tbuckley/cabot-search huggingface dataset:
Synergistic Anticancer Effects of Ganciclovir/Thymidine Kinase and 5-Fluorocytosine/Cytosine Deaminase Gene Therapies
Authors: M Aghi, C M Kramm, T C Chou, X O Breakefield, E A Chiocca
Journal: JNCI Journal of the National Cancer Institute (1998)

Background: A bacterial enzyme, Escherichia coli cytosine deaminase, which converts the prodrug 5-fluorocytosine into the toxic drug 5-fluorouracil, and a viral enzyme, herpes simplex virus thymidine kinase, which converts ganciclovir from an inactive prodrug to a cytotoxic agent by phosphorylation, are being actively investigated for use in gene therapy for cancer. The purpose of this study was to determine whether combining these prodrug-activating gene therapies might result in enhanced anticancer effects. Methods: Rat 9L gliosarcoma cells were transfected with plasmids containing the E. coli cytosine deaminase gene (9L/CD cells), with plasmids containing the herpes simplex virus thymidine kinase gene (9L/TK cells), or with both expression plasmids (9L/CD-TK cells). The drug sensitivities of the cell lines were evaluated; in addition, the sensitivities of 9L and 9L/CD-TK cells mixed in varied proportions were measured. The effects of prodrug treatment on 9L/CD-TK tumor growth (i.e., size and volume) in nude mice were monitored. The isobologram method of Loewe and the multiple drug-effect analysis method of Chou-Talalay were used to measure the interaction between the two prodrug-activating gene therapies. To elucidate the mechanism of interaction, the phosphorylation of ganciclovir in 9L/CD-TK cells after varying prodrug treatments was studied. Results and Conclusions: The presence of transfected cytosine deaminase and thymidine kinase genes in 9L gliosarcoma cells reduced cell survival, both in vitro and in vivo, following treatment with the relevant prodrugs; the effects of the two components appeared to be synergistic and related mechanistically to the enhancement of ganciclovir phosphorylation by thymidine kinase following 5-fluorouracil treatment.
SERUM INHIBITION OF STREPTOCOCCAL DIPHOSPHOPYRIDINE NUCLEOTIDASE IN UNCOMPLICATED STREPTOCOCCAL PHARYNGITIS AND IN RHEUMATIC FEVER *
Authors: Gerson C. Bernhard, Gene H. Stollerman
Journal: Journal of Clinical Investigation (1959)

One of the recently described extracellular prod- ucts of Group A streptococci is diphosphopyridine nucleotidase (DPNase) (1).This enzyme has received attention as a substance of possible im- portance in the etiology of either rheumatic fever or glomerulonephritis because a) it was isolated from cardiotoxic fractions of supernates of broth cultures of Group A streptococci (2, 3) and b) al- most all nephritogenic strains of Group A strepto- cocci studied produced it in vitro (4).Kellner, Freeman and Carlson (5) showed that the inhibition of DPNase by human sera of different age groups follows the pattern of other streptococcal antibodies and that DPNase neu- tralizing titers increase in response to streptococcal infection.F Studies in progress in this laboratory on rheu- matic fever and the human immune response to streptococcal infection afforded the opportunity to compare the behavior of the antibody response to DPNase with antibody responses to some other known antigenic extracellular enzymes of the streptococcus.This report presents further evidence that antistreptococcal DPNase activity (ASDA) of human sera behaves as a specific antibody and that it reflects streptococcal disease in rheumatic and nonrheumatic individuals in a manner very similar to antistreptolysin 0, anti- hyaluronidase and antistreptokinase titers.
Ventilation and gas exchange during sleep in patients with interstitial lung disease.
Authors: W T McNicholas, M Coffey, M X Fitzgerald
Journal: Thorax (1986)

Ventilation and gas exchange during overnight sleep was studied in a group of seven patients with severe interstitial lung disease (mean vital capacity 50%, mean diffusing capacity 46% predicted), to see whether clinically significant oxygen desaturation occurred. Patients with a history of loud snoring or clinically significant airflow obstruction were excluded. Sleep was fragmented in these patients, but all achieved rapid eye movement (REM) sleep. All patients showed episodes of oxygen desaturation during sleep--mean (SEM) awake arterial oxygen saturation (SaO2) was 92.9% (0.3%) compared with a mean minimum SaO2 during sleep of 83.2% (2.1%) (p less than 0.01). These episodes were, however, transient, and mean SaO2 showed only a slight fall between wakefulness and sleep (non-REM 91.5%, REM 90.4%; NS). Furthermore, SaO2 during non-REM sleep correlated well (p less than 0.001) with SaO2 during wakefulness. Respiratory frequency showed a significant fall between wakefulness and sleep--21.1 (1.8) versus 17.3 (1.5) breaths per minute (p less than 0.02). Our data suggest that nocturnal oxygen treatment need not be considered in patients with interstitial lung disease unless the level of oxygenation while they are awake indicates the need for such treatment.
Location Matters
Authors: Shikha Mishra, Charles B.B. Gray, Shigeki Miyamoto, Donald M. Bers, Joan Heller Brown
Journal: Circulation Research (2011)

Differential effects of δ(B) and δ(C) subtypes of Ca²⁺/calmodulin-dependent protein kinase (CaMKII) on cardiomyocyte Ca²⁺ handling and survival have been suggested to result from their respective nuclear versus cytosolic localizations. CaMKIIδ subtype localization and its relationship to enzyme activation and target phosphorylation have not, however, been systematically evaluated.To determine whether CaMKIIδ subtypes are restricted to a particular subcellular location and assess the relationship of localization to enzyme activation and function.CaMKIIδ is highly expressed in mouse heart and cardiomyocytes and concentrated in sarcoplasmic reticulum (SR)/membrane and nuclear fractions. CaMKIIδ(B) and δ(C) subtypes differ by a nuclear localization sequence, but both are present in nuclear and SR/membrane fractions. Nonselective subtype distribution is also seen in mice overexpressing CaMKIIδ(B) or δ(C), even in a CaMKIIδ null background. Fluorescently tagged CaMKIIδ(B) expressed in cardiomyocytes concentrates in nuclei whereas δ(C) concentrates in cytosol, but neither localization is exclusive. Mouse hearts exposed to phenylephrine show selective CaMKIIδ activation in the nuclear (versus SR) compartment, whereas caffeine selectively activates CaMKIIδ in SR (versus nuclei), independent of subtype. Compartmentalized activation extends to functional differences in target phosphorylation at CaMKII sites: phenylephrine increases histone deacetylase 5 phosphorylation (Ser498) but not phospholamban (Thr17), whereas the converse holds for caffeine.These studies demonstrate that CaMKIIδ(B) and δ(C) are not exclusively restricted to the nucleus and cytosol and that spatial and functional specificity in CaMKIIδ activation is elicited by mobilization of different Ca²⁺ stores rather than by compartmentalized subtype localization.
Human hypoxanthine-guanine phosphoribosyltransferase. Detection of a mutant allele by restriction endonuclease analysis.
Authors: J M Wilson, P Frossard, R L Nussbaum, C T Caskey, W N Kelley
Journal: Journal of Clinical Investigation (1983)

We have developed a method for the direct analysis of a hypoxanthine-guanine phosphoribosyltransferase (HPRT) allele associated with a deficiency of enzyme activity and an early onset of gout. The functionally abnormal enzyme coded for by this mutant allele (HPRTToronto) differs from the normal enzyme by an arginine-to-glycine substitution at position 50. A single base change in the codon for arginine 50 can explain this substitution. Direct analysis of this point mutation is based on the observation that it abolishes a Taq I recognition site in HPRT DNA. As predicted, DNA from individuals with the HPRTToronto allele exhibited an abnormal restriction pattern when digested with Taq I and probed with HPRT complimentary DNA: a normal 2.0-kb fragment is replaced by a 4.0-kb fragment. The 4.0/2.0-kb restriction fragment variation was used to detect the HPRTToronto allele in a heterozygote that was otherwise normal with respect to the classical techniques used to diagnose heterozygosity in HPRT deficiency.
Prevalence and risk factors for joint pain among men and women in the West of Scotland Twenty-07 study
Authors: J Adamson
Journal: Annals of the Rheumatic Diseases (2005)

<b>Objective:</b> To examine the association between three modifiable risk factors (obesity, smoking, and alcohol consumption) and reported joint pain. <b>Methods:</b> Cross sectional data were collected on 858 people aged 58 years living in the West of Scotland and on the same individuals four years later, aged 62 years. <b>Results:</b> There was a positive relation between obesity and reported pain in the hips, knees, ankles, and feet. The strongest relation was with knee pain (odds ratio = 2.42 (95% confidence interval, 1.65 to 3.56)). There were no strong consistent associations between smoking habits and pain in any joint after adjusting for sex, alcohol consumption, body mass index, social class, and occupational exposures. Similarly, alcohol was not consistently related to pain in any joint in the fully adjusted models. <b>Conclusions:</b> Obesity had consistent and readily explained associations with lower limb joint pain. The data suggest that smoking behaviour and alcohol consumption are not consistently associated with joint pain across the body.
Psychological Distress and Incidence of Type 2 Diabetes in High-Risk and Low-Risk Populations: The Whitehall II Cohort Study
Authors: Marianna Virtanen, Jane E. Ferrie, Adam G. Tabak, Tasnime N. Akbaraly, Jussi Vahtera, Archana Singh-Manoux, Mika Kivimäki
Journal: Diabetes Care (2014)

We examined whether psychological distress predicts incident type 2 diabetes and if the association differs between populations at higher or lower risk of type 2 diabetes.This was a prospective cohort of 5,932 diabetes-free adults (4,189 men and 1,743 women, mean age 54.6 years) with three 5-year data cycles (1991-2009): a total of 13,207 person-observations. Participants were classified into four groups according to their prediabetes status and Framingham Offspring Type 2 Diabetes Risk Score: normoglycemia with a risk score of 0-9, normoglycemia with a risk score of 10-19, prediabetes with a risk score of 10-19, and prediabetes with a risk score of >19. Psychological distress was assessed by the General Health Questionnaire. Incident type 2 diabetes was ascertained by 2-h oral glucose tolerance test, doctor diagnosis, or use of antihyperglycemic medication at the 5-year follow-up for each data cycle. Adjustments were made for age, sex, ethnicity, socioeconomic status, antidepressant use, smoking, and physical activity.Among participants with normoglycemia and among those with prediabetes combined with a low risk score, psychological distress did not predict type 2 diabetes. Diabetes incidence in these groups varied between 1.6 and 15.6%. Among participants with prediabetes and a high risk score, 40.9% of those with psychological distress compared with 28.5% of those without distress developed diabetes during the follow-up. The corresponding adjusted odds ratio for psychological distress was 2.07 (95% CI 1.19-3.62).These data suggest that psychological distress is associated with an accelerated progression to manifest diabetes in a subpopulation with advanced prediabetes.
Simeprevir versus telaprevir with peginterferon and ribavirin in previous null or partial responders with chronic hepatitis C virus genotype 1 infection (ATTAIN): a randomised, double-blind, non-inferiority phase 3 trial
Authors: K Rajender Reddy, Stefan Zeuzem, Fabien Zoulim, Ola Weiland, Andrzej Horban, Carol Stanciu, Federico Guillermo Villamil, Pietro Andreone, Jacob George, Elisabeth Dammers, Min Fu, Darryl Kurland, Oliver Lenz, Sivi Ouwerkerk-Mahadevan, Thierry Verbinnen, Jane Scott, Wolfgang Jessner
Journal: The Lancet Infectious Diseases (2014)
Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension
Authors: B Lavina, J Gracia-Sancho, A Rodriguez-Vilarrupla, Y Chu, D D Heistad, J Bosch, J C Garcia-Pagan
Journal: Gut (2008)

<h3>Background:</h3> Increased intrahepatic vascular tone in cirrhosis has been attributed to a decrease of hepatic nitric oxide (NO) secondary to disturbances in the post-translational regulation of the enzyme eNOS. NO scavenging by superoxide (O<sub>2</sub><sup>−</sup>) further contributes to a reduction of NO bioavailability in cirrhotic livers. <h3>Aim:</h3> To investigate whether removing increased O<sub>2</sub><sup>−</sup> levels could be a new therapeutic strategy to increase intrahepatic NO, improve endothelial dysfunction and reduce portal pressure in cirrhotic rats with portal hypertension. <h3>Methods:</h3> Adenoviral vectors expressing extracellular superoxide dismutase (SOD) (AdECSOD) or β-galactosidase (Adβgal) were injected intravenously in control and CCl<sub>4</sub>-induced cirrhotic rats. After 3 days, liver O<sub>2</sub><sup>−</sup> levels were determined by dihydroethidium staining, NO bioavailability by hepatic cGMP levels, nitrotyrosinated proteins by immunohistochemistry and western blot, and endothelial function by responses to acetylcholine in perfused rat livers. Mean arterial pressure (MAP) and portal pressure were evaluated in vivo. <h3>Results:</h3> Transfection of cirrhotic livers with AdECSOD produced a significant reduction in O<sub>2</sub><sup>−</sup> levels, a significant increase in hepatic cGMP, and a decrease in liver nitrotyrosinated proteins which were associated with a significant improvement in the endothelium-dependent vasodilatation to acetylcholine. In addition, in cirrhotic livers AdECSOD transfection produced a significant reduction in portal pressure (17.3 (SD 2) mm Hg vs 15 (SD 1.6) mm Hg; p&lt;0.05) without significant changes in MAP. In control rats, AdECSOD transfection prevents the increase in portal perfusion pressure promoted by an ROS-generating system. <h3>Conclusions:</h3> In cirrhotic rats, reduction of O<sub>2</sub><sup>−</sup> by AdECSOD increases NO bioavailability, improves intrahepatic endothelial function and reduces portal pressure. These findings suggest that scavenging of O<sub>2</sub><sup>−</sup> might be a new therapeutic strategy in the management of portal hypertension.
Regulating the regulators
Authors: Amy Maxmen
Journal: The Journal of Experimental Medicine (2009)

Crippled clock hinders healingDiabetic eye damage may start in bone marrow, suggest Busik and colleagues.Damaged bone marrow nerves and disrupted circadian genes hampered the release of progenitor cells that are required to repair diabetes-induced vessel injury in the eye.Up to 45% of diabetic adults in the US develop retinopathy, a potentially blinding condition.Although high glucose levels and oxidative stress may cause the initial eye injury, Busik et al. suggest that the inability to repair damage causes the real problem.Normally, endothelial progenitor cells (EPCs) exiting the bone marrow help to regenerate damaged vessels during sleep.This nocturnal EPC egress is faulty in patients with diabetes, creating abnormally low levels of nighttime EPCs.Here, the authors show that diabetic rats have similar EPC deficits during the day when they normally sleep.Diabetic rats showed signs of damage to bone marrow nerves, which trigger the signals required for EPC exit.Nerve damage coincided with a drop in the expression of circadian "clock" genes that control the ebb and flow of EPC migration.With fewer reparative EPCs on the move, damaged eye vessels accumulated in diabetic animals.Circadian rhythm disruption has also been blamed for the glucose and blood pressure complications characteristic of diabetes.Because nerve damage and clock gene irregularities preceded eye disease, the authors suggest that the resulting EPC malfunction leads to retinopathy.What triggers nerve damage and circadian disruption is not yet known.Senior author Maria Grant suspects a role for nitric oxide, a known regulator of circadian gene transcription that is commonly elevated in patients with diabetes.
Increasing Mixed Chimerism Is an Important Prognostic Factor for Unfavorable Outcome in Children With Acute Lymphoblastic Leukemia After Allogeneic Stem-Cell Transplantation: Possible Role For Pre-Emptive Immunotherapy?
Authors: Peter Bader, Hermann Kreyenberg, Walter Hoelle, Gregor Dueckers, Rupert Handgretinger, Peter Lang, Bernhard Kremens, Dagmar Dilloo, Karl-Walter Sykora, Martin Schrappe, Charlotte Niemeyer, Arend von Stackelberg, Bernd Gruhn, Günter Henze, Johann Greil, Dietrich Niethammer, Klaus Dietz, James F. Beck, Thomas Klingebiel
Journal: Journal of Clinical Oncology (2004)

Purpose We recently reported that children with acute leukemias who show increasing mixed chimerism (MC) after allogeneic stem-cell transplantation have a significantly enhanced risk of relapse. Here we present the results of a prospective multicenter study to investigate (1) whether relapse of acute lymphoblastic leukemia (ALL) can be determined in advance by serial analysis of chimerism, and (2) if outcome can be influenced by withdrawal of immunosuppression and/or by low-dose donor lymphocyte infusion when increasing MC is detected. Patients and Methods Serial and quantitative analysis of chimerism was performed using a fluorescent-based short-tandem-repeat–polymerase chain reaction in 163 children with ALL. Results One hundred one patients revealed complete chimerism (CC) or low-level MC (CC/low-level MC); increasing MC was found in 46 patients; and decreasing MC, in 16 patients. Relapse was significantly more frequent in patients with increasing MC (26 of 46) than in patients with CC/low-level MC (eight of 101) or in patients with decreasing MC (0 of 16; P &lt; .0001). The probability of 3-year event-free survival (EFS) was 54% for all patients, 66% for patients with CC/low-level MC (n = 101), 66% for patients with decreasing MC (n = 16), and 23% for patients with increasing MC (n = 46; P &lt; .0001). Of the 46 patients with increasing MC, 31 received immunotherapy. This group had a significantly higher 3-year EFS estimate (37%) than the 15 patients who did not receive immunotherapy (0%; P &lt; .001). Conclusion Serial analysis of chimerism reliably identifies patients at highest risk to relapse. The 3-year EFS of patients with increasing MC without immunotherapy was 0%, by which overt relapse could be prevented in a considerable group of patients.
Ocular complications of boxing
Authors: M Bianco, A S Vaiano, F Colella, F Coccimiglio, M Moscetti, V Palmieri, F Focosi, P Zeppilli
Journal: British Journal of Sports Medicine (2005)

To investigate the prevalence of ocular injuries in a large population of boxers over a period of 16 years, in particular, the most severe lesions that may be vision threatening.Clinical records of the medical archive of the Italian Boxing Federation were analysed. A total of 1032 boxers were examined from February 1982 to October 1998. A complete ophthalmological history was available for 956, who formed the study population (a total of 10 697 examinations). The following data were collected: age when started boxing; duration of competitive boxing career (from the date of the first bout); weight category; a thorough ocular history. The following investigations were carried out: measurement of visual acuity and visual fields, anterior segment inspection, applanation tonometry, gonioscopy, and examination of ocular fundus. Eighty age matched healthy subjects, who had never boxed, formed the control group.Of the 956 boxers examined, 428 were amateur (44.8%) and 528 professional (55.2%). The median age at first examination was 23.1 (4.3) years (range 15-36). The prevalence of conjunctival, corneal, lenticular, vitreal, ocular papilla, and retinal alterations in the study population was 40.9% compared with 3.1% in the control group (p< or =0.0001). The prevalence of serious ocular findings (angle, lens, macula, and peripheral retina alterations) was 5.6% in boxers and 3.1% in controls (NS).Boxing does not result in a higher prevalence of severe ocular lesions than in the general population. However, the prevalence of milder lesions (in particular with regard to the conjunctiva and cornea) is noteworthy, justifying the need for adequate ophthalmological surveillance.
Recurrence of Crohn's disease after primary excisional surgery
Authors: F. T. De Dombal, I. Burton, J. C. Goligher
Journal: Gut (1971)

The problems associated with recurrent Crohn9s disease were examined in a series of 168 patients who had undergone primary resection for this condition at the General Infirmary at Leeds from 1939 to 1968 inclusive. The overall recurrence rate was 34·2%. The risk of recurrence was less in patients with involvement mainly of large bowel rather than small. It was also affected by the age of the patient, being greatest in children or adolescents, less in adults, and least in those over 60 years of age. Recurrent disease was most commonly found in the small bowel proximal to an anastomosis, and usually manifested itself either in the first year or two after surgery or some five to 15 years later. Patients with `early9 recurrence had a shorter history of symptoms at operation, and a graver outlook than those with `late9 recurrence. The status of recurrent cases was much better than might have been anticipated in so far as nearly 70% of them were considered at review to be in very good or good general health. Moreover the risk of further recurrence after a second or third operation was found to be no greater than after a first operation.
Vascular Cell Adhesion Molecule-1 Is a Regulator of Ovarian Cancer Peritoneal Metastasis
Authors: Jill K. Slack-Davis, Kristen A. Atkins, Christine Harrer, E. Daniel Hershey, Mark Conaway
Journal: Cancer Research (2009)

Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5-year survival <25%). Vascular cell adhesion molecule-1 (VCAM-1) is a cell surface receptor that mediates leukocyte attachment and extravasation across endothelial and mesothelial monolayers at sites of inflammation. Membranous VCAM-1 expression was observed on the mesothelium of 13 of 14 women with ovarian cancer compared with 6 of 15 who were cancer-free. Using a cell culture model system of mesothelial invasion, highly tumorigenic SKOV-3 and ES-2 cells were 2.5 to 3 times more efficient in transmigration through the mesothelial monolayer compared with poorly tumorigenic OVCAR-3 cells. Blocking antibodies to, or small interfering RNA knockdown of, VCAM-1 or its ligand alpha(4)beta(1) integrin significantly decreased, but did not completely inhibit, transmigration of SKOV-3 cells through mesothelial monolayers. Furthermore, using a mouse model of ovarian cancer metastasis, treatment with VCAM-1 function-blocking antibodies decreased tumor burden and increased survival. Together, these observations implicate VCAM-1-alpha(4)beta(1) integrin interactions in the regulation of ovarian cancer cell mesothelial invasion and metastatic progression and offer the possibility of novel therapeutic targets.