tbuckley/cabot-search huggingface dataset:
Transdifferentiation of Vascular Smooth Muscle Cells to Macrophage-Like Cells During Atherogenesis
Authors: Susanne Feil, Birgit Fehrenbacher, Robert Lukowski, Frank Essmann, Klaus Schulze-Osthoff, Martin Schaller, Robert Feil
Journal: Circulation Research (2014)

Atherosclerosis is a widespread and devastating disease, but the origins of cells within atherosclerotic plaques are not well defined.To investigate the specific contribution of vascular smooth muscle cells (SMCs) to atherosclerotic plaque formation by genetic inducible fate mapping in mice.Vascular SMCs were genetically pulse-labeled using the tamoxifen-dependent Cre recombinase, CreER(T2), expressed from the endogenous SM22α locus combined with Cre-activatable reporter genes that were integrated into the ROSA26 locus. Mature SMCs in the arterial media were labeled by tamoxifen treatment of young apolipoprotein E-deficient mice before the development of atherosclerosis and then their fate was monitored in older atherosclerotic animals. We found that medial SMCs can undergo clonal expansion and convert to macrophage-like cells that have lost classic SMC marker expression and make up a major component of advanced atherosclerotic lesions.This study provides strong in vivo evidence for smooth muscle-to-macrophage transdifferentiation and supports an important role of SMC plasticity in atherogenesis. Targeting this type of SMC phenotypic conversion might be a novel strategy for the treatment of atherosclerosis, as well as other diseases with a smooth muscle component.
Impact of anti-tumour necrosis factor treatment on admissions to hospital and days of sick leave in patients with ankylosing spondylitis
Authors: J Listing
Journal: Annals of the Rheumatic Diseases (2004)

To analyse the impact of infliximab treatment on the number of hospital inpatient days and days of sick leave in patients with active ankylosing spondylitis (AS).The data of a 2 year open extension study of a 12 week, double blind, randomised, placebo controlled trial, in which all patients with AS were treated with 5 mg/kg infliximab, were used to investigate the effect of anti-TNF treatment on admissions to hospital and days of sick leave. All patients were interviewed at baseline and at regular intervals during the study to collect this information by questionnaires. Patients who completed 2 years of treatment (n = 49) and those who did not (n = 20) were analysed separately. Sick leave analysis was restricted to currently employed patients (n = 38).During the 12 months before the screening visit, 20/49 (41%) completers had been admitted to hospital. After 1 and 2 years of treatment this percentage was reduced to 5/49 (10%; p<0.01), corresponding to a significant decrease in the mean number of inpatient days: from 11.1 to 0.6 after 1 year (p<0.01) and 2.9 after 2 years (p<0.01), respectively. No changes were seen in the dropout group.The use of infliximab in patients with active AS reduces some important costs of AS, but additional studies with detailed cost calculations are needed.
Ouabain- and Marinobufagenin-Induced Proliferation of Human Umbilical Vein Smooth Muscle Cells and a Rat Vascular Smooth Muscle Cell Line, A7r5
Authors: Joel Abramowitz, Cuiping Dai, Karen K. Hirschi, Renata I. Dmitrieva, Peter A. Doris, Lijun Liu, Julius C. Allen
Journal: Circulation (2003)

We studied the growth-promoting effects of 2 sodium pump-selective cardiotonic steroids, ouabain and marinobufagenin, on cultured cells from vascular smooth muscle (VSMCs) from human umbilical vein and a rat VSMC line, A7r5.Both ouabain and marinobufagenin activated proliferation of these cells in a concentration-dependent manner, reflecting the cardiotonic steroid sensitivity of the specific alpha1 subunit contained within each cell source. The observed effective concentration ranges of both compounds was below that necessary to induce cytoplasmic ion alterations by sodium pump inhibition.These data indicate that the ouabain-activated proliferative effect previously observed in canine VSMCs occurs in other VSMC sources. This growth effect seems to be initiated by drug interaction with the sodium pump, reflected by the affinity of the steroid for the pump, and is independent of altered transmembrane ionic gradients.
Relationship Between Climate and Psychiatric Inpatient Length of Stay in Veterans Health Administration Hospitals
Authors: Edward J. Federman, Charles E. Drebing, Charles Boisvert, Walter Penk, Gregory Binus, Robert Rosenheck
Journal: American Journal of Psychiatry (2000)

The study examined whether climate has an impact on inpatient psychiatric length of stay in Veterans Health Administration hospitals (VHA).Data from the National Weather Service for eight climate variables for the locations of 134 VHA hospitals nationwide were factor analyzed, resulting in two climate factors representing temperature and precipitation. Factor scores were correlated with psychiatric mean lengths of stay from 1994 to 1998 for 99 VHA hospitals with inpatient psychiatric services and for the 22 VHA regional divisions (Veterans Integrated Service Networks).Climate factors correlated modestly but significantly with length of stay, with correlations ranging from -0. 25 to -0.37 at the hospital level and from -0.38 to -0.45 at the VHA regional level; hospitals in warmer and drier climates had shorter lengths of stay. Medical centers in colder climates had the longest lengths of stay in winter and fall. The significant correlation between climate and length of stay was not affected by recent reductions in length of stay in VHA hospitals.Higher clinical costs associated with longer lengths of stay in colder climates have implications for budget planning. Climate factors must also be recognized for their potential effect on performance monitoring systems focused on hospital utilization. Researchers must continue to consider broader contextual variables such as climate if they are to fully understand the determinants of health care utilization and psychiatric hospitalization costs.
Signal Transducer and Activator of Transcription 3 (STAT3) Regulates Human Telomerase Reverse Transcriptase (hTERT) Expression in Human Cancer and Primary Cells
Authors: Liza Konnikova, Marina C. Simeone, Matthew M. Kruger, Maciej Kotecki, Brent H. Cochran
Journal: Cancer Research (2005)

Abstract Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that plays a critical role in cytokine and growth factor signaling and is frequently activated in human tumors. Human telomerase reverse transcriptase (hTERT) is also often overexpressed in tumor cells and mediates cellular immortalization. Here we report that STAT3 directly regulates the expression of hTERT in a variety of human cancer cells. Moreover, STAT3 activity is required for the survival of many human tumors, and hTERT expression contributes to the survival of STAT3-dependent tumor cells. In addition, we find that growth factors and cytokines stimulate hTERT expression in primary human cells in a STAT3-dependent manner. Thus, STAT3 is a key regulator of hTERT expression in both normal and tumor cells.
‘23 and ½ h’ goes viral: top 10 learnings about making a health message that people give to one another
Authors: Michael F Evans
Journal: British Journal of Sports Medicine (2012)

In my day job as a Family Physician, I often wonder, ‘Is this bacterial or viral?’ In my other job, where I try to innovate on how to engage patients in more meaningful ways, my question is slightly different: ‘How can we make this viral instead of bacterial?’

‘23 ½ hours: what is the single most important thing you can do for your health?’1 (referred to as ‘23.5’ below and figure 1) is a video I posted on YouTube in December 2011. My objective in making the video was twofold: 1) to experiment in creating a new way of engaging patients about their health and 2) to answer what is the most important thing we can do for our health? I am a family doctor, not a sports medicine expert, so I was intrigued that my answer is exercise. I was intrigued as activity is something I ask my patients about but it is not something I have systematically assessed and counselled upon in my practice in the same way as other clinical problems such as blood pressure or cholesterol.

Like any good virus, my primary objective was spread. At the time of writing (22 February 2012) 23.5 has had 2 million people sit down and view it, has averaged about 25 000 views a day, generated over 1000 comments and has been ‘liked’ by over 16 000 people (and ‘disliked’ by 190). It has already been translated by the ‘community’ into Spanish and …
Recombinant Tissue Factor Pathway Inhibitor in Severe Community-acquired Pneumonia
Authors: Richard G. Wunderink, Pierre-François Laterre, Bruno Francois, Dominique Perrotin, Antonio Artigas, Luis Otero Vidal, Suzana M. Lobo, Jorge San Juan, Sung Chul Hwang, Thierry Dugernier, Steven LaRosa, Xavier Wittebole, Jean-Francois Dhainaut, Christopher Doig, Meryl H. Mendelson, Christian Zwingelstein, Guoqin Su, Steven Opal
Journal: American Journal of Respiratory and Critical Care Medicine (2011)

Rationale: Severe community-acquired pneumonia (sCAP) is a leading cause of death worldwide. Adjunctive therapies for sCAP are needed to further improve outcome. A systemic inhibitor of coagulation, tifacogin (recombinant human tissue factor pathway inhibitor) seemed to provide mortality benefit in the sCAP subgroup of a previous sepsis trial.Objectives: Evaluate the impact of adjunctive tifacogin on mortality in patients with sCAP.Methods: A multicenter, randomized, placebo-controlled, double-blind, three-arm study was conducted from July 2005 to June 2008 at 188 centers in North and South America, Europe, South Africa, Asia, Australia, and New Zealand. Adults with sCAP were randomized to receive a continuous intravenous infusion of tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, or matching placebo over 96 hours.Measurements and Main Results: Severity-adjusted 28-day all-cause mortality. Of 2,138 randomized patients, 946, 238, and 918 received tifacogin 0.025 mg/kg/h, tifacogin 0.075 mg/kg/h, and placebo, respectively. Tifacogin 0.075 mg/kg/h was discontinued after the first interim analysis according to prespecified futility criterion. The 28-day all-cause mortality rates were similar between the 0.025 mg/kg/h (18%) and placebo groups (17.9%) (P = 0.56). Greater reduction in prothrombin fragment 1+2 and thrombin antithrombin complexes levels relative to baseline throughout the first 96 hours was found with tifacogin 0.025 mg/kg/h than with placebo. The incidence of adverse events and serious adverse events were comparable between the tifacogin 0.025 mg/kg/h and placebo groups.Conclusions: Tifacogin showed no mortality benefit in patients with sCAP despite evidence of biologic activity.
Evolution of the "classical" cadherin family of cell adhesion molecules in vertebrates
Authors: W. J. Gallin
Journal: Molecular Biology and Evolution (1998)

The cadherins are major mediators of calcium-dependent cell-cell adhesion and are also involved in cell signaling pathways during development. The classical cadherins, which are the definitive group of the cadherin superfamily, are transmembrane proteins that consist of an extracellular domain of five cadherin repeats, including an HAV tripeptide conserved in one binding surface within the first domain, and a highly conserved cytoplasmic domain that interacts with the actin cytoskeleton via the catenin proteins. These cadherins play major roles in vertebrate morphogenesis; they are expressed widely throughout development, antibodies to specific cadherins perturb a variety of developmental processes, and many gene knockouts are lethal at early stages of development. Phylogenetic analysis of the "classical" cadherins shows that in the vertebrates there are four paralog families. The rate of evolutionary change is radically different between the different paralogs, indicating that there are significantly different selection pressures on the functions of the various cadherins, both between the different paralogs in a single organism lineage and between different organism lineages within a single paralog family. There is also evidence for gene conversion between the E-cadherin and P-cadherin paralogs in Gallus gallus and possibly Xenopus laevis, but not between the same paralogs in the mammalian lineages. A scheme for the origin of the paralogs within the vertebrate lineage based on these analyses indicates that the presence of the four paralog families is a characteristic of vertebrates and that variation of cadherin structure and function is a significant factor in morphological evolution of vertebrates.
Phase III Double-Blind Placebo-Controlled Study of Farnesyl Transferase Inhibitor R115777 in Patients With Refractory Advanced Colorectal Cancer
Authors: S. Rao, D. Cunningham, A. de Gramont, W. Scheithauer, M. Smakal, Y. Humblet, G. Kourteva, T. Iveson, T. Andre, J. Dostalova, A. Illes, R. Belly, J.J. Perez-Ruixo, Y.C. Park, P.A. Palmer
Journal: Journal of Clinical Oncology (2004)

To determine whether R115777 improves survival in patients with refractory advanced colorectal cancer (CRC) in a multicenter, double-blind, prospective randomized study.Three hundred sixty-eight patients were randomly assigned to R115777 (300 mg twice daily) orally for 21 days every 28 days or placebo in a 2:1 ratio. All patients received best supportive care. The primary end point was overall survival; secondary end points were progression free survival, tumor response, toxicity, and quality of life.The two treatment groups were well balanced for baseline demographics, including previous chemotherapy for advanced CRC. The median overall survival for R115777 was 174 days (95% CI, 157 to 198 days), and 185 days (95% CI, 158 to 238 days) for those patients receiving placebo (P =.376). One patient achieved a partial response in the R115777 arm. Stable disease (> 3 months) was observed in 24.3% patients in the R115777 group compared to 12.8% in the placebo arm. This did not translate into a statistically significant increase in progression-free survival. Overall, treatment was well tolerated. There was an increased incidence of reversible myelosuppression (neutropenia, thrombocytopenia), rash, and grade 1 to 2 diarrhea in the R115777 arm. There was no statistically significant difference in quality of life between arms.Single agent R115777, given at this dose and schedule, has an acceptable toxicity profile, but does not improve overall survival compared to best supportive care alone in refractory advanced CRC.
Increased sensitivity to radiochemotherapy in IDH1 mutant glioblastoma as demonstrated by serial quantitative MR volumetry
Authors: A. N. Tran, A. Lai, S. Li, W. B. Pope, S. Teixeira, R. J. Harris, D. C. Woodworth, P. L. Nghiemphu, T. F. Cloughesy, B. M. Ellingson
Journal: Neuro-Oncology (2013)

Isocitrate dehydrogenase 1 (IDH1) mutations have been linked to favorable outcomes in patients with glioblastoma multiforme (GBM). Recent in vitro experiments suggest that IDH1 mutation sensitizes tumors to radiation damage. We hypothesized that radiographic treatment response would be significantly different between IDH1 mutant versus wild-type GBMs after radiotherapy (RT) and concurrent temozolomide (TMZ).A total of 39 newly diagnosed GBM patients with known IDH1 mutational status (10 IDH1 mutants), who followed standard therapy and had regular post-contrast T1W (T1+C) and T2W/ fluid-attenuated inversion recovery (FLAIR) images in the 6-month period after starting RT, were enrolled. The volume of contrast-enhancing and FLAIR hyperintensity were calculated from each scan. Linear and polynomial regression techniques were used to estimate the rate of change and temporal patterns in tumor volumes.IDH1 mutant GBMs demonstrated a favorable response to RT/TMZ in the study period, as demonstrated by 10 of 10 mutants showing radiographic response (decreasing V(T1+C)), compared with 13 of 29 wild-types (P < .001). During the study period, V(T1+C) and V(FLAIR) changed at -3.6% per week and +0.6% per week in IDH1 mutant tumors, respectively, as compared with +0.8% per week and +5.2% per week in IDH1 wild-type tumors (P = .0076 and P = .0118, respectively). Amongst the radiographic responders, IDH1 mutant GBMs still demonstrated significant progression-free and overall survival benefit. Aggregated tumor kinetics by group showed significant lower rate in IDH1 mutant GBMs in specific periods: >105 days for V(FLAIR) and 95-120 and >150 days for V(T1+C) from starting RT/TMZ.The current study supports the hypothesis that IDH1 mutant GBMs are more sensitive to radiochemotherapy than IDH1 wild-type GBMs.
Maternally transmitted antigens are codominantly expressed by mouse cells containing two kinds of mitochondrial DNA.
Authors: J R Rodgers, R Smith, R R Rich
Journal: The Journal of Experimental Medicine (1987)

Mtf, a cytoplasmic, probably mitochondrial factor, controls Mta polymorphism. We tested for dominance between two forms of Mtf to determine whether Mta is controlled by positive or negative genetic mechanisms. We fused Mtf-disparate cells containing distinct mtDNA markers and selected for hybrids containing both. Such mtDNA heteroplasmons codominantly and stably express alternative Mta antigens. Stable codominance excludes negative genetic mechanisms as well as a model of induced nuclear compensation, and implies Mtf controls Mta expression through a positive genetic mechanism.
Scintigraphy versus manometry in patients with suspected biliary sphincter of Oddi dysfunction
Authors: A Craig, D Peter, Gino Saccone, Patrick Ziesing, Allan Wycherley, James Toouli
Journal: Gut (2003)

Sphincter of Oddi (SO) manometry is at present the "gold standard" investigation for patients with suspected biliary SO dysfunction. Non-invasive scintigraphy in cholecystectomised patients using a complex scoring system or the transit time from the hepatic hilum to the duodenum (HDTT) have been promoted as sensitive and specific alternatives.To evaluate the scintigraphic scoring system and HDTT in patients with suspected biliary SO dysfunction undergoing SO manometry.Cholecystectomised patients undergoing SO manometry for persistent biliary-type pain, as defined by the Rome II criteria, for which all other causes had been excluded, were prospectively studied. Scintigraphy with cholecystokinin octapeptide infusion was performed within a month prior to manometry. Scoring of the scans and measurement of HDTT was performed by independent blinded observers. Manometry of the biliary sphincter was performed per-endoscopically and defined as abnormal if basal pressure was > or = 40 mm Hg.Thirty two patients were enrolled (30 females, mean age 45.1 years). Three patients were excluded from analysis because manometry from the bile duct was not technically possible. Eight patients had abnormal manometry. Scintigraphic scoring had a sensitivity of 25-38%, a specificity of 86-89%, positive predictive value (PPV) of 40-60%, and a negative predictive value (NPV) of 75-79%. The coefficient of variation for interobserver variation in scores was 0.72. HDTT sensitivity was 13%, specificity 95%, PPV 50%, and NPV 74%.Our findings indicate that scintigraphy using these methods of analysis correlates poorly with manometry in post cholecystectomy patients with suspected biliary SO dysfunction.
Hemodynamic Changes in Fetal Lamb in Utero in Response to Asphyxia, Hypoxia, and Hypercapnia
Authors: N. S. Assali, L. W. Holm, N. Sehgal
Journal: Circulation Research (1962)

The effects of hypoxia (administration of 10 per cent O 2 in N 2 and constriction of the uterine arteries), of hypercapnia (administration of 8 per cent CO 2 in air), and of asphyxia (obstruction of the umbilical circulation) were studied on the fetus in utero in near-term pregnant ewes under spinal anesthesia. Hypoxia and hypercapnia produced increases in the maternal arterial pressure, maternal heart rate, and uterine blood flow. Fetal arterial pressure and carotid and umbilical blood flows increased, while the fetal heart rate decreased. Fetal femoral flow decreased during hypoxia and increased during hypercapnia. There was a delay of five to six minutes between the initiation of hypoxia or hypercapnia and the appearance of fetal circulatory changes. Transient reduction of uterine blood flow evoked insignificant hemodynamic alterations in the mother and fetus. A reduction of flow greater than 50 per cent of control values produced a fetal bradycardia along with increases in fetal arterial pressure, carotid and umbilical flows. Constriction of the umbilical veins with the umbilical arteries intact produced a prompt bradycardia together with a decrease in fetal arterial pressure and regional blood flows. Constriction of the umbilical arteries alone also produced a bradycardia with an initial rise in arterial pressure and carotid flow. Similar changes were observed after cutting the umbilical cord. Elimination of the low resistance of the placenta played a major role in these changes. Placing the lamb in the head-down position caused a marked increase in carotid blood flow without greatly modifying arterial pressure.
The Integrity of the Charged Pocket in the BTB/POZ Domain Is Essential for the Phenotype Induced by the Leukemia-Associated t(11;17) Fusion Protein PLZF/RARα
Authors: Elena Puccetti, Xiaomin Zheng, Daria Brambilla, Anita Seshire, Tim Beissert, Simone Boehrer, Heike Nürnberger, Dieter Hoelzer, Oliver Gerhard Ottmann, Clara Nervi, Martin Ruthardt
Journal: Cancer Research (2005)

Abstract Acute myeloid leukemia is characterized by a differentiation block as well as by an increased self-renewal of hematopoietic precursors in the bone marrow. This phenotype is induced by specific acute myeloid leukemia–associated translocations, such as t(15;17) and t(11;17), which involve an identical portion of the retinoic acid receptor α (RARα) and either the promyelocytic leukemia (PML) or promyelocytic zinc finger (PLZF) genes, respectively. The resulting fusion proteins form high molecular weight complexes and aberrantly bind several histone deacetylase–recruiting nuclear corepressor complexes. The amino-terminal BTB/POZ domain is indispensable for the capacity of PLZF to form high molecular weight complexes. Here, we studied the role of dimerization and binding to histone deacetylase–recruiting nuclear corepressor complexes for the induction of the leukemic phenotype by PLZF/RARα and we show that (a) the BTB/POZ domain mediates the oligomerization of PLZF/RARα; (b) mutations that inhibit dimerization of PLZF do the same in PLZF/RARα; (c) the PLZF/RARα-related block of differentiation requires an intact BTB/POZ domain; (d) the mutations interfering with either folding of the BTB/POZ domain or with its charged pocket prevent the self-renewal of PLZF/RARα-positive hematopoietic stem cells. Taken together, these data provide evidence that the dimerization capacity and the formation of a functionally charged pocket are indispensable for the PLZF/RARα-induced leukemogenesis.