tbuckley/cabot-search huggingface dataset:
Abstract 2548: Chemosensitization of cancer cells by KU-0060648: A dual inhibitor of DNA-PK and PI-3K
Authors: Michael A. Batey, Joanne M. Munck, Yan Zhao, Celine Cano, Michele Tavecchio, Julia Bardos, Roger J. Griffin, Helen Jenkins, Keith Menear, Graeme Smith, Pia Thommes, David R. Newell, Niall Martin, Nicola J. Curtin
Journal: Cancer Research (2011)

Abstract DNA double strand breaks (DSBs) are the most cytotoxic lesions induced by topoisomerase II poisons. Enzyme-mediated repair of DNA DSBs is a major mechanism of resistance to DNA DSB-inducing agents. Non-homologous end joining (NHEJ) is the major pathway for the repair of DSBs and requires DNA-PK activity. DNA-PK has close structural similarities to PI-3K, which promotes cell survival and proliferation and is up-regulated in many cancers. KU-0060648 is a dual inhibitor of DNA-PK and PI-3K in vitro. We investigated the therapeutic utility of KU-0060648, in models of human cancer. KU-0060648 was investigated in a panel of human breast and colon cancer cells, it inhibited cellular DNA-PK auto-phosphorylation with IC50 values of 0.019 µM (MCF7 cells) and 0.17 µM (SW620 cells), and PI-3K-mediated AKT phosphorylation with IC50 values of 0.039 µM (MCF7 cells) and &amp;gt;10 µM (SW620 cells). 5-day exposure to 1 µM KU-0060648 inhibited cell proliferation by &amp;gt; 95% in MCF7 cells, but only by 55% in SW620 cells. In clonogenic survival assays, KU-0060648 increased the cytotoxicity of etoposide and doxorubicin across the panel of DNA-PKcs-proficient cells, but not in DNA-PKcs-deficient cells, thus confirming that enhanced cytotoxicity was due to DNA-PK inhibition. In mice bearing SW620 and MCF7 xenografts, concentrations of KU-0060648 that were sufficient for in vitro growth inhibition and chemosensitisation were maintained within the tumour for at least 4 hours at non-toxic doses. KU-0060648 alone delayed the growth of MCF7 xenografts and increased etoposide-induced tumour growth delay in both SW620 and MCF7 xenografts by up to 4.5-fold, without exacerbating etoposide toxicity to unacceptable levels. The proof of principle in vitro and in vivo chemosensitisation with KU-0060648 justifies further evaluation and characterisation of dual DNA-PK and PI-3K inhibitors. 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 2548. doi:10.1158/1538-7445.AM2011-2548
Prior Alcohol Consumption and Mortality Following Acute Myocardial Infarction
Authors: Kenneth J. Mukamal
Journal: JAMA (2001)

ContextStudies have found that individuals who consume 1 alcoholic drink every 1 to 2 days have a lower risk of a first acute myocardial infarction (AMI) than abstainers or heavy drinkers, but the effect of prior drinking on mortality after AMI is uncertain.ObjectiveTo determine the effect of prior alcohol consumption on long-term mortality among early survivors of AMI.Design and SettingProspective inception cohort study conducted at 45 US community and tertiary care hospitals between August 1989 and September 1994, with a median follow-up of 3.8 years.PatientsA total of 1913 adults hospitalized with AMI between 1989 and 1994.Main Outcome MeasureAll-cause mortality, compared by self-reported average weekly consumption of beer, wine, and liquor during the year prior to AMI.ResultsOf the 1913 patients, 896 (47%) abstained from alcohol, 696 (36%) consumed less than 7 alcoholic drinks/wk, and 321 (17%) consumed 7 or more alcoholic drinks/wk. Compared with abstainers, patients who consumed less than 7 drinks/wk had a lower all-cause mortality rate (3.4 vs 6.3 deaths per 100 person-years; hazard ratio [HR], 0.55; 95% confidence interval [CI], 0.43-0.71) as did those who consumed 7 or more drinks/wk (2.4 vs 6.3 deaths per 100 person-years; HR, 0.38; 95% CI, 0.25-0.55; P<.001 for trend). After adjusting for propensity to drink and other potential confounders, increasing alcohol consumption remained predictive of lower mortality for less than 7 drinks/wk, with an adjusted HR of 0.79 (95% CI, 0.60-1.03), and for 7 or more drinks/wk, with an adjusted HR of 0.68 (95% CI, 0.45-1.05; P = .01 for trend). The association was similar for total and cardiovascular mortality, among both men and women, and among different types of alcoholic beverages.ConclusionSelf-reported moderate alcohol consumption in the year prior to AMI is associated with reduced mortality following infarction.
A non-linear elastic model of contraction of ischaemic segments
Authors: M. AKAISHI, R. M SCHNEIDER, P. A SEELAUS, L. W KLEIN, J. B AGARWAL, R. H HELFANT, W. S WEINTRAUB
Journal: Cardiovascular Research (1988)

Previous studies have characterised the motion of the myocardium using a linear time varying elastance model, ie, they have sought to characterise the relationship between left ventricular volume and internal pressure as linear, but with time varying slopes over the cardiac cycle. However, the motion of myocardium during regional ischaemia has not been characterised by such models. Studies of totally ischaemic tissue and of myocardium in diastole have characterised the relationship between tension or stress and segment length as exponential. It is the purpose of this study to present a new model in which myocardial contraction is expressed as an exponential, but time varying elastic relationship. In this model tension, T, is related to segment length according to the formula T=eα(t)L+β, where α(t) rises with systole and falls in diastole. This model was applied to the motion of hypokinetic segments noted in a series of conscious dogs studied for other purposes. Hypokinetic segments display early systolic bulging, decreased systolic shortening, and early diastolic recoil. These particular types of segment motion are naturally predicted by this model. Furthermore, the motion of myocardial segments as they become increasingly ischaemic may be predicted, including a gradual shift to the right and narrowing of the tension-length loop. α was noted to be independent of loading change, and thus may be viewed as an index of contractility. This model thus predicts the pattern of motion of hypokinetic segments and provides new insight into myocardial contractility.
Scientific Misconduct
Authors: Drummond Rennie
Journal: JAMA (1993)

The good behavior of scientists might seem remote from the concerns of the physician. But the practice of medicine is based on science, which means that it is grounded on the integrity of the biomedical research community. For that reason alone, the matter would deserve our attention, but in addition, many scientists have medical degrees. We expect those scientist-physicians to share the high standards of the medical profession, and when they do not, the profession is damaged in the eyes of the public. Finally, if medical editors unwittingly publish fraudulent work in journals, as happens from time to time, reputations are tarnished. It is for these reasons that we are all involved in the debate over what has come to be called "scientific misconduct," and why<i>JAMA</i>is publishing the article by Dresser in this issue.<sup>1</sup> Few medical articles are so uniquely important that patients would suffer were the
CRITERIA FOR COMPETENCY TO STAND TRIAL: A CHECKLIST FOR PSYCHIATRISTS
Authors: AMES ROBEY
Journal: American Journal of Psychiatry (1965)

Competency to stand trial is an extremely complex issue, and practice has required that the psychiatrist play a major role in its determination. Several points should be emphasized: 1. Because the law has provided only vague criteria, incompetency to stand trial has tended to be equated with mental illness by both psychiatrists and members of the legal profession. 2. Many patients are presently hospitalized prior to trial although examination using the above criteria as guidelines would reveal them able to face their charges. 3. The presence of mental illness does not preclude competency to stand trial. The defendant may show signs of mental illness and, indeed, even show delusional ideation, as long as it does not interfere with his comprehension of the courtroom proceedings and his ability to advise counsel. 4. The issue of competency to stand trial is entirely separate from the problem of criminal responsibility and involves different legal tests. 5. The psychiatrist does not make the decision as to the competency of an individual. His role is solely that of an advisor to the court. The criteria listed in this paper are offered as a guide for the examining psychiatrist. As with criminal responsibility, competency to stand trial is a subject for decision by the court on the basis of testimony it receives.
Adrenergic Control of the Force-Frequency Relation
Authors: John Ross, Toshiro Miura, Masashi Kambayashi, Gregory P. Eising, Kyu-Hyung Ryu
Journal: Circulation (1995)

Abstract This article briefly reviews recent experimental studies which show that β-adrenergic receptor stimulation produces an important enhancement of the force-frequency relation on myocardial contractility. The basic property of the force-frequency effect to progressively enhance myocardial contractility as heart rate increases is augmented at each level of increasing adrenergic stimulation. This newly described intrinsic mechanism for the control of cardiac inotropic state, graded β-adrenergic amplification of the force-frequency relation, is strongly manifested during normal exercise and infusion of a β-adrenergic agonist at rest, and it influences both systolic and diastolic ventricular function. Significant impairment of adrenergic amplification of the force-frequency relation is observed in experimental heart failure and could contribute to impaired cardiac function during stress or exercise in this setting.
Monocyte function in the acquired immune deficiency syndrome. Defective chemotaxis.
Authors: P D Smith, K Ohura, H Masur, H C Lane, A S Fauci, S M Wahl
Journal: Journal of Clinical Investigation (1984)

The ineffective immune response in patients with the acquired immune deficiency syndrome (AIDS) contributes to severe and widespread infections and unrestricted growth by certain tumors. To determine whether monocyte dysfunction contributes to this immunosuppressed condition, we investigated monocyte chemotaxis in patients with AIDS. Using three different chemotactic stimuli, N-formylmethionylleucylphenylalanine, lymphocyte-derived chemotactic factor, and C5a des Arg, we studied the chemotactic responses of monocytes from seven homosexual men with AIDS, three homosexuals with lymphadenopathy and an abnormal immunological profile, seven healthy homosexual men, and 23 heterosexual control individuals. Monocytes from each of the AIDS patients with Kaposi's sarcoma and/or opportunistic infection exhibited a marked reduction in chemotaxis to all stimuli compared with the healthy control subjects. The reduced chemotactic responses were observed over a wide range of concentrations for each stimulus. Monocytes from AIDS patients who had clinically apparent opportunistic infection(s) exhibited a greater reduction in monocyte migration to all three stimuli than monocytes from the AIDS patient with only Kaposi's sarcoma. Monocytes from each of three homosexuals with lymphadenopathy and an abnormal immunological profile exhibited decreased chemotactic responses that were intermediate between those of the AIDS patients and the healthy heterosexual control subjects. In contrast to these findings, monocytes from each of seven healthy homosexuals exhibited normal chemotactic responses to the same stimuli. In addition, monocytes from AIDS patients exhibited reduced chemotaxis to soluble products of Giardia lamblia, one of several protozoan parasites prevalent in AIDS patients. Thus the immune abnormality in AIDS, previously thought to involve only the T-, B-, and natural killer lymphocytes, extends to the monocyte-macrophage. Defective monocyte migratory function may contribute to the depressed inflammatory response to certain organisms and to the apparent unrestricted growth of certain neoplasms in patients with AIDS.
EXTREME HYPERGLYCEMIA IN DIABETIC COMA WITH RECOVERY
Authors: Ira M. Dixson
Journal: JAMA (1928)

Recovery from diabetic coma with hyperglycemia as high as 1.62 per cent has not yet been reported in the literature, and our case therefore seems sufficiently important to justify the following note: A girl, aged 18, entered the New England Deaconess Hospital under the care of Dr. E. P. Joslin, Aug. 28, 1924, for treatment of diabetes complicated by an abscess on the outer aspect of the left thigh. She had always enjoyed excellent health until September, 1923, when she developed diabetes and began the use of insulin in October of the same year. The fasting blood sugar during her stay varied from 0.34 to 0.20 per cent. She was discharged to the care of her local physician, Sept. 16, 1924, taking 10 units of insulin three times a day. Her next admission to the Deaconess Hospital was at 5:30 a. m., Sept. 18, 1927, in profound coma, and her
Pulmonary Blood Flow in Antitrypsin Deficiency
Authors: THOMAS J. SULLIVAN
Journal: Annals of Internal Medicine (1971)

Letters and Comments1 January 1971Pulmonary Blood Flow in Antitrypsin DeficiencyTHOMAS J. SULLIVAN, M.D.THOMAS J. SULLIVAN, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-74-1-145 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: I especially enjoyed the article on redistribution of pulmonary blood flow early in the course of alpha1-antitrypsin deficiency (Ann Intern Med 73: 397-401, 1970) by Levine and colleagues. It emphasizes the fact that redistribution of pulmonary blood flow is an important early radiographic sign, not only in congestive heart failure, but also in many forms of chronic bronchopulmonary disease, a fact, I think, not appreciated by many clinicians.I would like to offer another possible expanation for the cause of the early redistribution of flow seen in alpha1-antitrypsin deficiency. The authors state that possibly pulmonary parenchymal elastic...References1. ROBINALTMAN EM: By a waterfall: "zone I and zone II phenomena" in obstructive lung disease. Amer J Med Sci 258:219, 1969 CrossrefMedlineGoogle Scholar2. ALTMANROBIN KE: Platypnea (diffuse zone I phenomenon). New Eng J Med 281:1347, 1969 CrossrefMedlineGoogle Scholar1. SUTHERLANDKATSURAMILIC-EMILI PTJ: Previous volume history of the lung and regional distribution of gas. J Appl Physiol 25:566-574, 1968 CrossrefMedlineGoogle Scholar2. MILIC-EMILIHENDERSONDOLOVICH JJM: Regional distribution of inspired gas in the lung. J Appl Physiol 21:749-759, 1966 CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAuthors: THOMAS J. SULLIVAN, M.D.Affiliations: Department of Radiology Parkland Memorial Hospital Dallas, Tex. 75235 PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byAlpha-1-Antitrypsin 1 January 1971Volume 74, Issue 1Page: 145-146KeywordsBlood flowHeart diseasesHeart failurePulmonary diseases ePublished: 1 December 2008 Issue Published: 1 January 1971 PDF downloadLoading ...
Outbreaks of Short-Incubation Ocular and Respiratory Illness Following Exposure to Indoor Swimming Pools
Authors: Anna B. Bowen, James C. Kile, Charles Otto, Neely Kazerouni, Connie Austin, Benjamin C. Blount, Hong-Nei Wong, Michael J. Beach, Alicia M. Fry
Journal: Environmental Health Perspectives (2006)

Chlorination destroys pathogens in swimming pool water, but by-products of chlorination can cause human illness. We investigated outbreaks of ocular and respiratory symptoms associated with chlorinated indoor swimming pools at two hotels.We interviewed registered guests and companions who stayed at hotels X and Y within 2 days of outbreak onset. We performed bivariate and stratified analyses, calculated relative risks (RR), and conducted environmental investigations of indoor pool areas.Of 77 guests at hotel X, 47 (61%) completed questionnaires. Among persons exposed to the indoor pool area, 22 (71%) of 31 developed ocular symptoms [RR = 24; 95% confidence interval (CI), 1.5-370], and 14 (45%) developed respiratory symptoms (RR = 6.8; 95% CI, 1.0-47) with a median duration of 10 hr (0.25-24 hr). We interviewed 30 (39%) of 77 registered persons and 59 unregistered companions at hotel Y. Among persons exposed to the indoor pool area, 41 (59%) of 69 developed ocular symptoms (RR = 24; 95% CI, 1.5-370), and 28 (41%) developed respiratory symptoms (RR = 17; 95% CI, 1.1-260) with a median duration of 2.5 hr (2 min-14 days). Four persons sought medical care. During the outbreak, the hotel X's ventilation system malfunctioned. Appropriate water and air samples were not available for laboratory analysis. CONCLUSIONS AND RELEVANCE TO PROFESSIONAL PRACTICE: Indoor pool areas were associated with illness in these outbreaks. A large proportion of bathers were affected; symptoms were consistent with chloramine exposure and were sometimes severe. Improved staff training, pool maintenance, and pool area ventilation could prevent future outbreaks.
Cholesterol Intake and Serum Cholesterol Level
Authors: Antonio M. Gotto
Journal: New England Journal of Medicine (1991)

IN the 1967 film Cool Hand Luke, the character played by Paul Newman jumps to the top of the prison-camp pecking order by winning a bet to eat 50 eggs in an hour. But in the annals of cholesterol consumption, perhaps he is not as remarkable as the 88-year-old man described in this issue of the Journal, who has eaten 25 eggs a day for at least 15 years.1 This man's serum cholesterol level was normal despite his dietary habit. In every family there seems to be a story of a relative who lived to a ripe old . . .
The Occurrence of Extensor Spasm in Patients with Complete Transection of the Spinal Cord
Authors: Martin B. Macht, Robert A. Kuhn
Journal: New England Journal of Medicine (1948)

LONG survival of patients with complete severance of the spinal cord is rarely encountered in civilian life. During the recent world conflict, however, the high incidence of casualties from high-explosive missiles resulted in a moderate number of such injuries. The medical and surgical advances of recent years, together with rapid and efficient evacuation from the field of battle, have greatly increased the initial survival rates of these men. Paraplegia centers established during the war employed new technics of bladder management, assiduous hospital care and careful medical and physical rehabilitation. These and other factors combined to increase markedly individual and group . . .
Treatment of angina pectoris with nifedipine: importance of dose titration.
Authors: J Deanfield, C Wright, K Fox
Journal: BMJ (1983)

The effects of different doses of nifedipine on frequency of angina and objective measurements of myocardial ischaemia during exercise were studied in 10 patients with stable angina pectoris. In a single blind trial over nine weeks patients received one week's treatment each with placebo, nifedipine 10 mg, 20 mg, 30 mg, 40 mg, 30 mg, 20 mg, 10 mg, then placebo three times a day. The response to the different doses of nifedipine was highly variable. On exercising, three patients achieved a consistent improvement in workload attained before onset of ST segment depression and maximum ST depression during exercise testing during all active phases. Four patients improved with 10 mg three times a day but deteriorated at higher doses. In two patients there was no objective or subjective improvement with any dose of the drug, while in one patient anginal frequency increased and there was objective deterioration during exercise testing at doses above 10 mg three times a day. Thus a dose of nifedipine that is beneficial in one patient may have minimal or opposite effects in another. These results indicate the importance of careful titration of doses for individual patients if the maximum benefit from nifedipine is to be obtained in patients with exertional angina.
Phytosterols and phytostanols: is it time to rethink that supplemented margarine?
Authors: J. Kreuzer
Journal: Cardiovascular Research (2011)

The editorial refers to ‘Differential effects on inhibition of cholesterol absorption by plant stanol and plant sterol esters in apoE−/− mice’ by O. Weingartner et al., pp. 484–492, this issue. 

What are the pertinent questions with regard to dietary supplementation of phytosterols and -stanols? 

1.  Do they have beneficial effects?

2.  Do they have adverse effects in the vessel wall or other organs?

3.  Are there any differences between plant sterols and stanols?

4.  Should we continue to buy phytosterol/stanol-supplemented food or should it be dropped from the market?

For many years now it has generally been accepted that mechanisms leading to a decrease in serum cholesterol lead to a decrease in atherogenesis. Hence, for many years, the use of phytosterols and -stanols, molecules from plant cell membranes resembling cholesterol, has been advocated as a safe and efficient dietary adduct lowering serum LDL cholesterol.1 Just like zoosterols, phytosterols are taken up via the Niemann Pick C1-like 1 protein, thus competing for intestinal uptake. The standard western-type diet contains around 200–400 mg plant sterols, around 50 mg plant stanols, and about 300 mg cholesterol. Dietary addition of either phytosterols or phytostanols, the saturated form of plant sterols, leads to a comparable serum cholesterol …
Role of Glycogen Synthase Kinase 3β in Rapamycin-Mediated Cell Cycle Regulation and Chemosensitivity
Authors: JinJiang Dong, Junying Peng, Haixia Zhang, Wallace H. Mondesire, Weiguo Jian, Gordon B. Mills, Mien-Chie Hung, Funda Meric-Bernstam
Journal: Cancer Research (2005)

Abstract The mammalian target of rapamycin is a serine-threonine kinase that regulates cell cycle progression. Rapamycin and its analogues inhibit the mammalian target of rapamycin and are being actively investigated in clinical trials as novel targeted anticancer agents. Although cyclin D1 is down-regulated by rapamycin, the role of this down-regulation in rapamycin-mediated growth inhibition and the mechanism of cyclin D1 down-regulation are not well understood. Here, we show that overexpression of cyclin D1 partially overcomes rapamycin-induced cell cycle arrest and inhibition of anchorage-dependent growth in breast cancer cells. Rapamycin not only decreases endogenous cyclin D1 levels but also decreases the expression of transfected cyclin D1, suggesting that this is at least in part caused by accelerated proteolysis. Indeed, rapamycin decreases the half-life of cyclin D1 protein, and the rapamycin-induced decrease in cyclin D1 levels is partially abrogated by proteasome inhibitor N-acetyl-leucyl-leucyl-norleucinal. Rapamycin treatment leads to an increase in the kinase activity of glycogen synthase kinase 3β (GSK3β), a known regulator of cyclin D1 proteolysis. Rapamycin-induced down-regulation of cyclin D1 is inhibited by the GSK3β inhibitors lithium chloride, SB216763, and SB415286. Rapamycin-induced G1 arrest is abrogated by nonspecific GSK3β inhibitor lithium chloride but not by selective inhibitor SB216763, suggesting that GSK3β is not essential for rapamycin-mediated G1 arrest. However, rapamycin inhibits cell growth significantly more in GSK3β wild-type cells than in GSK3β-null cells, suggesting that GSK3β enhances rapamycin-mediated growth inhibition. In addition, rapamycin enhances paclitaxel-induced apoptosis through the mitochondrial death pathway; this is inhibited by selective GSK3β inhibitors SB216763 and SB415286. Furthermore, rapamycin significantly enhances paclitaxel-induced cytotoxicity in GSK3β wild-type but not in GSK3β-null cells, suggesting a critical role for GSK3β in rapamycin-mediated paclitaxel-sensitization. Taken together, these results show that GSK3β plays an important role in rapamycin-mediated cell cycle regulation and chemosensitivity and thus significantly potentiates the antitumor effects of rapamycin.