tbuckley/cabot-search huggingface dataset:
Targeting the Angiopoietin/Tie2 Pathway: Cutting Tumor Vessels With a Double-Edged Sword?
Authors: Tina Cascone, John V. Heymach
Journal: Journal of Clinical Oncology (2011)

Article Tools UNDERSTANDING THE PATHWAY Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2011.38.7621 Journal of Clinical Oncology - published online before print December 19, 2011 PMID: 22184396 Targeting the Angiopoietin/Tie2 Pathway: Cutting Tumor Vessels With a Double-Edged Sword? Tina CasconexTina CasconeSearch for articles by this author , John V. HeymachxJohn V. HeymachSearch for articles by this author Show More The University of Texas MD Anderson Cancer Center, Houston, TX https://doi.org/10.1200/JCO.2011.38.7621 First Page Full Text PDF Figures and Tables Supplements © 2011 by American Society of Clinical Oncology
Plasma Adiponectin and Gastric Cancer
Authors: Makoto Ishikawa, Joji Kitayama, Shinsuke Kazama, Takeyuki Hiramatsu, Kenji Hatano, Hirokazu Nagawa
Journal: Clinical Cancer Research (2005)

Recently, increased body weight has been associated with an increased risk of cancers at multiple specific sites, including gastric cancer. Adiponectin is a peptide hormone secreted by adipose tissue, affecting the proliferation and insulin sensitivity of various types of cells. Moreover, the circulating level of adiponectin has been reported to be inversely related to body mass index.Fasting plasma levels of adiponectin were determined in 75 patients with gastric cancer and 52 healthy controls using an ELISA. In these patients, we analyzed the association between plasma adiponectin level and gastric cancer risk as well as various clinicopathologic characteristics.Plasma adiponectin level was significantly lower in patients with gastric cancer than in healthy controls (9.1 +/- 6.2 versus 13.3 +/- 9.4 ng/mL, P < 0.01) and showed a significant modest inverse relation with the gastric cancer (odds ratio, 0.92; 95% confidence interval, 0.85-0.97; adjusted odds ratio, 0.89; 95% confidence interval, 0.84-0.95], although body mass index was not different. In addition, adiponectin level was extremely low in patients with upper gastric cancers (upper, 5.5 +/- 4.1 ng/mL; middle, 9.7 +/- 6.4 ng/mL; lower, 10.7 +/- 4.1 ng/mL; P = 0.012). Furthermore, adiponectin level tended to decrease as the tumor stage increased (stage I, 9.9 +/- 6.9 ng/mL; stage II, 8.7 +/- 5.5 ng/mL; stage III, 8.6 +/- 4.1 ng/mL; stage IV, 5.2 +/- 6.2 ng/mL; P = 0.34). Interestingly, in 32 patients with undifferentiated cancer, serum adiponectin showed a negative correlation with pathologic findings such as tumor size, depth of invasion, as well as tumor stage (P < 0.05), but no correlation in the remaining 43 patients with differentiated cancer.Our results suggest that a low plasma adiponectin level is associated with an increased risk for gastric cancer and raise the possibility that adiponectin has a potential role in the progression of gastric cancer, especially in undifferentiated type cancers in the upper stomach.
Clinical Breast Examination: Preliminary Results from a Cluster Randomized Controlled Trial in India
Authors: R. Sankaranarayanan, K. Ramadas, S. Thara, R. Muwonge, J. Prabhakar, P. Augustine, M. Venugopal, G. Anju, B. S. Mathew
Journal: JNCI Journal of the National Cancer Institute (2011)

A cluster randomized controlled trial was initiated in the Trivandrum district (Kerala, India) on January 1, 2006, to evaluate whether three rounds of triennial clinical breast examination (CBE) can reduce the incidence rate of advanced disease incidence and breast cancer mortality. A total of 275 clusters that included 115 652 healthy women, aged 30–69 years, were randomly allocated to intervention (CBE; 133 clusters; 55 844 women) or control (no screening; 142 clusters; 59 808 women) groups. Performance characteristics (sensitivity, specificity, false-positive rate, and positive predictive value) of CBE were evaluated. An intention-to-treat analysis was performed for comparison of incidence rates between the intervention and control groups. Preliminary results for incidence are based on follow-up until May 31, 2009, when the first round of screening was completed. Of the 50 366 women who underwent CBE, 30 breast cancers were detected among 2880 women with suspicious findings in CBE screening that warranted further investigations. Sensitivity, specificity, false-positive rate, and positive predictive value of CBE were 51.7% (95% confidence interval [CI] = 38.2% to 65.0%), 94.3% (95% CI = 94.1% to 94.5%), 5.7% (95% CI = 5.5% to 5.9%), and 1.0% (95% CI = 0.7% to 1.5%), respectively. The age-standardized incidence rates for early-stage (stage IIA or lower) breast cancer were 18.8 and 8.1 per 100 000 women and for advanced-stage (stage IIB or higher) breast cancer were 19.6 and 21.7 per 100 000 women, in the intervention and control groups, respectively.
Fatal Pulmonary Reaction From Low Doses of Bleomycin
Authors: John R. lacovino
Journal: JAMA (1976)

There were two cases of fatal interstitial pneumonia secondary to bleomycin sulfate administration. Although bleomycin pulmonary toxicity is generally thought to be dose-related and occurs infrequently with a total cumulative dose less than 300 to 400 units, the two reactions reported here occurred with doses of 105 and 165 units. Fatal bleomycin-induced pneumonia has been previously reported at these low dosages, and physicians should be aware that this toxic reaction may occur as an idiosyncratic response. Previous thoracic irradiation may be a predisposing factor. Patients receiving bleomycin should be meticulously monitored by interrogation for cough, dyspnea, and chest pain; by auscultation for rales; by serial chest roentgenograms; and by determinations of vital capacity and single-breath carbon monoxide diffusing capacity. (<i>JAMA</i>235:1253-1255, 1976)
TB vaccine development: where are we and why is it so difficult?
Authors: M. E. M. Wilkie, H. McShane
Journal: Thorax (2014)

The development of an effective TB vaccine remains paramount to achieving the goal of global eradication of TB by 2050. The only licensed vaccine, BCG, has variable efficacy and is poorly effective in high burden countries. The development of promising candidate vaccines to either 'boost' a BCG primed immune system or replace BCG altogether is a key area for innovative research. Here, we discuss some of the issues encountered in the development of potential candidate vaccines and the future challenges.
Tumor Growth Enhances Cross-Presentation Leading to Limited T Cell Activation without Tolerance
Authors: Linh T. Nguyen, Alisha R. Elford, Kiichi Murakami, Kristine M. Garza, Stephen P. Schoenberger, Bernhard Odermatt, Daniel E. Speiser, Pamela S. Ohashi
Journal: The Journal of Experimental Medicine (2002)

Using a tumor model of spontaneously arising insulinomas expressing a defined tumor-associated antigen, we investigated whether tumor growth promotes cross-presentation and tolerance of tumor-specific T cells. We found that an advanced tumor burden enhanced cross-presentation of tumor-associated antigens to high avidity tumor-specific T cells, inducing T cell proliferation and limited effector function in vivo. However, contrary to other models, tumor-specific T cells were not tolerized despite a high tumor burden. In fact, in tumor-bearing mice, persistence and responsiveness of adoptively transferred tumor-specific T cells were enhanced. Accordingly, a potent T cell–mediated antitumor response could be elicited by intravenous administration of tumor-derived peptide and agonistic anti-CD40 antibody or viral immunization and reimmunization. Thus, in this model, tumor growth promotes activation of high avidity tumor-specific T cells instead of tolerance. Therefore, the host remains responsive to T cell immunotherapy.
Juvenile temporal arteritis and activated protein C resistance
Authors: B Granel
Journal: Annals of the Rheumatic Diseases (2004)

A high affinity binding site for [3H]dihydrotetrabenazine is thought to be present on the monoamine transport protein from chromaffin granules. We describe a procedure for purification of this binding activity from frozen bovine adrenal tissue, and we partially characterize the purified preparation. Binding activity solubilized with sodium cholate and soybean lecithin was fractionated on wheat germ lectin-Sepharose, phenyl-Sepharose, Mono Q, and hydroxylapatite. Denaturing electrophoresis of the purified binding activity, followed by silver staining, revealed a single broad band centered at an apparent molecular weight of 85,000. This preparation bound [3H]dihydrotetrabenazine with an apparent dissociation constant of 2.7 nM and had a site density of 10 nmol/mg. Treatment of the purified protein with neuraminidase reduced the apparent molecular weight by 9000, indicating the presence of terminal sialic acids on the oligosaccharide portion of this molecule.
Caveolae and sarcoplasmic reticular coupling in smooth muscle cells of pressurised arteries: The relevance for Ca2+ oscillations and tone
Authors: L SHAW, M SWEENEY, S ONEILL, C JONES, C AUSTIN, M TAGGART
Journal: Cardiovascular Research (2006)

A close association of caveolae and sarcoplasmic reticulum (SR) has been suggested to be important for contractile activation of smooth muscle. Here, we investigate the presence of such arrangements in pressurised resistance arteries and examine the influence of two agents purported to disrupt caveolae and/or SR conformations by different mechanisms of action.Rat mesenteric small arteries (RMSA) were mounted on a pressure myograph and the functional (lumen diameter and Ca(2+) oscillations) and ultrastructural effects of the phosphatase inhibitor calyculin-A (cal-A), or the cholesterol binding agent methyl-beta-cyclodextrin (mbetacd), examined by light and electron microscopy.Smooth muscle cells of RMSA exhibited a prominent peripheral SR that often encircled individual caveolae. The peripheral SR on occasion was observed to make contact with centrally located SR allowing for a structural association of caveoale-SR-myofilaments. Cal-A maximally constricted RMSA and disrupted the regular SR-caveolae appearance such that concentrated swirls of SR not enveloping caveolae were evident. Mbetacd treatment, in contrast, inhibited agonist contractility and reduced the appearance of caveolae whilst peripheral SR apposition to the plasmalemma could still be observed. Treatment with either agent inhibited agonist-mediated smooth muscle Ca(2+) oscillations.We present data that supports a structural arrangement of caveolae and underlying peripheral SR in smooth muscle cells of pressurised resistance arteries that serves to regulate Ca(2+) oscillations and contractile activation.
Deferasirox Reduces Serum Ferritin and Labile Plasma Iron in RBC Transfusion–Dependent Patients With Myelodysplastic Syndrome
Authors: Alan F. List, Maria R. Baer, David P. Steensma, Azra Raza, Jason Esposito, Noelia Martinez-Lopez, Carole Paley, John Feigert, Emmanuel Besa
Journal: Journal of Clinical Oncology (2012)

This 3-year, prospective, multicenter trial assessed the safety and efficacy of deferasirox in low- or intermediate-1-risk myelodysplastic syndrome (MDS).Eligible patients had serum ferritin ≥ 1,000 μg/L and had received ≥ 20 units of RBCs with ongoing transfusion requirements. The starting dose of deferasirox was 20 mg/kg/d, with dose escalation up to 40 mg/kg/d permitted.A total of 176 patients were enrolled, and 173 patients received therapy. Median serum ferritin decreased 23% in the 53% of patients who completed 12 months of treatment (n = 91), 36.7% in patients who completed 2 years (n = 49), and 36.5% in patients who completed 3 years (n = 33) despite continued transfusion requirement. Reduction in serum ferritin significantly correlated with ALT improvement (P < .001). Labile plasma iron (LPI) was measured quarterly during the first year of the study. Sixty-eight patients (39.3%) had elevated LPI at baseline. By week 13, LPI levels normalized in all patients with abnormal baseline level. Fifty-one (28%) of 173 patients experienced hematologic improvement by International Working Group 2006 criteria; of these, only seven patients received growth factors or MDS therapy. Over the 3-year study, 138 (79.8%) of 173 patients discontinued therapy, 43 patients (24.8%) because of adverse events or disease progression and 23 patients (13.2%) because of abnormal laboratory values. The most common drug-related adverse events were gastrointestinal disturbances and increased serum creatinine. There were 28 deaths, none of which were considered related to deferasirox.Deferasirox reduces serum ferritin and LPI in transfusion-dependent patients with MDS. A subset of patients had an improvement in hematologic and hepatic parameters.
Defining the roles of inflammatory and anabolic cytokines in cartilage metabolism
Authors: M B Goldring, M Otero, K Tsuchimochi, K Ijiri, Y Li
Journal: Annals of the Rheumatic Diseases (2008)

In osteoarthritis (OA), adult articular chondrocytes undergo phenotypic modulation in response to alterations in the environment owing to mechanical injury and inflammation. These processes not only stimulate the production of enzymes that degrade the cartilage matrix but also inhibit repair. With the use of in vitro and in vivo models, new genes, not known previously to act in cartilage, have been identified and their roles in chondrocyte differentiation during development and in dysregulated chondrocyte function in OA have been examined. These new genes include growth arrest and DNA damage (GADD)45beta and the epithelial-specific ETS (ESE)-1 transcription factor, induced by bone morphogenetic protein (BMP)-2 and inflammatory cytokines, respectively. Both genes are induced by NF-kappaB, suppress COL2A1 and upregulate matrix meatalloproteinase-13 (MMP-13) expression. These genes have also been examined in mouse models of OA, in which discoidin domain receptor 2 is associated with MMP-13-mediated remodelling, in order to understand their roles in physiological cartilage homoeostasis and joint disease.
Airborne Endotoxin Predicts Symptoms in Non–Mouse-sensitized Technicians and Research Scientists Exposed to Laboratory Mice
Authors: Karin A. Pacheco, Charles McCammon, Andrew H. Liu, Peter S. Thorne, Marsha E. O'Neill, John Martyny, Lee S. Newman, Richard F. Hamman, Cecile S. Rose
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Research scientists, laboratory technicians, and animal handlers who work with animals frequently report respiratory and skin symptoms from exposure to laboratory animals (LA). However, on the basis of prick skin tests or RASTs, only half are sensitized to LA. We hypothesized that aerosolized endotoxin from mouse work is responsible for symptoms in nonsensitized workers. We performed a cross-sectional study of 269/310 (87%) workers at a research institution. Subjects completed a questionnaire and underwent prick skin tests (n = 254) or RASTs (n = 16) for environmental and LA allergens. We measured airborne mouse allergen and endotoxin in the animal facility and in research laboratories. Of 212 workers not sensitized to mice, 34 (16%) reported symptoms compared with 26 (46%) of mouse-sensitized workers (p < 0.001). Symptomatic workers were more likely to be atopic, regardless of mouse sensitization status. Symptomatic non-mouse-sensitized workers spent more time performing animal experiments in the animal facility (p = 0.0001) and in their own laboratories (p < 0.0001) and had higher daily endotoxin exposure (p = 0.008) compared with asymptomatic coworkers. In a multivariate model, daily endotoxin exposure most strongly predicted symptoms to mice in non-mouse-sensitized workers (odds ratio = 30.8, p = 0.003). We conclude that airborne endotoxin is associated with respiratory symptoms to mice in non-mouse-sensitized scientists and technicians.
VIBRIO CHOLERAE NON-01 ISOLATED FROM FIVE PEOPLE WITH DIARRHOEA IN LIMA
Authors: BradfordA. Kay, R. Bradley Sack, WilliamM. Spira, H. Edda Guerra, CesarE. Guerrero, Eduardo Chaparro, AgustoE. Yi, Eduardo Salazar-Lindo, Elsa Chea, I. Kaye Wachsmuth, BettyR. Davis
Journal: The Lancet (1984)
Breast cancer phenotype, nodal status and palpability may be useful in the detection of overdiagnosed screening-detected breast cancers
Authors: O. Brouckaert, A. Schoneveld, C. Truyers, E. Kellen, C. Van Ongeval, I. Vergote, P. Moerman, G. Floris, H. Wildiers, M.R. Christiaens, E. Van Limbergen, P. Neven
Journal: Annals of Oncology (2013)
Long-Term Results of TPMT Activity Monitoring in Azathioprine-Treated Renal Allograft Recipients
Authors: ERIC THERVET, DANY ANGLICHEAU, NATHALIE TOLEDANO, ANNE-MARIE HOULLIER, LAURE-HÉLE[Combining Grave Accent]NE NOEL, HENRI KREIS, PHILIPPE BEAUNE, CHRISTOPHE LEGENDRE
Journal: Journal of the American Society of Nephrology (2001)

Abstract. Thiopurine methyltransferase (TPMT) is implicated in the metabolism of azathioprine. The consequences of differential TPMT activity induction by azathioprine on the long-term results after renal transplantation were investigated. The erythrocyte TPMT activity in 82 patients on days 0, 7, and 30 was prospectively evaluated. Because various patterns of TPMT activity variation were noted, the population was subsequently divided between inductors ( n = 47) and noninductors ( n = 35). Data regarding patient and graft survival and acute rejection episodes were collected. Renal allograft assessment was performed at 3 mo and 2 yr to evaluate the renal function and the histologic lesions on routine biopsies. Data regarding azathioprine-related toxicity also were collected. In a subgroup of patients ( n = 19), azathioprine blood levels were determined at day 7 and day 30. The graft survival censoring death was statistically improved in TPMT inductor patients when compared with non-TPMT inductors ( P &lt; 0.05). Among TPMT inductors, an acute rejection episode was observed in 34% of the patients versus 69% among non-TPMT inductors ( P = 0.002). At 3 mo, serum creatinine was significantly lower among TPMT inductors when compared with non-TPMT inductors (123.1 ± 7.6 and 161.4 ± 13.9 μmol/L, respectively; P = 0.01). On routine allograft biopsies at 2 yr ( n = 61), grade 2 or 3 chronic lesions were present in 19% versus 25%, respectively ( P = NS). At days 7 and 30, the azathioprine blood levels were higher among patients who experienced acute rejection ( P &lt; 0.02). TPMT activity induction was observed in 57% of renal transplant recipients who received azathioprine. This induction was associated with better graft outcome. The appropriate conversion from azathioprine, which is a pro-drug, into 6-mercaptopurine could explain both better graft outcome and TPMT induction. Assessing the ability of azathioprine metabolism at an individualized level before transplantation may allow a more accurate choice among the different immunosuppressive treatments.
Ammonia induces RNA oxidation in cultured astrocytes and brain<i>in vivo</i>
Authors: Boris Görg, Natalia Qvartskhava, Verena Keitel, Hans J. Bidmon, Oliver Selbach, Freimut Schliess, Dieter Häussinger
Journal: Hepatology (2008)

Oxidative stress plays a major role in cerebral ammonia toxicity and the pathogenesis of hepatic encephalopathy (HE). As shown in this study, ammonia induces a rapid RNA oxidation in cultured rat astrocytes, vital mouse brain slices, and rat brain in vivo. Ammonia-induced RNA oxidation in cultured astrocytes is reversible and sensitive to MK-801, 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, apocynin, epigallocatechin gallate, and polyphenon 60, suggesting the involvement of N-methyl-D-aspartic acid (NMDA) receptor activation, Ca(2+), nicotinamide adenine dinucleotide phosphate, and reduced form (NADPH) oxidase-dependent oxidative stress. Also, hypo-osmolarity, tumor necrosis factor alpha (TNF-alpha), and diazepam increase RNA oxidation in cultured astrocytes, suggesting that the action of different HE-precipitating factors converges at the level of RNA oxidation. Among the oxidized RNA species, 18S-rRNA and the messenger RNA (mRNA) coding for the glutamate/aspartate transporter (GLAST) were identified. Cerebral RNA oxidation in acutely ammonia-loaded rats in vivo is reversible and predominates in neuronal soma and perivascular astrocyte processes. In neuronal dendrites, oxidized RNA colocalizes with the RNA-binding splicing protein neurooncological ventral antigen (NOVA)-2 within putative RNA transport granules, which are also found in close vicinity to postsynaptic spines. This indicates that oxidized RNA species may participate in postsynaptic protein synthesis, which is a biochemical substrate for learning and memory consolidation. Neuronal and astroglial RNA oxidation increases also in vital mouse brain slices treated with ammonia and TNF-alpha, respectively.Cerebral RNA oxidation is identified as a not yet recognized consequence of acute ammonia intoxication. RNA oxidation may affect gene expression and local protein synthesis and thereby provide another link between reactive oxygen species (ROS)/reactive nitrogen oxide species (RNOS) production and ammonia toxicity.
Cardiac ryanodine receptors control heart rate and rhythmicity in adult mice
Authors: M. J. Bround, P. Asghari, R. B. Wambolt, L. Bohunek, C. Smits, M. Philit, T. J. Kieffer, E. G. Lakatta, K. R. Boheler, E. D. W. Moore, M. F. Allard, J. D. Johnson
Journal: Cardiovascular Research (2012)

The molecular mechanisms controlling heart function and rhythmicity are incompletely understood. While it is widely accepted that the type 2 ryanodine receptor (Ryr2) is the major Ca2+ release channel in excitation–contraction coupling, the role of these channels in setting a consistent beating rate remains controversial. Gain-of-function RYR2 mutations in humans and genetically engineered mouse models are known to cause Ca2+ leak, arrhythmias, and sudden cardiac death. Embryonic stem-cell derived cardiomyocytes lacking Ryr2 display slower beating rates, but no supporting in vivo evidence has been presented. The aim of the present study was to test the hypothesis that RYR2 loss-of-function would reduce heart rate and rhythmicity in vivo. We generated inducible, tissue-specific Ryr2 knockout mice with acute ∼50% loss of RYR2 protein in the heart but not in other tissues. Echocardiography, working heart perfusion, and in vivo ECG telemetry demonstrated that deletion of Ryr2 was sufficient to cause bradycardia and arrhythmia. Our results also show that cardiac Ryr2 knockout mice exhibit functional and structural hallmarks of heart failure, including sudden cardiac death. These results illustrate that the RYR2 channel plays an essential role in pacing heart rate. Moreover, we find that RYR2 loss-of-function can lead to fatal arrhythmias typically associated with gain-of-function mutations. Given that RYR2 levels can be reduced in pathological conditions, including heart failure and diabetic cardiomyopathy, we predict that RYR2 loss contributes to disease-associated bradycardia, arrhythmia, and sudden death.