tbuckley/cabot-search huggingface dataset:
A SUMOylation-Dependent Pathway Regulates SIRT1 Transcription and Lung Cancer Metastasis
Authors: Lina Sun, He Li, Junliang Chen, Vanessa Dehennaut, Yuhao Zhao, Yuyu Yang, Yasumasa Iwasaki, Brigitte Kahn-Perles, Dominique Leprince, Qi Chen, Aiguo Shen, Yong Xu
Journal: JNCI Journal of the National Cancer Institute (2013)

Epithelial-to-mesenchymal transition (EMT) plays a pivotal role in lung cancer metastasis. The class III deacetylase sirtuin 1 (SIRT1) possesses both pro- and anticarcinogenic properties. The role of SIRT1 in lung cancer EMT is largely undefined.The effect of SIRT1 on migration of lung cancer cells was evaluated by wound healing assay in vitro and metastasis assay in nude mice in vivo. Protein expression in human lung cancers and cultured lung cancer cells was assessed by western blotting and immunohistochemistry. Interaction between protein and DNA was measured by chromatin immunoprecipitation assay. SIRT1 promoter activity was determined by reporter assay.SIRT1 activation antagonized migration of lung cancer cells by suppressing EMT in vitro. Activation of SIRT1 by resveratrol also statistically significantly hampered (by 68.33%; P < .001, two-sided test) lung cancer cell metastasis in vivo. Hypoxia repressed SIRT1 transcription through promoting the competition between Sp1 and HIC1 on the SIRT1 proximal promoter in a SUMOylation-dependent manner. Disruption of SUMOylation by targeting either Ubc9 or PIASy restored SIRT1 expression in and favored an epithelial-like phenotype of cancer cells, thereby preventing metastasis. Decreased SIRT1 combined with elevated PIASy expression was implicated in more-invasive types of lung cancers in humans.We have identified a novel pathway that links SIRT1 down-regulation to hypoxia-induced EMT in lung cancer cells and may shed light on the development of novel antitumor therapeutics.
Pulmonary Alveolar Type II Cells Isolated from Rats
Authors: Leland G. Dobbs, Robert J. Mason
Journal: Journal of Clinical Investigation (1979)

It is unclear what factors control the secretion of pulmonary surface active material from alveolar type II cells in vivo. Other workers have suggested that cholinergic stimuli, adrenergic stimuli, and prostaglandins may all stimulate secretion. We isolated type II cells from the lungs of rats by treatment with elastase, discontinuous density centrifugation, and adherence in primary culture. β-Adrenergic agonists, but not cholinergic agonists, caused an increase in the release of [14C]disaturated phosphatidylcholine, the major component of surface-active material, from type II cells in culture. The β-adrenergic effect was stereo-selective, (−)-isoproterenol being 50 times more potent than (+)-isoproterenol. Terbutaline, 10 μM, a noncatecholamine β-2 adrenergic agonist, caused a release of 2.0±0.5 (mean±SD) times the basal release of [14C]disaturated phosphatidylcholine in 3 h; the concentration of terbutaline causing half maximal stimulation was 800 nM. The terbutaline effect was blocked by propranolol, a β-adrenergic antagonist (calculated Kd = 6 nM), but not by phentolamine, an α-adrenergic antagonist. Isobutylmethylxanthine, a phosphodiesterase inhibitor, and 8-Br cyclic AMP, but not 8-Br cyclic guanosine monophosphate, also stimulated release. We conclude that type II cells secrete disaturated phosphatidylcholine in response to treatment with adrenergic stimulation.
Comparative evaluation of diaphragmatic activity during pressure support ventilation and intermittent mandatory ventilation in animal model.
Authors: A Uchiyama, H Imanaka, N Taenaka, S Nakano, Y Fujino, I Yoshiya
Journal: American Journal of Respiratory and Critical Care Medicine (1994)

The aim of the present study is a comparative evaluation of the effects of pressure support ventilation (PSV) and intermittent mandatory ventilation (IMV) on diaphragmatic activity in rabbit model of neonate. The animals were divided into a PSV group and an IMV group. In the IMV group, spontaneous breathing and four kinds of IMV rate (5, 10, 15, and 20/min) were applied (Ventilator: Bear BP200, peak inspiratory pressure [PIP]: 12 cm H2O, inspiratory time: 0.6 s). In the PSV group, spontaneous breathing and four levels of PSV (3, 6, 9, and 12 cm H2O) were applied (Ventilator: VIP Bird, flow triggering). Airway pressure (Paw), flow (V), esophageal pressure (Pes), integrated diaphragmatic electromyogram (Edi), and arterial gas data were measured. Amplitudes of Pes and Edi were expressed as percentages (% Edi and % Pes) of the control value during spontaneous breathing to evaluate diaphragmatic activity. Lower IMV rates did not reduce diaphragmatic activity. Approximately half of diaphragmatic activity of control remained even at IMV 15/min. Diaphragmatic activity disappeared at IMV20/min. In contrast, PSV reduced Edi and Pes linearly according to support level. In conclusion, diaphragmatic activity could be reduced more gradually with PSV than IMV by altering ventilatory support level.
Epigenetic Modifications of Stem Cells
Authors: Yonggang Zhou, Johnny Kim, Xuejun Yuan, Thomas Braun
Journal: Circulation Research (2011)

Stem cells of all types are characterized by the ability to self-renew and to differentiate. Multiple lines of evidence suggest that both maintenance of stemness and lineage commitment, including determination of the cardiomyogenic lineage, are tightly controlled by epigenetic mechanisms such as DNA methylation, histone modifications, and ATP-dependent chromatin remodeling. Epigenetic mechanisms are intrinsically reversible, interdependent, and highly dynamic in regulation of chromatin structure and specific gene transcription programs, thereby contributing to stem cell homeostasis. Here, we review the current understanding of epigenetic mechanisms involved in regulation of stem cell self-renewal and differentiation and in the control of cardiac progenitor cell commitment during heart development. Further progress in this area will help to decipher the epigenetic landscape in stem and progenitor cells and facilitate manipulation of stem cells for regenerative applications.
Phase I Trial of the Irreversible EGFR and HER2 Kinase Inhibitor BIBW 2992 in Patients With Advanced Solid Tumors
Authors: Timothy A. Yap, Laura Vidal, Jan Adam, Peter Stephens, James Spicer, Heather Shaw, Jooern Ang, Graham Temple, Susan Bell, Mehdi Shahidi, Martina Uttenreuther-Fischer, Peter Stopfer, Andrew Futreal, Hilary Calvert, Johann S. de Bono, Ruth Plummer
Journal: Journal of Clinical Oncology (2010)

Preclinical data have demonstrated that BIBW 2992 is a potent irreversible inhibitor of ErbB1 (EGFR/HER1) and mutated ErbB1 receptors including the T790M variant, as well as ErbB2 (HER2). A phase I study of continuous once-daily oral BIBW 2992 was conducted to determine safety, maximum-tolerated dose, pharmacokinetics (PK), food effect, and preliminary antitumor efficacy.Patients with advanced solid tumors were treated. PK evaluation was performed after the first dose and at steady-state.Fifty-three patients received BIBW 2992 at 10 to 50 mg/d. BIBW 2992 was generally well-tolerated. The most common adverse effects included diarrhea, nausea, vomiting, rash, and fatigue. Dose-limiting toxicities included grade 3 rash (n = 2) and reversible dyspnea secondary to pneumonitis (n = 1). The recommended phase II dose was 50 mg/d. PK was dose proportional with a terminal elimination half-life ranging between 21.3 and 27.7 hours on day 1 and between 22.3 and 67.0 hours on day 27; BIBW 2992 exposure decreased after food intake. Three patients with non-small-cell lung carcinoma (NSCLC; two with in-frame exon 19 mutation deletions) experienced confirmed partial responses (PR) sustained for 24, 18, and 34 months, respectively. Two other patients (esophageal carcinoma and NSCLC) had nonconfirmed PRs. A patient with a PR at 10 mg/d progressed and developed symptomatic brain metastases, which subsequently regressed with an increased dose of 40 mg/d of BIBW 2992. A further seven patients had disease stabilization lasting > or = 6 months.Continuous, daily, oral BIBW 2992 is safe and has durable antitumor activity. It is currently being evaluated in phase III trials.
Effect of a somatostatin analogue on gastric motor and sensory functions in healthy humans
Authors: A Foxx-Orenstein, M Camilleri, D Stephens, D Burton
Journal: Gut (2003)

<b>Background:</b> Pharmacological approaches to alter satiation may have an impact on functional upper gastrointestinal disorders and potentially change food intake in obesity. <b>Aim:</b> Our aim was to compare the effects of two doses of octreotide and placebo on postprandial symptoms, gastric accommodation, and gastric emptying using validated non-invasive techniques. <b>Methods:</b> In a randomised, parallel group, two dose, double blind, placebo controlled study, 39 healthy participants (13 per group) were randomised to 30 or 100 µg octreotide or placebo, administered subcutaneously, 30 minutes before each study. Studies were performed on three separate days and included scintigraphic gastric emptying of solids and liquids, <sup>99m</sup>Tc SPECT imaging to measure fasting stomach volume and gastric accommodation following a 300 ml Ensure meal, and a standardised nutrient drink test to measure maximum tolerated volume and postprandial symptoms. <b>Results:</b> Relative to placebo, both doses of octreotide delayed gastric emptying of solids (not liquids), increased fasting gastric volume, reduced the change in gastric volume post meal, and decreased the sensation of fullness after a satiating meal. <b>Conclusion:</b> The somatostatin analogue octreotide significantly alters human gastric functions, including inhibition of the normal reflex responses of gastric volume increase and emptying of the meal. These pharmacological effects suggest studies of the medication in disorders of satiation, including obesity and dyspepsia, are warranted.
Early preservation of effector functions followed by eventual T cell memory depletion: a model for the delayed onset of the effect of thiopurines
Authors: S Ben-Horin, I Goldstein, E Fudim, O Picard, Z Yerushalmi, I Barshack, I Bank, Y Goldschmid, S B. Meir, L Mayer, Y Chowers
Journal: Gut (2008)

<h3>Objective:</h3> The onset of the effect of thiopurines is delayed for several months. The aim of this study was to investigate immune mechanisms for this delay. <h3>Methods:</h3> The effects of thiopurines on human peripheral blood T cells and on lamina propria lymphocytes were investigated for apoptosis induction by Annexin V/propidium iodide (PI) and for cytokine secretion by intracellular staining and ELISA assays. To investigate the mechanism of the effect of thiopurines in vivo, Balb/C mice were co-immunised with HEL/OVA (hen egg lysozyme/ovalbumin) antigens, and then repeatedly challenged by HEL only, while being treated by mercaptopurine or vehicle alone for either 4 or 20 weeks. The memory response of CD4+ splenocytes towards HEL/OVA was then determined by CFSE (carboxyfluorescein succinimidyl ester) dilution. <h3>Results:</h3> Thiopurines arrested the proliferation of stimulated T cells but did not enhance the apoptosis of either resting T cells or activated T cells until day 5 poststimulation. Despite the proliferation arrest, stimulated T cells successfully differentiated into effector cells, as evidenced by their capacity for proinflammatory cytokine secretion, potent adhesion and cytotoxicity. Prolonged mercaptopurine treatment of mice for 20 weeks selectively reduced the CD4+ memory response to a repeatedly encountered HEL antigen, but did not affect the T cell memory pool to the previously presented OVA antigen. A shorter, 4 weeks, treatment with mercaptopurine did not inhibit the memory response to either antigen. <h3>Conclusions:</h3> T cells arrested from cycling by thiopurines can still differentiate into potent effector cells capable of propagating the inflammatory process. Thiopurine treatment results in depletion of antigen-specific memory T cells, but this effect is dependent upon repeated encounters with the antigen over a prolonged time course.
Molecular assays for the detection of microRNAs in prostate cancer
Authors: Amara C Siva, Luke J Nelson, Chad L Fleischer, Mehrdad Majlessi, Michael M Becker, Robert L Vessella, Mark A Reynolds
Journal: Molecular Cancer (2009)

MicroRNAs (miRNAs) are small non-coding RNAs (about 21 to 24 nucleotides in length) that effectively reduce the translation of their target mRNAs. Several studies have shown miRNAs to be differentially expressed in prostate cancer, many of which are found in fragile regions of chromosomes. Expression profiles of miRNAs can provide information to separate malignancies based upon stage, progression and prognosis. Here we describe research prototype assays that detect a number of miRNA sequences with high analytical sensitivity and specificity, including miR-21, miR-182, miR-221 and miR-222, which were identified through expression profiling experiments with prostate cancer specimens. The miRNAs were isolated, amplified and quantified using magnetic bead-based target capture and a modified form of Transcription-Mediated Amplification (TMA).Analytical sensitivity and specificity were demonstrated in model system experiments using synthetic mature microRNAs or in vitro miRNA hairpin precursor transcripts. Research prototype assays for miR-21, miR-182, miR-221 and miR-222 provided analytical sensitivities ranging from 50 to 500 copies of target per reaction in sample transport medium. Specific capture and detection of mature miR-221 from complex samples was demonstrated in total RNA isolated from human prostate cancer cell lines and xenografts.Research prototype real-time TMA assays for microRNAs provide accurate and reproducible quantitation using 10 nanograms of input total RNA. These assays can also be used directly with tissue specimens, without the need for a preanalytic RNA isolation step, and thus provide a high-throughput method of microRNA profiling in clinical specimens.
Reply to Letter to the Editor “Late local recurrences in a randomized trial comparing conservative treatment with total mastectomy in early breast cancer patients: the impact of receptor status on local relapse” by Altundag et al. (Ann Oncol 2004: 15; 990)
Authors: R. Arriagada, M.G. Lê, A. Dunant
Journal: Annals of Oncology (2004)
The effect of vagotomy on gastric adaptation
Authors: D. C. Carter, H. N. Whitfield, I. B. Macleod
Journal: Gut (1972)

Gastric adaptation was impaired immediately after the performance of complete vagotomy in a series of 20 acute experiments in the dog. Preliminary isolation of the intact vagi in 10 of these animals produced alterations in adaptation similar to those seen after vagal division. It is concluded that alterations in gastric adaptation are not a reliable intraoperative aid to complete vagotomy. These findings may be significant in the interpretation of all intraoperative tests for vagotomy.
The use of iloprost in early pregnancy in patients with pulmonary arterial hypertension
Authors: C. A. Elliot, P. Stewart, V. J. Webster, G. H. Mills, S. P. Hutchinson, E. S. Howarth, F. A. Bu'Lock, R. A. Lawson, I. J. Armstrong, D. G. Kiely
Journal: European Respiratory Journal (2005)

In patients with pulmonary hypertension, pregnancy is associated with a high risk of maternal death. Such patients are counselled to avoid pregnancy, or if it occurs, are offered early interruption. Some patients, however, decide to continue with their pregnancy and others may present with symptoms for the first time whilst pregnant. Pulmonary vasodilator therapy provides a treatment option for these high-risk patients. The present study describes three patients with pulmonary arterial hypertension of various aetiologies who were treated with the prostacyclin analogue iloprost during pregnancy, and the post-partum period. Nebulised iloprost commenced as early as 8 weeks of gestation and patients were admitted to hospital between 24–36 weeks of gestation. All pregnancies were completed with a duration of between 25–36 weeks and all deliveries were by caesarean section under local anaesthetic. All patients delivered children free from congenital abnormalities, and there was no post-partum maternal or infant mortality. In conclusion, although pregnancy is strongly advised against in those with pulmonary hypertension, the current authors have achieved a successful outcome for mother and foetus with a multidisciplinary approach and targeted pulmonary vascular therapy.
Social Perception as a Mediator of the Influence of Early Visual Processing on Functional Status in Schizophrenia
Authors: Mark J. Sergi, Yuri Rassovsky, Keith H. Nuechterlein, Michael F. Green
Journal: American Journal of Psychiatry (2006)

OBJECTIVE: The potential of social cognition as a mediator of relations between neurocognition and functional status in schizophrenia has been suggested by correlational studies that link neurocognition to social cognition or link social cognition to functional status. The authors used structural equation modeling to test more directly whether one aspect of social cognition (social perception) mediates relations between basic visual perception and functional status in patients with schizophrenia. METHOD: Seventy-five outpatients with schizophrenia were administered measures of early visual processing (computerized visual masking procedures), social perception (Half Profile of Nonverbal Sensitivity), and functional status (Role Functioning Scale). RESULTS: Structural equation modeling supported social perception as a mediator of relations between early visual processing and functional status in schizophrenia. The mediation model indicated that early visual processing is linked to functional status through social perception, thereby supporting a significant indirect relationship. The direct relationship between early visual processing and functional status was significant in a model that did not include social perception but was not significant in the mediation model that included social perception. CONCLUSIONS: Social cognition appears to be a key determinant of functional status in schizophrenia. Using a very basic measure of visual perception, the present study found that social perception mediates the influence of early visual processing on functional status in schizophrenia.
In Vivo Human Brachial Artery Elastic Mechanics
Authors: Alan J. Bank, Daniel R. Kaiser, Scott Rajala, Anthony Cheng
Journal: Circulation (1999)

Background —–The effects of smooth muscle relaxation on arterial wall mechanics are controversial. We used a new, in vivo, noninvasive technique to measure brachial artery wall mechanics under baseline conditions and following smooth muscle relaxation with nitroglycerin (NTG). Methods and Results —Eight healthy, normal subjects (6 male, 2 female; age 30±3.1 years) participated in the study. The nondominant brachial artery was imaged through a water-filled blood pressure cuff using an external ultrasound wall-tracking system at baseline and following 0.4 mg sublingual NTG. Simultaneous radial artery pressure waveforms were recorded by tonometry. Transmural pressure (TP) was reduced by increasing water pressure in the cuff. Brachial artery area, unstressed area, compliance, stress, strain, incremental elastic modulus (E inc ), and pulse wave velocity (PWV) were measured over a TP range from 0 to 100 mm Hg. Baseline area versus TP curves generated 30 minutes apart were not significantly different. NTG significantly shifted area versus TP ( P &lt;0.0001) and compliance versus TP ( P &lt;0.001) curves upward, whereas the E inc versus TP ( P &lt;0.05) and PWV versus TP ( P &lt;0.01) curves were shifted downward. NTG also significantly shifted stress versus strain ( P &lt;0.01) and E inc versus strain ( P &lt;0.01) curves to the right. Conclusions —We conclude that brachial artery elastic mechanics can be reproducibly measured over a wide range of TP and smooth muscle tone using a new noninvasive ultrasound technique. Smooth muscle relaxation with NTG increases isobaric compliance and decreases isobaric E inc and PWV in the human brachial artery.
Biologically Active Intercellular Adhesion Molecule-1 Is Shed as Dimers by a Regulated Mechanism in the Inflamed Pleural Space
Authors: Mario Melis, Elisabetta Pace, Liboria Siena, Mario Spatafora, Annalisa Tipa, Mirella Profita, Anna Bonanno, Antonio M. Vignola, Giovanni Bonsignore, Christopher H. Mody, Mark Gjomarkaj
Journal: American Journal of Respiratory and Critical Care Medicine (2003)

Intercellular adhesion molecule-1 (ICAM-1) is an adhesion molecule that plays a crucial role in cell–cell interactions involved in the recruitment of cells and immune responses. Under some circumstances, ICAM-1 is found as a soluble protein that has the potential to influence the nature of immunoinflammatory responses. By examining cells and fluid from the pleural compartment of patients with cancer, tuberculosis, and congestive heart failure, the cellular source, conformation, control, and biological activity of soluble ICAM-1 (sICAM-1) were investigated. The results suggest that dimeric sICAM-1 was released locally in the pleural compartment of tuberculous and malignant effusions. sICAM-1 was shed from preexpressed surface ICAM-1 rather than produced de novo, and both CD45-positive leukocytes and cytokeratin-positive epithelial and mesothelial cells expressed ICAM-1, suggesting multiple cellular sources for sICAM-1. The expression of sICAM-1 was regulated because pleural macrophages caused release of sICAM-1 via a tumor necrosis factor-α-dependent mechanism. The functional significance of sICAM-1 was demonstrated by showing that pleural sICAM-1 interfered with conjugate formation between LAK cells and K562 cells, suggesting that pleural sICAM-1 plays an immunosuppressive role by inhibiting adhesion of cytotoxic lymphocytes and tumor cells. Thus, sICAM-1 is shed from the surface of cells in a regulated manner and has the potential to influence the immune response in the pleural space.
Healthy subjects produce both anti-factor VIII and specific anti-idiotypic antibodies.
Authors: J G Gilles, J M Saint-Remy
Journal: Journal of Clinical Investigation (1994)

Anti-Factor VIII (FVIII) antibodies were prepared by a combination of salt precipitation, gel filtration chromatography, and specific adsorption over insolubilized FVIII from the serum of 10 healthy subjects with normal levels of FVIII. Antibody specificity was confirmed by the capacity to recognize soluble and insolubilized FVIII and to neutralize FVIII cofactor activity in FX activation. Epitope mapping was carried out using a competition ELISA in which affinity-purified human antibodies inhibited the binding of labeled monoclonal antibodies. In most cases, a single region of the A3 domain of the FVIII light chain was recognized by the antibodies, while the reactivity toward heavy chain epitopes differed from one antibody preparation to the other. Sera or IgG fractions of the serum before immunoadsorption over insolubilized FVIII did not bind to FVIII. The IgG fraction that was not retained on the FVIII immunosorbent contained IgG that bound to the variable part of anti-FVIII mouse monoclonal antibodies and inhibited the binding of labeled FVIII; in addition, the IgG fraction inhibited the binding of affinity-purified human antibodies to FVIII, thereby strongly suggesting the presence of anti-idiotypic antibodies. These findings indicate that the presence of anti-FVIII antibodies is a more universal phenomenon than previously thought and that anti-idiotypic antibodies capable of inhibiting the binding of anti-FVIII antibodies to FVIII are produced spontaneously.