tbuckley/cabot-search huggingface dataset:
The α1A/C- and α1B-adrenergic receptors are required for physiological cardiac hypertrophy in the double-knockout mouse
Authors: Timothy D. O’Connell, Shinji Ishizaka, Akihiro Nakamura, Philip M. Swigart, M.C. Rodrigo, Gregory L. Simpson, Susanna Cotecchia, D. Gregg Rokosh, William Grossman, Elyse Foster, Paul C. Simpson
Journal: Journal of Clinical Investigation (2003)

Catecholamines and α1-adrenergic receptors (α1-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single KOs of the main α1-AR subtypes, α1A/C and α1B. Here we tested whether α1-ARs are required for developmental cardiac hypertrophy by generating α1A/C and α1B double KO (ABKO) mice, which had no cardiac α1-AR binding. In male ABKO mice, heart growth after weaning was 40% less than in WT, and the smaller heart was due to smaller myocytes. Body and other organ weights were unchanged, indicating a specific effect on the heart. Blood pressure in ABKO mice was the same as in WT, showing that the smaller heart was not due to decreased load. Contractile function was normal by echocardiography in awake mice, but the smaller heart and a slower heart rate reduced cardiac output. α1-AR stimulation did not activate extracellular signal–regulated kinase (Erk) and downstream kinases in ABKO myocytes, and basal Erk activity was lower in the intact ABKO heart. In female ABKO mice, heart size was normal, even after ovariectomy. Male ABKO mice had reduced exercise capacity and increased mortality with pressure overload. Thus, α1-ARs in male mice are required for the physiological hypertrophy of normal postnatal cardiac development and for an adaptive response to cardiac stress.
Antitumor Efficacy of a Bispecific Antibody That Targets HER2 and Activates T Cells
Authors: Teemu T. Junttila, Ji Li, Jennifer Johnston, Maria Hristopoulos, Robyn Clark, Diego Ellerman, Bu-Er Wang, Yijin Li, Mary Mathieu, Guangmin Li, Judy Young, Elizabeth Luis, Gail Lewis Phillips, Eric Stefanich, Christoph Spiess, Andrew Polson, Bryan Irving, Justin M. Scheer, Melissa R. Junttila, Mark S. Dennis, Robert Kelley, Klara Totpal, Allen Ebens
Journal: Cancer Research (2014)

Abstract Clinical results from the latest strategies for T-cell activation in cancer have fired interest in combination immunotherapies that can fully engage T-cell immunity. In this study, we describe a trastuzumab-based bispecific antibody, HER2-TDB, which targets HER2 and conditionally activates T cells. HER2-TDB specifically killed HER2-expressing cancer cells at low picomolar concentrations. Because of its unique mechanism of action, which is independent of HER2 signaling or chemotherapeutic sensitivity, HER2-TDB eliminated cells refractory to currently approved HER2 therapies. HER2-TDB exhibited potent antitumor activity in four preclinical model systems, including MMTV-huHER2 and huCD3 transgenic mice. PD-L1 expression in tumors limited HER2-TDB activity, but this resistance could be reversed by anti–PD-L1 treatment. Thus, combining HER2-TDB with anti–PD-L1 yielded a combination immunotherapy that enhanced tumor growth inhibition, increasing the rates and durability of therapeutic response. Cancer Res; 74(19); 5561–71. ©2014 AACR.
Assessment of the European classification criteria for Sjogren's syndrome in a series of clinically defined cases: results of a prospective multicentre study. The European Study Group on Diagnostic Criteria for Sjogren's Syndrome.
Authors: C Vitali, S Bombardieri, H M Moutsopoulos, J Coll, R Gerli, P Y Hatron, L Kater, Y T Konttinen, R Manthorpe, O Meyer, M Mosca, P Ostuni, R A Pellerito, Y Pennec, S R Porter, A Richards, B Sauvezie, M Schiodt, M Sciuto, Y Shoenfeld, F N Skopouli, J S Smolen, F Soromenho, M Tishler, M J Wattiaux
Journal: Annals of the Rheumatic Diseases (1996)

OBJECTIVE: To assess the recently proposed preliminary criteria for the classification of Sjögren9s syndrome (SS) in a multicentre European study of a new series of clinically defined cases. METHODS: The criteria included six items: I = ocular symptoms; II = oral symptoms; III = evidence of keratoconjunctivitis sicca; IV = focal sialoadenitis by minor salivary gland biopsy; V = instrumental evidence of salivary gland involvement; VI = presence of autoantibodies. Each centre was asked to provide five patients with primary SS, five with secondary SS, five with connective tissue diseases (CTD) but without SS, and five controls (patients with ocular or oral features that may simulate SS). The preliminary six item classification criteria set was applied to both the SS patients and the non-SS controls, and the performance of the criteria in terms of sensitivity and specificity was tested. RESULTS: The criteria set was tested on a total of 278 cases (157 SS patients and 121 non-SS controls) collected from 16 centres in 10 countries. At least four of the six items in the criteria set (limiting item VI to the presence of Ro(SS-A) or La(SS-B) antibodies) were present in 79 of 81 patients initially classified as having primary SS (sensitivity 97.5%), but in only seven of 121 non-SS controls (specificity 94.2%). When the presence of item I or II plus any two of items III-V of the criteria set was considered as indicative of secondary SS, 97.3% (71 of 73) of the patients initially defined as having this disorder and 91.8% (45 of 49) of the control patients with CTD without SS were correctly classified. CONCLUSION: This prospective study confirmed the high validity and reliability of the classification criteria for SS recently proposed by the European Community Study Group.
Effect of lidocaine on the electrophysiological properties of ventricular muscle and Purkinje fibers
Authors: J. Thomas Bigger, William J. Mandel
Journal: Journal of Clinical Investigation (1970)

Preparations of right ventricular papillary muscle and false tendon (Purkinje fiber) were obtained from dog hearts, placed in a bath perfused with Tyrode solution, and observed both under control conditions and during exposure to lidocaine in concentrations from 1 × 10-7 to 5 × 10-4 mole/liter. Transmembrane voltages were recorded from both ventricular muscle (VM) and Purkinje fibers (PF) of spontaneously beating and electrically driven preparations. Low concentrations (1 × 10-6 and 1 × 10-5 mole/liter) attenuated or abolished phase 4 (diastolic) depolarization and spontaneous firing in PF without decreasing their diastolic excitability. Concentrations of 1 × 10-5 mole/liter produced maximal shortening of both action potential duration (APD) and effective refractory period (ERP) and made the ERP long relative to APD; the latter alteration was more prominent in VM. At concentrations ≤ 1 × 10-5 mole/liter, lidocaine either caused a slight increase or no change in peak maximum rate of phase 0 depolarization (Vmax) and membrane responsiveness, the relationship between transmembrane activation voltage (MAV) and Vmax of the resultant action potential; these concentrations had no significant effect on resting potential (RP) in VM, maximal diastolic transmembrane voltage (DTMVmax) in PF, or action potential amplitude in either fiber type.
Replacement of the mitral valve, aortic valve, and ascending aorta with coronary transplantation in a child with the Marfan syndrome
Authors: P. K. Caves, M. Paneth
Journal: Thorax (1972)

A girl with the Marfan syndrome is described who developed mitral regurgitation, an aneurysm of the ascending aorta, and severe aortic regurgitation. Complete surgical correction required mitral valve, aortic valve, and ascending aorta replacement with transplantation of the origin of the coronary arteries. The cardiovascular complications of the Marfan syndrome are discussed and the previously described surgical techniques for dealing with aortic or mitral involvement are briefly reviewed. A simpler and safer method for replacement of the complete ascending aorta with coronary artery transplantation is described.
Renal Hypodysplasia Associates with a Wnt4 Variant that Causes Aberrant Canonical Wnt Signaling
Authors: Asaf Vivante, Michal Mark-Danieli, Miriam Davidovits, Orit Harari-Steinberg, Dorit Omer, Yehudit Gnatek, Roxana Cleper, Daniel Landau, Yael Kovalski, Irit Weissman, Israel Eisenstein, Michalle Soudack, Haike Reznik Wolf, Naomi Issler, Danny Lotan, Yair Anikster, Benjamin Dekel
Journal: Journal of the American Society of Nephrology (2013)

Abnormal differentiation of the renal stem/progenitor pool into kidney tissue can lead to renal hypodysplasia (RHD), but the underlying causes of RHD are not well understood. In this multicenter study, we identified 20 Israeli pedigrees with isolated familial, nonsyndromic RHD and screened for mutations in candidate genes involved in kidney development, including PAX2, HNF1B, EYA1, SIX1, SIX2, SALL1, GDNF, WNT4, and WT1. In addition to previously reported RHD-causing genes, we found that two affected brothers were heterozygous for a missense variant in the WNT4 gene. Functional analysis of this variant revealed both antagonistic and agonistic canonical WNT stimuli, dependent on cell type. In HEK293 cells, WNT4 inhibited WNT3A induced canonical activation, and the WNT4 variant significantly enhanced this inhibition of the canonical WNT pathway. In contrast, in primary cultures of human fetal kidney cells, which maintain WNT activation and more closely represent WNT signaling in renal progenitors during nephrogenesis, this mutation caused significant loss of function, resulting in diminished canonical WNT/β-catenin signaling. In conclusion, heterozygous WNT4 variants are likely to play a causative role in renal hypodysplasia.
Recruitment of Phosphorylated NPM1 to Sites of DNA Damage through RNF8-Dependent Ubiquitin Conjugates
Authors: Ayaka Koike, Hiroyuki Nishikawa, Wenwen Wu, Yukinori Okada, Ashok R. Venkitaraman, Tomohiko Ohta
Journal: Cancer Research (2010)

Protein accumulation at DNA double-strand breaks (DSB) is essential for genome stability; however, the mechanisms governing these events are not fully understood. Here, we report a new role for the nucleophosmin protein NPM1 in these mechanisms. Thr199-phosphorylated NPM1 (pT199-NPM1) is recruited to nuclear DNA damage foci induced by ionizing radiation (IR). Foci formation is impaired by depletion of the E3 ubiquitin ligases RNF8 and RNF168 or the E2 Ubc13, and pT199-NPM1 binds to Lys63-linked ubiquitin polymers in vitro. Thus, phosphorylated NPM1 may interact with RNF8-dependent ubiquitin conjugates at sites of DNA damage. The interaction was found to rely on T199 phosphorylation, an acidic tract, and an adjacent ubiquitin-interacting motif-like domain. Depletion of the breast cancer suppressor BRCA1 or its partner, RAP80, enhanced IR-induced NPM1 foci and prolonged persistence of the foci, possibly implicating BRCA1 in pT199-NPM1 action and dynamics. Replacement of endogenous NPM1 with its nonphosphorylable T199A mutant prolonged persistence of IR-induced RAD51 foci accompanied by unrepaired DNA damage. Collectively, our findings suggest that phosphorylated NPM1 is a novel component in DSB repair that is recruited by ubiquitin conjugates downstream of RNF8 and RNF168.
Correlation of Intravascular Ultrasound Findings With Histopathological Analysis of Thrombus Aspirates in Patients With Very Late Drug-Eluting Stent Thrombosis
Authors: Stéphane Cook, Elena Ladich, Gaku Nakazawa, Parham Eshtehardi, Michel Neidhart, Rolf Vogel, Mario Togni, Peter Wenaweser, Michael Billinger, Christian Seiler, Steffen Gay, Bernhard Meier, Werner J. Pichler, Peter Jüni, Renu Virmani, Stephan Windecker
Journal: Circulation (2009)

Intravascular ultrasound of drug-eluting stent (DES) thrombosis (ST) reveals a high incidence of incomplete stent apposition (ISA) and vessel remodeling. Autopsy specimens of DES ST show delayed healing and hypersensitivity reactions. The present study sought to correlate histopathology of thrombus aspirates with intravascular ultrasound findings in patients with very late DES ST.The study population consisted of 54 patients (28 patients with very late DES ST and 26 controls). Of 28 patients with very late DES ST, 10 patients (1020+/-283 days after implantation) with 11 ST segments (5 sirolimus-eluting stents, 5 paclitaxel-eluting stents, 1 zotarolimus-eluting stent) underwent both thrombus aspiration and intravascular ultrasound investigation. ISA was present in 73% of cases with an ISA cross-sectional area of 6.2+/-2.4 mm(2) and evidence of vessel remodeling (index, 1.6+/-0.3). Histopathological analysis showed pieces of fresh thrombus with inflammatory cell infiltrates (DES, 263+/-149 white blood cells per high-power field) and eosinophils (DES, 20+/-24 eosinophils per high-power field; sirolimus-eluting stents, 34+/-28; paclitaxel-eluting stents, 6+/-6; P for sirolimus-eluting stents versus paclitaxel-eluting stents=0.09). The mean number of eosinophils per high-power field was higher in specimens from very late DES ST (20+/-24) than in those from spontaneous acute myocardial infarction (7+/-10), early bare-metal stent ST (1+/-1), early DES ST (1+/-2), and late bare-metal stent ST (2+/-3; P from ANOVA=0.038). Eosinophil count correlated with ISA cross-sectional area, with an average increase of 5.4 eosinophils per high-power field per 1-mm(2) increase in ISA cross-sectional area.Very late DES thrombosis is associated with histopathological signs of inflammation and intravascular ultrasound evidence of vessel remodeling. Compared with other causes of myocardial infarction, eosinophilic infiltrates are more common in thrombi harvested from very late DES thrombosis, particularly in sirolimus-eluting stents, and correlate with the extent of stent malapposition.
The importance of the physical activity bout lengths in lung-healthy elderly people
Authors: Sandra Ortlieb, Stefan Karrasch, Annette Peters, Barbara Thorand, Eva Grill, Alexander Horsch, Holger Schulz
Journal: European Respiratory Journal (2014)

Background:  For beneficial health effects, physical activity (PA) recommendations suggest that the elderly should spend at least 150 minutes in moderate to vigorous PA (MVPA) per week, performed in bouts of at least 10 min.   Aims and objectives:  This study aims to determine the proportion of people meeting the PA recommendations under consideration of different bout lengths and to describe the associations between different bout length criteria in MVPA with multimorbidity and disability in lung-healthy elderly using accelerometry.   Methods:  PA was measured in 168 lung-healthy subjects (aged 65-89), using triaxial GT3X accelerometers for ten days. Each bout length referred to the minimal number of consecutive minutes in MVPA required for inclusion in the calculation of accumulated time in MVPA.   Results:  55% of the time in MVPA was performed in bouts of one minute. 35.7% of the participants met the current PA recommendations of performing at least 150 min of MVPA, regardless of the bout length, and 11.9% reached this in bouts of at least 10 minutes. Differences between people with and without a diagnosis of disability or multimorbidity were stronger under consideration of short bouts instead of only using longer bouts, and more obvious with regard to disablity compared to multimorbidity. There was little difference between disabled individuals and those which were both disabled and multimorbid.   Conclusions:  In the lung-healthy elderly, the accumulated time in MVPA shows a stronger relationship with health and functioning under inclusion of shorter bouts than just considering longer bouts. If people are both disabled and multimorbid, disability seems to be the limiting factor for the performance of MVPA.
Effect of Fasting and Streptozotocin Diabetes on Insulin Binding and Action in the Isolated Mouse Soleus Muscle
Authors: Y. Le Marchand-Brustel, P. Freychet
Journal: Journal of Clinical Investigation (1979)

To investigate whether skeletal muscle is resistant to insulin in insulinopenic states, insulin binding and biological effects on glucose utilization were studied in isolated soleus muscles from 24- or 48-h-fasted mice and from streptozotocin-diabetic mice. Both 48-h fasting and diabetes led to an increase in insulin binding at insulin concentrations <3.4 nM. In both states, submaximal concentrations of insulin were also more effective in stimulating muscle 2-deoxyglucose uptake and glycogen synthesis, and in activating glycogen synthase. This resulted in a two- to fourfold leftward shift in the insulin dose-response curves in muscles from both groups compared with control. No change in insulin binding or biological effects was detected in muscles from 24-h-fasted mice. Maximal insulin effectiveness on 2-deoxyglucose uptake and glycolysis was either unchanged or only slightly enhanced in 48-h-fasted mice and in diabetic animals, compared with controls. Maximal insulin effects on glycogen synthesis and glycogen synthase activation were unaltered by fasting or diabetes. Basal glucose uptake and glycolysis were similar in all groups of mice. In conclusion, when soleus muscles from 48-h-fasted mice and from diabetic mice are compared with controls it can be observed that, (a) at low insulin concentrations insulin binding is increased and insulin effectiveness in stimulating glucose transport and metabolism is enhanced; (b) biological responses to maximally effective insulin concentrations are either unaltered or slightly increased; (c) basal rates of glucose transport and metabolism are essentially unaltered. These results indicate that in insulinopenic states soleus muscle is not insulin resistant in vitro but is hypersensitive to low concentrations of insulin, and normally responsive to maximally effective doses of the hormone.
Firing characteristics of single-fiber carotid sinus baroreceptors.
Authors: J L Seagard, J F van Brederode, C Dean, F A Hopp, L A Gallenberg, J P Kampine
Journal: Circulation Research (1990)

This study examined firing patterns of single-fiber carotid baroreceptors in response to slow ramp increases in carotid sinus pressure (1-2 mm Hg/sec) in vascularly isolated carotid sinus preparations in thiopental-anesthetized dogs (25 mg/kg, plus 10 mg/kg/hr). Two general types of baroreceptor discharge patterns were obtained: 1) type I, a discontinuous, hyperbolic pattern characterized by a sudden onset of discharge at threshold pressure with a relatively high threshold frequency, which gradually increased to a higher saturation firing rate and 2) type II, a continuous, sigmoidal pattern characterized by a gradual increase in discharge above threshold pressure and a relatively low threshold frequency and saturation firing rate. Type II baroreceptor curves typically showed spontaneous discharge below threshold pressure and significantly lower sensitivities, threshold frequency, saturation firing rate, and threshold pressure than those of type I receptors. However, the saturation pressures and operating ranges of the type II receptors were greater than those of type I receptors, and the pressure at which type II receptors had their greatest sensitivity was greater than that for type I receptors. Type I baroreceptors generally had large myelinated afferent A fibers; type II baroreceptors generally had smaller A and unmyelinated C fibers, based on conduction velocities. The presence of spontaneous activity with type II baroreceptors, combined with significantly lower sensitivities and wider pressure operating ranges seen relative to type I baroreceptors, suggests that these receptors may primarily serve to provide information on tonic, or baseline, levels of arterial blood pressure to the central cardiovascular centers. The sudden onset of discharge, higher sensitivities, and narrower operating ranges of type I baroreceptors suggest that their primary role may be to provide information on dynamic, sudden changes in arterial pressure.
Results from the first three rounds of the Scottish demonstration pilot of FOBT screening for colorectal cancer
Authors: R J C Steele, P L McClements, G Libby, R Black, C Morton, J Birrell, N A G Mowat, J A Wilson, M Kenicer, F A Carey, C G Fraser
Journal: Gut (2008)

<h3>Objectives:</h3> To assess the effects of the first three rounds of a pilot colorectal screening programme based on guaiac faecal occult blood testing (gFOBT) and their implications for a national population-based programme. <h3>Methods:</h3> A demonstration pilot programme was conducted in three Scottish NHS Boards. Residents aged between 50 and 69 years registered on the Community Health Index were included in the study. <h3>Results:</h3> In the first round, the uptake was 55.0%, the positivity rate was 2.07% and the cancer detection rate was 2.1/1000 screened. In the second round, these were 53.0%, 1.90% and 1.2/1000, respectively, and in the third round, 55.3%, 1.16% and 0.7/1000, respectively. In the first round, the positive predictive value of the gFOBT was 12.0% for cancer and 36.5% for adenoma; these fell to 7.0% and 30.3% in the second round and were maintained at 7.5% and 29.1% in the third round. The percentage of screen-detected cancers diagnosed at Dukes' stage A was 49.2% in the first round, 40.1% in the second round and 36.3% in the third round. <h3>Conclusions:</h3> These results are compatible with those of previous randomised trials done in research settings, demonstrating that population-based colorectal cancer screening is feasible in Scotland and should lead to a comparable reduction in disease-specific mortality.
Successful intelligence: finding a balance
Authors: Robert J. Sternberg
Journal: Trends in Cognitive Sciences (1999)

Human intelligence has long been on the borderline between a scientific and a quasi-scientific field within the scope of psychological science. This is partially because its study and measurement have been particularly susceptible to socio-political agendas, but also because empirical tests of theories of intelligence have too often ranged from inadequate to nonexistent. In this article it is argued that two extremes have prevailed in the study of intelligence. At one extreme are general-ability (g) theorists, who have collected large amounts of data to test the theory of general intelligence, but often using restricted ranges of participants, materials or situational contexts. They also show a tendency to limit their methods of data analysis (e.g. to exploratory factor analysis). At another extreme are theorists arguing for new, multiple intelligences, whose theories have been subjected to few or no empirical tests. I argue that a middle ground is needed that recognizes the multifarious nature of intelligence and of people's conceptions of it, but that also is subjected to rigorous empirical tests.
Helodermin-loaded nanoparticles: Characterization and transport across an in vitro model of the follicle-associated epithelium
Authors: Anne des Rieux, Virginie Fievez, Maryam Momtaz, Christophe Detrembleur, Maria Alonso-Sande, Jan Van Gelder, Annick Cauvin, Yves-Jacques Schneider, Véronique Préat
Journal: Journal of Controlled Release (2006)