tbuckley/cabot-search huggingface dataset:
PTEN promoter methylation and activation of the PI3K/Akt/mTOR pathway in pediatric gliomas and influence on clinical outcome
Authors: S. Mueller, J. Phillips, A. Onar-Thomas, E. Romero, S. Zheng, J. K. Wiencke, S. M. McBride, C. Cowdrey, M. D. Prados, W. A. Weiss, M. S. Berger, N. Gupta, D. A. Haas-Kogan
Journal: Neuro-Oncology (2012)

The signaling pathways that underlie the pathogenesis of pediatric gliomas are poorly understood. We characterized the PI3K/Akt/mTOR pathway in pediatric gliomas of all grades. Using immunohistochemistry, we assessed activation of the PI3K/Akt/mTOR pathway by evaluating the downstream signaling molecules phospho(p)-S6, phospho(p)-4BP1, and phospho(p)-PRAS40; PTEN; and PTEN promoter methylation, as well as the MIB labeling index. We correlated these findings with the clinical outcomes of 48 children with gliomas. Eighty percent of high-grade gliomas (12/15) showed activation of the PI3K/Akt/mTOR pathway based on p-S6 and p-4EBP1 expression. The majority of high-grade gliomas were negative for PTEN expression (10/15), and 50% had PTEN promoter methylation (grade III: 2/4; grade IV: 3/6). Low-grade gliomas demonstrated PI3K/Akt/mTOR pathway activation in 14/32 (43.8%) by p-S6 and 16/32 (50%) by p-4EBP1. Over 50% of grade I (6/11) and almost all grade II tumors (6/7) showed PTEN promoter methylation. Tumor grade correlated negatively with PTEN expression and positively with expression of p-S6 and p-4EBP1 (PTEN: P = .0025; pS6: P = .0075; p-4EBP1: P = .0066). There was a trend toward inverse correlation of methylation of the PTEN promoter with expression of PTEN protein (P= .0990) and direct correlation of expression of p-S6 and p-4EBP1 with poorer clinical outcome, as measured by progression-free survival (p-S6: P= .0874; p-4EBP1: P= .0475). Tumors with no PTEN expression had a higher MIB labeling index (P= .007). The majority of pediatric gliomas show activation of the PI3K/Akt/mTOR pathway, with methylation of the PTEN promoter occurring commonly in these tumors.
Additional Antiproteinuric Effect of Ultrahigh Dose Candesartan
Authors: Roland E. Schmieder, Arnfried U. Klingbeil, Erwin H. Fleischmann, Roland Veelken, Christian Delles
Journal: Journal of the American Society of Nephrology (2005)

Proteinuria indicates future renal and cardiovascular morbidity, and, conversely, its reduction is associated with improved outcome. In a randomized, double-blind trial with parallel group design, the antiproteinuric effect of candesartan at high doses was analyzed. Patients with normal or mildly impaired renal function, protein excretion rate of 1 to 10 g/d, and treatment with an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker for 3 mo were eligible. After a 4-wk treatment with 16 mg/d candesartan, patients (n = 32) were allocated to double-blind therapy with either 32 or 64 mg/d candesartan for 12 wk (including 4 wk of uptitration), followed again by 4 wk of candesartan 16 mg/d. Proteinuria at study entry was similar in both groups (geometric mean [95% confidence interval (CI)]; 32 mg/d candesartan 2.14 g/d [95% CI, 1.45 to 3.17]; 64 mg/d candesartan 2.54 g/d [95% CI, 1.91 to 3.40]; NS). After the double-blind treatment phase, proteinuria was reduced to 1.42 g/d (0.85 to 2.37) in the 64-mg/d group (P = 0.017), without any change in the 32-mg/d group (2.02 g/d [95% CI, 1.26 to 3.26]). The change in proteinuria differed between the two groups in absolute (P = 0.025) and relative terms (-29 +/- 50 versus -0 +/- 26%; P = 0.012). After downtitration to 16 mg/d candesartan, proteinuria increased again to 2.38 g/d (1.57 to 3.62) in the 64-mg/d group (P = 0.001) but remained unchanged in the 32-mg/d group (2.04 g/d [95% CI, 1.17 to 3.57]; NS). No change in BP was noticed in response to the different doses of candesartan. These data indicate an additive antiproteinuric effect of ultrahigh dose of the angiotensin receptor blocker candesartan compared with standard dose.
Ischaemic Heart Disease and Pregnancy
Authors: H. O. Nicholson
Journal: BMJ (1965)

latrogenic Ulcers of the Small Intestine SIR,--We should like to report another possible case of ileal ulceration and perforation in a patient receiving enteric-coated potassium-chloride tablets but not chlorothiazide.In June, 1964, a woman aged 58 was diagnosed as having pemphigus vulgaris.
Guidelines for initiation of anti-tumour necrosis factor therapy in rheumatoid arthritis: similarities and differences across Europe: Table 1
Authors: P Emery, R Van Vollenhoven, M Ostergaard, E Choy, B Combe, W Graninger, K Krueger, M Matucci-Cerinic, F Navarro, P van Riel, L Settas, S Steinfeld
Journal: Annals of the Rheumatic Diseases (2009)

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease. In the majority of patients the course is progressive and leads to destruction of joints, functional disability, reduced quality of life and increased morbidity and mortality. Advances in treatment for RA have been associated with an improvement in the health status of patients with RA in recent years.1 While the management of RA varies widely across Europe,2 the underlying pathophysiology does not differ between countries. A cross-sectional comparison of patients with RA in 15 different countries (largely European) revealed great variation in the drug management of patients with RA, including the delay in starting a disease-modifying antirheumatic drug (DMARD) ranging from  12 months, use of methotrexate ( 40% in France and Ireland vs. <10% in Serbia and Poland).3 It is also noteworthy that disease activity scores varied and were highest, on average, in Serbia and Poland.3

Although tumour necrosis factor (TNF) inhibitors have undoubtedly significantly advanced the treatment of RA, they are a higher cost treatment option and may not be suitable for all patients.4 Hence, guidelines have been developed in order to assist the appropriate use of TNF inhibitors within individual countries.

In order to establish the level of access to TNF inhibitors across Europe, European guidelines were translated and reviewed with regard to their similarities and differences in the recommended criteria for the initiation of TNF inhibition. Particular attention was paid to recommended duration of disease and prior treatment with DMARDs, as well as disease activity levels.

The guidelines selected for inclusion were those from Belgium,5 Czech Republic,6 Denmark,7 France,8 9 Germany,10 Italy,11 Romania,12 Spain,13 Sweden14 and the …
Th1 Adaptive Immune Responses in Cardiac Graft Arteriosclerosis
Authors: George Tellides
Journal: Circulation (2006)

eart transplants are not rejected in the absence of adaptive immune responses, eg, in transplantations between genetically identical donors and hosts or to recipients with severe combined immunodeficiencies.Activation of adaptive immunity to an allograft causes destructive responses against donor parenchymal or vascular cells, called acute rejection.In the presence of adequate immunosuppression, acute rejection is suppressed; however, chronic rejection may occur, manifesting as conduit arterial lumen loss resulting from expansion of the tunica intima and remodeling of vessel size, called graft arteriosclerosis. 1 The differences in pathological findings and in sensitivity to immunosuppressive agents suggest that chronic graft failure arises from different mechanisms operative in separate allograft compartments than in acute graft rejection.The precise pathogenesis of graft arteriosclerosis is unknown, although there is broad consensus that it is, at least in part, an alloimmune process in that the arteriosclerotic changes are limited to the vascular bed of the allograft and spare the host vasculature.Adaptive immunity may activate a variety of effector mechanisms that cause chronic graft rejection in murine transplantation models. 1 Although it is not the only factor that can cause graft arteriosclerosis, the evidence for the signature Th1 cytokine, interferon (IFN)-␥, is particularly compelling.In mouse transplantation models, serological neutralization or the genetic absence of IFN-␥ reduces intimal expansion of graft arteries. 2,3Moreover, in a chimeric human-mouse model, antibody neutralization of IFN-␥ prevents allogeneic T cellmediated endothelial dysfunction, intimal thickening, and outward vascular remodeling; administration of IFN-␥ accelerates these effects; and exogenous IFN-␥ in the absence of leukocytes is sufficient to cause the arteriosclerotic changes. 4 -6However, definitive evidence for a pathogenetic role of IFN-␥ in clinical cardiac transplantation is lacking.
Cellular Origins of Type IV Collagen Networks in Developing Glomeruli
Authors: Dale R Abrahamson, Billy G Hudson, Larysa Stroganova, Dorin-Bogdan Borza, Patricia L St John
Journal: Journal of the American Society of Nephrology (2009)

Laminin and type IV collagen composition of the glomerular basement membrane changes during glomerular development and maturation. Although it is known that both glomerular endothelial cells and podocytes produce different laminin isoforms at the appropriate stages of development, the cellular origins for the different type IV collagen heterotrimers that appear during development are unknown. Here, immunoelectron microscopy demonstrated that endothelial cells, mesangial cells, and podocytes of immature glomeruli synthesize collagen alpha 1 alpha 2 alpha1(IV). However, intracellular labeling revealed that podocytes, but not endothelial or mesangial cells, contain collagen alpha 3 alpha 4 alpha 5(IV). To evaluate the origins of collagen IV further, we transplanted embryonic kidneys from Col4a3-null mutants (Alport mice) into kidneys of newborn, wildtype mice. Hybrid glomeruli within grafts containing numerous host-derived, wildtype endothelial cells never expressed collagen alpha 3 alpha 4 alpha 5(IV). Finally, confocal microscopy of glomeruli from infant Alport mice that had been dually labeled with anti-collagen alpha 5(IV) and the podocyte marker anti-GLEPP1 showed immunolabeling exclusively within podocytes. Together, these results indicate that collagen alpha 3 alpha 4 alpha 5(IV) originates solely from podocytes; therefore, glomerular Alport disease is a genetic defect that manifests specifically within this cell type.
AS1411 Alters the Localization of a Complex Containing Protein Arginine Methyltransferase 5 and Nucleolin
Authors: Yun Teng, Allicia C. Girvan, Lavona K. Casson, William M. Pierce, Mingwei Qian, Shelia D. Thomas, Paula J. Bates
Journal: Cancer Research (2007)

Abstract AS1411 is a quadruplex-forming oligonucleotide aptamer that targets nucleolin. It is currently in clinical trials as a treatment for various cancers. We have proposed that AS1411 inhibits cancer cell proliferation by affecting the activities of certain nucleolin-containing complexes. Here, we report that protein arginine methyltransferase 5 (PRMT5), an enzyme that catalyzes the formation of symmetrical dimethylarginine (sDMA), is a nucleolin-associated protein whose localization and activity are altered by AS1411. Levels of PRMT5 were found to be decreased in the nucleus of AS1411-treated DU145 human prostate cancer cells, but increased in the cytoplasm. These changes were dependent on nucleolin and were not observed in cells pretreated with nucleolin-specific small interfering RNA. Treatment with AS1411 altered levels of PRMT5 activity (assessed by sDMA levels) in accord with changes in its localization. In addition, our data indicate that nucleolin itself is a substrate for PRMT5 and that distribution of sDMA-modified nucleolin is altered by AS1411. Because histone arginine methylation by PRMT5 causes transcriptional repression, we also examined expression of selected PRMT5 target genes in AS1411-treated cells. For some genes, including cyclin E2 and tumor suppressor ST7, a significant up-regulation was noted, which corresponded with decreased PRMT5 association with the gene promoter. We conclude that nucleolin is a novel binding partner and substrate for PRMT5, and that AS1411 causes relocalization of the nucleolin-PRMT5 complex from the nucleus to the cytoplasm. Consequently, the nuclear activity of PRMT5 is decreased, leading to derepression of some PRMT5 target genes, which may contribute to the biological effects of AS1411.
Factors influencing options in primary breast cancer treatment.
Authors: W H Wolberg, M A Tanner, E P Romsaas, D L Trump, J F Malec
Journal: Journal of Clinical Oncology (1987)

Primary breast cancer treatment is determined by tumor factors and by patient preference. Breast cancer treatments that preserve the cosmetic appearance of the breast are appealing and effective for appropriately selected patients; long-term survival following tumor excision and breast irradiation appears to be comparable to that for mastectomy. Since April 1981, when a protocol was developed and treatment options were offered, factors influencing treatment selection have been analyzed in 206 consecutive primary breast cancer patients. Mastectomy was dictated by tumor-related factors in 96 patients (47%); 110 patients (53%) had the option of mastectomy or conservation--tumor excision plus radiotherapy to the breast. Among these 110 eligible patients, 54 chose conservation (49%) and 56 chose mastectomy (51%). Intraoperative findings for ten patients electing conservation necessitated mastectomy, so conservation was accomplished for 44 (21%) of those treated for breast cancer. Beginning in July 1982, breast cancer patients took a battery of psychosexual assessments before any operation (Profile of Mood States [POMS], Health Locus of Control Scale [HLCS] Locke-Wallace Marital Adjustment Test [MAT], Psychosocial Adjustment to Illness Scale [PAIS], Derogatis Sexual Function Inventory [DSFI], Millon Clinical Multiaxial Inventory [MCMI], and a Breast Cancer Information Test [BCIT]). Comparisons of psychologic and demographic variables were made between patients who chose mastectomy and those who chose conservation. No demographic variable was statistically significantly related to choice, although older women tended to select mastectomy more than younger women. Compared with those who elected conservation, women who elected mastectomy were more tense and anxious (P less than .01), more introverted (P less than .01), felt more depressed and dejected (P less than .05), and reported more sexual problems (P less than .05). Those who elected conservation valued their physical appearance more highly (P less than .01) and were generally more self-interested (P less than .05). Mastectomy was dictated by medical considerations for approximately half of patients with breast cancer. Among candidates for breast conservation, the importance of retaining the breast appeared to be determined to a significant degree by measurable psychological factors.
Early Increase in Blood Glucose in Patients Resuscitated From Out-of-Hospital Ventricular Fibrillation Predicts Poor Outcome
Authors: Jouni Nurmi, James Boyd, Niko Anttalainen, Jukka Westerbacka, Markku Kuisma
Journal: Diabetes Care (2012)

To describe the trend of blood glucose immediately after successful resuscitation from out-of-hospital ventricular fibrillation.Data from cardiac arrest registry supplemented with blood glucose data were analyzed in this population-based observational study. Between 2005 and 2009, a total of 170 adult patients survived to hospital admission after resuscitation from bystander-witnessed cardiac arrest of cardiac origin and ventricular fibrillation as an initial rhythm.Sufficient data for analysis were available in 134 (79%) patients, of whom 87 (65% [95% CI 57-73]) survived to hospital discharge in Cerebral Performance Category 1 or 2. Blood glucose did not change significantly between prehospital (10.5 ± 4.1 mmol/L) and admission (10.0 ± 3.7 mmol/L) in survivors (P = 0.3483), whereas in nonsurvivors, blood glucose increased from 11.8 ± 4.6 to 13.8 ± 3.3 mmol/L (P = 0.0025).Patients who are resuscitated from out-of-hospital ventricular fibrillation, but whose outcome is unfavorable are characterized by significant increase of blood glucose in the ultraacute postresuscitation phase.
On the Role of Ca <sup>2+</sup> - and Voltage-Dependent Inactivation in Ca <sub>v</sub> 1.2 Sensitivity for the Phenylalkylamine (-)Gallopamil
Authors: Stanislav Sokolov, Eugen Timin, Steffen Hering
Journal: Circulation Research (2001)

Abstract— L-type calcium channels (Ca v 1.m) inactivate in response to elevation of intracellular Ca 2+ (Ca 2+ -dependent inactivation) and additionally by conformational changes induced by membrane depolarization (fast and slow voltage-dependent inactivation). Molecular determinants of inactivation play an essential role in channel inhibition by phenylalkylamines (PAAs). The relative impacts, however, of Ca 2+ -dependent and voltage-dependent inactivation in Ca v 1.2 sensitivity for PAAs remain unknown. In order to analyze the role of the different inactivation processes, we expressed Ca v 1.2 constructs composed of different β-subunits (β 1a -, β 2a -, or β 3 -subunit) in Xenopus oocytes and estimated their (-)gallopamil sensitivity by means of the two-microelectrode voltage clamp with either Ba 2+ or Ca 2+ as charge carrier. Ca v 1.2 consisting of the β 2a -subunit displayed the slowest inactivation and the lowest apparent sensitivity for the PAA (-)gallopamil. A significantly higher apparent (-)gallopamil-sensitivity with Ca 2+ as charge carrier was observed for all 3 β-subunit compositions. The kinetics of Ca 2+ -dependent inactivation and slow voltage-dependent inactivation were not affected by drug. The higher sensitivity of the Ca v 1.2 channels for (-)gallopamil with Ca 2+ as charge carrier results from slower recovery (τ rec,Ca ≈15 seconds versus τ rec,Ba ≈3 to 5 seconds) from a PAA-induced channel conformation. We propose a model where (-)gallopamil promotes a fast voltage-dependent component in Ca v 1.2 inactivation. The model reproduces the higher drug sensitivity in Ca 2+ as well as the lower sensitivity of slowly inactivating Ca v 1.2 composed of the β 2a -subunit.
HG-829 Is a Potent Noncompetitive Inhibitor of the ATP-Binding Cassette Multidrug Resistance Transporter <i>ABCB1</i>
Authors: Gisela Caceres, Robert W. Robey, Lubomir Sokol, Kathy L. McGraw, Justine Clark, Nicholas J. Lawrence, Said M. Sebti, Michael Wiese, Alan F. List
Journal: Cancer Research (2012)

Transmembrane drug export mediated by the ATP-binding cassette (ABC) transporter P-glycoprotein contributes to clinical resistance to antineoplastics. In this study, we identified the substituted quinoline HG-829 as a novel, noncompetitive, and potent P-glycoprotein inhibitor that overcomes in vitro and in vivo drug resistance. We found that nontoxic concentrations of HG-829 restored sensitivity to P-glycoprotein oncolytic substrates. In ABCB1-overexpressing cell lines, HG-829 significantly enhanced cytotoxicity to daunorubicin, paclitaxel, vinblastine, vincristine, and etoposide. Coadministration of HG-829 fully restored in vivo antitumor activity of daunorubicin in mice without added toxicity. Functional assays showed that HG-829 is not a Pgp substrate or competitive inhibitor of Pgp-mediated drug efflux but rather acts as a noncompetitive modulator of P-glycoprotein transport function. Taken together, our findings indicate that HG-829 is a potent, long-acting, and noncompetitive modulator of P-glycoprotein export function that may offer therapeutic promise for multidrug-resistant malignancies.
Current practices in determining return to play following head injury in professional football in the UK
Authors: Jo Price, Peter Malliaras, Zoe Hudson
Journal: British Journal of Sports Medicine (2012)

Objective To investigate the awareness of English football team doctors of the ‘Consensus in Sport’ (CIS) guidelines for the assessment and management of concussion, and to identify adherence to these internationally accepted recommendations. Method A questionnaire was sent to Club Medical Officers of all the 92 English Football league teams. Results The majority (55.6%) of teams in the English Football Association (FA) do not routinely follow the CIS guidelines. Only 21% of teams routinely record an approved preseason cognitive score and only 42% complete a recommended postconcussion assessment. One-third are still using outdated fixed periods of abstinence following a concussion. Conclusions FA players are not being treated according to the guidelines recommended by International sporting organisations. The endorsement of the CIS guidelines by the English FA would ensure that all medical teams have a sound and safe protocol for managing concussed players and making return to play decisions.
Phase II trial of first-line high-dose ifosfamide in advanced soft tissue sarcomas of the adult: A study of the Spanish Group for Research on Sarcomas (GEIS)
Authors: J.M. Buesa, A. López-Pousa, J. Martín, A. Antón, J. García del Muro, J. Bellmunt, F. Arranz, V. Valentí, P. Escudero, D. Menéndez, A. Casado, A. Poveda
Journal: Annals of Oncology (1998)
Ambulatory Ventricular Arrhythmias in Patients With Heart Failure Do Not Specifically Predict an Increased Risk of Sudden Death
Authors: John R. Teerlink, Muhammad Jalaluddin, Susan Anderson, Marrick L. Kukin, Eric J. Eichhorn, Gary Francis, Milton Packer, Barry M. Massie
Journal: Circulation (2000)

Background —Ventricular arrhythmias are a frequent finding in congestive heart failure (CHF) patients and a cause of concern for physicians caring for them. Previous studies have reached conflicting conclusions regarding the importance of ventricular arrhythmias as predictors of sudden death in patients with CHF. This study examined the independent predictive value of ventricular arrhythmias for sudden death and all-cause mortality in PROMISE (Prospective Randomized Milrinone Survival Evaluation). Methods and Results —Ventricular arrhythmias were analyzed and quantified by use of prespecified criteria on baseline ambulatory ECGs from 1080 patients with New York Heart Association (NYHA) class III/IV symptoms and a left ventricular ejection fraction ≤35% enrolled in PROMISE. The relationship of ventricular arrhythmias and other clinical parameters to overall mortality and sudden death classified by an independent, blinded mortality committee was determined. There were 290 deaths, of which 139 were classified as sudden. Of the several measures of ventricular ectopy that were univariate predictors, the frequency of nonsustained ventricular tachycardia (NSVT) was the most powerful predictor and remained a significant independent predictor when included with other clinical variables in multivariate models of both sudden death mortality and non–sudden death mortality. However, multiple logistic analysis with models including the clinical variables with and without the NSVT variable demonstrated that the frequency of NSVT did not add significant information beyond the clinical variables. Conclusions —This study demonstrates that ventricular arrhythmias do not specifically predict sudden death in patients with moderate-to-severe heart failure. Thus, the finding of asymptomatic NSVT on ambulatory ECG does not identify specific candidates for antiarrhythmic or device therapy.