tbuckley/cabot-search huggingface dataset:
FoxP3 mRNA Expression in Regulatory T Cells from Patients with Tuberculosis
Authors: Lidia Gazzola, Camilla Tincati, Andrea Gori, Marina Saresella, Ivana Marventano, Fabio Zanini
Journal: American Journal of Respiratory and Critical Care Medicine (2006)

We read with great interest the article by Guyot-Revol and colleagues (1) assessing the role of T regulatory cells (Tregs) in tuberculosis (TB) pathogenesis. Guyot-Revol and coworkers found that in patients with TB, percentages of CD4 CD25 T cells and levels of FoxP3 mRNA expression in peripheral blood mononuclear cells were both significantly higher in comparison with controls. To better comprehend Tregs’ mechanism of action, the authors investigated whether the increased levels of FoxP3 mRNA that they had observed were effectively caused by increased gene expression, or were simply the result of increasedCD4 CD25high frequency.FoxP3mRNAinCD4 CD25 T cells was compared between patients with TB and control subjects. As no quantitative difference was observed, the authors suggest that the greater levels of FoxP3 mRNA are simply an effect of increases in Treg frequency rather than a result of an up-regulated gene expression. The transcription factor FoxP3 is the most specific molecular marker for Tregs available to date, and its correct evaluation is crucial (2–4). In the analysis of Treg dynamics, an assessment of what happens in the frequency and level of FoxP3 mRNA expression at the single cell level is mandatory. The recent literature demonstrates a strong correlation between levels of CD25 expression and the frequency of FoxP3-positive cells in healthy donors (4), and suggests that to correctly evaluate FoxP3 expression in Tregs, mRNA should be quantified in CD4 CD25 rather than in CD4 CD25 T cells (5). We are currently performing a prospective study to evaluate Tregs in patients with TB. Analysis of CD4 CD25 percentage on CD4 T cells at TB diagnosis showed similar levels of Tregs among patients with TB and controls (median percentage: 2.1% [IQR, 1.8–6.6] vs. 1.9% [IQR, 1.5–2.2]). Unlike Guyot-Revol and coworkers, we evaluated FoxP3 mRNA expression by real-time polymerase chain reaction in CD4 CD25 T cells, purified using an EPICSALTRACell Sorter (Beckman-Coulter; purity 93.6%). A considerable increase of FoxP3 mRNA expression in patients with TB with respect to control subjects was clearly observed (median: 39.1 [IQR, 5.1–109] vs. 1.6 [IQR, 0.8–2.8]; p 0.0062). These data implicate FoxP3 gene overexpression as a probable mechanism involving Tregs in the pathogenesis of TB, and suggest a possible role of FoxP3 gene up-regulation in the outcome of chronic infections. Our results underscore the importance of using the correct methodology in evaluating Treg cell dynamics, and prove that an accurate evaluation of FoxP3 mRNA expression in Treg cells may lead to the identification of previously unknown mechanisms of Treg cell involvement in disease pathogenesis.
Can developmentally significant spatial patterning of the egg be discounted in mammals?
Authors: R. Gardner
Journal: Human Reproduction Update (1996)

Mammals are generally held to be exceptions to the rule that organization of the egg plays a role in specifying the differentiation of cells, axes, or other aspects of patterning in the early embryo. However, there are several grounds for questioning this conclusion. Not only do certain experimental findings remain unexplained but, more importantly, nearly all have been interpreted specifically in terms of the differentiation of trophectoderm versus inner cell mass. The possibility that egg organization is instrumental in patterning of the early embryo in mammals has so far been almost entirely neglected, notwithstanding evidence that the mouse blastocyst becomes bilaterally symmetrical before it implants. Difficulties confronting attempts to tackle the issue of the significance of egg organization in mammals are discussed with respect to polarity and cytoplasmic differentiation in the oocyte and zygote. Evidence for an enduring influence of the maternal genome during early development is reviewed and weaknesses in the case against a role for egg organization are exposed. Finally, consideration is given to what needs to be done if this issue is to be resolved.
2-Methoxyestradiol Inhibits the Anaphase-Promoting Complex and Protein Translation in Human Breast Cancer Cells
Authors: Rajendra Bhati, Yesim Gökmen-Polar, George W. Sledge, Cheng Fan, Harikrishna Nakshatri, David Ketelsen, Christoph H. Borchers, Michael J. Dial, Cam Patterson, Nancy Klauber-DeMore
Journal: Cancer Research (2007)

Abstract 2-Methoxyestradiol (2ME2), an estradiol metabolite with antiproliferative and antiangiogenic activities, is in phase I/II clinical trials for breast cancer. 2ME2 inhibits microtubule polymerization and causes cells to arrest in G2-M. The purpose of this study was to further elucidate the molecular mechanism of 2ME2. MDA-MB-435 breast cancer cells were treated with 2ME2 (2 μmol/L) or vehicle alone. RNA was extracted and genomic profiling was done using 22k Agilent microarrays. Expression Analysis Systematic Explorer was used to determine enrichment of Gene Ontology categories. Protein isolates were subjected to Western blot analysis. Protein synthesis was measured with a [35S]methionine pulse assay. An MDA-MB-435 cell line with two β-tubulin mutations (2ME2R) was used to determine whether novel mechanisms were tubulin-dependent. Gene Ontology categories enriched include genes that regulate the mitotic spindle assembly checkpoint, apoptosis, and the cytosolic ribosome. The target of the mitotic spindle assembly checkpoint is the anaphase-promoting complex (APC). APC inhibition was confirmed by measuring protein levels of its targets securin and cyclin B1, which were increased in 2ME2-treated cells. Because gene expression in the cytosolic ribosome category was decreased, we evaluated whether 2ME2 decreases protein translation. This was confirmed with a pulse assay, which showed decreased isotope incorporation in 2ME2-treated cells, which was maintained in the tubulin-resistant 2ME2R cells. APC inhibition was not maintained in 2ME2R cells. 2ME2 induces tubulin-dependent cell cycle arrest through regulation of genes involved in the mitotic spindle assembly checkpoint, which results in inhibition of the APC and tubulin-independent inhibition of protein translation. [Cancer Res 2007;67(2):702–8]
Human Evidence That the Apolipoprotein A-II Gene Is Implicated in Visceral Fat Accumulation and Metabolism of Triglyceride-Rich Lipoproteins
Authors: Ferdinand M. van ’t Hooft, Giacomo Ruotolo, Susanna Boquist, Ulf de Faire, Gösta Eggertsen, Anders Hamsten
Journal: Circulation (2001)

Background Apolipoprotein (apo) A-II is a major structural protein of plasma HDLs, but little is known regarding its functions. Methods and Results To investigate the physiological role of apoA-II in humans, we screened the promoter region of the apoA-II gene for a functional polymorphism and used this polymorphism as a tool in association studies. A common, functional polymorphism in the promoter region of the apoA-II gene, a T to C substitution at position −265, was found. Electrophoretic mobility shift assays demonstrated that the −265T/C polymorphism influences the binding of nuclear proteins, whereas transient transfection studies in human hepatoma cells showed a reduced basal rate of transcription of the −265C allele compared with the −265T allele. The −265C allele was associated with decreased plasma apoA-II concentration and decreased waist circumference in healthy 50-year-old men. In addition, oral fat tolerance tests provided evidence that the −265C allele enhances postprandial metabolism of large VLDLs. Conclusions ApoA-II appears to promote visceral fat accumulation and impair metabolism of large VLDLs.
Review of aldosterone- and angiotensin II-induced target organ damage and prevention
Authors: A Struthers
Journal: Cardiovascular Research (2004)

Aldosterone is well recognized as a cause of sodium reabsorption, water retention, and potassium and magnesium loss; however, it also produces a variety of other actions that lead to progressive target organ damage in the heart, vasculature, and kidneys. Aldosterone interacts with mineralocorticoid receptors to promote endothelial dysfunction, facilitate thrombosis, reduce vascular compliance, impair baroreceptor function, and cause myocardial and vascular fibrosis. Although angiotensin II has been considered the major mediator of cardiovascular damage, increasing evidence suggests that aldosterone may mediate and exacerbate the damaging effects of angiotensin II. While angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers reduce plasma aldosterone levels initially, aldosterone rebound, or 'escape' may occur during long-term therapy. Therefore, aldosterone blockade is required to reduce the risk of progressive target organ damage in patients with hypertension and heart failure. This may be achieved nonselectively with spironolactone or with use of the selective aldosterone blocker eplerenone. While both agents have been demonstrated to be effective antihypertensive agents, eplerenone may produce improved target organ protection as witnessed in a variety of clinical settings, without the antiandrogenic and progestational effects commonly observed with spironolactone.
Predictors of primary atrial fibrillation and concomitant clinical and hemodynamic changes in patients with chronic heart failure: a prospective study in 344 patients with baseline sinus rhythm
Authors: Massimo Pozzoli, Giovanni Cioffi, Egidio Traversi, Gian Domenico Pinna, Franco Cobelli, Luigi Tavazzi
Journal: Journal of the American College of Cardiology (1998)
Interferon γ Gene Expression in Sensory Neurons: Evidence for Autocrine Gene Regulation
Authors: Harald Neumann, Hannes Schmidt, Elke Wilharm, Lüder Behrens, Hartmut Wekerle
Journal: The Journal of Experimental Medicine (1997)

We explored expression and possible function of interferon-gamma (IFN-gamma) in cultured fetal (E15) rat dorsal root ganglion neurons combining whole cell patch-clamp electrophysiology with single cell reverse transcriptase polymerase chain reaction and confocal laser immunocytochemistry. Morphologically, we located IFN-gamma protein in the cytoplasm of the neurons in culture as well as in situ during peri- and postnatal development. Transcripts for classic IFN-gamma and for its receptor were determined in probes of cytoplasm sampled from individual cultured neurons, which had been identified by patch clamp electrophysiology. In addition, the cultured neurons expressed both chains of the IFN-gamma receptor. Locally produced IFN-gamma acts back on its cellular source. Phosphorylation and nuclear translocation of the IFN-inducible transcriptional factor STAT1 as well as IFN-gamma-dependent expression of major histocompatibility complex class I molecules on the neuronal membrane were noted in untreated cultures. However, both processes were substantially blocked in the presence of antibodies neutralizing IFN-gamma. Our findings indicate a role of IFN-gamma in autocrine regulation of sensory neurons.
In Vivo Activation of cAMP Signaling Induces Growth Arrest and Differentiation in Acute Promyelocytic Leukemia
Authors: Marie-Claude Guillemin, Emmanuel Raffoux, Dominique Vitoux, Scott Kogan, Hassane Soilihi, Valérie Lallemand-Breitenbach, Jun Zhu, Anne Janin, Marie-Thérèse Daniel, Bernard Gourmel, Laurent Degos, Hervé Dombret, Michel Lanotte, Hugues de Thé
Journal: The Journal of Experimental Medicine (2002)

Differentiation therapy for acute myeloid leukemia uses transcriptional modulators to reprogram cancer cells. The most relevant clinical example is acute promyelocytic leukemia (APL), which responds dramatically to either retinoic acid (RA) or arsenic trioxide (As2O3). In many myeloid leukemia cell lines, cyclic adenosine monophosphate (cAMP) triggers growth arrest, cell death, or differentiation, often in synergy with RA. Nevertheless, the toxicity of cAMP derivatives and lack of suitable models has hampered trials designed to assess the in vivo relevance of theses observations. We show that, in an APL cell line, cAMP analogs blocked cell growth and unraveled As2O3-triggered differentiation. Similarly, in RA-sensitive or RA-resistant mouse models of APL, continuous infusions of 8-chloro-cyclic adenosine monophosphate (8-Cl-cAMP) triggered major growth arrest, greatly enhanced both spontaneous and RA- or As2O3-induced differentiation and accelerated the restoration of normal hematopoiesis. Theophylline, a well-tolerated phosphodiesterase inhibitor which stabilizes endogenous cAMP, also impaired APL growth and enhanced spontaneous or As2O3-triggered cell differentiation in vivo. Accordingly, in an APL patient resistant to combined RA–As2O3 therapy, theophylline induced blast clearance and restored normal hematopoiesis. Taken together, these results demonstrate that in vivo activation of cAMP signaling contributes to APL clearance, independently of its RA-sensitivity, thus raising hopes that other myeloid leukemias may benefit from this therapeutic approach.
Emily Dickinson Revisited: A Study of Periodicity in Her Work
Authors: John F. McDermott
Journal: American Journal of Psychiatry (2001)

Emily Dickinson, arguably one of America's foremost poets, is characterized by critics as able to capture extreme emotional states in her greatest work. Recent dating of her poems offers the periodicity of her writing as a behavior that can be examined for patterns of affective illness that may relate to these states.The bulk of Dickinson's work was written during a clearly defined 8-year period when she was age 28-35. Poems written during that period, 1858-1865, were grouped by year and examined for annual and seasonal distribution.Her 8-year period of productivity was marked by two 4-year phases. The first shows a seasonal pattern characterized by greater creative output in spring and summer and a lesser output during the fall and winter. This pattern was interrupted by an emotional crisis that marked the beginning of the second phase, a 4-year sustained period of greatly heightened productivity and the emergence of a revolutionary poetic style.These data, supported by excerpts from letters to friends during this period of Dickinson's life, demonstrate seasonal changes in mood during the first four years of major productivity, followed by a sustained elevation of creative energy, mood, and cognition during the second. They suggest, as supported by family history, a bipolar pattern previously described in creative artists.
Hydroa vacciniforme: a review of ten cases
Authors: T.S. SONNEX, J.L.M. HAWK
Journal: British Journal of Dermatology (1988)

Ten patients with hydroa vacciniforme are reported. The condition appears to be a distinct clinical and histological entity. Haematological, biochemical, immunological, bacteriological and viral investigations were negative. Three patients demonstrated low minimal erythema doses (MEDs) following monochromatic ultraviolet (UVA) irradiation of back skin; such UVA sensitivity may be a feature of hydroa vacciniforme. Treatment was unsatisfactory, although spontaneous improvement in the condition tended to occur and regular application of sunscreens with high protection factors against both UVA and UVB was helpful.
Cellular Factors Promoting Resistance to Effective Treatment of Glioma with Oncolytic Myxoma Virus
Authors: Franz J. Zemp, Brienne A. McKenzie, Xueqing Lun, Karlyne M. Reilly, Grant McFadden, V. Wee Yong, Peter A. Forsyth
Journal: Cancer Research (2014)

Oncolytic virus therapy is being evaluated in clinical trials for human glioma. While it is widely assumed that the immune response of the patient to the virus infection limits the utility of the therapy, investigations into the specific cell type(s) involved in this response have been performed using nonspecific pharmacologic inhibitors or allogeneic models with compromised immunity. To identify the immune cells that participate in clearing an oncolytic infection in glioma, we used flow cytometry and immunohistochemistry to immunophenotype an orthotopic glioma model in immunocompetent mice after Myxoma virus (MYXV) administration. These studies revealed a large resident microglia and macrophage population in untreated tumors, and robust monocyte, T-, and NK cell infiltration 3 days after MYXV infection. To determine the role on the clinical utility of MYXV therapy for glioma, we used a combination of knockout mouse strains and specific immunocyte ablation techniques. Collectively, our experiments identify an important role for tumor-resident myeloid cells and overlapping roles for recruited NK and T cells in the clearance and efficacy of oncolytic MYXV from gliomas. Using a cyclophosphamide regimen to achieve lymphoablation prior and during MYXV treatment, we prevented treatment-induced peripheral immunocyte recruitment and, surprisingly, largely ablated the tumor-resident macrophage population. Virotherapy of cyclophosphamide-treated animals resulted in sustained viral infection within the glioma as well as a substantial survival advantage. This study demonstrates that resistance to MYXV virotherapy in syngeneic glioma models involves a multifaceted cellular immune response that can be overcome with cyclophosphamide-mediated lymphoablation.
Rhinovirus stimulation of interleukin-6 in vivo and in vitro. Evidence for nuclear factor kappa B-dependent transcriptional activation.
Authors: Z Zhu, W Tang, A Ray, Y Wu, O Einarsson, M L Landry, J Gwaltney, J A Elias
Journal: Journal of Clinical Investigation (1996)

To further understand the biology of rhinovirus (RV), we determined whether IL-6 was produced during RV infections and characterized the mechanism by which RV stimulates lung cell IL-6 production. In contrast to normals and minimally symptomatic volunteers, IL-6 was detected in the nasal washings from patients who developed colds after RV challenge. RV14 and RV1A, major and minor receptor group RVs, respectively, were potent stimulators of IL-6 protein production in vitro. These effects were associated with significant increases in IL-6 mRNA accumulation and gene transcription. RV was also a potent stimulator of IL-6 promoter-driven luciferase activity. This stimulation was modestly decreased by mutation of the nuclear factor (NF)-IL-6 site and abrogated by mutation of the NF-kappa B site in this promoter. An NF-kappa B-DNA binding activity, mediated by p65, p50, and p52 NF-kappa B moieties, was rapidly induced in RV-infected cells. Activator protein 1-DNA binding was not similarly altered. These studies demonstrate that IL-6 is produced during symptomatic RV infections, that RVs are potent stimulators of IL-6 elaboration, and that RV stimulation IL-6 production is mediated by an NF-kappa B-dependent transcriptional stimulation pathway. IL-6 may play an important role in the pathogenesis of RV infection, and NF-kappa B activation is likely to be an important event in RV-induced pathologies.
Central adiposity, obesity during early adulthood, and pancreatic cancer mortality in a pooled analysis of cohort studies
Authors: J.M. Genkinger, C.M. Kitahara, L. Bernstein, A. Berrington de Gonzalez, M. Brotzman, J.W. Elena, G.G. Giles, P. Hartge, P.N. Singh, R.Z. Stolzenberg-Solomon, E. Weiderpass, H.-O. Adami, K.E. Anderson, L.E. Beane-Freeman, J.E. Buring, G.E. Fraser, C.S. Fuchs, S.M. Gapstur, J.M. Gaziano, K.J. Helzlsouer, J.V. Lacey, M.S. Linet, J.J. Liu, Y. Park, U. Peters, M.P. Purdue, K. Robien, C. Schairer, H.D. Sesso, K. Visvanathan, E. White, A. Wolk, B.M. Wolpin, A. Zeleniuch-Jacquotte, E.J. Jacobs
Journal: Annals of Oncology (2015)
Variable Tidal Volume Ventilation Improves Lung Mechanics and Gas Exchange in a Rodent Model of Acute Lung Injury
Authors: STEPHEN P. AROLD, RENE MORA, KENNETH R. LUTCHEN, EDWARD P. INGENITO, BÉLA SUKI
Journal: American Journal of Respiratory and Critical Care Medicine (2002)

Random variations in breath rate and tidal volume during mechanical ventilation in the setting of acute lung injury have been shown to improve arterial oxygen tension. To test whether this improvement occurs over a specific range of variability, we examined several ventilation protocols in guinea pigs with endotoxin-induced lung injury. In Group I (n = 10), after 30 min of conventional volume-cycled ventilation, animals were ventilated with variable ventilation for 30-min intervals, during which time tidal volume was randomly varied by 10, 20, 40, and 60% of the mean, while simultaneously adjusting the frequency to maintain constant minute ventilation. In a second group of animals (Group II, n = 4), conventional volume-cycled ventilation was administered for 3 h. Variable ventilation significantly improved lung function over conventional volume-cycled ventilation. In Group I, lung elastance decreased, and blood oxygenation increased significantly during periods of 40 and 60% variable ventilation (p < 0.05) compared with conventional ventilation. These data indicate that variable ventilation is effective in improving lung function and gas exchange during acute lung injury.
"Unidirectional" Atrioventricular Conduction Studied by Microelectrodes
Authors: TOYOMI SANO, EHCHI OHTSUKA, TAKIO SHIMAMOTO
Journal: Circulation Research (1960)

By applying microelectrode technic in isolated dog hearts, the nature of the so-called unidirectional conduction of the atrioventricular conduction was investigated. Retrograde conduction, i.e., conduction from the ventricle, occurred frequently in the isolated whole heart from which the sinus node was removed, or in a preparation composed of the interatrial septum, right atrium, right ventricle, interventricular septum, and atrioventricular conduction system. Retrograde conduction was blocked just as frequently. In such cases, this unidirectional block was found not to be ascribed solely to the refractory period of the atrioventricular node or of the atrial muscle fibers. The site of unidirectional block was found to be located in the domain of the ventricle, i.e., in the region adjacent to the postero-inferior margin of the membranous portion of the interventricular septum. This site is of a very limited extension. This point responded to ventricular stimuli, frequently by localized depolarization only, or in the manner of decremental conduction, whereas following atrial stimuli, it responded with full-sized action potential. By histologic examination, it was found that this point is situated in the ventricular portion of the bundle of His, just above the bifurcating point to the right and left branches.