tbuckley/cabot-search huggingface dataset:
SYNERGY AMONG RESPONDING LYMPHOID CELLS IN THE ONE-WAY MIXED LYMPHOCYTE REACTION
Authors: Wolfgang Tittor, Maria Gerbase-Delima, Roy L. Walford
Journal: The Journal of Experimental Medicine (1974)

The present studies have shown that two subpopulations of thymus-dependent lymphocytes may act synergistically in the mixed lymphocyte reaction (MLR) in the mouse. One subpopulation was well represented in the young adult thymus and the other in lymph nodes. For optimum synergy, both populations must be allogeneic to the stimulator cells. Pretreatment of either population with mitomycin-C abolished synergy. Anti-θ serum abolished both MLR responding and synergizing activities of lymphoid cells. The two thymus-dependent subpopulations were both present in the spleen, and displayed different migratory patterns when injected into irradiated mice: one population went to spleens of the irradiated mice, the other to lymph nodes. The effects of anti-thymocyte serum on the MLR and upon synergy were assessed. While minor differences exist and are herein described, our overall results strongly suggest that in our experiments with synergy in MLR, we may be dealing with the same T1- and T2-cell subpopulations described by Cantor and Asofsky and coworkers (1, 2, 4, 5, 14) as displaying synergy in the graft-vs.-host reaction.
Critical Illness Myopathy and GLUT4
Authors: Steffen Weber-Carstens, Joanna Schneider, Tobias Wollersheim, Anke Assmann, Jeffrey Bierbrauer, Andreas Marg, Hadi Al Hasani, Alexandra Chadt, Katrin Wenzel, Susanne Koch, Jens Fielitz, Christian Kleber, Katharina Faust, Knut Mai, Claudia D. Spies, Friedrich C. Luft, Michael Boschmann, Joachim Spranger, Simone Spuler
Journal: American Journal of Respiratory and Critical Care Medicine (2012)

Critical illness myopathy (CIM) has no known cause and no treatment. Immobilization and impaired glucose metabolism are implicated.We assessed signal transduction in skeletal muscle of patients at risk for CIM. We also investigated the effects of evoked muscle contraction.In a prospective observational and interventional pilot study, we screened 874 mechanically ventilated patients with a sepsis-related organ-failure assessment score greater than or equal to 8 for 3 consecutive days in the first 5 days of intensive care unit stay. Thirty patients at risk for CIM underwent euglycemic-hyperinsulinemic clamp, muscle microdialysis studies, and muscle biopsies. Control subjects were healthy. In five additional patients at risk for CIM, we performed corresponding analyses after 12-day, daily, unilateral electrical muscle stimulation with the contralateral leg as control.We performed successive muscle biopsies and assessed systemic insulin sensitivity and signal transduction pathways of glucose utilization at the mRNA and protein level and glucose transporter-4 (GLUT4) localization in skeletal muscle tissue. Skeletal muscle GLUT4 was trapped at perinuclear spaces, most pronounced in patients with CIM, but resided at the sarcolemma in control subjects. Glucose metabolism was not stimulated during euglycemic-hyperinsulinergic clamp. Insulin signal transduction was competent up to p-Akt activation; however, p-adenosine monophosphate-activated protein kinase (p-AMPK) was not detectable in CIM muscle. Electrical muscle stimulation increased p-AMPK, repositioned GLUT4, locally improved glucose metabolism, and prevented type-2 fiber atrophy.Insufficient GLUT4 translocation results in decreased glucose supply in patients with CIM. Failed AMPK activation is involved. Evoked muscle contraction may prevent muscle-specific AMPK failure, restore GLUT4 disposition, and diminish protein breakdown. Clinical trial registered with http://www.controlled-trials.com (registration number ISRCTN77569430).
Non-invasive characterization of the area-at-risk using magnetic resonance imaging in chronic ischaemia
Authors: M. Wu, J. D'hooge, J. Ganame, V. Ferferieva, K. R. Sipido, F. Maes, S. Dymarkowski, J. Bogaert, F. E. Rademakers, P. Claus
Journal: Cardiovascular Research (2010)

we investigated the performance of quantitative stress perfusion magnetic resonance imaging (MRI) as a basis for identifying and characterizing the area-at-risk subtending a chronic coronary artery (CA) stenosis.pigs underwent a percutaneous copper-coated stent implantation in the circumflex CA (n = 11) or a sham operation (n = 5). After 6 weeks, angiography and MRI were performed including cine (rest, low- and high-dose dobutamine stress), dual-bolus first-pass perfusion (rest and adenosine stress), and contrast-enhanced imaging to quantify myocardial infarction (MI). Myocardial blood flow (MBF) was quantified based on Fermi-model deconvolution and compared with microsphere measurements. On the basis of Evan's blue staining, MBF thresholds to define the area-at-risk were determined by receiver-operating characteristic (ROC) analysis. CA stenosis was 94 ± 7% and infarct size (IS) 7.3 ± 3.1% of left ventricular mass. Segmental thresholds of hyperaemic MBF yielded the best performance for detecting area-at-risk. There was a good correlation between MRI and microsphere perfusion (r(2) = 0.84, P < .0001). The area-at-risk presented a mixed substrate of non-infarcted (non-MI), <50% infarcted (MI+), and >50% infarcted (MI++) segments. MBF was reduced in at-risk vs. remote segments at rest (non-MI, 0.50 ± 0.21; MI+, 0.47 ± 0.14; MI++, 0.42 ± 0.14; remote, 0.84 ± 0.25 mL/min/g) and during stress (non-MI, 0.69 ± 0.09; MI+, 0.66 ± 0.14; MI++, 0.51 ± 0.11; remote, 1.70 ± 0.36 mL/min/g). Segmental wall thickening showed different responses to stress (remote, progressive increase during incremental stress; non-MI, increase at low-dose and discontinued at high-dose; MI+, initial increase and decrease at high-dose; MI++, progressive decrease).quantitative hyperaemic perfusion MRI accurately defines segments in the area-at-risk in chronic ischaemia, which present with different functional response to stress related to segmental IS.
Lower Serotonin Transporter Binding Potential in the Human Brain During Major Depressive Episodes
Authors: Ramin V Parsey, Ramin S Hastings, Maria A Oquendo, Yung-yu Huang, Norman Simpson, Julie Arcement, Yiyun Huang, R Todd Ogden, Ronald L Van Heertum, Victoria Arango, J John Mann
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: CSF analysis, neuroendocrine challenges, serotonin depletion studies, and treatment studies implicate the serotonergic system in the pathophysiology of major depressive disorder. On the basis of postmortem and imaging studies, the authors hypothesized that subjects with major depressive disorder in a major depressive episode have fewer serotonin transporter sites, compared with healthy subjects. METHOD: Serotonin transporter binding potential (f1Bmax/Kd) was determined using positron emission tomography with [11C]McN 5652 in six brain regions in 25 medication-free subjects with DSM-IV major depressive disorder during a major depressive episode and in 43 healthy volunteer comparison subjects. All subjects had arterial lines placed to determine metabolite-corrected arterial input functions. RESULTS: Serotonin transporter binding potential differed significantly by brain region and group. Post hoc analysis revealed lower binding potential in subjects with major depressive disorder, relative to the comparison subjects, in the amygdala and midbrain. The lower binding potential was more pronounced in the depressed subjects who had never received antidepressants. No correlation was found between binding potential in the midbrain and severity of depression or number of days without medication. Binding potential did not differ between suicide attempters and nonattempters. CONCLUSIONS: Subjects in a major depressive episode have lower serotonin transporter binding potential in the amygdala and midbrain, compared to healthy subjects.
p53 integrates host defense and cell fate during bacterial pneumonia
Authors: Jennifer H. Madenspacher, Kathleen M. Azzam, Kymberly M. Gowdy, Kenneth C. Malcolm, Jerry A. Nick, Darlene Dixon, Jim J. Aloor, David W. Draper, John J. Guardiola, Maria Shatz, Daniel Menendez, Julie Lowe, Jun Lu, Pierre Bushel, Leping Li, B. Alex Merrick, Michael A. Resnick, Michael B. Fessler
Journal: The Journal of Experimental Medicine (2013)

Cancer and infection are predominant causes of human mortality and derive, respectively, from inadequate genomic and host defenses against environmental agents. The transcription factor p53 plays a central role in human tumor suppression. Despite its expression in immune cells and broad responsiveness to stressors, it is virtually unknown whether p53 regulates host defense against infection. We report that the lungs of naive p53−/− mice display genome-wide induction of NF-κB response element–enriched proinflammatory genes, suggestive of type 1 immune priming. p53-null and p53 inhibitor–treated mice clear Gram-negative and -positive bacteria more effectively than controls after intrapulmonary infection. This is caused, at least in part, by cytokines produced by an expanded population of apoptosis-resistant, TLR-hyperresponsive alveolar macrophages that enhance airway neutrophilia. p53−/− neutrophils, in turn, display heightened phagocytosis, Nox-dependent oxidant generation, degranulation, and bacterial killing. p53 inhibition boosts bacterial killing by mouse neutrophils and oxidant generation by human neutrophils. Despite enhanced bacterial clearance, infected p53−/− mice suffer increased mortality associated with aggravated lung injury. p53 thus modulates host defense through regulating microbicidal function and fate of phagocytes, revealing a fundamental link between defense of genome and host during environmental insult.
Competing Risks and Multistate Models
Authors: Claudia Schmoor, Martin Schumacher, Jürgen Finke, Jan Beyersmann
Journal: Clinical Cancer Research (2012)

Abstract Complex clinical endpoints are present in studies in cancer. Especially in studies on hematopoietic stem-cell transplantation (HSCT), various risks exist after HSCT. Patients can experience acute and chronic graft versus host disease (GVHD) or need to undergo immunosuppressive therapy (IST), a relapse can occur, or patients can die after relapse or without former relapse (nonrelapse mortality, NRM). Sometimes, endpoints can be reasonably combined in a composite endpoint, as, for example, relapse and NRM are combined into disease-free survival (DFS). In this case, standard survival techniques, as Kaplan–Meier estimation of the DFS probability, can be applied. Often, interest focuses on endpoints for which competing risks are present, as, for example, GVHD, with death without prior GVHD as competing risk. This results in a competing risks model, a special case of a multistate model. A more complex multistate model is required when the effects of events occurring in the course of the study on further disease process shall be investigated, as, for example, the effect of GVHD on relapse and NRM. Another endpoint of interest is time under IST. As patients usually experience multiple episodes of IST, thus switching back and forth between “IST” and “no IST” during follow-up, the multistate model used for analysis must be adapted for this event structure. The aim of this nontechnical report is to explain use and interpretation of Cox-type regression models suitable for the different situations in a randomized trial on the effects of anti-T-cell globulin as GVHD prophylaxis. Clin Cancer Res; 19(1); 12–21. ©2012 AACR.
Differential Regulation of Interleukin (IL)-12 p35 and p40 Gene Expression and Interferon (IFN)-γ–primed IL-12 Production by IFN Regulatory Factor 1
Authors: Jianguo Liu, Shanjin Cao, Lisa M. Herman, Xiaojing Ma
Journal: The Journal of Experimental Medicine (2003)

Interleukin (IL)-12 is a heterodimeric cytokine consisting of the p40 and p35 chains encoded on separate chromosomes. Coordinated expression of the two constituent genes is crucial for appropriate immune responses in timing, location, and magnitude. Interferon (IFN)-γ priming of IL-12 production by macrophages represents an important physiological process in vivo for escalated cellular response to microbial infections. We provide evidence that IFN regulatory factor (IRF)-1–deficient macrophages have a selective impairment in mRNA synthesis of IL-12 p35 but not the p40 gene, and a strong deficiency in the production of IL-12 p70 but not p40. We demonstrate that the levels of IL-12 p35 protein stimulated by IFN-γ and lipopolysaccharide (LPS) correspond to those of its mRNA, and that the nuclear factor κB signaling pathway is essential for the induction of IL-12 p35 transcription by LPS. IRF-1 plays a major role in the transcriptional activation of the IL-12 p35 gene, but not of the p40 gene, by physically interacting with an inverted IRF element within the IL-12 p35 promoter upon IFN-γ activation. Moreover, IRF-1–mediated transcriptional activation of the p35 promoter requires the cooperation of two adjacent Sp1 elements. Thus, IRF-1 acts as a critical component of IFN-γ signaling in the selective activation of IL-12 p35 transcription in synergy with LPS-mediated events.
Pulmonary responses to 5-hydroxytryptamine and endothelin-1 in a rabbit model of left ventricular dysfunction
Authors: G Deuchar
Journal: Cardiovascular Research (1998)

Objective: To determine whether pulmonary hypertension developed in a coronary artery-ligated rabbit model of left ventricular dysfunction (LVD) and to examine the effects of i.v. 5-hydroxytryptamine (5-HT) and endothelin-1 (ET-1) on pulmonary arterial pressure (PAP). Methods: Eight weeks after experimental coronary artery ligation or sham operation, ejection fractions were assessed by echocardiography. The rabbits were later anaesthetised and pulmonary arterial pressure was measured via a catheter inserted into the pulmonary artery via the right external jugular vein. 5-HT (1–400 μg/kg) and ET-1 (0.001–4 nmol/kg) were administered i.v. Results: Ejection fraction was significantly decreased from 76.6±1.4% in sham-operated to 42.2±1.3% in coronary artery-ligated rabbits (n=9 in each group; P<0.001), consistent with LVD. Baseline mean pulmonary arterial pressure was significantly increased in the coronary artery-ligated group compared to the shams, (16.5±0.5 vs. 11.5±0.8 mmHg; P<0.001). A significant degree of right ventricular hypertrophy was found in the coronary artery-ligated rabbits (0.70±0.04 g/kg final body weight (f.b.wt.), n=8 cf. 0.48±0.02 g/kg f.b.wt. in sham-operated controls, n=8; P<0.001). There was a significant increase in the percentage of muscularised pulmonary vessels adjacent to alveolar ducts and alveoli <60 μm i.d. in the LVD rabbits compared with their sham-operated controls (8.5±0.4 cf. 20±0.5%; P<0.0005). 5-HT produced a greater response in the coronary artery-ligated rabbits (a maximum increase of 8.7±1.0 mmHg in mean pulmonary artery pressure vs. 4.6±1.5 mmHg for sham-operated controls; P<0.05). ET-1 did not have any effect on pulmonary arterial pressure in either group. Conclusion: In the rabbit, LVD secondary to coronary artery ligation, causes right ventricular hypertrophy, pulmonary vascular remodelling, and an increased PAP consistent with the onset of pulmonary hypertension (PHT). The greater PAP response to i.v. 5-HT in the PHT group supports the hypothesis that this substance could be involved in the development of PHT. A role for ET-1 cannot be excluded, despite its lack of effect on PAP when intravenously administered in either group.
BRCA1 and E-Cadherin Promoter Hypermethylation and Gene Inactivation in Cancer--Association or Mechanism?
Authors: E. R. Fearon
Journal: JNCI Journal of the National Cancer Institute (2000)

The abnormal properties of cancer cells are attributable to alterations in gene sequence and expression. The genes that are mutated in cancer can be grouped into two classes: protooncogenes and tumor suppressor genes. Proto-oncogenes are affected by gain-of-function mutations in cancer, generating oncogenic variant copies (or alleles) with increased or novel functions, while tumor suppressor genes are inactivated. Tumor suppressor genes were initially hypothesized to be inactivated in cancer cells as a result of genetic defects of both alleles (i.e., the Knudson two-hit hypothesis). Many studies have validated this concept, demonstrating localized mutations in both tumor suppressor gene alleles or a localized mutation in one allele coupled with a loss of heterozygosity (LOH) in the other allele. However, there is now evidence that epigenetic events, such as hypermethylation of cytosine‐guanine (CpG) sites in regulatory regions (e.g., the promoter), may be a critical alternative mechanism of tumor suppressor gene inactivation, including von Hippel‐ Lindau inactivation in some clear-cell renal cancers, p16 INK4a inactivation in some lung and other cancers, and MLH1 inactivation in many sporadic colon cancers with microsatellite instability (1‐3).Two reports (4,5) in this issue of the Journal provide additional data consistent with the view that hypermethylation of the promoter regions of certain tumor suppressor genes may play an important role in extinguishing gene expression in cancer. However, before accepting the conclusion that hypermethylation
Activation of the Fas-FasL Signaling Pathway by MDA-7/IL-24 Kills Human Ovarian Cancer Cells
Authors: Began Gopalan, Anya Litvak, Sikha Sharma, Abner M. Mhashilkar, Sunil Chada, Rajagopal Ramesh
Journal: Cancer Research (2005)

The tumor-suppressive activity of melanoma differentiation-associated gene-7 (mda-7), also known as interleukin 24 (IL-24), has been shown in a spectrum of human cancer cells in vitro and in vivo. However, mechanisms responsible for antitumor activity of mda-7 in human ovarian cancer cells have not been identified. We investigated the therapeutic activity and underlying mechanisms of adenovirus-mediated mda-7 gene (Ad-mda7) transfer in human ovarian cancer cells. Ad-mda7 treatment resulted in overexpression of MDA-7/IL-24 protein in both ovarian cancer and normal ovarian epithelial cells. However, Ad-mda7 significantly (P = 0.001) inhibited cell proliferation and induced apoptosis only in tumor cells and not in normal cells. Studies addressing the mechanism of action of Ad-mda7-induced tumor cell apoptosis revealed early activation of the transcription factors c-Jun and activating transcription factor 2, which in turn stimulated the transcription of an immediate downstream target, the death-inducer Fas ligand (FasL), and its cognate receptor Fas. Associated with the activation of Fas-FasL was the activation of nuclear factor kappaB and induction of Fas-associated factor 1, Fas-associated death domain, and caspase-8. Promoter-based reporter gene analyses showed that Ad-mda7 specifically activated the Fas promoter. Inhibition of Fas using small interfering RNA resulted in a significant decrease in Ad-mda7-mediated tumor cell death. Additionally, blocking of FasL with NOK-1 antibody abrogated Ad-mda7-mediated apoptosis. Collectively, these results show that Ad-mda7-mediated killing of human ovarian cancer cells involves activation of the Fas-FasL signaling pathway, a heretofore unrecognized mediator of MDA-7 apoptosis induction.
Expression Microarray Analysis and Oligo Array Comparative Genomic Hybridization of Acquired Gemcitabine Resistance in Mouse Colon Reveals Selection for Chromosomal Aberrations
Authors: Mark A. van de Wiel, Jose L. Costa, Kees Smid, Cees B.M. Oudejans, Andries M. Bergman, Gerrit A. Meijer, Godefridus J. Peters, Bauke Ylstra
Journal: Cancer Research (2005)

Gemcitabine is a commonly used therapy for many solid tumors. Acquired resistance to this nucleoside analogue, however, diminishes the long-term effectiveness in a majority of patients. To better define the molecular background of gemcitabine resistance, a mouse colon tumor was selected during successive rounds of transplantation with continued treatment of gemcitabine. Expression microarray analysis was applied to determine which genes are consistently and highly overexpressed or underexpressed in the resistant versus the nonresistant tumor. For the statistical interpretation of the microarray data, a parametric model was implemented, which returns model-based differential gene expression (log-) ratios and their uncertainties. This defined a set of 13 genes, putatively responsible for the gemcitabine resistance in solid tumors. One of these, RRM1, was previously identified as an important marker for gemcitabine resistance in human cell lines. Five of the 13 genes, including RRM1, are located within a 3 Mb region at chromosome 7E1 of which four are highly overexpressed, suggesting a chromosomal amplification. Therefore, chromosomal copy number changes were measured, using oligo array comparative genomic hybridization. A narrow and high amplification area was identified on 7E1 that encompassed all five genes. In addition, reduced RNA expression of two other genes at 8E1 encoding COX4I1 and RPL13 could be explained by a decrease in chromosomal copy number on chromosome 8. In conclusion, the array comparative genomic hybridization biologically validates our statistical approach and shows that gemcitabine is capable to select for chromosomally aberrant tumor cells, where changed gene expression levels lead to drug resistance.
DIVERGENT ROLES FOR F<scp>c</scp>RECEPTORS AND COMPLEMENT IN VIVO
Authors: Jeffrey V. Ravetch, Raphael A. Clynes
Journal: Annual Review of Immunology (1998)

▪ Abstract Recent results obtained in mice deficient in either FcRs or complement have revealed distinct functions for these two classes of molecules. While each is capable of interacting with antibodies or immune complexes, the two systems mediate distinct biological effector responses. Complement-deficient mice are unable to mediate innate immune responses to several bacterial pathogens and bacterial toxins, yet respond normally to the presence of cytotoxic antibodies and pathogenic immune complexes. In contrast, FcR-deficient mice display no defects in innate immunity or susceptibility to a variety of pathogens, yet they are unable to mediate inflammatory responses to cytotoxic IgG antibodies or IgG immune complexes, despite the presence of a normal complement system. These results lead to the surprising conclusion that these two systems have evolved distinct functions in host immunity, with complement and its receptors mediating the interaction of natural antibodies (IgM) with pathogens to effect protection, while FcRs couple the interaction of IgG antibodies to effector cells to trigger inflammatory sequelae. These results necessitate a fundamental revision of the role of these antibody-binding systems in the immune response.
Does modulation of P-glycoprotein have clinical relevance in pediatric acute myeloid leukemia?
Authors: Christian Michel Zwaan, Monique L. den Boer, Karin M. Kazemier, Karel Hählen, Anne H. Loonen, Dirk Reinhardt, Ursula Creutzig, Gertjan J. L. Kaspers, Rob Pieters
Journal: Blood (2006)