tbuckley/cabot-search huggingface dataset:
Abstract 600: The HSV-2 oncolytic virus ΔPK induces multiple death and inflammatory programs associated with inhibition of melanoma tumor growth
Authors: Aric Colunga, Biquan Li, Laure Aurelian
Journal: Cancer Research (2011)

Abstract Metastatic melanoma is a highly aggressive and drug resistant cancer. Oncolytic virotherapy is a novel therapeutic strategy designed to circumvent cancer resistance through virus replication-induced cancer cell lysis. Unfortunately, its clinical efficacy is modest, apparently related to poor virus replication within the tumors and the failure to stimulate inflammatory/immunotherapeutic pathways. The growth compromised herpes simplex virus type 2 (HSV-2) mutant ΔPK causes metastatic melanoma cell death through activation of multiple non-redundant death pathways. Activation of calpain and caspases-3 and -7 provide the bulk of the death programs, as evidenced by the finding of 80% protection in cells treated with the combination of calpain (PD150606) and pancaspase (zVAD-fmk) inhibitors. In addition, ΔPK upregulates the autophagy proteins Beclin-1 and LC-II and the autophagy inhibitor 3-methyladenine (3-MA) reduces ΔPK-induced cell death by 15-17%. Cell death is further decreased (to a total of 28-34%) by treatment with 3-MA together with the JNK inhibitor SP600125, indicating that JNK signaling and autophagy contribute independently to ΔPK-induced cell death. Inflammatory-related pathways contribute to ΔPK-induced melanoma cell death, as evidenced by caspase-1 activation, interleukin (IL)-1β release into the conditioned medium and upregulation of pro-apoptotic/stress signaling molecules and pro-inflammatory cytokines and chemokines identified by microarray analysis. These include BAD, BIK, BOK, NLRC4, CIDEB, IL-1β, IL-6, IL-8, IL-12α, IL-12β, LTα, CXCL-10, c-JUN and caspases-4, -5, -6, -8, and -10. Tumor burden is significantly reduced by intratumoral injection of ΔPK and xenografts generated from a fresh clinical isolate, were completely eliminated for a period of 1 year following treatment. Growth inhibition is associated with activation of calpain and caspases-3, -7 and -1 and expression of the inflammatory cytokine TNF-α. Collectively, the data indicate that ΔPK eliminates tumor burden through the simultaneous activation of multiple non-redundant death programs and pro-inflammatory signaling, providing a distinct and promising virotherapeutic approach. 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 600. doi:10.1158/1538-7445.AM2011-600
Role of adenosine on ventricular overdrive suppression in isolated guinea pig hearts and Purkinje fibers.
Authors: R C Wesley, L Belardinelli
Journal: Circulation Research (1985)

The present study was undertaken to demonstrate and characterize potentiation of ventricular overdrive suppression by adenosine. To substantiate that adenosine has an enhanced effect on overdrive suppression, it would be necessary to demonstrate that adenosine increases pause duration independent of slowing spontaneous pre-drive rate. In isolated perfused guinea pig hearts with surgically induced complete atrioventricular block, the effect of adenosine (2-20 microM) on pause duration was compared to two alternative means of slowing the pre-drive rate, i.e., hypothermia (28.0 degrees C to 34.0 degrees C) and cesium chloride (0.3-1.0 mM). The slope value of the linear regression line describing the relationship between pre-drive cycle length and pause duration for adenosine (15.8) was significantly greater than control (1.7), hypothermia (1.7), and cesium chloride (5.4). The competitive adenosine antagonist, aminophylline (60 microM), when infused at the initiation of overdrive during adenosine administration, significantly reduced the effect of adenosine on pause duration by 72.9 +/- 4.2% (mean +/- SEM). The reduction in pause duration by aminophylline was specific for adenosine and did not occur under control conditions or during cesium chloride administration. During hypoxia, aminophylline and adenosine deaminase, when infused at the initiation of overdrive, caused 72.3 +/- 5.6 and 63.3 +/- 6.1% reductions in pause duration, respectively. Endogenous adenosine levels rose significantly with hypoxia (1,687 +/- 202 vs. 36 +/- 4 pmol/min per g during normoxia) and increased significantly further during hypoxic overdrive (3,004 +/- 323 pmol/min per g). In isolated guinea pig Purkinje fibers (n = 4), adenosine (20 microM) increased pause duration by 73.6 +/- 9.9% while only minimally affecting the pre-drive cycle length (7.6 +/- 3.8%). These fibers, when stimulated at 1.5 Hz, also displayed an adenosine-induced reduction in action potential duration at 90% repolarization (16 +/- 2 msec). In addition, we demonstrated that adenosine had an enhanced effect on pause duration in the presence of ouabain (1 microM)-induced attenuation of overdrive suppression. Thus, in isolated Purkinje fibers, it is unlikely that the potentiating effect of adenosine on pause duration, which is independent of its chronotropic effect, is mediated via an enhancement of sodium potassium adenosine triphosphatase pump activity. The effect of adenosine is likely to be secondary to a direct action on outward potassium conductance.(ABSTRACT TRUNCATED AT 400 WORDS)
Quantitatively Determined Survivin Expression Levels Are of Prognostic Value in Human Gliomas
Authors: Arnab Chakravarti, Elizabeth Noll, Peter McL. Black, Daniel F. Finkelstein, Dianne M. Finkelstein, Nicholas J. Dyson, Jay S. Loeffler
Journal: Journal of Clinical Oncology (2002)

PURPOSE: Survivin is a novel antiapoptotic gene that has been recently cloned and characterized. Its expression has been found to be of prognostic significance in several tumor types. This is the first study on the prognostic significance of survivin expression in human gliomas. MATERIALS AND METHODS: We used quantitative Western blot analysis with densitometry to determine survivin protein expression levels in 92 glioma cases for which frozen tissue was available for analysis. Survivin positivity and expression levels were correlated with histopathologic features of the tumors, apoptosis (as measured by cleaved, or activated, caspase 3 levels), and clinical outcome. RESULTS: Survivin expression has clear prognostic value in human gliomas. Patients with detectable survivin expression had significantly shorter overall survival times (P &lt; .0001) compared with those without detectable expression when all glioma patients were considered. Although glioblastoma multiforme (GBM) patients had significantly higher rates of survivin positivity and higher levels of survivin expression (P &lt; .0001) than their non-GBM counterparts, the prognostic value of survivin expression seemed to be independent of histology alone. Survivin-positive GBM patients had significantly shorter overall survival times compared with survivin-negative GBM patients (P &lt; .0001). Likewise, survivin-positive non-GBM patients had shorter survival times compared with survivin-negative non-GBM patients (P = .029). Furthermore, increasing levels of survivin expression significantly correlated with reduced survival times when all glioma patients were considered, and markedly so for GBM patients (P &lt; .0001). Increasing survivin levels significantly correlated with reduced expression of cleaved caspase 3, indicating its association with antiapoptotic activity. CONCLUSION: Survivin positivity and protein expression levels, as determined quantitatively, are of significant prognostic value in human gliomas and seem to be associated with reduced apoptotic capacity of these tumors.
Local Subcutaneous Atrophy
Authors: Elmer W. Fisherman
Journal: JAMA (1962)

IN THE COURSE of evaluating the clinical effectiveness of a new long-acting parenteral form of triamcinolone, a peculiar local effect was observed. It is the purpose of this communication to describe the lesions produced and to discuss their possible significance. The anti-inflammatory agent, triamcinolone diacetate, as a fine suspension of 40 mg. of active steroid per milliliter, was given intramuscularly or deeply subcutaneously in the upper arms, usually in doses of 40 mg. and sometimes of 20 mg. Injections were administered on a 3 to 14 day schedule to 27 patients with such allergic conditions as severe generalized atopic eczema or contact dermatitis, persistent asthma, or severe allergic rhinitis with obstructing polyps. Onset of clinical relief varied between 24 and 48 hours, usually occurring 48 hours after injection. Duration of clinical effectiveness in these patients ranged between 4 and 12 days, in most instances being less than 7 days. Patients
Comparative analysis of predicted HLA binding of immunoglobulin idiotype sequences indicates T cell–mediated immunosurveillance in follicular lymphoma
Authors: Anna-Maria Strothmeyer, Dimitrios Papaioannou, Marcus Dühren-von Minden, Marcelo Navarrete, Katja Zirlik, Kristina Heining-Mikesch, Hendrik Veelken
Journal: Blood (2010)
Bacillus anthracis cell wall produces injurious inflammation but paradoxically decreases the lethality of anthrax lethal toxin in a rat model
Authors: Xizhong Cui, Junwu Su, Yan Li, Joseph Shiloach, Steven Solomon, Jeanne B. Kaufman, Haresh Mani, Yvonne Fitz, Jia Weng, Laith Altaweel, Virginia Besch, Peter Q. Eichacker
Journal: Intensive Care Medicine (2009)
Coronary venous drug infusion in the ischaemic-reperfused isolated rat heart
Authors: Y. Uriuda, Q.-D. Wang, X.-S. Li, P.-O. Sjoquist, R. Nordlander, L. Ryden
Journal: Cardiovascular Research (1996)

Objectives: Coronary venous retroinfusion (CVR) has been used experimentally in large animals for selective drug delivery into ischaemic myocardium. It would be an advantage if CVR could also be used in isolated perfused rat heart models. The aim of the present paper is to develop a regional ischaemic model in the isolated perfused rat heart combined with CVR. Method: Pharmacokinetic study: The spatial distribution of retrogradely infused felodipine (used as a tracer) during regional myocardial ischaemia was investigated. Following occlusion of the left coronary artery, felodipine was administered over a period of 5 min by CVR. Ischaemia-reperfusion study: Following 30 min of stabilisation, 14 rat hearts were subjected to 60 min of regional ischaemia followed by 60 min of reperfusion. Felodipine (0.7 nmol/kg, n = 7) or vehicle (n = 7) was administered by means of CVR. The infusion was given during the last 5 min of ischaemia at a rate of 0.6 ml/min. Results: Pharmacokinetic study: By means of CVR, the compound was distributed specifically into the ischaemic myocardium. The highest tissue concentration was obtained when the coronary vein was occluded during CVR. The maximal concentration in the ischaemic myocardium was 20–70 times that in the non-ischaemic areas. A transmyocardial gradient was noted with higher drug concentration in the subepicardial zone. Ischaemia-reperfusion study: At the end of reperfusion, the recovery of coronary flow, left ventricular developed pressure and double product (DP; LVDP × HR) was 101 ± 7% (mean ± s.e.m.), 99 ± 8% and 98 ± 4% of the pre-ischaemic values, respectively. This was significantly different from the vehicle group (78 ± 5, P < 0.05, 74 ± 6, P < 0.01 and 78 ± 3, P < 0.05). Conclusion: CVR could easily be accomplished in the isolated perfused rat heart. The drug was specifically delivered into the ischaemic myocardium. Felodipine exerted a myocardioprotective effect in isolated rat hearts subjected to 60 min of regional ischaemia followed by 60 min of reperfusion.
Penicillin prophylaxis in children with sickle cell disease in Brent.
Authors: D Cummins, R Heuschkel, S C Davies
Journal: BMJ (1991)

To assess compliance with oral penicillin prophylaxis in children with sickle cell disease and identify possible reasons for poor compliance.Closed questionnaires given to parents of children with sickle cell disease and general practitioners in Brent. Urine samples from 23 children were tested for penicillin.Paediatric haematology clinic, Central Middlesex Hospital, and general practices in Brent.50 children (aged less than or equal to 16) attending clinic with sickle cell disease over six months (33 HbSS, 12 HbSC, five HbS beta thalassaemia). 30 general practitioners: 15 with the greatest number of patients with sickle cell disease on the Brent register; 15 selected randomly from family practitioner committee's list.Reported compliance with and awareness of importance of penicillin prophylaxis. Results of urine tests for penicillin.31 parents claimed that their children received penicillin every day and 19 that they received it most days (greater than or equal to 5 days a week). Penicillin was detected in only 10 of 23 urine samples tested. Parents and doctors seemed not to appreciate the importance of treatment: only eight parents were aware of the risk of death if penicillin were discontinued, and 16 doctors were unaware that regular penicillin prophylaxis prevents pneumococcal septicaemia and death in these children.Education for families with children with sickle cell disease must be improved. Specialised information and training are needed for doctors working in areas with a high prevalence of the disorder.
RECENT INVESTIGATIONS ON THE ETIOLOGY OF DIABETES.
Authors: S. P. KRAMER
Journal: JAMA (1892)

The pathogenesis of diabetes mellitus has been a fertile field for speculation. Bouchard was able to count twenty-seven theories of the disease. Nearly all of these have been based upon the classic investigations of Claude-Bernard, on the formation and excretion of sugar in the body. Since the contributions of Bouchardat, the association of diseases in the pancreas with diabetes has been frequently noted; so that Senator assumes that pathological changes in the pancreas occur in about one-half of all cases of diabetes. Baumel maintains that disease of the pancreas is found in all cases; in the milder forms microscopical, in the more severe cases, gross, pathological changes are found. This frequency precludes the possibility of accidental association. According to the view of Klebs, lesions of the cœliac plexus are the cause of this association. Either the disease is primarily in the pancreas from whence it encroaches upon the plexus, or
Haemodynamic sequelae of pulmonary fibrosis following intratracheal bleomycin in rats
Authors: J. H Williams, P. Bodell, S. Hosseini, H. Tran, K. M Baldwin
Journal: Cardiovascular Research (1992)

Objective: Intratracheal instillation of bleomycin in rats has been extensively used as an animal model of pulmonary fibrosis in humans, although it produces a patchy, airway based response. We proposed that the haemodynamic sequelae of the bleomycin model might be less severe than those associated with more diffuse lung injury. Methods: Pulmonary and systemic haemodynamic indices were examined in adult Sprague-Dawley rats (∼400 g, n=10) both at rest and during submaximal exercise on a rodent treadmill, approximately 60 days after intratracheal bleomycin (6 units·kg−1), and the results compared to a control group (n=6). Results: Compared to controls, mean pulmonary artery pressure (PPA) was increased by intratracheal bleomycin (p=0.02) both at rest [24.5 (SEM 2.6) v 18.2(0.9) mm Hg] and during exercise [34.7(3.0) v 26.7(0.7) mm Hg]. PPA-pulse product was also increased, with a similar trend in right ventricular work index, but cardiac index was not altered. Right ventricular hypertrophy was noted on necropsy examination. Consistent with pulmonary fibrosis, lung dry weight, total protein, and hydroxyproline were also raised, and these values correlated strongly with (mean) PPA at rest (r2=0.86, 0.81, 0.69, respectively) and during exercise (r1=0.81, 0.79, 0.65, respectively). Packed cell volume was increased by intratracheal bleomycin, at 49(1) v 45(1)%, p=0.02. CaO2 tended to decrease with exercise in the bleomycin group, although this was not statistically significant, while systemic oxygen delivery and consumption were not altered. Conclusions: Pulmonary hypertension and right ventricular hypertrophy occur in this model of lung fibrosis, and correlate with the severity of fibrosis. However, these sequelae were less severe than those previously demonstrated in association with crotalaria ingestion. We suggest that the haemodynamic sequelae of the intratracheal bleomycin model are consistent with patchy, airway based fibrosis, but reflect less well the haemodynamic sequelae of more diffuse fibrotic injury associated with systemic processes.
Current law has led to unregulated and dangerous practices, doctors tell commission on assisted dying
Authors: C. Dyer
Journal: BMJ (2011)

The United Kingdom’s current attitude to assisted dying will seem “inhumane” and “barbaric” in future if the law is changed to allow it , doctors from a group of healthcare professionals supporting the change have told the Commission on Assisted Dying.

Healthcare Professionals for Assisted Dying, which has around 400 members, was set up six months ago (as Dignity in Dying: Healthcare Professionals for Change) to press for reform of the law ( BMJ 2010;341:c5498, doi:10.1136/bmj.c5498). Chaired by Ann McPherson, a retired GP who is dying from pancreatic cancer, it includes 43 consultants, 205 other doctors, and more than 50 nurses among its members.

Dr McPherson told the commission, chaired by the former lord chancellor Charles Falconer, that …
Use of biosynthetic human C-peptide in the measurement of insulin secretion rates in normal volunteers and type I diabetic patients.
Authors: K S Polonsky, J Licinio-Paixao, B D Given, W Pugh, P Rue, J Galloway, T Karrison, B Frank
Journal: Journal of Clinical Investigation (1986)

We undertook this study to examine the accuracy of plasma C-peptide as a marker of insulin secretion. The peripheral kinetics of biosynthetic human C-peptide (BHCP) were studied in 10 normal volunteers and 7 insulin-dependent diabetic patients. Each subject received intravenous bolus injections of BHCP as well as constant and variable rate infusions. After intravenous bolus injections the metabolic clearance rate of BHCP (3.8 +/- 0.1 ml/kg per min, mean +/- SEM) was not significantly different from the value obtained during its constant intravenous infusion (3.9 +/- 0.1 ml/kg per min). The metabolic clearance rate of C-peptide measured during steady state intravenous infusions was constant over a wide concentration range. During experiments in which BHCP was infused at a variable rate, the peripheral concentration of C-peptide did not change in proportion to the infusion rate. Thus, the infusion rate of BHCP could not be calculated accurately as the product of the C-peptide concentration and metabolic clearance rate. However, the non-steady infusion rate of BHCP could be accurately calculated from peripheral C-peptide concentrations using a two-compartment mathematical model when model parameters were derived from the C-peptide decay curve in each subject. Application of this model to predict constant infusions of C-peptide from peripheral C-peptide concentrations resulted in model generated estimates of the C-peptide infusion rate that were 101.5 +/- 3.4% and 100.4 +/- 2.8% of low and high dose rates, respectively. Estimates of the total quantity of C-peptide infused at a variable rate over 240 min based on the two-compartment model represented 104.6 +/- 2.4% of the amount actually infused. Application of this approach to clinical studies will allow the secretion rate of insulin to be estimated with considerable accuracy. The insulin secretion rate in normal subjects after an overnight fast was 89.1 pmol/min, which corresponds with a basal 24-h secretion of 18.6 U.
Estimation of Serum Enzymes
Authors: W. H. S. George
Journal: BMJ (1965)

MBITAJOSULAnother equally harmless, and also common, eruption is seen over the upper third of the bicipital surface of the upper arm.This consists of an oval area of petechiae and perhaps some slight bruising, about i in.(2 cm.) long.It is due to the child sucking himself, though most children will for some reason deny that they have done so.Since vest purpura is not limited to young children, it may well be met in adults, but since Dr. Kibel and I are both paediatricians we have had less chance of seeing it in older subjects.-Iam, etc., Bath, Somerset.S. D. V. WELLER. Hyponatraemia and BronchialCarcinoma SIR,-We were most interested to read the article on " Hyponatraemia and Bronchial Carcinoma" by Drs. A. L. Linton and I. Hutton (31 July, p. 277), as we re- cently had an example of this syndrome and agree that treatment presents certain problems.
Prospective Teaching of Braille
Authors: William S. Reveno
Journal: JAMA (1969)

<h3>To the Editor:—</h3> In the editorial, "Better Braille for Blind Diabetics" (<b>208</b>:2330, 1969), the discussion is concerned with the additional handicap that neuropathy imposes on blind diabetics rendering them incapable of perceiving the individual points in braille reading. The suggested improvement in braille type offers a promising but remote solution. As a more practical interim approach it would seem that the diabetic with beginning retinopathy, whether or not afflicted with neuropathy elsewhere, would gain an important advantage in learning to read braille.
Polymyalgia Rheumatica and Blindness
Authors: W. J. Fessel, Carl M. Pearson
Journal: New England Journal of Medicine (1967)

THE condition that is called by the English polymyalgia rheumatica and by the French pseudopolyarthrite rhizomélique and has had many synonyms1 is characterized by pain and stiffness in the muscles of the shoulder girdle, neck, back and, to a lesser degree, pelvic girdle in older patients. Aside from local muscle tenderness there are no notable physical signs. The only laboratory abnormality is a fast erythrocyte sedimentation rate – usually about 100 mm. per hour by the Westergren method. There is no evidence of inflammation in the muscles: the serum enzymes that often reflect muscle necrosis are normal; muscle biopsy shows . . .