tbuckley/cabot-search huggingface dataset:
Akt Inhibition Enhances Expansion of Potent Tumor-Specific Lymphocytes with Memory Cell Characteristics
Authors: Joseph G. Crompton, Madhusudhanan Sukumar, Rahul Roychoudhuri, David Clever, Alena Gros, Robert L. Eil, Eric Tran, Ken-ichi Hanada, Zhiya Yu, Douglas C. Palmer, Sid P. Kerkar, Ryan D. Michalek, Trevor Upham, Anthony Leonardi, Nicolas Acquavella, Ena Wang, Francesco M. Marincola, Luca Gattinoni, Pawel Muranski, Mark S. Sundrud, Christopher A. Klebanoff, Steven A. Rosenberg, Douglas T. Fearon, Nicholas P. Restifo
Journal: Cancer Research (2014)

Abstract Adoptive cell therapy (ACT) using autologous tumor-infiltrating lymphocytes (TIL) results in complete regression of advanced cancer in some patients, but the efficacy of this potentially curative therapy may be limited by poor persistence of TIL after adoptive transfer. Pharmacologic inhibition of the serine/threonine kinase Akt has recently been shown to promote immunologic memory in virus-specific murine models, but whether this approach enhances features of memory (e.g., long-term persistence) in TIL that are characteristically exhausted and senescent is not established. Here, we show that pharmacologic inhibition of Akt enables expansion of TIL with the transcriptional, metabolic, and functional properties characteristic of memory T cells. Consequently, Akt inhibition results in enhanced persistence of TIL after adoptive transfer into an immunodeficient animal model and augments antitumor immunity of CD8 T cells in a mouse model of cell-based immunotherapy. Pharmacologic inhibition of Akt represents a novel immunometabolomic approach to enhance the persistence of antitumor T cells and improve the efficacy of cell-based immunotherapy for metastatic cancer. Cancer Res; 75(2); 296–305. ©2014 AACR.
Reversal of Disease-Related Pathologies in the Fragile X Mouse Model by Selective Activation of GABA <sub>B</sub> Receptors with Arbaclofen
Authors: Christina Henderson, Lasani Wijetunge, Mika Nakamoto Kinoshita, Matthew Shumway, Rebecca S. Hammond, Friso R. Postma, Christopher Brynczka, Roger Rush, Alexia Thomas, Richard Paylor, Stephen T. Warren, Peter W. Vanderklish, Peter C. Kind, Randall L. Carpenter, Mark F. Bear, Aileen M. Healy
Journal: Science Translational Medicine (2012)

Pharmacological activation of the GABA B receptor with arbaclofen in a mouse model of fragile X syndrome corrects neuronal defects associated with the disease.
Hemoglobin connecticut (β21(b3) Asp→Gly): A hemoglobin variant with low oxygen affinity
Authors: W. F. Moo‐Penn, P. McPhedran, S. Bobrow, M. H. Johnson, D. L. Jue, K. W. Olsen
Journal: American Journal of Hematology (1981)

Abstract Electrophoretic analysis of a hemolysate from a young man undergoing a routine physical examination revealed an abnormal hemoglobin with a mobility similar to Hb S on cellulose acetate (pH, 8.4). This new variant, designated Hb Connecticut, was found in three generations of a family of Polish descent. Several individuals possessing the variant exhibited mild anemia. Structural analysis of the abnormal β‐chain indicated that the amino acid substitution was at position 21(B3), and involved the replacement of aspartic acid with glycine. Oxygen dissociation studies revealed low oxygen affinity. The alkaline Bohr effect and the degree of cooperativity were unchanged. Analysis of the crystal structure of the variant suggested that the low oxygen affinity was due to the possible disruption of salt bridges between aspartic acid 21(B3) and lysines 61(E5) and 65(E9), changes that could lead to steric interference in oxygen binding.
Osteopontin in antineutrophil cytoplasmic autoantibody-associated vasculitis: relation to disease activity, organ manifestation and immunosuppressive therapy
Authors: Johan Lorenzen, Svjetlana Lovric, Robert Krämer, Hermann Haller, Marion Haubitz
Journal: Annals of the Rheumatic Diseases (2010)

Osteopontin is a pleiotropic cytokine involved in the recruitment and retention of neutrophils to sites of inflammation, which are the primary targets cells in antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV). Osteopontin may play a role in the pathogenesis of AAV.24 patients with systemic AAV and six patients with limited granulomatous disease were included. 19 patients were followed up at 6 and 12 months after the initiation of immunosuppressive therapy. 21 matched healthy volunteers and 20 body mass index and glomerular filtration rate-matched patients with IgA nephropathy were included as controls. Plasma levels of osteopontin were measured by ELISA. Disease activity was gauged by the Birmingham vasculitis activity score (BVAS) and C-reactive protein (CRP).Osteopontin levels are elevated compared with controls (healthy p<0.001; IgA p<0.001).Osteopontin levels decrease significantly during follow-up (p=0.02). Osteopontin levels correlate with disease activity (BVAS r=0.93; CRP r=0.73; all p<0.001) as well as erythrocyturia (r=0.7, p<0.001) and proteinuria (r=0.54, p=0.007).Active AAV is characterised by increased plasma levels of osteopontin, which decrease dramatically with successful therapy. Osteopontin may mediate the inflammatory process in AAV through the recruitment of neutrophils.
RED CELL, PLASMA, AND BLOOD VOLUME IN HEALTHY WOMEN MEASURED BY RADIOCHROMIUM CELL-LABELING AND HEMATOCRIT*
Authors: E. Brown, J. Hopper, J. L. Hodges, B. Bradley, R. Wennesland, H. Yamauchi
Journal: Journal of Clinical Investigation (1962)

In a previous study of 201 healthy men (1), red cell volume (Vrbc) was measured by a modification of Sterling and Gray's radiochromium method (2), and whole blood and plasma volumes (Vwb and Vpl) were derived from venous he- miatocrits.The influence of factors other than body size on the variance of the data was studied, and standards for predicting normal volumes were derived.The present report describes a similar examination of 101 women. SUBJECTS AND METHODSThe women, all of whom volunteered for study, were actively employed as housewives, laboratory personnel, nurses, or office workers, and most were white (Table I).None were taking medications regularly or were subject to dietary control other than mild voluntary caloric restriction, and none were pregnant.Although some engaged in sports regularly, none were trained athletes.All had been living at sea level for at least a year.Cases of gross clinical obesity were not included.No subject was a regular blood donor, and none had given blood within 10 weeks.Health screening tech- niques included a medical history, physical examination, chest X-ray, and urinalysis.A hematocrit below 37 per cent, the limit of normal as defined by Wintrobe (3), caused exclusion of only one volunteer.In no subject was the arterial blood pressure over 140 mm Hg systolic or 90 mm Hg diastolic.The method' of labeling the autologous cells with NaCr5O4 and of determining their volume of distri- bution (VCr"1) was as described in the study on men (1, 4).Tests were performed before breakfast or, rarely, in the afternoon when lunch had been omitted.Subjects lay down for at least 30 minutes before the labeled cells were delivered and until sampling was completed no less than 35 minutes later.
Two splice-factor mutant leukemia subgroups uncovered at the boundaries of MDS and AML using combined gene expression and DNA-methylation profiling
Authors: Erdogan Taskesen, Marije Havermans, Kirsten van Lom, Mathijs A. Sanders, Yvette van Norden, Eric Bindels, Remco Hoogenboezem, Marcel J. T. Reinders, Maria E. Figueroa, Peter J. M. Valk, Bob Löwenberg, Ari Melnick, Ruud Delwel
Journal: Blood (2014)
Coordinated Multisite Regulation of Cellular Energy Metabolism
Authors: D P Jones, X Shan, Y Park
Journal: Annual Review of Nutrition (1992)

PERSPECTIVES AND OVERVIEW  327 PRINCIPLES OF ENERGY REGULATION ....       328 ENERGY METABOLISM IN CONFORMERS AND REGULATORS      329 COORDINATED MULTISITE REGULATION    .   ... 331 Sites of Regulation.                          ......              ........   331 Evidence for Multisite Regulation                           ..                  .......          334 Coordination of Multisite Regulation           .........   337 NUTRITIONAL RELEVANCE OF THE COORDINATED MULTISITE REGULATION OF MITOCHONDRIAL RESPIRATION  338 CONCLUSIONS    ..      .. .. .. ..       ..         340
Evidence that urodilatin, rather than ANP, regulates renal sodium excretion.
Authors: K Goetz, C Drummer, J L Zhu, R Leadley, F Fiedler, R Gerzer
Journal: Journal of the American Society of Nephrology (1990)

Urodilatin, a closely related member of the atrial peptide family, was discovered recently in human urine. Urodilatin (ANP 95-126) is believed to be produced within the kidney and is natriuretic; evidence indicates that most of the ANP-like immunoreactivity in the kidney elutes with urodilatin rather than with ANP. Moreover, urodilatin is little affected by renal enzymes that inactivate atriopeptin. To determine the relative importance of urodilatin versus ANP in the regulation of renal sodium excretion, we studied intact and cardiac-denervated conscious dogs under three experimental conditions: (1) spontaneous sodium excretion, (2) intravenous infusion of saline, and (3) left atrial distension. Urodilatin was measured in urine with a newly developed radioimmunoassay that selectively measures urodilatin without any cross-reactivity with alpha-human atrial natriuretic peptide (alpha-hANP); alpha-hANP was measured in plasma by radio-immunoassay because it is rapidly inactivated in the kidney by enzymatic activity. In each group of experiments, sodium excretion correlated better with urodilatin than it did with circulating alpha-hANP. The correlation coefficient (r value) between urodilatin excretion and renal sodium excretion exceeded 0.8 in 13 of 18 experiments and was below 0.6 in only 2 experiments. On the other hand, the correlation between circulating atriopeptin and sodium excretion exceeded 0.8 in only 3 of 18 experiments and was below 0.6 in 10 experiments. A negative correlation between plasma atriopeptin and renal sodium excretion was observed during left atrial distension in the cardiac-denervated dogs. These results and other considerations suggest that urodilatin, rather than atriopeptin, is the member of the ANP family that is primarily involved in the regulation of renal sodium excretion.
Beta 2-microglobulin is selectively associated with H-2 and TL alloantigens on murine lymphoid cells.
Authors: E S Vitetta, M D Poulik, J Klein, J W Uhr
Journal: The Journal of Experimental Medicine (1976)

We have used a rabbit antiserum prepared against purified rat beta2-microglobulin to immunoprecipitate molecules from lysates of radioiodinated murine thymocytes and splenocytes. All the molecules that are reactive with this serum have subunits of 44,000 and 12,000 and can be identified as H-2 and TL antigens. Thus, the anti-beta2mu serum can deplete lysates of the majority of the TL and H-2 atigens which can be subsequently recognized by alloantisera. If TL and H-2 are precipitated from the lysates before the addition of anti-beta2mu, no beta2mu-reactive molecules remain. Our results indicate that Ia antigens cannot be depleted from the lysates with anti-beta2mu. The studies also suggest that TL and H-2 heavy chains can exist as both monomers and dimers. These observations are discussed with regard to previous studies concerning the native structure of H-2 and TL antigens.
Treatment of Thrombus Formation Associated With the MicroMed DeBakey VAD Using Recombinant Tissue Plasminogen Activator
Authors: Markus Rothenburger, Markus J. Wilhelm, Dieter Hammel, Christoph Schmidt, Tonny D. T. Tjan, Dirk Böcker, Hans H. Scheld, Christof Schmid
Journal: Circulation (2002)

Background The latest generation of left ventricular assist devices consists of nonpulsatile impeller pumps. In these small pumps, thrombus formation inside the device does not lead to thromboembolic end-organ dysfunction but may dramatically impair pump flow. We report on our experience with thrombus-related pump dysfunctions of the MicroMed DeBakey left ventricular assist device and its treatment. Methods Eight of 22 patients with a MicroMed DeBakey VAD presented with a critically reduced pump flow. In 7 cases, an increased power demand indicative of progressive thrombus formation associated with the device was evident, whereas 1 case presented with thrombus formation within the inflow conduit associated with a very low power demand. Brief spontaneously resolving pump stops had been noted in 6 patients. All 8 patients were treated with 100 mg of recombinant tissue plasminogen activator (rt-PA), administered via an IV line. Results Rt-PA lysis led to an increase of pump flow along with a reduction of power demand within a short time in all patients. No severe bleeding complications occurred. However, 4 patients experienced transient epistaxis. All patients could be discharged from intensive care immediately after discontinuation of thrombolytic therapy. Conclusion Rt-PA lysis is a very effective tool for thrombus-related pump dysfunction in patients with impeller pumps, which renders emergency surgical exchange unnecessary in most cases.
Need for a three-focused approach to nonalcoholic fatty liver disease
Authors: Giovanni Musso, Roberto Gambino, Maurizio Cassader
Journal: Hepatology (2010)

We read with interest the reviews by Ghouri et al.1 and Martinez et al.2 Ghouri et al. analyzed the association of nonalcoholic fatty liver disease (NAFLD) with cardiovascular disease (CVD) and concluded that although a diagnosis of NAFLD should prompt diabetes screening, it is insufficient for considering patients to be at high risk for CVD. Martinez et al. evaluated noninvasive methods for assessing liver fibrosis and recommended that those tests with the highest diagnostic accuracy be validated against liver biopsy to facilitate their implementation in clinical practice. The two NAFLD histological subtypes, simple steatosis (SS) and nonalcoholic steatohepatitis (NASH), have different risks of liver-related complications: SS progresses to cirrhosis in less than 5% of cases; NASH progresses to cirrhosis in 10% to 15% of cases over 10 years and in 25% to 30% of cases in the presence of advanced fibrosis.3 NAFLD patients have a 1.44- to 2.05-fold higher rate of CVD (depending on whether the diagnosis is based on an aminotransferase elevation or radiological/histological criteria) than the general population; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Importantly, CVD mortality did not differ among NAFLD histological subtypes.3 NAFLD conveys a 2-fold increased risk of developing diabetes in comparison with the general population3; restricting the analysis to studies adjusting for metabolic syndrome did not change the risk. Whether the risk of diabetes differs among NAFLD histological subtypes remains unclear: in a community-based study, the 13-year incidence of diabetes was 2.98-fold higher in NASH patients versus SS patients.3 According to our analysis, a diagnosis of NAFLD should prompt a thorough three-focus assessment of cardiovascular, metabolic, and liver-related risks (Table 1).4 Liver-related risk assessment remains problematic because it requires liver histology. Three noninvasive methods have been extensively validated: enzyme-linked immunosorbent assay-detected cytokeratin 18 fragments (9 studies enrolling 856 participants) for the detection of NASH and the NAFLD fibrosis score (13 studies enrolling 3064 participants) and FibroScan (6 studies enrolling 563 participants) for the detection of advanced fibrosis. We believe that these methods should be promptly implemented in diagnostic algorithms to select patients for liver biopsy in routine clinical practice while we continue to search for the ideal noninvasive marker. Giovanni Musso M.D.*, Roberto Gambino Ph.D. , Maurizio Cassader Ph.D. , * Gradenigo Hospital Turin, Italy, Department of Internal Medicine, University of Turin, Turin, Italy.
Gastro-oesophageal reflux
Authors: J. Martin
Journal: Journal of the Royal Society of Medicine (2003)

In the article by Mr Issing and Mr Karkos (October 2003 JRSM1) I was surprised that my presenting symptom was not mentioned. Perhaps I am unique. I first experienced gastrooesophageal reflux disease (GORD) when I was in a hotel room in a large US city. I was woken at 2 am by laryngeal spasm and stridor so severe that I was convinced I was going to asphyxiate and die. It passed off in about 25–30 s. It happened every few months after that: my terror decreasing only slightly with each episode (my wife was the recipient of ‘surrogate terror’, the first time she saw and heard me gasping and making that horrific inspiratory screech). It was so bad that I have since wondered whether laryngeal spasm due to reflux might be a cause of otherwise unexplained and unwitnessed solitary deaths in bed, particularly in the elderly and those weakened by disease. After a few of these episodes I eventually did have an endoscopy and now sleep undisturbed courtesy of my proton pump inhibitors.
TOWARD A SYSTEM OF CANCER SCREENING IN THE UNITED STATES: Trends and Opportunities
Authors: Nancy Breen, Helen I. Meissner
Journal: Annual Review of Public Health (2004)

▪ Abstract The hard work of public health officials, physicians, and disease advocacy groups to educate Americans about the importance of early detection has resulted in uptake of screening tests at levels equivalent to or higher than in countries with organized cancer screening programs. However, the societal costs of high screening rates are larger in the United States than in other countries, including higher prices for screening, more unnecessary testing, and inefficiencies in delivery, especially in small practices. Further, screening rates are not evenly distributed across population groups, and the national expenditure on clinical and community research to promote cancer screening among individuals has not been matched by research efforts that focus on policy or clinical systems to increase screening widely throughout the population. We identify opportunities for organizational change that improve access to use, improve quality, and promote cost effectiveness in cancer screening delivery.
Identification of Gating Modes in Single Native Na <sup>+</sup> Channels From Human Atrium and Ventricle
Authors: Thomas Böhle, Mathias C. Brandt, Michael Lindner, Dirk J. Beuckelmann
Journal: Circulation Research (2002)

The aim of the present study was to investigate the single-channel properties of different gating modes in the native human cardiac Na+ channel. Patch-clamp experiments were performed at low noise using ultrathick-walled pipettes. In 17 cell-attached patches containing only one channel, fast back and forth switching between five different Na+-channel gating modes (F-mode, M1-mode, M2-mode, S-mode, and P-mode) was identified, but no difference in the gating properties was found between normal and diseased cardiomyocytes from atrium or ventricle, respectively. Hodgkin-Huxley fits to the ensemble-averaged currents yielded the activation-time (tau(m)) and inactivation-time (tau(h)) constants. tau(m) was comparably fast in the F-mode, M1-mode, M2-mode, and S-mode (0.15 ms) and slow in the P-mode (0.3 ms). tau(h) ranged from 0.35 ms (F-mode) to 4.5 ms (S-mode and P-mode). The mean open-channel lifetime (tau(o)) was shortest in the F-mode and P-mode (0.15 ms) and longest in the S-mode (1.25 ms). The time before which half of the first channel openings occurred (t(0.5)) was comparably short in the F-mode, M1-mode, M2-mode, and S-mode (0.3 ms) and long in the P-mode (0.9 ms). It is concluded that (1) a single native human cardiac Na+ channel can be recorded at low noise, (2) this channel can change its gating properties at a time scale of milliseconds, (3) lifetimes of the observed gating modes are short ranging from milliseconds to seconds only, and (4) the gating modes are characterized by specific activation and inactivation kinetics and differ at least in their mean open time and first latency.
Improving detection of coronary morphological features from digital angiograms. Effect of stenosis-stabilized display.
Authors: N L Eigler, M P Eckstein, K N Mahrer, J S Whiting
Journal: Circulation (1994)

BACKGROUND We have developed a digital display method that stabilizes the motion of a stenosis in sequential frames of a coronary angiogram, allowing it to be scrutinized at high display frame rates. The purpose of this study was to determine whether this technique improves visual detection of low-contrast luminal morphological features. METHODS AND RESULTS An observer detection study was conducted using computer-simulated arterial segments containing known target features, inserted into clinical digital coronary angiograms. Four observers performed a forced-choice detection of a simulated filling defect in each of 320 angiograms using the conventional and stenosis-stabilized dynamic displays (at 7.5, 15, and 32 frames per second) and a single-frame static display (total of 8960 detections). In a second simulated clinical task, three observers detected a bridging stenotic lumen in 600 angiograms using the two displays (3600 detections). In a third experiment, two angiographers rated the likelihood of intraluminal thrombus in 89 right coronary digital angiograms by consensus reading with both dynamic displays. Detectability of the simulated filling defect was similar for both dynamic display methods at 7.5 frames per second (averaging twice that for static images). As display rate was increased to 32 frames per second, detectability for the conventional display declined, whereas the stabilized display detectability increased for all observers (P &lt; .05). On average, stabilization allowed detection of filling defects equivalent to a 71% increase in feature contrast. Response time for the conventional display averaged 12.9 +/- 4.7 seconds. For the stenosis-stabilized display, response time fell with increased frame rate (P &lt; .05) to 4.9 +/- 1.2 seconds at 32 Hz, similar to the time for static images (4.6 +/- 0.8 seconds). The detectability of the bridging stenotic lumen was increased by 62% with the stabilization compared with conventional dynamic display (P &lt; .00001). Consensus reading of coronary angiograms showed differences between the two dynamic display methods (kappa = 0.11) that may be explained by an improvement in observer uncertainty. A rating of definite for thrombus present or absent was more frequent with the stabilized display (39% versus 15%, P &lt; .0001). CONCLUSIONS These data suggest that stabilized display of coronary angiograms significantly increases detectability, reduces the time required for detection, and improves observer uncertainty for the presence of small luminal morphological features. The method of angiographic display may thus have an impact on clinical coronary angiographic interpretation.
Impact of High-Dose N-Acetylcysteine Versus Placebo on Contrast-Induced Nephropathy and Myocardial Reperfusion Injury in Unselected Patients With ST-Segment Elevation Myocardial Infarction Undergoing Primary Percutaneous Coronary Intervention
Authors: Holger Thiele, Lysann Hildebrand, Carmen Schirdewahn, Ingo Eitel, Volker Adams, Georg Fuernau, Sandra Erbs, Axel Linke, Klaus-Werner Diederich, Marek Nowak, Steffen Desch, Matthias Gutberlet, Gerhard Schuler
Journal: Journal of the American College of Cardiology (2010)