tbuckley/cabot-search huggingface dataset:
Dopamine Enhances Model-Based over Model-Free Choice Behavior
Authors: Klaus Wunderlich, Peter Smittenaar, Raymond J. Dolan
Journal: Neuron (2012)

Decision making is often considered to arise out of contributions from a model-free habitual system and a model-based goal-directed system. Here, we investigated the effect of a dopamine manipulation on the degree to which either system contributes to instrumental behavior in a two-stage Markov decision task, which has been shown to discriminate model-free from model-based control. We found increased dopamine levels promote model-based over model-free choice.
Lethal graft-versus-host disease after bone marrow transplantation across minor histocompatibility barriers in mice. Prevention by removing mature T cells from marrow.
Authors: R Korngold, J Sprent
Journal: The Journal of Experimental Medicine (1978)

In two situations, transfer of normal unsensitized bone marrow cells into heavily irradiated H-2-identical allogeneic mice caused a high incidence of lethal chronic graft-versus-host disease (GVHD), i.e. mortality occuring between days of 20 and 80 postirradiation. Minor histocompatibility determinants appeared to be the main target for eliciting GVHD. Removing mature T cells from the marrow with anti-Thy 1.2 serum and complement before injection prevented GVHD. On the basis of adding purified T cells to T-cell-depleted marrow cells, it was concluded that contamination of the marrow with as few as 0.3% T cells was sufficient to cause a high incidence of lethal GVHD in certain situations. No GVHD was found with the injection of non-T cells (Thy 1.2-negative cells) or with tolerant T cells. Irradiated recipients of T-cell-depleted marrow cells remained in good health for prolonged periods. These mice showed extensive chimerism with respect to the donor marrow, normal numbers of T and B cells and were immunocompetent. The data provide no support for the view that chronic GVHD developing after bone marrow transplantation in man is the result of an attack by the progeny of the donor stem cells. The results imply that mature T cells contaminating marrow inocula are probably the main cause of GVHD seen in the clinical situation.
Lectins do not distinguish between heterogenous IgE molecules as defined by differential activity of an IgE-dependent histamine releasing factor
Authors: Jörg Kleine-Tebbe, Anne Kagey-Sobotka, Donald W. MacGlashan, Lawrence M. Lichtenstein, Susan M. MacDonald
Journal: Journal of Allergy and Clinical Immunology (1996)

It has been suggested that the differential histamine-releasing activity of an IgE-dependent histamine-releasing factor (HRF), which has recently been cloned, is related to carbohydrate differences in the IgE molecule. Lectins are able to recognize specific glycoforms and might therefore be useful in characterizing the proposed heterogeneity of IgE molecules. As one test of this hypothesis, we examined the histamine release potency of several well-characterized lectins on basophils passively sensitized with serum containing IgE molecules that support HRF-induced histamine release (IgE+) or serum that does not support release by this stimulus (IgE−). Histamine release was induced by challenging basophils with different concentrations of concanavalin A, Lens culinaris (LcH), and Pisum sativum (PSA). Dose-response curves revealed that LcH caused 30% histamine release at 2 μg/ml with IgE+ sensitized cells, whereas the same release with IgE− cells required sixfold higher concentrations. Similar values for PSA showed a sevenfold difference. With concanavalin A, the selectivity was reversed in that it was fourfold more active on IgE−-sensitized cells. Another pair of sera (IgE+ vs IgE−) revealed the same result for concanavalin A, but no difference occurred in LcH and PSA induced release between the IgE+- and IgE−-sensitized cells. These contrasting findings with different pairs of IgE+- and IgE−-containing sera indicated that the lectins LcH and PSA are not able to discriminate between IgE+- and IgE−-sensitized cells as does HRF and therefore cannot be used to further define the proposed heterogeneity of IgE. This conclusion was supported by experiments in which basophil preparations from donors possessing natural sensitivity or insensitivity to HRF (having IgE+ or IgE− on their surface) were examined for their response to these lectins. No difference was found in the sensitivity of the cells to challenge with LcH or PSA, and the response to concanavalin A was the opposite of that found when passively sensitized cells were used (30% histamine release at 0.9 vs 3.5 μg/ml for IgE+ vs IgE− donors, respectively). We conclude that oligosaccharide-specific lectins do not differentiate between HRF-reactive and HRF-nonreactive IgE molecules on basophils. (J ALLERGY CLIN IMMUNOL 1996;98:181-8.)
Rectal compliance and rectal sensation in constipated adolescents, recovered adolescents and healthy volunteers
Authors: M. M. van den Berg, W. P. Voskuijl, G. E. Boeckxstaens, M. A. Benninga
Journal: Gut (2007)

<h3>Objectives:</h3> A subgroup of children with functional constipation (FC) are unresponsive to conventional treatment. Abnormal rectal function due to increased distensibility (compliance) might be an underlying mechanism of therapy-resistant FC. It is hypothesised that rectal compliance is normal in patients who are successfully recovered from FC (RC). <h3>Methods:</h3> Using a barostat, a pressure-controlled intermittent distension protocol was performed in FC patients, RC subjects free of symptoms for at least 4 years and healthy volunteers (HVs). Rectal compliance was calculated using a non-linear mixed-effect model for volume–pressure curves. <h3>Results:</h3> Forty-seven FC patients, median (range) age of 12 (11–17) years, and 20 RC subjects, 15 (11–18) years, were studied and compared with 22 HVs, 14 (8–16) years. The median (5th–95th percentile) rectal compliance in HVs was 16 (12–20) ml/mm Hg. FC patients had a median rectal compliance of 25 (13–47) ml/mm Hg and RC subjects 20 (12–35) ml/mm Hg, which was significantly higher compared with HVs (p&lt;0.001 and p = 0.003). RC subjects had lower rectal compliance when compared with FC patients (p = 0.02). Forty-five percent of RC subjects had a rectal compliance above the upper limit of normal (&gt;95th percentile of HVs), which was significantly less compared with 75% of FC patients (p = 0.02). <h3>Conclusion:</h3> While rectal compliance in RC subjects is lower when compared with adolescents with FC, almost half of the RC subjects showed an increased rectal compliance. The role of rectal compliance in therapy-resistant FC seems limited, because recovery is possible despite an increased rectal compliance.
Tolerance of T cell receptor gamma/delta cells in the intestine.
Authors: T A Barrett, Y Tatsumi, J A Bluestone
Journal: The Journal of Experimental Medicine (1993)

The present study examined the mechanism(s) of tolerance induction for intestinal intraepithelial lymphocytes (iIELs) using an alloantigen (Ag)-specific gamma/delta T cell receptor (TCR gamma/delta) transgenic (Tg) model. In Tg Ag-bearing H-2b/d mice (Tgb/d), Tg iIELs were Thy-1-, CD44+, CD45R (B220)+, and CD5+, whereas in syngeneic Tgd/d mice, iIELs were Thy-1+, CD44-, and CD45R- with a subset of CD5+ cells. Previously, we had shown that tolerance for Tgb/d iIELs involved functional anergy and deletion (Barrett, T. A., M. L. Delvy, D. M. Kennedy, L. Lefrancois, L. A. Matis, A. L. Dent, S. M. Hedrick, and J. A. Bluestone. 1992. J. Exp. Med. 175:65). In this study we demonstrate that Tgb/d iIELs expressing dull levels of Thy-1 proliferated in the presence of exogenous rIL-2. A direct precursor-product relationship between the Thy-1+-responsive iIELs and the tolerant Thy-1dul/- iIELs was demonstrated by adoptive transfer into severe combined immunodeficient (SCID) mice. Tg Thy-1+ iIELs reconstituting Ag+ but not Ag- SCID mice downregulated Thy-1 after Ag exposure in vivo. Analysis of bone marrow (BM) chimeras demonstrated the persistence of Tg IELs in all Ag+ chimeras although a modest degree of clonal deletion was apparent. The greatest percentage of Tg IELs were detected when Ag was restricted to radioresistant cells (e.g., epithelial cells) compared with BM-derived antigen-presenting cells (APC). This was especially apparent in thymectomized chimeric mice. Consistent with the notion that Ag-bearing epithelial cells may be poor APC, isolated intestinal epithelial cells from Ag-bearing mice failed to stimulate Tg iIELs compared with splenic APC. These studies suggest that the major population of TCR gamma/delta iIELs were probably extrathymically derived and encountered self-Ag on intestinal epithelial cells. The induction of tolerance likely involved an activation event resulting in downregulation of Thy-1. These mechanisms of tolerance for TCR gamma/delta iIELs led to the persistence of a reservoir of self-reactive T cells with the potential for mediating autoimmune disease.
Spatiotemporal Heterogeneity Characterizes the Genetic Landscape of Pheochromocytoma and Defines Early Events in Tumorigenesis
Authors: Joakim Crona, Samuel Backman, Rajani Maharjan, Markus Mayrhofer, Peter Stålberg, Anders Isaksson, Per Hellman, Peyman Björklund
Journal: Clinical Cancer Research (2015)

Abstract Purpose: Pheochromocytoma and paraganglioma (PPGL) patients display heterogeneity in the clinical presentation and underlying genetic cause. The degree of inter- and intratumor genetic heterogeneity has not yet been defined. Experimental Design: In PPGLs from 94 patients, we analyzed LOH, copy-number variations, and mutation status of SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, NF1, RET, TMEM127, MAX, and HRAS using high-density SNP array and targeted deep sequencing, respectively. Genetic heterogeneity was determined through (i) bioinformatics analysis of individual samples that estimated absolute purity and ploidy from SNP array data and (ii) comparison of paired tumor samples that allowed reconstruction of phylogenetic trees. Results: Mutations were found in 61% of the tumors and correlated with specific patterns of somatic copy-number aberrations (SCNA) and degree of nontumoral cell admixture. Intratumor genetic heterogeneity was observed in 74 of 136 samples using absolute bioinformatics estimations and in 22 of 24 patients by comparison of paired samples. In addition, a low genetic concordance was observed between paired primary tumors and distant metastases. This allowed for reconstructing the life history of individual tumors, identifying somatic mutations as well as copy-number loss of 3p and 11p (VHL subgroup), 1p (Cluster 2), and 17q (NF1 subgroup) as early events in PPGL tumorigenesis. Conclusions: Genomic landscapes of PPGL are specific to mutation subtype and characterized by genetic heterogeneity both within and between tumor lesions of the same patient. Clin Cancer Res; 21(19); 4451–60. ©2015 AACR.
Effect of coronary stenotic lesions on regional myocardial blood flow at rest.
Authors: A B Nichols, C Brown, J Han, E L Nickoloff, P D Esser
Journal: Circulation (1986)

To determine the effect of atherosclerotic coronary lesions on myocardial blood flow in patients at rest, regional myocardial blood flow was measured distal to stenotic lesions in 29 patients with isolated proximal lesions of the left anterior descending artery. Severity of coronary stenosis was measured by computer-assisted cinevideodensitometric analysis of digitized coronary arteriograms. Regional myocardial blood flow was measured from the clearance rate of intracoronary 133Xe injected into the left main coronary artery and recorded with a multicrystal scintillation camera. In 21 patients with stenotic lesions ranging from 19% to 84% area reduction, distal regional myocardial blood flow was normal. In all eight patients with reduced regional myocardial blood flow distal to left anterior descending lesions, the minimum area of each stenotic lesion was less 0.80 mm2 (mean 0.34 +/- 0.2 mm2), minimum calculated diameter was less than 1 mm (mean 0.59 +/- 0.3 mm), and percent stenosis, based on the reduction in cross-sectional area, was greater than 85% (mean 94 +/- 4%). For all patients, distal flow, expressed as a fraction of normal flow, correlated with the lesion cross-sectional area (r = .84), minimum luminal diameter (r = .84), and percent area stenosis (r = -.70). Thus, resting myocardial blood flow distal to stenotic lesions of the proximal coronary arteries remains normal until the degree of narrowing is severe. The dimensions observed for critical coronary stenotic lesions correlate well with theoretical predictions based on fluid mechanics and with experimental preparations in laboratory animals.
Prospective International Multicenter Phase II Trial of Intravenous Pegylated Liposomal Doxorubicin Monochemotherapy in Patients With Stage IIB, IVA, or IVB Advanced Mycosis Fungoides: Final Results From EORTC 21012
Authors: Reinhard Dummer, Pietro Quaglino, Jürgen C. Becker, Baktiar Hasan, Matthias Karrasch, Sean Whittaker, Stephen Morris, Michael Weichenthal, Rudolf Stadler, Martine Bagot, Antonio Cozzio, Maria G. Bernengo, Robert Knobler
Journal: Journal of Clinical Oncology (2012)

Purpose Mycosis fungoides (MF) is the most common primary cutaneous T-cell lymphoma. There is a need for multicenter trials involving defined patient populations using rigorous assessment criteria. We have investigated pegylated liposomal doxorubicin (PLD) in a clearly defined patient population with advanced MF. Patients and Methods Eligible patients had stage IIB, IVA, or IVB MF, refractory or recurrent after at least two previous systemic therapies. Patients were registered to receive a maximum of six cycles of PLD 20 mg/m 2 on days 1 and 15, every 28 days (one cycle). The primary end point was response rate (RR). Results Nine centers recruited 49 eligible patients. The median number of chemotherapy cycles received was five. There were no grade 3 to 4 hematologic toxicities. Grade 3 or 4 nonhematologic/nonbiochemical toxicities included cardiac symptom (2%), allergy/hypersensitivity (2%), constitutional symptom (4%), hand and foot reaction (2%), other dermatologic toxicity (6%), other GI toxicity (4%), infection (4%), pulmonary embolism (2%), and cardiac ischemia (2%). Of 49 patients, 20 (40.8%) were responders (complete clinical response [CCR] or partial response [PR] as overall response): three (6.1%) experienced CCRs, and 17 (34.7%) experienced PRs. A 50% or greater reduction of cutaneous manifestations was observed in 26 (60.5%) of 43 assessable patients. Two early deaths were reported, resulting from related cardiovascular toxicity and disease progression. The lower limit of the one-sided 90% CI for RR was 31.2%. Median time to progression and median duration of response were 7.4 and 6 months, respectively. Conclusion PLD has an acceptable safety profile in patients with advanced MF. The efficacy of PLD seems promising.
TNFα antagonists for acute exacerbations of COPD: a randomised double-blind controlled trial
Authors: Shawn D Aaron, Katherine L Vandemheen, François Maltais, Stephen K Field, Don D Sin, Jean Bourbeau, Darcy D Marciniuk, J Mark FitzGerald, Parameswaran Nair, Ranjeeta Mallick
Journal: Thorax (2012)

<h3>Background</h3> The purpose of this randomised double-blind double-dummy placebo-controlled trial was to investigate whether etanercept, a tumour necrosis factor α (TNFα) antagonist, would provide more effective anti-inflammatory treatment for acute exacerbations of chronic obstructive pulmonary disease (COPD) than prednisone. <h3>Methods</h3> We enrolled 81 patients with acute exacerbations of COPD and randomly assigned them to treatment with either 40 mg oral prednisone given daily for 10 days or to 50 mg etanercept given subcutaneously at randomisation and 1 week later. Both groups received levofloxacin for 10 days plus inhaled bronchodilators. The primary endpoint was the change in the patient9s forced expiratory volume in 1 s (FEV<sub>1</sub>) 14 days after randomisation. Secondary endpoints included 90-day treatment failure rates and dyspnoea and quality of life. <h3>Results</h3> At 14 days the mean±SE change in FEV<sub>1</sub> from baseline was 20.1±5.0% and 15.2±5.7% for the prednisone and etanercept groups, respectively. The mean between-treatment difference was 4.9% (95% CI −10.3% to 20.2%), p=0.52. Rates of treatment failure at 90 days were similar in the prednisone and etanercept groups (32% vs 40%, p=0.44), as were measures of dyspnoea and quality of life. Subgroup analysis revealed that patients with serum eosinophils &gt;2% at exacerbation tended to experience fewer treatment failures if treated with prednisone compared with etanercept (22% vs 50%, p=0.08). <h3>Conclusions</h3> Etanercept was not more effective than prednisone for treatment of acute exacerbations of COPD. Efficacy of prednisone was most apparent in patients who presented with serum eosinophils &gt;2%. <h3>Clinical Trials</h3> gov number NCT 00789997.
A Multicenter, First-in-Pediatrics, Phase 1, Pharmacokinetic and Pharmacodynamic Study of Ridaforolimus in Patients with Refractory Solid Tumors
Authors: Lia Gore, Tanya M. Trippett, Howard M. Katzenstein, Jessica Boklan, Aru Narendran, Amy Smith, Margaret E. Macy, Katherine Rolla, Narayana Narashimhan, Rachel M. Squillace, Christopher D. Turner, Frank G. Haluska, Michael Nieder
Journal: Clinical Cancer Research (2013)

Abstract Purpose: Ridaforolimus (MK-8669, AP23573) is a potent and selective mammalian target of rapamycin (mTOR) inhibitor. Preclinically, ridaforolimus displays antiproliferative activity against a variety of human tumors in vitro and tumor xenograft models in vivo, with additive or synergistic activity when combined with other anticancer agents. Antitumor activity has been confirmed in adults. This phase I study determined the safety, pharmacological, biologic, and toxicity profiles of ridaforolimus in pediatric patients with refractory malignancies. Experimental Design: Eligible children ages 1 to 18 years with advanced solid tumors were enrolled in a 3 + 3 dose escalation design, to determine the safety, tolerability, and maximum tolerated dose (MTD)/dose-limiting toxicity (DLT) of ridaforolimus. Toxicities, pharmacokinetics, and pharmacodynamics were characterized. Results: Fifteen patients were treated. No DLT was observed at any dose level tested; therefore, an MTD was not identified. Most adverse events were mild to moderate; the most common grades 3 and 4 adverse events were hematologic, including thrombocytopenia and anemia. Nonhematologic adverse events were mostly electrolyte disturbances. The observed pharmacokinetic profile of ridaforolimus in children was consistent with that previously showed in adults. Pharmacodynamic confirms that the dose range tested has pharmacological/pharmacodynamic activity. Forty percent of patients achieved stable disease including four of six with central nervous system tumors and two of eight with sarcomas. Conclusions: This first-in-pediatrics study shows that the second-generation mTOR inhibitor ridaforolimus is well tolerated in heavily pretreated children with refractory solid tumors. No DLTs were observed over the dose range tested. Ridaforolimus may represent a therapeutic option for use in pediatric malignancies. Clin Cancer Res; 19(13); 3649–58. ©2013 AACR.
Retraction Note: Inactivation of MAP kinase signalling in Myc Transformed Cells and Rescue by LiCl inhibition of GSK3
Authors: Osama Al-Assar, Dorothy H Crouch
Journal: Molecular Cancer (2005)

The corresponding author submitted this article 1 to Molecular Cancer on the assumption that the co-author had agreed to the submission. Since this is not the case, the authors are retracting the article. The corresponding author is deeply sorry for any inconvenience this may have caused to the editorial and publishing staff. An apology is also extended to the readers.
A Critical Assessment of Storytelling: Gene Ontology Categories and the Importance of Validating Genomic Scans
Authors: Pavlos Pavlidis, Jeffrey D. Jensen, Wolfgang Stephan, Alexandros Stamatakis
Journal: Molecular Biology and Evolution (2012)

In the age of whole-genome population genetics, so-called genomic scan studies often conclude with a long list of putatively selected loci. These lists are then further scrutinized to annotate these regions by gene function, corresponding biological processes, expression levels, or gene networks. Such annotations are often used to assess and/or verify the validity of the genome scan and the statistical methods that have been used to perform the analyses. Furthermore, these results are frequently considered to validate "true-positives" if the identified regions make biological sense a posteriori. Here, we show that this approach can be potentially misleading. By simulating neutral evolutionary histories, we demonstrate that it is possible not only to obtain an extremely high false-positive rate but also to make biological sense out of the false-positives and construct a sensible biological narrative. Results are compared with a recent polymorphism data set from Drosophila melanogaster.
Apoptosis and hepatobiliary disease
Authors: Tushar Patel, Gregory J. Gores
Journal: Hepatology (1995)

Cell death is a key phenomenon in many clinical conditions.Therefore, insight into the cellular mechanisms leading to cell death is of relevance to understanding human disease.In particular, the common occurrence of cell death in a wide range of hepatobiliary diseases emphasizes the importance in understanding the cellular mechanisms causing loss of cell viability.Apoptosis is a f o ~m of cell death that permits the removal of damaged, senescent, or unwanted cells in multicellular organisms, without damage to the cellular microenvironment.Indeed, apoptosis is increasingly being recognized as a key biological regulatory process.Apoptotic cell death plays a complementary yet distinctly opposite role to mitosis in the maintenance of cellular and tissue homeostasis.Indeed, while mitosis causes cell replication, tissue hyperplasia, and organ hypertrophy, apoptosis leads to cell drop-out, tissue hypoplasia, and organ atrophy.'Because apoptosis plays a critical role in deleting cells from tissues, it is not surprising that failure of apoptosis leads to imbalanced cell prolifixation and is now recognized as a mechanism of carcinogenesis.In addition, perturbations of apoptosis have been implicated in a wide range of pathophysiological states, such as autoimmune disease, viral diseases, degenerative disorders, and aging.Furthermore, the importance of apoptosis as a toxicological response to adverse environmental conditions is increasingly being appreciated.Emerging data indicate that apoptosis occurs in several hepatobiliary diseases.Thus, it is now topical and timely to review the Abbreviations: TGF-(I, transforming growth factor-Beta; TNF, tumor necronis factor; TNF-R, TNF-receptor; CTL,
"Gamekeeper's thumb". Injuries of the ulnar collateral ligament of the metacarpophalangeal joint.
Authors: A. Ganel, Z. Aharonson, J. Engel
Journal: British Journal of Sports Medicine (1980)

The condition of chronic instability of the MP (metacarpophalangeal) joint of the thumb, may be the resultant of chronic strain of the ulnar collateral liga- ment of the MP joint.This condition was described in Scottish gamekeepers who used to kill hunted animals by a special manoeuvre subjecting the thumb to extension abduction force, and was termed "Gamekeeper's Thumb" (Campbell, 1955).Nowadays, such a chronic strain has been replaced by relatively frequent acute strains and tears subjected to the thumb during sport activities.The MP joint of the thumb, being a vulnerable one, is subjected to trauma on falling down with arms extended, during hand ball or volley-ball