tbuckley/cabot-search huggingface dataset:
Abstract 4166: Tumor suppressor activity of the ERK/MAPK pathway by promoting selective protein degradation
Authors: Xavier Deschênes-Simard, Marie-France Gaumont-Leclerc, Véronique Bourdeau, Olga Moiseeva, Valérie Forest, Frédérick A. Mallette, Frédéric Lessard, Fred Saad, Anne-Marie Mes-Masson, Gerardo Ferbeyre
Journal: Cancer Research (2012)

Abstract We report that ERK/MAPK signaling mediates tumor suppression. Oncogenic forms of ras are found in approximately 25% of all human cancers and are generally associated with uncontrolled proliferation of cancer cells. However, expression of oncogenic ras in normal cells is associated with cellular senescence. In primary cells expressing oncogenic ras, ERK knockdown by shRNA prevented the activation of the DNA damage response, p53, p16INK4a/Rb and senescence and cooperated with hTERT in transformation. In human prostate neoplasms, high levels of phosphorylated-ERK were found in benign lesions while in malignant lesions lower levels correlated with a higher Gleason score and earlier disease relapse after treatment. Mechanistically, the antitumor effects of ERK/MAPK signaling included the selective proteasome-dependent degradation of proteins required for cell cycle progression, mitochondrial functions and cell signaling and the inhibition of the phosphoinositide-3-kinase/AKT (PI3K/AKT) signaling pathway. We thus show for the first time that the outcome of ERK/MAPK signaling can be controlled at the level of ERK1/2, the final members of the pathway. A quantitative control at the end of the pathway provides a mechanism for specific modulation of ERK/MAPK signaling since controlling the input may also affect the numerous signaling pathways activated by membrane receptors. The data also indicate that the levels of the ERK kinases control a binary switch between cell proliferation and senescence and explain the maintenance of the senescence phenotype despite the presence of constitutively activated growth factor signaling pathways. Since inhibitors of the ERK pathway are under consideration for clinical use, we caution that they may trigger the escape of dormant senescent cells leading to malignant tumors. 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 4166. doi:1538-7445.AM2012-4166
Arrhythmia and prognosis in infants, children and adolescents with hypertrophic cardiomyopathy
Authors: William J McKenna, Rodney C.G Franklin, Petros Nihoyannopoulos, Killian C Robinson, John E Deanfield, Shaughan Dickie, Shirley J Krikler
Journal: Journal of the American College of Cardiology (1988)
Outpatient chemotherapy for breast cancer.
Authors: G W Hill, M Roach
Journal: BMJ (1978)

had a stillbirth rate of 10 1 per 1000.A decline in the hospital stillbirth rate for this minimalrisk group from 117 to 101 per 1000 is rela- tively less than that achieved outside, from 4 2 to 34-hardly an impressive vindication of the current policy of moving towards hospitalisation for all.Thus the more recent evidence on stillbirths fails to support the conclusion drawn by Mrs Fedrick and Professor Butler from 1958 data.The need for further research is as great as ever.
Immunosuppressive Effects of Cytosine Arabinoside and Methotrexate in Man
Authors: MALCOLM S. MITCHELL
Journal: Annals of Internal Medicine (1969)

Thirty-six patients with nonlymphoid solid tumors who were undergoing therapy with cytosine arabinoside (ara-C) or methotrexate (MTX) were immunized with Escherichia coli Vi antigen and tetanus toxoid to test the primary and secondary immune responses. Ara-C was given as 2 mg/kg body weight intravenous injections for 5 days, or as 10 mg/kg body weight infusions every 4 days for three doses. MTX was administered as infusions of 240 mg/m2 body surface area, every 4 days, followed each time by citrovorum factor (Leucovorin®) for as many as 11 consecutive infusions. These relatively nontoxic schedules of ara-C injections and MTX infusions suppressed primary and anamnestic antibody synthesis during therapy. An antibody response occurred in 40% of the patients without further injection of antigen approximately 2 weeks after cessation of therapy. In a delayed primary response only IgM antibody was produced. Ara-C infusions completely inhibited the primary and secondary response during the 4-week period studied but were accompanied by leukopenia. It is postulated that these antimetabolites did not interfere with the recognition of antigen but rather killed a proportion of proliferating lymphocytes. After cessation of therapy, remaining lymphocytes may have multiplied, producing normal titers of serum antibody, although the normal sequence of globulin formation was prevented.
Controlled trial of physical training in chronic heart failure. Exercise performance, hemodynamics, ventilation, and autonomic function.
Authors: A J Coats, S Adamopoulos, A Radaelli, A McCance, T E Meyer, L Bernardi, P L Solda, P Davey, O Ormerod, C Forfar
Journal: Circulation (1992)

Many secondary abnormalities in chronic heart failure (CHF) may reflect physical deconditioning. There has been no prospective, controlled study of the effects of physical training on hemodynamics and autonomic function in CHF.In a controlled crossover trial of 8 weeks of exercise training, 17 men with stable moderate to severe CHF (age, 61.8 +/- 1.5 years; left ventricular ejection fraction, 19.6 +/- 2.3%), increased exercise tolerance (13.9 +/- 1.0 to 16.5 +/- 1.0 minutes, p less than 0.001), and peak oxygen uptake (13.2 +/- 0.9 to 15.6 +/- 1.0 ml/kg/min, p less than 0.01) significantly compared with controls. Training increased cardiac output at submaximal (5.9-6.7 l/min, p less than 0.05) and peak exercise (6.3-7.1 l/min, p less than 0.05), with a significant reduction in systemic vascular resistance. Training reduced minute ventilation and the slope relating minute ventilation to carbon dioxide production (-10.5%, p less than 0.05). Sympathovagal balance was altered by physical training when assessed by three methods: 1) RR variability (+19.2%, p less than 0.05); 2) autoregressive power spectral analysis of the resting ECG divided into low-frequency (-21.2%, p less than 0.01) and high-frequency (+51.3%, p less than 0.05) components; and 3) whole-body radiolabeled norepinephrine spillover (-16%, p less than 0.05). These measurements all showed a significant shift away from sympathetic toward enhanced vagal activity after training.Carefully selected patients with moderate to severe CHF can achieve significant, worthwhile improvements with exercise training. Physical deconditioning may be partly responsible for some of the associated abnormalities and exercise limitation of CHF, including abnormalities in autonomic balance.
A prospective, randomized, split-face, controlled trial of salicylic acid peels in the treatment of melasma in Latin American women
Authors: Sreedevi Kodali, Ian L. Guevara, Christina R. Carrigan, Seema Daulat, Gabriela Blanco, Andreas Boker, Linda S. Hynan, Amit G. Pandya
Journal: Journal of the American Academy of Dermatology (2010)
Remuneration in Rural Areas
Authors: J. E. Outhwaite
Journal: BMJ (1948)

Two inhibitors of acetylcholinesterase, physostigmine and diisopropylfluorophosphate, potentiated morphine antinociception, as measured by inhibition of the tail-flick response, in both nontolerant mice and in mice rendered tolerant to morphine by pellet implantation for three days. Although the response to morphine was modified in tolerant animals, inhibition of acetylcholinesterase did not alter the development of tolerance. Physostigmine and diisopropylfluorophosphate also caused pronounced inhibition of naloxone-precipitated withdrawal jumping; however, development of physical dependence on morphine, as measured by body weight loss during abrupt withdrawal, was not affected by the two drugs. These results suggest that some of the actions of morphine might be mediated in part by acetylcholine and, although acetylcholinesterase inhibition may modify the tolerant and dependent state, the mechanism involved primarily in their development is not materially affected.
Why not ask “Does the chimpanzee have a soul?”
Authors: William M. Baum
Journal: Behavioral and Brain Sciences (1998)

The question, “Does the chimpanzee have a theory of mind?” is logically identical to the question, “Does the chimpanzee have a soul?” It is a peculiarity of our culture that we talk about anyone having a mind, and such talk is unhelpful for a science of behavior. The label “killjoy hypothesis” is an ad hominem attack.
Perinatal Transmission of HIV-1-Reply
Authors: Ruth Dickover
Journal: JAMA (1996)

<h3>In Reply.</h3> —Dr Asakura and colleagues correctly point out the potential importance of the role of HIV phenotype as manifested by macrophage tropism in perinatal transmission. Several studies have suggested that macrophage-tropic, non— syncytial-inducing HIV virus isolates are more likely to be transmitted.<sup>1,2</sup>In a subset of the patients in our cohort, we also observed that non—syncytial-inducing HIV isolates were preferentially transmitted even in women who harbored syncytial-inducing HIV strains. In one case of syncytial-inducing virus transmission in our study, both the mother and infant had rapid progression to the acquired immunodeficiency syndrome (AIDS). Husson et al<sup>3</sup>have reported a similar phenomenon. The reasons for preferential transmission of non— syncytial-inducing strains in perinatal, parenteral, and sexual transmission are not clear, but are the subject of intense research. Our study addressed the question of the quantity (not the quality) of virus present in maternal blood and showed that the level of
The Earliest Roentgenographic Signs of Carcinoma of the Lung
Authors: Leo G. Rigler
Journal: JAMA (1966)

Despite the more general use of sputum cytology and bronchoscopy, the most available, least expensive, and simplest method for the detection of a malignant lesion in the lung, when it is small, is roentgen examination.<sup>4</sup>A single posteroanterior roentgenogram made in inspiration is an effective method for finding cases in their presymptomatic stage. An additional number of small lesions would be discovered if it were possible to add a second film so that stereoscopic or posteroanterior and lateral views would be made in each case. Obviously, additional roentgenograms, such as those made in the oblique positions, apical lordosis, and in expiration would increase the productivity, but it is impractical to make such elaborate examinations in asymptomatic individuals. The presence of symptoms which are at all suggestive of carcinoma of the lung should lead to such a thorough investigation, to which should be added body-section roentgenography and, if needed, bronchography.
False-positive Radiocolloid Liver Image Due to a Subphrenic Abscess
Authors: WEI-JEN SHIH, TERRI DANIEL, FRANK H. DeLAND, PEGGY A. DOMSTAD, MARC L. DILLON
Journal: Clinical Nuclear Medicine (1986)

A false-positive radiocolloid liver image can occur in various disease processes from extrinsic structures adjacent to the liver. A patient whose radiocolloid liver imaging showed an apparent photopenic area in the liver is presented; the abdominal CT demonstrated a low-density lesion located anterior to the liver, and at surgery the lesion was confirmed to be a right anterior subphrenic abscess.
Aging decreases the capacity of human skin to produce vitamin D3.
Authors: J MacLaughlin, M F Holick
Journal: Journal of Clinical Investigation (1985)

An evaluation of surgically obtained skin (age range, 8-92 yr) revealed that there is an age-dependent decrease in the epidermal concentrations of provitamin D3 (7-dehydrocholesterol). To ascertain that aging indeed decreased the capacity of human skin to produce vitamin D3, some of the skin samples were exposed to ultraviolet radiation and the content of previtamin D3 was determined in the epidermis and dermis. The epidermis in the young and older subjects was the major site for the formation of previtamin D3, accounting for greater than 80% of the total previtamin D3 that was produced in the skin. A comparison of the amount of previtamin D3 produced in the skin from the 8- and 18-yr-old subjects with the amount produced in the skin from the 77- and 82-yr-old subjects revealed that aging can decrease by greater than twofold the capacity of the skin to produce previtamin D3. Recognition of this difference may be extremely important for the elderly, who infrequently expose a small area of skin to sunlight and who depend on this exposure for their vitamin D nutritional needs.
Leukopenia Following Treatment With Thiothixene and Haloperidol
Authors: Neal R. Cutler
Journal: JAMA (1979)

BLOOD dyscrasias are known to occur in patients treated with phenothiazine-like antipsychotic drugs but are rarely associated with both thiothixene and haloperidol.<sup>1</sup>We report a case of leukopenia that developed in a patient on two separate occasions following treatment with thiothixene and haloperidol, respectively. <h3>Report of a Case</h3> A 27-year-old man was hospitalized after lye ingestion with suicidal intent. Physical examination was remarkable only for severe burns of the pharynx, trachea, and esophagus. His initial hematologic evaluation showed the following values: hemoglobin, 13.3 g/dL; hematocrit, 42.6%; leukocytes, 13,000/cu mm, with 93% polymorphonuclear leukocytes, 6% lymphocytes, and 1% monocytes; and platelets, 235,000/cu mm. The patient had no history of allergies or hematologic problems. Results of both a physical and a laboratory examination, including a complete blood cell count (CBC), four months before admission were normal. His condition had been diagnosed as paranoid schizophrenic for the past four years, and for
A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung
Authors: M. L. Thomson, D. Pavia, M. W. McNicol
Journal: Thorax (1973)

<b>Thomson, M. L., Pavia, D., and McNicol, M. W. (1973).</b><i>Thorax</i>, <b>28</b>, 742-747. <b>A preliminary study of the effect of guaiphenesin on mucociliary clearance from the human lung.</b> The effect of guaiphenesin (administered as Robitussin<sup>1</sup>) on mucociliary clearance has been assessed in 15 subjects from the rate of removal from the lung of previously inhaled radioactive tracer particles. The guaiphenesin was compared with a positive control preparation consisting of the guaiphenesin vehicle only in two double-blind crossover trials. The first trial examined eight aged `healthy9 volunteer subjects and the second trial examined seven chronic bronchitic patients. Sequential gamma counts were made from the whole lung by scintillation counters for 6 hours after inhalation and the chest was also scanned rectilinearly. In the first 5 hours after inhalation the mean rate of removal of particles and therefore of secretions was faster after guaiphenesin than after the control preparation. This difference was not statistically significant in the healthy volunteers but achieved significance (P &lt;0·05) in the chronic bronchitic patients. Lung scans after inhaling the tracer aerosol indicated that on average the initial penetration of the particles into the lung was similar in the guaiphenesin and control runs. The faster clearance after guaiphenesin was unlikely to be due to bulk movements of mucus caused by coughing since the mean frequency of coughing during the experiment was somewhat less after the drug.
QUANTITATIVE HISTOCHEMISTRY OF THE NEPHRON. VI. HYDROXYPROLINE IN THE HUMAN GLOMERULUS*
Authors: Sjoerd L. Bonting, Hendrina De Bruin, Victor E. Pollak
Journal: Journal of Clinical Investigation (1961)

Staining reactions characteristic of collagen and reticulin are found in pathologically altered glo- meruli (1, 2), and fibrils with the periodicity of collagen fibrils have been observed occasionally in electron micrographs of severely damaged glomer- ular tufts.However, as far as we are aware, fibrils have not been found by light or electron microscopy in the normal glomerular tuft, except at the hilus; and, in particular, no fibrils with the periodicity of collagen fibrils have been seen in the normal glomerular capillary basement mem- brane (3-6).Hydroxyproline estimations are widely used as a measure of collagen because no other known ani- mal protein contains appreciable amounts of this amino acid (7, 8).Goodman, Greenspon and Krakower used sonic vibration to separate glo- merular basement membrane from healthy canine glomeruli and found that the hydroxyproline con- tent of their basement membrane preparations was 7 per cent (9).They suggested, therefore, that glomerular capillary basement membrane con- tained a considerable amount of collagen.As their results appeared to conflict with the morpho- logical evidence, the hydroxyproline content of the human glomerulus was reinvestigated, using a microdissection and microassay technique in which glomerular tufts were dissected out intact and free of Bowman's capsules for hydroxyproline assay.METHODS
Glucose-Insulin-Potassium Therapy in Patients With ST-Segment Elevation Myocardial Infarction
Authors: Rafael Díaz, Abhinav Goyal, Shamir R. Mehta, Rizwan Afzal, Denis Xavier, Prem Pais, Susan Chrolavicius, Jun Zhu, Khawar Kazmi, Lisheng Liu, Andrzej Budaj, Mohammad Zubaid, Alvaro Avezum, Mikhail Ruda, Salim Yusuf
Journal: JAMA (2007)

The clinical benefit of glucose-insulin-potassium (GIK) infusion in patients with ST-segment elevation myocardial infarction (STEMI) is unclear. While some smaller trials suggest benefit, in the CREATE-ECLA trial, GIK infusion had no effect on 30-day mortality in 20,201 patients.To determine the association between GIK infusion therapy and 30-day and 6-month outcomes in patients with STEMI.Primary analysis of the OASIS-6 GIK randomized controlled trial of 2748 patients with acute STEMI; prespecified analyses of the combined trial data from the OASIS-6 GIK and CREATE-ECLA GIK trial populations of 22,943 patients with acute STEMI; subgroup analysis on the timing of initiation of GIK infusion therapy and outcomes; and post hoc analyses exploring whether GIK infusion may cause early harm by increasing glucose and potassium levels and net fluid gain.High-dose GIK solution consisting of 25% glucose, 50 U/L of regular insulin, and 80 mEq/L of potassium infused at 1.5 mL/kg per hour for 24 hours.Mortality rates at 30 days and 6 months in the OASIS-6 GIK trial and rates of death, heart failure, and the composite of death or heart failure at 3 and 30 days in the combined OASIS-6 GIK and CREATE-ECLA GIK trial populations.At 6 months, 148 (10.8%) GIK infusion patients and 143 (10.4%) control patients died in the OASIS-6 trial (hazard ratio [HR], 1.04; 95% CI, 0.83-1.31; P = .72); 153 (11.1%) GIK patients and 185 (13.5%) control patients had heart failure (HR, 0.83; 95% CI, 0.67-1.02; P = .08); and 240 (17.5%) GIK patients and 264 (19.2%) control patients had a composite of death or heart failure (HR, 0.91; 95% CI, 0.76-1.08; P = .27). In the prespecified analyses of the combined trial data, there were 712 deaths (6.2%) in the GIK group and 632 deaths (5.5%) in the control group at 3 days (HR, 1.13; 95% CI, 1.02-1.26; P = .03). This difference disappeared by 30 days, with 1108 deaths (9.7%) in the GIK group and 1068 (9.3%) in the control group (HR, 1.04; 95% CI, 0.96-1.13; P = .33). GIK therapy increased levels of glucose, potassium, and net fluid gain postinfusion, all 3 of which predicted death after adjusting for multiple confounders. Adjusting for glucose, potassium, and net fluid gain eliminated the apparent increase in mortality at 3 days observed with GIK infusion, suggesting a direct association with these factors. Administration of GIK infusion within 4 hours of symptom onset yielded no benefit compared with later initiation.Infusion of GIK provided no benefit and may cause early harm following STEMI. Avoidance of infusion-related hyperglycemia, hyperkalemia, and net fluid gain may be advisable in future studies of metabolic modulation in patients with STEMI.clinicaltrials.gov Identifier: NCT00064428.
Development of human CD4+FoxP3+ regulatory T cells in human stem cell factor–, granulocyte-macrophage colony-stimulating factor–, and interleukin-3–expressing NOD-SCID IL2Rγnull humanized mice
Authors: Eva Billerbeck, Walter T. Barry, Kathy Mu, Marcus Dorner, Charles M. Rice, Alexander Ploss
Journal: Blood (2011)
Less Smad2 is good for you! A scientific update on coffee's liver benefits
Authors: Olav A. Gressner
Journal: Hepatology (2009)

Abstract Scientists at the National Institutes of Health have reported that increased coffee consumption is associated with a slower progression of fibrogenesis in patients with chronic and particularly alcoholic liver disease and a reduced incidence of heptocellular carcinoma. However, a causal mechanistic explanation was pending. New results indicate that the methylxanthine caffeine—a major component of coffee and the most widely consumed pharmacologically active substance in the world—might be responsible for this phenomenon, because it inhibits the synthesis of connective tissue growth factor (CTGF/CCN2) in liver parenchymal and nonparenchymal cells, primarily by inducing degradation of Smad2 (and to a much lesser extent Smad3) and thus impairment of transforming growth factor β (TGF-β) signaling. CTGF and TGF-β play crucial roles in the fibrotic remodeling of various organs, and, ultimately, carcinogenesis. This article summarizes the clinical-epidemiological observations as well as the pathophysiological background and provides suggestions for the therapeutic use of (methyl)xanthine derivatives in the management of fibro-/carcinogenic (liver) diseases. (Hepatology 2009.)
A rational approach to parenteral nutrition
Authors: T. T Irvin
Journal: BMJ (1976)

dissented from the view that the possibility" of a direct relationship between multiple exposure to halothane and postoperative liver damage existed.They asked why the committee had not sought "expert opinion," presumably from anaesthetists, before publishing their circular letter.It is apparent that the two groups who were working contemporaneously have now come to the same conclusion.As a general practitioner who is also a very part-time worker for the CSM I hope I am not out of order in expressing the view that it is a pity that some degree of effective communication, co-operation, and co-ordination between the two groups was not effected at an early stage and the hope that a lesson has been learnt for the future.
Letter: Folic acid supplements for pregnant epileptics.
Authors: M J Landon, F E Hytten
Journal: BMJ (1974)

acceptable-the convulsions or the toxic effects.If extrapyramidal movements do in fact represent toxic damage to the cere- bellum it would seem advisable to us to discontinue phenytoin in such a case and sulbstitute one of the other drugs in the steadily expanding anticonvulsant armamentarium.-Weare, etc.,
P710 EFFECT OF ALISPORIVIR (ALV) ON THE PHARMACOKINETICS (PK), SAFETY, AND TOLERABILITY OF METHADONE IN HEALTHY SUBJECTS AND OPIOID-DEPENDENT PATIENTS ON STABLE METHADONE MAINTENANCE THERAPY (MMT)
Authors: S.J. Kovacs, J. Ke, A. Barve, L.R. Webster, Y. Cheng, J. Zhang, R. Maietta, G. Sunkara, D.S. Stein
Journal: Journal of Hepatology (2014)