax (2010)

<h3>Introduction and objectives</h3> Occupational lung disease is prevalent and costly. Population-based studies show that up to 20 cases of occupational lung disease per 100 000 workers per year should be identified.<sup>1</sup> The Health and Safety Executive estimates the cost of occupational asthma to our society to be over £1.1 billion for each 10 year period.<sup>2</sup> The prognosis of these individuals is better if they are removed from exposure quickly; however, this policy leads to unnecessary job loss in cases where the diagnosis is wrong.<sup>3</sup> Little is known about the number of workers who present to primary care with work-related symptoms, or what proportion of these are referred for hospital specialist advice once a work-related element has been identified. <h3>Methods</h3> The Health &amp; Occupation Reporting network in General Practice (THOR-GP) at the University of Manchester, collects work-related ill-health data from between 250 and 300 GPs trained to diploma level in occupational medicine. Cases of undiagnosed respiratory disease, reported as unspecified work-related respiratory symptoms between 2006 and 2009 were retrospectively identified. The cases were subdivided into exposure (if known) and categorised as referred if sent to a hospital specialist for further investigation. <h3>Results</h3> In 2006–2009 GPs reported 4902 cases of work-related ill-health, of which 115 (2%) were reports of respiratory disease. 27 cases of non-specified work-related respiratory illness were identified. Only 26% (7/27) were referred for a specialist opinion despite uncertainty of diagnosis. Of those not referred, the majority (17/20) were exposed to known asthmagens as illustrated in Abstract P6 Figure 1 (consensus view after exposure review from three occupational/respiratory physicians). <h3>Conclusions</h3> More than three quarters of the cases with undiagnosed work-related symptoms identified in primary care were not referred to secondary care for diagnostic clarification. 85% of these cases were exposed to known asthmagens. The lack of diagnosis and/or specialist assessment in these cases may have significant impact on disease prognosis, disability and socio-economic cost to society.
Differential regulation of right and left ventricular beta-adrenergic receptors in newborn lambs with experimental cyanotic heart disease.
Authors: D Bernstein, E Voss, S Huang, R Doshi, C Crane
Journal: Journal of Clinical Investigation (1990)

To determine whether chronic hypoxemia secondary to an intracardiac right-to-left shunt alters regulation of the myocardial beta-adrenergic receptor/adenylate cyclase system, we produced chronic hypoxemia in nine newborn lambs by creating right ventricular outflow obstruction and an atrial septal defect. Oxygen saturation was reduced to 65-74% for 2 wk. Eight lambs served as normoxemic controls. beta-receptor density (Bmax) and ligand affinity (KD) were determined with the radio-ligand [125I]iodocyanopindolol and adenylate cyclase activity determined during stimulation with isoproterenol, sodium fluoride (NaF), and forskolin. During chronic hypoxemia, Bmax decreased 45% (hypoxemic, 180.6 +/- 31.5 vs. control, 330.5 +/- 60.1 fmol/mg) in the left ventricle (exposed to hypoxemia alone) but was unchanged in the right ventricle (exposed to hypoxemia and pressure overload). KD was not different from control in either ventricle. Left ventricular isoproterenol-stimulated adenylate cyclase activity was decreased by 39% (30.0 +/- 4.3% increase vs. 44.1 +/- 9.5% increase) whereas right ventricular adenylate cyclase activity was unchanged. Stimulation of adenylate cyclase with NaF or forskolin was not different from control in either ventricle. Circulating epinephrine was increased fourfold whereas circulating and myocardial norepinephrine were unchanged. These data demonstrate a down-regulation of the left ventricular beta-adrenergic receptor/adenylate cyclase system during chronic hypoxemia secondary to an intracardiac right-to-left shunt.
Polycythemia (Erythrocytosis) Associated with Uterine Fibroids: A Case Report with Erythropoietic Activity Demonstrated in the Tumor.
Authors: Edward J. Hertko
Journal: Annals of Internal Medicine (1968)

s1 May 1968Polycythemia (Erythrocytosis) Associated with Uterine Fibroids: A Case Report with Erythropoietic Activity Demonstrated in the Tumor.Edward J. Hertko, M.D., F.A.C.P.Edward J. Hertko, M.D., F.A.C.P.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-68-5-1169_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptSince 1953 the association of polycythemia with uterine fibroids has been reported 13 times. Various theories have been advanced as to the possible cause of the polycythemia, but none have been proved. One of the theories advanced was that the tumor might produce erythropoietin (erythrocytosis stimulating factor—ESF). This factor has been shown to be the etiological agent in the development of polycythemia associated with other tumors, such as renal carcinoma, cerebellar hemangioblastoma, and renal cysts.I have had a recent patient with polycythemia associated with uterine fibroids. After surgical removal of the fibroids her blood count returned to normal levels... This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Des Moines, Iowa PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited ByMore Than a Myoma: A Review of Myomatous Erythrocytosis SyndromeMesenchymal Tumors of the UterusErythrocytosis Associated with a Dermoid Cyst of the Ovary and Erythropoietic Activity of the Tumour FluidParaneoplastische endokrine SyndromePolycythaemia and Erythropoietin Producing Uterine FibromyomaErythrocytosis Associated with Multiple Cutaneous Leiomyomata: Report of a Case with Demonstration of Erythropoietic Activity in the TumourErythrocytosis due to erythropoietin-producing uterine fibromyomaECTOPIC HORMONE PRODUCTION BY NON-ENDOCRINE TUMOURSStudies on the Mechanism of Erythrocytosis Associated with a Uterine FibromyomaSecondary Polycythaemia due to a Uterine Fibromyoma Producing ErythropoietinPRIMARY BENIGN ERYTHROCYTOSIS AND ABNORMAL RENAL PERFUSIONUTERINE FIBROMYOMATA AND SECONDARY POLYCYTHAEMIA 1 May 1968Volume 68, Issue 5Page: 1169-1169KeywordsBlood countsErythropoietinPolycythemia Issue Published: 1 May 1968 PDF DownloadLoading ...
Vincristine-loaded platelet infusion for treatment of refractory autoimmune hemolytic anemia and chronic immune thrombocytopenia: Rethinking old cures
Authors: Lev Shvidel, Erica Sigler, Mordechai Shtalrid, Alain Berrebi
Journal: American Journal of Hematology (2006)

We report our experience with vincristine-loaded platelet infusion in patients with refractory immune thrombocytopenia (ITP), autoimmune hemolytic anemia (AIHA), and Evans syndrome. Ten patients with symptomatic thrombocytopenia and/ or hemolytic anemia who failed to respond to two to six different treatment modalities, including corticosteroids and splenectomy, were treated with infusion of vincristine-loaded platelets. Platelets were harvested by plateletpheresis from a healthy ABO compatible blood donor and incubated with 5 mg vincristine. Excess of vincristine was removed, and platelets were resuspended in 50 ml plasma and infused over 30 min. All 10 patients responded, and 6 of them achieved complete remission. The response was prompt, occurring 3–8 days after vincristine-loaded platelet infusion. Two patients with AIHA are still in remission 9 and 8 years posttreatment with no maintenance treatment. Three ITP patients achieved persisted partial response for 6 years, 5 years, and 11 months; in the remaining 5 patients the response lasted for 2–5 months. No side effects were seen. Our results suggest that this inexpensive and well-tolerated treatment modality may be a useful approach in patients with ITP and AIHA refractory to primary therapy. Am. J. Hematol. 81:423–425, 2006. © 2006 Wiley-Liss, Inc.
Roche employee wins partial victory
Authors: Madeline Brettingham
Journal: BMJ (2006)

A former senior manager at the pharmaceutical giant Roche has won her claim for unfair dismissal. But it is only a partial victory because a secondary claim of whistle blowing was not upheld.

Dr Ryta Kuzel, a former head of UK regulatory affairs at the company, which manufactures Herceptin (trastuzumab), Tamiflu (oseltamivir), and Lariam (mefloquine), launched legal proceedings against the firm after they escorted her from the company's premises in March 2005.

The tribunal's written judgment described Mike Doherty, Roche's head of regulatory affairs, as acting in an “autocratic and irrational manner” and said they were confused as to why Dr Kuzel's actions had justified her …
Anti-IL-5 treatment (mepolizumab) reduces eosinophil-associated TGF-$beta;*1Relationship to deposition of extracellular matrix proteins in the bronchial subepithelial basement membrane of mild atopic asthmatics
Authors: P. Flood-Page, A.N. Menzies-Gow, S. Phipps, S. Ying, A. Wangoo, M.S. Ludwig, N.C. Barnes, D.S. Robinson, A.B. Kay
Journal: Journal of Allergy and Clinical Immunology (2004)
The Colorado Ice Decision Not Final.
Authors: William P. Munn
Journal: JAMA (1896)

Bureau of Health, Denver, Colo., June 10, 1896. <h3>To the Editor:</h3> —I have noted with some interest the editorial excerpt published in last week's issue of a recent decision of the Colorado Court of Appeals in regard to the limitations of the power of a health commissioner to condemn ice. Inasmuch as the opinion as rendered is quite misleading and has deliberately ignored, or in some instances contradicts the record as certified in the lower court, and also because the decision as rendered by the court of appeals is not final, the case being now pending in the supreme court of the State of Colorado, I deem it entirely proper to state certain facts in connection with the case which will at least militate against the acceptance of the decision as rendered as either good law or as justice. The record as certified showed that the order prohibiting the sale
Prevalence of Advanced Colorectal Neoplasia in White and Black Patients Undergoing Screening Colonoscopy in a Safety-Net Hospital
Authors: Paul C. Schroy, Alison Coe, Clara A. Chen, Michael J. O’Brien, Timothy C. Heeren
Journal: Annals of Internal Medicine (2013)

Chinese translationBlack persons are more likely than white persons to be diagnosed with colorectal cancer and to die from it. The extent to which genetic or biological factors versus disparities in screening rates explain this variance remains controversial.To define the prevalence and location of presymptomatic advanced colorectal neoplasia (ACN) among white and black persons undergoing screening colonoscopy, controlling for other epidemiologic risk factors.Cross-sectional survey between 22 March 2005 and 31 January 2012.Urban, open-access, academic, safety-net hospital in Massachusetts.Asymptomatic, average-risk white (n = 1172) and black (n = 1681) persons aged 50 to 79 years undergoing screening colonoscopy.Adjusted prevalence and location of ACN, defined as a tubular adenoma 10 mm or more in size, any adenoma with villous features or high-grade dysplasia, any dysplastic serrated lesion, or invasive cancer.The prevalence of ACN was higher among white patients than black patients (6.8% vs. 5.0%; P = 0.039) but varied by sex (white vs. black men, 9.3% vs. 5.7%; white vs. black women, 3.5% vs. 4.3%; interaction P = 0.034). After controlling for many risk factors, black men were 41% less likely than white men (adjusted odds ratio [AOR], 0.59 [95% CI, 0.39 to 0.89]) to have ACN. No statistically significant difference was seen for women (AOR, 1.32 [CI, 0.73 to 2.40]). Black patients with ACN had a higher percentage of proximal disease (52% vs. 39%) after adjustment for age and sex (P = 0.055).Single-institution study with inadequate statistical power for subgroup analyses and recall bias.Black men are less likely than white men to have ACN at screening colonoscopy in a safety-net health care setting. Disparities in access to screening and differential exposure to modifiable risk factors rather than genetic or biological factors may be largely responsible for the higher incidence of CRC among black men. Genetic or biological factors may explain the predilection for proximal disease.
Seasickness: the bane of cruises
Authors: C. Bulstrode
Journal: BMJ (2013)

“I should never have come on this cruise,” she groaned. “It was my husband who wanted us to go. I hate ships and loathe the sea, and now I feel sooo … ill.” This is Stage 1, or mild seasickness—nausea accompanied by self pity and, most importantly, the conviction that it is all someone else’s fault.

In Stage 2, moderate seasickness, I am called out in the night to a darkened cabin where, as the ship gently rolls along, …
Interdepartmental Teaching — Vapor or Virus? — Help for the Doctor
Authors: John Lister
Journal: New England Journal of Medicine (1965)

IT has often been said that medicine is a lifelong study, and following upon the upgrading of the peripheral hospitals in Great Britain has come the development of regional postgraduate centers where improved facilities are being provided for the continuing education of practicing physicians and surgeons.At a recent conference on the function of these centers, organized by the Association for the Study of Medical Education, Dr. B. Lennox, of the Department of Pathology in Glasgow, read a stimulating paper on interdepartmental teaching.He said that departmental teaching may be simple, undistracting and relatively cheap, but it may offer no . . .
Are taxes on fatty foods having their desired effects on health?
Authors: S. Smed, A. Robertson
Journal: BMJ (2012)

We don’t know because governments are not instigating the most appropriate evaluations 

In October 2011 Denmark introduced a tax on saturated fat, which was part of wider tax reforms adopted one year earlier. These reforms were intended to cut the highest rates of income tax from 62.8% to 56.1%.1 

All food sold in Denmark is uniformly VAT rated at 25%—probably the highest food tax in Europe. Some confectionery products and sugary drinks are also subjected to additional taxes mainly to generate revenue. In 2007 a disease prevention commission recommended the introduction of even higher taxes on alcohol, tobacco, and confectionery as well as a new tax on saturated fat. The aim was to improve public health and increase life expectancy in Denmark.

Other governments have implemented similar “health” taxes,2 and others continue to debate whether to do so. But can health outcomes be improved through taxing food, and how should the impact of such taxes be evaluated?

Taxing saturated fats is controversial partly because saturated fats are naturally present in many foods, and only consumption greater than 10% of total energy intake is considered unhealthy.3 The fat tax in Denmark amounts to an additional 3%, for example, on the price of minced beef, 14.6% on whipped cream, 13-16% on rapeseed and sunflower oils, and 30% …