tbuckley/cabot-search huggingface dataset:
The Proliferative Capacity of Individual Naive CD4<b>+</b>T Cells Is Amplified by Prolonged T Cell Antigen Receptor Triggering
Authors: Adam G. Schrum, Laurence A. Turka
Journal: The Journal of Experimental Medicine (2002)

Strong antigenic encounter by T cells rapidly induces immunological synapse formation and surface T cell receptor (TCR) downregulation. Although surface TCR expression can remain low for several days, T cells can still sustain antigenic signaling. It has been unclear whether prolonged antigenic signaling occurs in the absence of surface TCR replenishment, being maintained by a few “nondownregulatable” surface TCRs that might reside in a synaptosomal structure. Alternatively, the low surface TCR level induced by antigen might represent a dynamic state of expression involving continual surface TCR replenishment, reengagement by antigen, and ongoing downregulation. To resolve this issue, we studied in vivo–generated, dual-specificity primary naive CD4+ T cells. On these cells, antigenic stimulus exclusively downregulated antigen-specific, but not antigen-nonspecific, TCRs. In addition to providing a means to track TCR engagement, this also allowed us to use the antigen nonspecific TCR to track TCR expression in isolation from TCR engagement by antigen. Surface TCR replenishment began within the first day of stimulation, and occurred synchronously with continuous antigen-specific TCR engagement and downregulation. Furthermore, by enhancing CD25 expression, extended signaling through surface-replenishing TCRs significantly amplified the number of daughter cells generated by naive CD4+ T cells that had already committed to proliferate. This effect required TCR engagement and could not be substituted for by interleukin 2. These data demonstrate that TCR triggering and consumption can occur over an extended period of time, with a significant impact on the effector responses evoked from naive CD4+ T cells.
EpCAM/CD3-Bispecific T-cell Engaging Antibody MT110 Eliminates Primary Human Pancreatic Cancer Stem Cells
Authors: Michele Cioffi, Jorge Dorado, Patrick A. Baeuerle, Christopher Heeschen
Journal: Clinical Cancer Research (2011)

Abstract Purpose: Tumor-initiating cells with stem-like properties, also termed cancer stem cells (CSC), have been shown to sustain tumor growth as well as metastasis and are highly resistant to chemotherapy. Because pancreatic CSCs have been isolated on the basis of EpCAM expression, we investigated whether a targeted immunotherapy to EpCAM using the bispecific T-cell–engaging antibody MT110 is capable of eradicating CSCs. Experimental Design: We studied in vitro and in vivo the effects of MT110 on CSCs using both established cell lines as well as primary cells of human pancreatic cancer. Results: Although established cell lines were more responsive to MT110-engaged T cells, also primary cells showed a time- and dose-dependent response to treatment with the bispecific antibody. In addition, the population of highly tumorigenic CSCs was efficiently targeted by the EpCAM/CD3-bispecific antibody MT110 in vitro and in vivo using a mouse model of established primary pancreatic cancer. Pancreatic cancer cells derived from metastases were slightly more resistant to MT110 treatment on the basis of in vivo tumorigenicity studies. This appeared to be related to a higher frequency of an EpCAM-negative subpopulation of CSCs. Conclusions: Cytotoxic T cells can be effectively redirected against primary human pancreatic cancer cells by T-cell–engaging BiTE antibody MT110 including a subpopulation of highly tumorigenic CSCs. Clin Cancer Res; 18(2); 465–74. ©2011 AACR.
Prolonged hypoxia augments l-citrulline transport by System A in the newborn piglet pulmonary circulation
Authors: Candice D. Fike, Marta Sidoryk-Wegrzynowicz, Michael Aschner, Marshall Summar, Lawrence S. Prince, Gary Cunningham, Mark Kaplowitz, Yongmei Zhang, Judy L. Aschner
Journal: Cardiovascular Research (2012)

Pulmonary arterial endothelial cells (PAECs) express the enzymes needed for generation of l-arginine from intracellular l-citrulline but do not express the enzymes needed for de novo l-citrulline synthesis. Hence, l-citrulline levels in PAECs are dependent on l-citrulline transport. Once generated, l-arginine can be converted to l-citrulline and nitric oxide (NO) by the enzyme NO synthase. We sought to determine whether hypoxia, a condition aetiologically linked to pulmonary hypertension, alters the transport of l-citrulline and the expression of the sodium-coupled neutral amino acid transporters (SNATs) in PAECs from newborn piglets.PAECs isolated from newborn piglets were cultured under normoxic and hypoxic conditions and used to measure SNAT1, 2, 3, and 5 protein expression and (14)C-l-citrulline uptake. SNAT1 protein expression was increased, while SNAT2, SNAT3, and SNAT5 expression was unaltered in hypoxic PAECs. (14)C-l-citrulline uptake was increased in hypoxic PAECs. Studies with inhibitors of System A (SNAT1/2) and System N (SNAT3/5) revealed that the increased (14)C-l-citrulline uptake was largely due to System A-mediated transport. Additional studies were performed to evaluate SNAT protein expression and l-citrulline levels in lungs of piglets with chronic hypoxia-induced pulmonary hypertension and comparable age controls. Lungs from piglets raised in chronic hypoxia exhibited greater SNAT1 expression and higher l-citrulline levels than lungs from controls.Increased SNAT1 expression and the concomitant enhanced ability to transport l-citrulline in PAECs could represent an important regulatory mechanism to counteract NO signalling impairments known to occur during the development of chronic hypoxia-induced pulmonary hypertension in newborns.
Co-existent medial collateral ligament injury seen following transient patellar dislocation: observations at magnetic resonance imaging
Authors: J F Quinlan, C Farrelly, G Kelly, S Eustace
Journal: British Journal of Sports Medicine (2008)

This study reports on a series of patients who were diagnosed as having had a transient lateral patellar dislocation by magnetic resonance imaging (MRI). The images were reviewed with specific reference to the medial collateral ligament (MCL), a heretofore undescribed concomitant injury. Eighty patients were diagnosed on MRI as having had transient lateral patellar dislocation. Their mean age was 23.9 years (SD 7.5). Forty patients (50.0%) had co-existent MCL injuries. These injuries were classified as grade 1 (n = 20), grade 2 (n = 17) and grade 3 (n = 3). These results suggest that MCL injury commonly accompanies transient lateral patella dislocation, most likely due to a shared valgus injury. It appears to occur more commonly in male patients and if unidentified may explain both delayed recovery and persistent morbidity in more severe cases. In this setting, without specifically excluding co-existent MCL injury, the current vogue for early rehabilitation should be adopted with caution.
High-Dose Interferon Alfa-2b Significantly Prolongs Relapse-Free and Overall Survival Compared With the GM2-KLH/QS-21 Vaccine in Patients With Resected Stage IIB-III Melanoma: Results of Intergroup Trial E1694/S9512/C509801
Authors: John M. Kirkwood, Joseph G. Ibrahim, Jeffrey A. Sosman, Vernon K. Sondak, Sanjiv S. Agarwala, Marc S. Ernstoff, Uma Rao
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Vaccine alternatives to high-dose interferon alfa-2b therapy (HDI), the current standard adjuvant therapy for high-risk melanoma, are of interest because of toxicity associated with HDI. The GM2 ganglioside is a well-defined melanoma antigen, and anti-GM2 antibodies have been associated with improved prognosis. We conducted a prospective, randomized, intergroup trial to evaluate the efficacy of HDI for 1 year versus vaccination with GM2 conjugated to keyhole limpet hemocyanin and administered with QS-21 (GMK) for 96 weeks (weekly × 4 then every 12 weeks × 8). PATIENTS AND METHODS: Eligible patients had resected stage IIB/III melanoma. Patients were stratified by sex and number of positive nodes. Primary end points were relapse-free survival (RFS) and overall survival (OS). RESULTS: Eight hundred eighty patients were randomized (440 per treatment group); 774 patients were eligible for efficacy analysis. The trial was closed after interim analysis indicated inferiority of GMK compared with HDI. For eligible patients, HDI provided a statistically significant RFS benefit (hazard ratio [HR] = 1.47, P = .0015) and OS benefit (HR = 1.52, P = .009) for GMK versus HDI. Similar benefit was observed in the intent-to-treat analysis (RFS HR = 1.49; OS HR = 1.38). HDI was associated with a treatment benefit in all subsets of patients with zero to ≥ four positive nodes, but the greatest benefit was observed in the node-negative subset (RFS HR = 2.07; OS HR = 2.71 [eligible population]). Antibody responses to GM2 (ie, titers ≥ 1:80) at days 29, 85, 365, and 720 were associated with a trend toward improved RFS and OS (P 2 = .068 at day 29). CONCLUSION: This trial demonstrated a significant treatment benefit of HDI versus GMK in terms of RFS and OS in melanoma patients at high risk of recurrence.
c-Myc is essential for urokinase plasminogen activator expression on hypoxia-induced vascular smooth muscle cells
Authors: Y HOU, C OKAMOTO, K OKADA, N KAWAO, S KAWATA, S UESHIMA, O MATSUO
Journal: Cardiovascular Research (2007)

The purpose of this study was to investigate whether c-Myc regulates expression of urokinase plasminogen activator (uPA) on hypoxia-induced vascular smooth muscle cells (VSMCs).VSMCs were isolated from thoracic aorta of wild-type (WT), tissue plasminogen activator (tPA) and uPA-deficient mice. Gene and protein expression levels were examined by reverse-transcription PCR and Western blotting, respectively. c-Myc and uPA transcriptional activity were determined by luciferase analysis. Zymography analysis was used to test the activity of matrix metalloproteinases (MMPs), tPA, and uPA.Hypoxia significantly promoted WT and tPA-/- VSMC migration and invasion. However, uPA-/- severely decreased hypoxia-induced VSMC migration and invasion. Hypoxia increased uPA and MMP-2 activity, while uPA-/- decreased hypoxia-induced MMP-2 activity. c-Myc expression and transcriptional activity were increased in response to hypoxia, and silenced c-Myc abolished hypoxia-induced uPA and MMP-2 activity. In addition, hypoxia-induced Bcl2 expression and Bcl2 binding to c-Myc led to enhanced c-Myc-mediated uPA and MMP-2 activity in response to hypoxia.The results show that c-Myc was essential for hypoxia-induced uPA expression and activity, resulting in VSMC migration and invasion. In addition, Bcl2 enhanced the c-Myc-mediated uPA/MMP-2 pathway.
Darwin's mistake: Explaining the discontinuity between human and nonhuman minds
Authors: Derek C. Penn, Keith J. Holyoak, Daniel J. Povinelli
Journal: Behavioral and Brain Sciences (2008)

Abstract Over the last quarter century, the dominant tendency in comparative cognitive psychology has been to emphasize the similarities between human and nonhuman minds and to downplay the differences as “one of degree and not of kind” (Darwin 1871). In the present target article, we argue that Darwin was mistaken: the profound biological continuity between human and nonhuman animals masks an equally profound discontinuity between human and nonhuman minds. To wit, there is a significant discontinuity in the degree to which human and nonhuman animals are able to approximate the higher-order, systematic, relational capabilities of a physical symbol system (PSS) (Newell 1980). We show that this symbolic-relational discontinuity pervades nearly every domain of cognition and runs much deeper than even the spectacular scaffolding provided by language or culture alone can explain. We propose a representational-level specification as to where human and nonhuman animals' abilities to approximate a PSS are similar and where they differ. We conclude by suggesting that recent symbolic-connectionist models of cognition shed new light on the mechanisms that underlie the gap between human and nonhuman minds.
Relationship Between Intradermal Tumor Suppression and Tumor Immunity 2
Authors: Gerald L. Bartlett, John W. Kreider, Dallas M. Purnell
Journal: JNCI Journal of the National Cancer Institute (1976)

Journal Article Relationship Between Intradermal Tumor Suppression and Tumor Immunity Get access Gerald L. Bartlett, Gerald L. Bartlett 3Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pa. 170335Department of Microbiology, The Milton S. Hershey Medical Center, The Pennsylvania State University Search for other works by this author on: Oxford Academic PubMed Google Scholar John W. Kreider, John W. Kreider 3Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pa. 170335Department of Microbiology, The Milton S. Hershey Medical Center, The Pennsylvania State University Search for other works by this author on: Oxford Academic PubMed Google Scholar Dallas M. Purnell Dallas M. Purnell 3Department of Pathology, The Milton S. Hershey Medical Center, The Pennsylvania State University, Hershey, Pa. 17033 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 57, Issue 6, December 1976, Pages 1297–1303, https://doi.org/10.1093/jnci/57.6.1297 Published: 01 December 1976 Article history Received: 02 February 1976 Revision received: 17 May 1976 Published: 01 December 1976
Combined oro-caecal scintigraphy and lactulose hydrogen breath testing demonstrate that breath testing detects oro-caecal transit, not small intestinal bacterial overgrowth in patients with IBS
Authors: D. Yu, F. Cheeseman, S. Vanner
Journal: Gut (2010)

<h3>Objectives</h3> Recent studies using the lactulose hydrogen breath test (LHBT) suggest most patients with irritable bowel syndrome (IBS) have small intestinal bacterial overgrowth (SIBO). However, the validity of the LHBT has been questioned, particularly as this test could reflect changes in oro-caecal transit. Therefore, we combined oro-caecal scintigraphy with LHBT in 40 patients who were Rome II positive for IBS to determine if the increase in hydrogen is due to the test meal reaching the caecum. <h3>Design</h3> Patients ingested the test meal containing <sup>99m</sup>Tc and 10 g lactulose and simultaneous measurements of the location of the test meal using scintigraphic scanning and breath hydrogen levels were obtained every 10 min for 3 h. The LHBT was considered positive when the rise in H<sub>2</sub> above baseline was &gt;20 ppm within 90 and/or 180 min. The combined test was negative for SIBO if ≥5% of the test meal was in the caecum at the time the LHBT was positive. <h3>Results</h3> 63% had an abnormal LHBT at 180 min and 35% at 90 min. The oro-caecal transit time based on scintigraphic scanning ranged from 10 to 220 min and correlated with IBS sub-type. At the time of increase in H<sub>2</sub>, the % accumulation of <sup>99m</sup>Tc in the caecum was ≥5% in 88% of cases (22/25). <h3>Conclusions</h3> These findings demonstrate that an abnormal rise in H<sub>2</sub> measured in the LHBT can be explained by variations in oro-caecal transit time in patients with IBS and therefore do not support the diagnosis of SIBO.
Computational Maps in the Brain
Authors: E I Knudsen, S Lac, S D Esterly
Journal: Annual Review of Neuroscience (1987)

The nervous system performs computations to process information that is biologically important. Some of these computations occur in maps--arrays of neurons in which the tuning of neighboring neurons for a particular parameter value varies systematically. Computational maps transform the representation of information into a place-coded probability distribution that represents the computed values of parameters by sites of maximum relative activity. Numerous computational maps have been discovered, including visual maps of line orientation and direction of motion, auditory maps of amplitude spectrum and time interval, and motor maps of orienting movements. The construction of the auditory map of space is the most thoroughly understood: information about interaural delays and interaural intensity differences is processed in parallel by separate computational maps, and the outputs of these maps feed into a higher order processor that integrates sets of cues corresponding to sound source locations and creates a map of auditory space. Computational maps represent ranges of parameter values that are relevant to the animal, and may differentially magnify the representation of values that are of particular importance. The tuning of individual neurons for values of a mapped parameter is broad relative to the range of the map. Consequently, neurons throughout a large portion of a computational map are activated by any given stimulus, and precise information about the mapped parameter is coded by the locations of peak activity. There are a number of advantages of performing computations in maps. First, information is processed rapidly because the computations are preset and are executed in parallel. Second, maps simplify the schemes of connectivity required for processing and utilizing the information. Third, a common, mapped representation of the results of different kinds of computations allows the nervous system to employ a single strategy for reading the information. Finally, maps enable several classes of neuronal mechanisms to sharpen tuning in a manner not possible for information that is represented in a non-topographic code.
The Genetics of Pulmonary Arterial Hypertension
Authors: Eric D. Austin, James E. Loyd
Journal: Circulation Research (2014)

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease for which there is an ever-expanding body of genetic and related pathophysiological information on disease pathogenesis. Many germline gene mutations have now been described, including mutations in the gene coding bone morphogenic protein receptor type 2 ( BMPR2 ) and related genes. Recent advanced gene-sequencing methods have facilitated the discovery of additional genes with mutations among those with and those without familial forms of PAH ( CAV1 , KCNK3 , EIF2AK4 ). The reduced penetrance, variable expressivity, and female predominance of PAH suggest that genetic, genomic, and other factors modify disease expression. These multi-faceted variations are an active area of investigation in the field, including but not limited to common genetic variants and epigenetic processes, and may provide novel opportunities for pharmacological intervention in the near future. They also highlight the need for a systems-oriented multi-level approach to incorporate the multitude of biological variations now associated with PAH. Ultimately, an in-depth understanding of the genetic factors relevant to PAH provides the opportunity for improved patient and family counseling about this devastating disease.
Controlled trial of respiratory muscle training in chronic airflow limitation.
Authors: G Guyatt, J Keller, J Singer, S Halcrow, M Newhouse
Journal: Thorax (1992)

BACKGROUND: Whether respiratory muscle training is of benefit to patients with chronic airflow limitation is controversial. The objective of the study was to determine the effect of resistance breathing training on physiological and functional measures in patients with chronic airflow obstruction. METHODS: The design was a randomised, double blind, controlled trial with a six month follow up. Eighty two patients with a forced expiratory volume in one second (FEV1) of less than 70% predicted, and an FEV1/vital capacity ratio of less than 0.7, were randomised to receive training for 10 minutes five times daily with progressively larger resistances through a resistive breathing device (PFLEX) as tolerated or to a sham device which gave minimal resistance. The main outcome measures, respiratory muscle strength and endurance, a progressive exercise test, a six minute walk test and physical and emotional function (chronic respiratory questionnaire) were assessed at monthly intervals. Patients in both groups were also randomised to wear or not wear nose clips during their training. RESULTS: No significant differences were observed between treatment and control groups, with or without nose clips, for any of the outcomes. Confidence intervals on the difference between treatments were narrow, excluding clinically important difference in any major outcome. CONCLUSION: This training regimen fails to strengthen respiratory muscles or improve exercise or functional capacity in patients with chronic airflow limitation.
Differential Expression of T- and L-Type Voltage-Dependent Calcium Channels in Renal Resistance Vessels
Authors: Pernille B. Hansen, Boye L. Jensen, Ditte Andreasen, Ole Skøtt
Journal: Circulation Research (2001)

The distribution of voltage-dependent calcium channels in kidney pre- and postglomerular resistance vessels was determined at the molecular and functional levels. Reverse transcription-polymerase chain reaction analysis of microdissected rat preglomerular vessels and cultured smooth muscle cells showed coexpression of mRNAs for T-type subunits (Ca(V)3.1, Ca(V)3.2) and for an L-type subunit (Ca(V)1.2). The same expression pattern was observed in juxtamedullary efferent arterioles and outer medullary vasa recta. No calcium channel messages were detected in cortical efferent arterioles. Ca(V)1.2 protein was demonstrated by immunochemical labeling of rat preglomerular vasculature and juxtamedullary efferent arterioles and vasa recta. Cortical efferent arterioles were not immunopositive. Recordings of intracellular calcium concentration with digital fluorescence imaging microscopy showed a significant increase of calcium in response to K(+) (100 mmol/L) in isolated afferent arterioles (140+/-25%) and in juxtamedullary efferent arterioles (118+/-21%). These calcium responses were attenuated by the L-type antagonist calciseptine and by the T-type antagonist mibefradil. Intracellular calcium increased in response to K(+) in cortical efferent arterioles (21+/-9%). Mibefradil and nickel concentration dependently blocked K(+)-induced contraction of perfused rabbit afferent arterioles. Calciseptine blocked the contraction mediated by K(+) (EC(50) 8x10(-14)). S-(-)-Bay K 8644 had no effect on vascular diameter in the afferent arteriole. We conclude that voltage-dependent L- and T-type calcium channels are expressed and of functional significance in renal cortical preglomerular vessels, in juxtamedullary efferent arterioles, and in outer medullary vasa recta, but not in cortical efferent arterioles.