tbuckley/cabot-search huggingface dataset:
Abnormal Myocardial Presynaptic Norepinephrine Recycling in Patients With Brugada Syndrome
Authors: Peter Kies, Thomas Wichter, Michael Schäfers, Matthias Paul, Klaus P. Schäfers, Lars Eckardt, Lars Stegger, Eric Schulze-Bahr, Ornella Rimoldi, Günter Breithardt, Otmar Schober, Paolo G. Camici
Journal: Circulation (2004)

Life-threatening ventricular tachyarrhythmias can occur in young patients without structural heart disease (idiopathic forms). In many patients, these are typically triggered by an increased sympathetic tone, eg, by physical or mental stress. In contrast, in Brugada syndrome, ventricular tachyarrhythmias more often occur during rest or sleep when the vagal tone is predominant. Furthermore, adrenergic agonists can reduce the level of ST-segment elevation, whereas it is increased by parasympathetic agonists or adrenergic antagonists. The aim of this study was to investigate presynaptic and postsynaptic myocardial sympathetic function in patients with Brugada syndrome.Nine patients with Brugada syndrome (6 male, 3 female; age, 41+/-13 years) were enrolled in this study. The cardiac autonomic nervous system was assessed noninvasively, quantifying myocardial presynaptic and postsynaptic sympathetic function by means of positron emission tomography with the norepinephrine analogue 11C-Hydroxyephedrine (11C-HED) and the nonselective beta-blocker 11C-CGP 12177 (11C-CGP). Presynaptic sympathetic norepinephrine recycling, assessed by 11C-HED, was globally increased in patients with Brugada syndrome compared with a group of age-matched healthy control subjects (92.9+/-16.2 mL/g versus 69.1+/-14.2 mL/g; P<0.05), whereas postsynaptic beta-adrenoceptor density, assessed by 11C-CGP, was similar in patients and control subjects (10.4+/-6.7 pmol/g versus 10.2+/-2.9 pmol/g; P=NS).The present study on autonomic innervation in Brugada syndrome describes an enhanced presynaptic norepinephrine recycling with preserved beta-adrenoceptor density, further supporting the hypothesis of an autonomic dysfunction in Brugada syndrome. This is a further step toward the understanding of the pathophysiology of the disease with potential future impact on therapeutic strategies.
Markedly Reduced Expression of Platelet c-mpl Receptor in Essential Thrombocythemia
Authors: Yoko Horikawa, Itaru Matsumura, Koji Hashimoto, Masamichi Shiraga, Satoru Kosugi, Seiji Tadokoro, Takashi Kato, Hiroshi Miyazaki, Yoshiaki Tomiyama, Yoshiyuki Kurata, Yuji Matsuzawa, Yuzuru Kanakura
Journal: Blood (1997)
Randomized Comparison of Every-2-Week Darbepoetin Alfa and Weekly Epoetin Alfa for the Treatment of Chemotherapy-Induced Anemia: The 20030125 Study Group Trial
Authors: John Glaspy, Saroj Vadhan-Raj, Ravi Patel, Linda Bosserman, Eddie Hu, Richard E. Lloyd, Ralph V. Boccia, Dianne Tomita, Greg Rossi
Journal: Journal of Clinical Oncology (2006)

Purpose Chemotherapy-induced anemia is widely treated in the United States with darbepoetin alfa (DA) or epoetin alfa (EA). This noninferiority study systematically compares efficacy and safety of DA and EA using common doses and schedules used in clinical practice. Methods Patients had a diagnosis of nonmyeloid malignancy with ≥ 8 weeks of planned chemotherapy, age ≥ 18 years, and anemia (hemoglobin ≤ 11 g/dL). Patients were randomly assigned 1:1 to DA 200 μg every two weeks (Q2W) or EA 40,000 units every week (QW) for up to 16 weeks with identical dose adjustment rules. Efficacy was assessed by the incidence of RBC transfusion (Kaplan-Meier estimate). The definition of noninferiority was that the upper 95% CI limit of the observed difference in RBC transfusions between groups was less than 11.5%; this noninferiority margin was based on the treatment effect observed in placebo-controlled EA studies. Results Of 1,220 patients randomly assigned, 1,209 received ≥ one dose of the study drug. Common tumor types were lung (26%), breast (21%), and gastrointestinal (18%). Transfusion incidence from week 5 to the end of the treatment phase (the primary end point) was 21% in the DA group and 16% in the EA group; noninferiority was concluded because the upper 95% CI limit of the difference between groups (10.8%) was below the prespecified noninferiority margin. Sensitivity analyses using alternate statistical methods and analysis sets yielded similar results. Hemoglobin, quality of life, and safety end points further support equivalency of the erythropoietic therapies. Conclusion This large, phase III study demonstrates comparable efficacy of DA Q2W and EA QW. Less frequent dosing offers potential benefits for patients, caregivers and health care providers.
L-asparagine depletion and L-asparaginase activity in children with acute lymphoblastic leukemia receiving i.m. or i.v. Erwinia C. or E. coli L-asparaginase as first exposure
Authors: C. Rizzari, M. Zucchetti, V. Conter, L. Diomede, A. Bruno, L. Gavazzi, M. Paganini, P. Sparano, L. Lo Nigro, M. Aricò, M. Milani, M. D'lncalci
Journal: Annals of Oncology (2000)
Evaluation of a general practitioner with special interest service for dermatology: randomised controlled trial
Authors: Chris Salisbury, Alison Noble, Sue Horrocks, Zoe Crosby, Viv Harrison, Joanna Coast, David de Berker, Tim Peters
Journal: BMJ (2005)

<h3>Abstract</h3> <b>Objective</b> To assess the effectiveness, accessibility, and acceptability of a general practitioner with special interest service for skin problems compared with a hospital dermatology clinic. <b>Design</b> Randomised controlled trial. <b>Setting</b> General practitioner with special interest dermatology service and hospital dermatology clinic. <b>Participants</b> Adults referred to a hospital dermatology clinic and assessed by a consultant or the general practitioner with special interest service,. Suitable patients had non-urgent skin problems and had been identified from the referral letter as suitable for management by a general practitioner with special interest. <b>Interventions</b> Participants were randomised in 2:1 ratio to receive management by a general practitioner with special interest or usual hospital outpatient care. <b>Main outcome measures</b> Primary outcomes were disease related quality of life (dermatology life quality index) and improvement in patients9 perception of access to services, assessed nine months after randomisation. Secondary outcomes were patient satisfaction, preference for site of care, proportion of failed appointments, and waiting times to first appointment. <b>Results</b> 49% of the participants were judged suitable for care by the general practitioner with special interest service. Of 768 patients eligible, 556 (72.4%) were randomised (354 to general practitioner with special interest, 202 to hospital outpatient care). After nine months, 422 (76%) were followed up. No noticeable differences were found between the groups in clinical outcome (median dermatology life quality index score = 1 both arms, ratio of geometric means 0.99, 95% confidence interval 0.85 to 1.15). The general practitioner with special interest service was more accessible (difference between means on access scale 14, 11 to 19) and waited a mean of 40 (35 to 46) days less. Patients expressed slightly greater satisfaction with consultations with a general practitioner with special interest (difference in mean satisfaction score 4, 1 to 7), and at baseline and after nine months 61% said they preferred care at the service. <b>Conclusions</b> The general practitioner with special interest service for dermatology was more accessible and preferred by patients than hospital outpatient care, achieving similar clinical outcomes. <b>Trial registration</b>ISRCTN31962758.
Uncovering Molecular Mechanisms Involved in Activation of G Protein-Coupled Receptors
Authors: Ulrik Gether
Journal: Endocrine Reviews (2000)

G protein-coupled, seven-transmembrane segment receptors (GPCRs or 7TM receptors), with more than 1000 different members, comprise the largest superfamily of proteins in the body. Since the cloning of the first receptors more than a decade ago, extensive experimental work has uncovered multiple aspects of their function and challenged many traditional paradigms. However, it is only recently that we are beginning to gain insight into some of the most fundamental questions in the molecular function of this class of receptors. How can, for example, so many chemically diverse hormones, neurotransmitters, and other signaling molecules activate receptors believed to share a similar overall tertiary structure? What is the nature of the physical changes linking agonist binding to receptor activation and subsequent transduction of the signal to the associated G protein on the cytoplasmic side of the membrane and to other putative signaling pathways? The goal of the present review is to specifically address these questions as well as to depict the current awareness about GPCR structure-function relationships in general.
Induction of Apoptosis in Human Myeloid Leukemic Cells by 1′-Acetoxychavicol Acetate through a Mitochondrial- and Fas-Mediated Dual Mechanism
Authors: Keisuke Ito, Tomonori Nakazato, Akira Murakami, Kenji Yamato, Yoshitaka Miyakawa, Taketo Yamada, Nobumichi Hozumi, Hajime Ohigashi, Yasuo Ikeda, Masahiro Kizaki
Journal: Clinical Cancer Research (2004)

Abstract Purpose: The purpose of this investigation was to determine the antileukemic effects of 1′-acetoxychavicol acetate (ACA) obtained from rhizomes of the commonly used ethno-medicinal plant Languas galanga (Zingiberaceae). Experimental Design: We evaluated the effects of ACA on various myeloid leukemic cells in vitro and in vivo. We further examined the molecular mechanisms of ACA-induced apoptosis in myeloid leukemic cells. Results: Low-dose ACA dramatically inhibited cellular growth of leukemic cells by inducing apoptosis. Because NB4 promyelocytic leukemic cells were most sensitive to ACA, we used NB4 cells for further analyses. Production of reactive oxygen species triggered ACA-induced apoptosis. ACA-induced apoptosis in NB4 cells was in association with the loss of mitochondrial transmembrane potential (ΔΨm) and activation of caspase-9, suggesting that ACA-induced death signaling is mediated through a mitochondrial oxygen stress pathway. In addition, ACA activated Fas-mediated apoptosis by inducing of casapse-8 activity. Pretreatment with the thiol antioxidant N-acetyl-l-cysteine (NAC) did not inhibit caspase-8 activation, and the antagonistic anti-Fas antibody ZB4 did not block generation of reactive oxygen species, indicating that both pathways were involved independently in ACA-induced apoptosis. Furthermore, ACA had a survival advantage in vivo in a nonobese diabetic/severe combined immunodeficient mice leukemia model without any toxic effects. Conclusions: We conclude that ACA induces apoptosis in myeloid leukemic cells via independent dual pathways. In addition, ACA has potential as a novel therapeutic agent for the treatment of myeloid leukemia.
Dendritic Cell Vaccination with Xenogenic Polypeptide Hormone Induces Tumor Rejection in Neuroendocrine Cancer
Authors: Claudia Papewalis, Margret Wuttke, Jochen Seissler, Yvonne Meyer, Caroline Kessler, Benedikt Jacobs, Evelyn Ullrich, Holger S. Willenberg, Sven Schinner, Thomas Baehring, Werner A. Scherbaum, Matthias Schott
Journal: Clinical Cancer Research (2008)

Abstract Purpose: No relevant breakthrough has yet been achieved in the identification of tumor antigens in many neuroendocrine cancer types that exist, such as malignant gastrinoma, insulinoma, or medullary thyroid carcinoma. The aim of this study was to proof the concept of dendritic cell immunization with a tumor cell-specific polypeptide hormone as a target molecule in a transgenic mouse model for medullary thyroid carcinoma (Ret/Cal mice). Experimental Design: Ret/Cal mice were repeatedly immunized for up to 6 months with amino acid–modified (xenogenic) calcitonin-pulsed dendritic cells. Xenogenic calcitonin was chosen for immunization due to its higher immunogenicity as compared with murine calcitonin. Results: Lymph nodes from control protein-immunized mice did not show any macroscopic abnormalities, whereas tumor peptide-treated mice revealed in general profoundly enlarged lymph nodes. In tetramer analysis of paratumorous lymph nodes, 1.9% to 3.1% of all infiltrating CD8+ T cells were specific for one of three tumor epitopes tested. Analysis of the activated IFN-γ-secreting component in splenic cells revealed an average of 2.8% tumor epitope-specific CD8+ cells. Immunohistochemistry revealed strong CD8+ tumor infiltration in calcitonin-vaccinated mice. In addition, these cells also showed strong in vitro lysis capacity at up to 63.3%. Most importantly, calcitonin-immunized mice revealed largely diminished tumor outgrowth (−74.3%) compared with control mice (P &amp;lt; 0.0001). Likewise, serum calcitonin levels in calcitonin-vaccinated Ret/Cal mice were lower than in the control group. Conclusion: These results have a major effect, as they are the first to establish a role for xenogenic polypeptide hormones as target molecules for immunotherapy in endocrine malignancies.
<i>IDH1</i> Mutation Induces Reprogramming of Pyruvate Metabolism
Authors: Jose L. Izquierdo-Garcia, Pavithra Viswanath, Pia Eriksson, Larry Cai, Marina Radoul, Myriam M. Chaumeil, Michael Blough, H. Artee Luchman, Samuel Weiss, J. Gregory Cairncross, Joanna J. Phillips, Russell O. Pieper, Sabrina M. Ronen
Journal: Cancer Research (2015)

Mutant isocitrate dehydrogenase 1 (IDH1) catalyzes the production of 2-hydroxyglutarate but also elicits additional metabolic changes. Levels of both glutamate and pyruvate dehydrogenase (PDH) activity have been shown to be affected in U87 glioblastoma cells or normal human astrocyte (NHA) cells expressing mutant IDH1, as compared with cells expressing wild-type IDH1. In this study, we show how these phenomena are linked through the effects of IDH1 mutation, which also reprograms pyruvate metabolism. Reduced PDH activity in U87 glioblastoma and NHA IDH1 mutant cells was associated with relative increases in PDH inhibitory phosphorylation, expression of pyruvate dehydrogenase kinase-3, and levels of hypoxia inducible factor-1α. PDH activity was monitored in these cells by hyperpolarized (13)C-magnetic resonance spectroscopy ((13)C-MRS), which revealed a reduction in metabolism of hyperpolarized 2-(13)C-pyruvate to 5-(13)C-glutamate, relative to cells expressing wild-type IDH1. (13)C-MRS also revealed a reduction in glucose flux to glutamate in IDH1 mutant cells. Notably, pharmacological activation of PDH by cell exposure to dichloroacetate (DCA) increased production of hyperpolarized 5-(13)C-glutamate in IDH1 mutant cells. Furthermore, DCA treatment also abrogated the clonogenic advantage conferred by IDH1 mutation. Using patient-derived mutant IDH1 neurosphere models, we showed that PDH activity was essential for cell proliferation. Taken together, our results established that the IDH1 mutation induces an MRS-detectable reprogramming of pyruvate metabolism, which is essential for cell proliferation and clonogenicity, with immediate therapeutic implications.
The Intraepithelial Lesion: More Problems and Few Data
Authors: R. Marshall Austin
Journal: JAMA (1990)

To the Editor.—  I recently read with interest the article by Dr Ohrt 1 and his reply to the letter by Dr Keffer. 2 I was particularly interested in his comments on the preferred method of follow-up for mild atypias not diagnostic for dysplasia. He stated: Many of us are confident that mild atypia does regress spontaneously in a large majority of cases and that those cases that fail to regress can be followed up successfully with repeated testing and treatment. I am not aware of data that suggest that this type of conservative management should be abandoned.  Dr Ohrt's attention should be drawn to the work of Jones and Creasman 3 entitled Evaluation of the Atypical Pap Smear. The authors studied 236 consecutively referred patients with atypical but not dysplastic Papanicolaou smears, found 58 follow-up biopsyproved cases of dysplasia (25%), and noted that repeated Papanicolaou smears identified only
Genetically Modified T cells Targeting Interleukin-11 Receptor α-Chain Kill Human Osteosarcoma Cells and Induce the Regression of Established Osteosarcoma Lung Metastases
Authors: Gangxiong Huang, Ling Yu, Laurence J.N. Cooper, Mario Hollomon, Helen Huls, Eugenie S. Kleinerman
Journal: Cancer Research (2011)

The treatment of osteosarcoma pulmonary metastases remains a challenge. T cells genetically modified to express a chimeric antigen receptor (CAR), which recognizes a tumor-associated antigen, have shown activity against hematopoietic malignancies in clinical trials, but this requires the identification of a specific receptor on the tumor cell. In the current study, we found that interleukin (IL)-11Rα was selectively expressed on 14 of 16 osteosarcoma patients' lung metastases and four different human osteosarcoma cell lines, indicating that IL-11Rα may be a novel target for CAR-specific T-cell therapy. IL-11Rα expression was absent or low in normal organ tissues, with the exception of the gastrointestinal tract. IL-11Rα-CAR-specific T cells were obtained by non-viral gene transfer of Sleeping Beauty DNA plasmids and selectively expanded ex vivo using artificial antigen-presenting cells derived from IL-11Rα + K562 cells genetically modified to coexpress T-cell costimulatory molecules. IL-11Rα-CAR(+) T cells killed all four osteosarcoma cell lines in vitro; cytotoxicity correlated with the level of IL-11Rα expression on the tumor cells. Intravenous injection of IL-11Rα-CAR(+) T cells into mice resulted in the regression of osteosarcoma pulmonary metastases with no organ toxicity. Together, the data suggest that IL-11Rα-CAR T cells may represent a new therapy for patients with osteosarcoma pulmonary metastases.
Faster time to peak tension and velocity of shortening in right versus left ventricular trabeculae and papillary muscles of dogs.
Authors: J L Rouleau, P Paradis, H Shenasa, C Juneau
Journal: Circulation Research (1986)

Some of the mechanical characteristics of papillary muscles and trabeculae (n = 14) isolated from the free wall of the right ventricle of dogs were compared to those obtained from the free wall of the left ventricle (n = 14). Peak total tension (7.2 +/- 1.6 versus 7.9 +/- 1.7 g/mm2, p = NS) and peak velocity of tension development (31 +/- 8 vs. 28 +/- 4 g/mm2/sec, p = NS) were similar in both groups of muscles. However, right ventricular muscles shortened faster over nearly all loading conditions, and during isometric contraction, their time to attain peak total tension was shorter (336 +/- 26 vs. 401 +/- 42 msec, p less than 0.005) than that of left ventricular muscles. Varying stimulation rates (6, 12, 24, and 36 stimuli/min), increasing calcium concentration from 2.54 to 6.35 mM or adding norepinephrine 50 microM, did not significantly alter these differences. There were no differences in myosin isozymes (V1, V2, or V3) between ventricles to explain these differences. These results indicate that important mechanical differences exist between right and left ventricular myocardium and that these differences should be considered when extrapolations are made from myocardium of one area of the heart to another.
Immune Regulatory Function of B Cells
Authors: Claudia Mauri, Anneleen Bosma
Journal: Annual Review of Immunology (2012)

B cells are regarded for their capacity to produce antibody. However, recent advances in B cell biology have capitalized on old findings and demonstrated that B cells also release a broad variety of cytokines. As with T helper cells, B cells can be classified into subsets according to the cytokine milieu that they produce. One functional B cell subset, regulatory B cells (Bregs), has recently been shown to contribute to the maintenance of the fine equilibrium required for tolerance. Bregs restrain the excessive inflammatory responses that occur during autoimmune diseases or that can be caused by unresolved infections. Pivotal to Breg function is interleukin-10 (IL-10), which inhibits proinflammatory cytokines and supports regulatory T cell differentiation. This review reports and discusses the factors that are important for Breg differentiation and for their effector function in both mouse and human.
Clinical outcomes in relation to the daily dose of recombinant follicle-stimulating hormone for ovarian stimulation in in vitro fertilization in presumed normal responders younger than 39 years: a meta-analysis
Authors: M. D. Sterrenburg, S. M. Veltman-Verhulst, M. J. C. Eijkemans, E. G. Hughes, N. S. Macklon, F. J. Broekmans, B. C. J. M. Fauser
Journal: Human Reproduction Update (2010)

The optimal ovarian stimulation dose to obtain the best balance between the probability of pregnancy and the risk of complications, while maximizing cost-effectiveness of in vitro fertilization (IVF) treatment, is yet to be established.A systematic search of the electronic databases PubMed, EMBASE and Cochrane library, from 1984 until October 2009 for randomized controlled trials comparing different doses of recombinant FSH in IVF, was performed.Ten studies (totaling 1952 IVF cycles) were included in the present meta-analysis, comprising patients younger than 39 years with regular menstrual cycle, normal basal FSH levels and two normal ovaries. Comparison was made between studies using a daily dose of 100 versus 200 IU recFSH, and between 150 versus 200 IU recFSH or higher. Although oocyte yield was greater in the >200 IU/day dose group, pregnancy rates were similar compared with lower dose groups. The risk of insufficient response to ovarian stimulation was greatest in the 100 IU/day dose group. The risk of developing ovarian hyperstimulation syndrome was greater in the >200 IU/day dose group. The number of embryos available for cryopreservation was lowest in the 100 IU/day group, but similar comparing the 150 IU/day and the >200 IU/day dose groups.This meta-analysis suggests that the optimal daily recFSH stimulation dose is 150 IU/day in presumed normal responders younger than 39 years undergoing IVF. Compared with higher doses, this dose is associated with a slightly lower oocyte yield, but similar pregnancy and embryo cryopreservation rates. Furthermore, the wide spread adherence to this optimal dose will allow for a considerable reduction in IVF costs and complications.
Multicentric, Randomized, Controlled Trial to Evaluate Blood Glucose Control by the Model Predictive Control Algorithm Versus Routine Glucose Management Protocols in Intensive Care Unit Patients
Authors: Jack J.M. Ligtenberg, John H. Meertens, Wilma E. Monteban-Kooistra, Jaap E. Tulleken, Jan G. Zijlstra
Journal: Diabetes Care (2006)

In the February issue of Diabetes Care , Plank et al. (1) reported the results of their computer-assisted model predictive control (MPC) algorithm versus routine glucose management in 60 postoperative thoracosurgical patients in three different hospitals. We agree that better glycemic control is worth …
Study of human liver disease with P-31 magnetic resonance spectroscopy.
Authors: R Oberhaensli, B Rajagopalan, G J Galloway, D J Taylor, G K Radda
Journal: Gut (1990)

Liver metabolism and energetics of 24 patients with liver disease were studied using phosphorus-31 magnetic resonance spectroscopy. Significant abnormalities were detected in the majority of these patients. A striking diversity in metabolic patterns was observed. Patients with acute viral hepatitis had low liver phosphodiesters and high phosphomonoesters, possibly phosphocholine and phosphoethanolamine. In alcoholic hepatitis phosphomonoesters were raised. Intracellular inorganic phosphate and inorganic phosphate/ATP ratios were decreased in primary biliary cirrhosis and in some patients with hepatitis. These spectroscopic results were evaluated in respect of the pattern of liver damage and cellular regeneration. Liver tumours had raised phosphomonoesters and also showed evidence for altered spin-lattice relaxation of the phosphorus nucleus in various metabolites. In iron overload the liver ATP resonances were broadened. The line broadening correlated with the degree of iron overload suggesting the potential use of P-31 magnetic resonance spectroscopy for measuring liver iron.